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| 357955 | Articolo in rivista | The Lack of the Essential LptC Protein in the Trans-Envelope Lipopolysaccharide Transport Machine Is Circumvented by Suppressor Mutations in LptF, an Inner Membrane Component of the Escherichia coli Transporter. | Benedet, Mattia, Falchi, Federica A, Puccio, Simone, Di Benedetto, Cristiano, Peano, Clelia, Polissi, Alessandra, Deho, Gianni | The lipopolysaccharide (LPS) transport (Lpt) system is responsible for transferring LPS from the periplasmic surface of the inner membrane (IM) to the outer leaflet of the outer membrane (OM), where it plays a crucial role in OM selective permeability. In E. coli seven essential proteins are assembled in an Lpt trans-envelope complex, which is conserved in gamma-Proteobacteria. LptBFG constitute the IM ABC transporter, LptDE form the OM translocon for final LPS delivery, whereas LptC, an IM-anchored protein with a periplasmic domain, interacts with the IM ABC transporter, the periplasmic protein LptA, and LPS. Although essential, LptC can tolerate several mutations and its role in LPS transport is unclear. To get insights into the functional role of LptC in the Lpt machine we searched for viable mutants lacking LptC by applying a strong double selection for lptC deletion mutants. Genome sequencing of viable DeltalptC mutants revealed single amino acid substitutions at a unique position in the predicted large periplasmic domain of the IM component LptF (LptFSupC). In complementation tests, lptFSupC mutants suppress lethality of both DeltalptC and lptC conditional expression mutants. Our data show that mutations in a specific residue of the predicted LptF periplasmic domain can compensate the lack of the essential protein LptC, implicate such LptF domain in the formation of the periplasmic bridge between the IM and OM complexes, and suggest that LptC may have evolved to improve the performance of an ancestral six-component Lpt machine. | PloS one 11 (2016). | 2016 | PUCCIO SIMONE, PEANO CLELIA | E. coli, lipopolysaccharide transport system | 10.1371/journal.pone.0161354 |
| 357957 | Articolo in rivista | Transcriptional, epigenetic and retroviral signatures identify regulatory regions involved in hematopoietic lineage commitment | Romano, Oriana, Peano, Clelia, Tagliazucchi, Guidantonio Malagoli, Petiti, Luca, Poletti, Valentina, Cocchiarella, Fabienne, Rizzi, Ermanno, Severgnini, Marco, Cavazza, Alessia, Rossi, Claudia, Pagliaro, Pasqualepaolo, Ambrosi, Alessandro, Ferrari, Giuliana, Bicciato, Silvio, De Bellis, Gianluca, Mavilio, Fulvio, Miccio, Annarita | Genome-wide approaches allow investigating the molecular circuitry wiring the genetic and epigenetic programs of human somatic stem cells. Hematopoietic stem/progenitor cells (HSPC) give rise to the different blood cell types; however, the molecular basis of human hematopoietic lineage commitment is poorly characterized. Here, we define the transcriptional and epigenetic profile of human HSPC and early myeloid and erythroid progenitors by a combination of Cap Analysis of Gene Expression (CAGE), ChIP-seq and Moloney leukemia virus (MLV) integration site mapping. Most promoters and transcripts were shared by HSPC and committed progenitors, while enhancers and super-enhancers consistently changed upon differentiation, indicating that lineage commitment is essentially regulated by enhancer elements. A significant fraction of CAGE promoters differentially expressed upon commitment were novel, harbored a chromatin enhancer signature, and may identify promoters and transcribed enhancers driving cell commitment. MLV-targeted genomic regions co-mapped with cell-specific active enhancers and super-enhancers. Expression analyses, together with an enhancer functional assay, indicate that MLV integration can be used to identify bona fide developmentally regulated enhancers. Overall, this study provides an overview of transcriptional and epigenetic changes associated to HSPC lineage commitment, and a novel signature for regulatory elements involved in cell identity. | Scientific reports (Nature Publishing Group) 6 (2016). | 2016 | PETITI LUCA, DE BELLIS GIANLUCA, PEANO CLELIA, SEVERGNINI MARCO | hematopoietic stem cells, epigenetics, differentiation | 10.1038/srep24724 |
| 357960 | Articolo in rivista | Dynamic Transcriptional and Epigenetic Regulation of Human Epidermal Keratinocyte Differentiation | Cavazza, Alessia, Miccio, Annarita, Romano, Oriana, Petiti, Luca, Tagliazucchi, Guidantonio Malagoli, Peano, Clelia, Severgnini, Marco, Rizzi, Ermanno, De Bellis, Gianluca, Bicciato, Silvio, Mavilio, Fulvio | Human skin is maintained by the differentiation and maturation of interfollicular stem and progenitors cells. We used DeepCAGE, genome-wide profiling of histone modifications and retroviral integration analysis, to map transcripts, promoters, enhancers, and super-enhancers (SEs) in prospectively isolated keratinocytes and transit-amplifying progenitors, and retrospectively defined keratinocyte stem cells. We show that >95% of the active promoters are in common and differentially regulated in progenitors and differentiated keratinocytes, while approximately half of the enhancers and SEs are stage specific and account for most of the epigenetic changes occurring during differentiation. Transcription factor (TF) motif identification and correlation with TF binding site maps allowed the identification of TF circuitries acting on enhancers and SEs during differentiation. Overall, our study provides a broad, genome-wide description of chromatin dynamics and differential enhancer and promoter usage during epithelial differentiation, and describes a novel approach to identify active regulatory elements in rare stem cell populations. | Stem Cell Reports 6 (2016): 618-632. | 2016 | PETITI LUCA, DE BELLIS GIANLUCA, PEANO CLELIA, SEVERGNINI MARCO | keratinocyte differentiation, epigenetics | 10.1016/j.stemcr.2016.03.003 |
| 362232 | Articolo in rivista | ICESpy009, a conjugative genetic element carrying mef(E) in Streptococcus pyogenes | Del Grosso, Maria, Camilli, Romina, Rizzi, Ermanno, Rizzi, Ermanno, Pietrelli, Alessandro, Pietrelli, Alessandro, De Bellis, Gianluca, Pantosti, Annalisa | Efflux-mediated macrolide resistance due to mef(E) and mel, carried by the mega element, is common in Streptococcus pneumoniae, for which it was originally characterized, but it is rare in Streptococcus pyogenes. In S. pyogenes, mega was previously found to be enclosed in Tn2009, a composite genetic element of the Tn916 family containing tet(M) and conferring erythromycin and tetracycline resistance. In this study, S. pyogenes isolates containing mef(E), apparently not associated with other resistance determinants, were examined to characterize the genetic context of mega. By whole-genome sequencing of one isolate, MB56Spyo009, we identified a novel composite integrative and conjugative element (ICE) carrying mega, designated ICESpy009, belonging to the ICESa2603 family. ICESpy009 was 55 kb long, contained 61 putative open reading frames (ORFs), and was found to be integrated into hylA, a novel integration site for the ICESa2603 family. The modular organization of the ICE was similar to that of members of the ICESa2603 family carried by different streptococcal species. In addition, a novel cluster of accessory resistance genes was found inside a region that encloses mega. PCR mapping targeting ICESpy009 revealed the presence of a similar ICE in five other isolates under study. While in three isolates the integration site was the same as that of ICESpy009, in two isolates the ICE was integrated into rplL, the typical integration site of the ICESa2603 family. ICESpy009 was able to transfer macrolide resistance by conjugation to both S. pyogenes and S. pneumoniae, showing the first evidence of the transferability of mega from S. pyogenes. | Antimicrobial agents and chemotherapy (Print) 60 (2016): 3906-3912. | 2016 | DE BELLIS GIANLUCA, RIZZI ERMANNO | NGS | 10.1128/AAC.03082-15 |
| 362233 | Articolo in rivista | A Unique Tryptophan C-Prenyltransferase from the Kawaguchipeptin Biosynthetic Pathway | Parajuli, Anirudra, Kwak, Daniel H., Dalponte, Luca, Dalponte, Luca, Leikoski, Niina, Galica, Tomas, Galica, Tomas, Galica, Tomas, Umeobika, Ugochukwu, Trembleau, Laurent, Bent, Andrew, Sivonen, Kaarina, Wahlsten, Matti, Wang, Hao, Rizzi, Ermanno, De Bellis, Gianluca, Naismith, James, Jaspars, Marcel, Liu, Xinyu, Houssen, Wael, Houssen, Wael, Houssen, Wael, Fewer, David Peter | Cyanobactins are a rapidly growing family of linear and cyclic peptides produced by cyanobacteria. Kawaguchipeptins A and B, two macrocyclic undecapeptides reported earlier from Microcystis aeruginosa NIES-88, are shown to be products of the cyanobactin biosynthetic pathway. The 9 kb kawaguchipeptin (kgp) gene cluster was identified in a 5.26 Mb draft genome of Microcystis aeruginosa NIES-88. We verified that this gene cluster is responsible for the production of the kawaguchipeptins through heterologous expression of the kgp gene cluster in Escherichia coli. The KgpF prenyltransferase was overexpressed and was shown to prenylate C-3 of Trp residues in both linear and cyclic peptides in vitro. Our findings serve to further enhance the structural diversity of cyanobactins to include tryptophan-prenylated cyclic peptides. | Angewandte Chemie (Int. ed., Print) 55 (2016): 3596-3599. | 2016 | DE BELLIS GIANLUCA, RIZZI ERMANNO | biosynthesis, cyanobactins, peptides, prenylation, prenyltransferases | 10.1002/anie.201509920 |
| 348546 | Articolo in rivista | The Proteomic Landscape of Human Ex Vivo Regulatory and Conventional T Cells Reveals Specific Metabolic Requirements. | Claudio Procaccini, 1, 11 Fortunata Carbone, 1, 11 Dario Di Silvestre, 2 Francesca Brambilla, 2 Veronica De Rosa, 1, 3 Mario Galgani, 1 Deriggio Faicchia, 4 Gianni Marone, 4 Donatella Tramontano, 5 Marco Corona, 6 Carlo Alviggi, 7 Antonio Porcellini, 8 Antonio La Cava, 9 Pierluigi Mauri, 2, 10, Giuseppe Matarese1, 5 | Human CD4+CD25hiFoxp3+CD127 Treg and CD4+ CD25Foxp3 Tconv cell functions are governed by their metabolic requirements. Here we report a comprehensive comparative analysis between ex vivo human Treg and Tconv cells that comprises analyses of the proteomic networks in subcellular compartments. We identified a dominant proteomic signature at the metabolic level that primarily impacted the highly-tuned balance between glucose and fatty-acid oxidation in the two cell types. Ex vivo Treg cells were highly glycolytic while Tconv cells used predominantly fatty-acid oxidation (FAO). When cultured in vitro, Treg cells engaged both glycolysis and FAO to proliferate, while Tconv cell proliferation mainly relied on glucose metabolism. Our unbiased proteomic analysis provides a molecular picture of the impact of metabolism on ex vivo human Treg versus Tconv cell functions that might be relevant for therapeutic manipulations of these cells. | Immunity (Camb. Mass.) 44 (2016): 406-421. | 2016 | DE ROSA VERONICA, BRAMBILLA FRANCESCA, CARBONE FORTUNATA, CORONA MARCO, MATARESE GIUSEPPE, DI SILVESTRE DARIO, PROCACCINI CLAUDIO, GALGANI MARIO, MAURI PIETRO LUIGI | Treg, Tconv, Proteomics, fatty-acid oxidation, glycolysis | 10.1016/j.immuni.2016.01.028 |
| 357111 | Articolo in rivista | RISC-mediated control of selected chromatin regulators stabilizes ground state pluripotency of mouse embryonic stem cells | Pandolfini, Luca, Luzi, Ettore, Bressan, Dario, Ucciferri, Nadia, Bertacchi, Michele, Brandi, Rossella, Rocchiccioli, Silvia, D'Onofrio, Mara, Cremisi, Federico | Background: Embryonic stem cells are intrinsically unstable and differentiate spontaneously if they are not shielded from external stimuli. Although the nature of such instability is still controversial, growing evidence suggests that protein translation control may play a crucial role. Results: We performed an integrated analysis of RNA and proteins at the transition between naive embryonic stem cells and cells primed to differentiate. During this transition, mRNAs coding for chromatin regulators are specifically released from translational inhibition mediated by RNA-induced silencing complex (RISC). This suggests that, prior to differentiation, the propensity of embryonic stem cells to change their epigenetic status is hampered by RNA interference. The expression of these chromatin regulators is reinstated following acute inactivation of RISC and it correlates with loss of stemness markers and activation of early cell differentiation markers in treated embryonic stem cells. Conclusions: We propose that RISC-mediated inhibition of specific sets of chromatin regulators is a primary mechanism for preserving embryonic stem cell pluripotency while inhibiting the onset of embryonic developmental programs. | GenomeBiology.com (Lond., Print) 17 (2016). | 2016 | D'ONOFRIO MARA, UCCIFERRI NADIA, CREMISI FEDERICO | SELF-RENEWAL; NAIVE PLURIPOTENCY; MICRORNA CONTROL; IN-VIVO; DNA; EXPRESSION; DIFFERENTIATION; TRANSCRIPTION; NANOG; REPRESSION | 10.1186/s13059-016-0952-x |
| 357543 | Contributo in atti di convegno | Clustering protein structures with Hadoop | G. Paschina, L. Roverelli, D. D'Agostino, F. Chiappori, I. Merelli | Machine learning is a widely used technique in structural biology, since the analysis of large conformational ensembles originated from single protein structures (e.g. derived from NMR experiments or molecular dynamics simulations) can be approached by partitioning the original dataset into sensible subsets, revealing important structural and dynamics behaviours. Clustering is a good unsupervised approach for dealing with these ensembles of structures, in order to identify stable conformations and driving characteristics shared by the different structures. A common problem of the applications that implement protein clustering is the scalability of the performance, in particular concerning the data load into memory. In this work we show how it is possible to improve the parallel performance of the GROMOS clustering algorithm by using Hadoop. The preliminary results show the validity of this approach, providing a hint for future development in this field. | Computational Intelligence Methods for Bioinformatics and Biostatistics (CIBB), pp. 141-153, Naples, Italy, 10-12/9/2015 | 2016 | CHIAPPORI FEDERICA, PASCHINA GIACOMO, ROVERELLI LUCA, D'AGOSTINO DANIELE, MERELLI IVAN | Hadoop Clustering, protein structures, Molecular dynamics, Data parallel | 10.1007/978-3-319-44332-4_11 |
| 367071 | Articolo in rivista | Meta-Analysis of Differential Connectivity in Gene Co-Expression Networks in Multiple Sclerosis | Creanza, Teresa Maria, Liguori, Maria, Liuni, Sabino, Nuzziello, Nicoletta, Ancona, Nicola | Differential gene expression analyses to investigate multiple sclerosis (MS) molecular pathogenesis cannot detect genes harboring genetic and/or epigenetic modifications that change the gene functions without affecting their expression. Differential co-expression network approaches may capture changes in functional interactions resulting from these alterations. We re-analyzed 595 mRNA arrays from publicly available datasets by studying changes in gene co-expression networks in MS and in response to interferon (IFN)-beta treatment. Interestingly, MS networks show a reduced connectivity relative to the healthy condition, and the treatment activates the transcription of genes and increases their connectivity in MS patients. Importantly, the analysis of changes in gene connectivity in MS patients provides new evidence of association for genes already implicated in MS by single-nucleotide polymorphism studies and that do not show differential expression. This is the case of amiloride-sensitive cation channel 1 neuronal (ACCN1) that shows a reduced number of interacting partners in MS networks, and it is known for its role in synaptic transmission and central nervous system (CNS) development. Furthermore, our study confirms a deregulation of the vitamin D system: among the transcription factors that potentially regulate the deregulated genes, we find TCF3 and SP1 that are both involved in vitamin D3-induced p27Kip1 expression. Unveiling differential network properties allows us to gain systems-level insights into disease mechanisms and may suggest putative targets for the treatment. | International journal of molecular sciences (Online) 17 (2016). | 2016 | ANCONA NICOLA, LIGUORI MARIA, LIUNI SABINO, CREANZA TERESA MARIA | gene expression, multiple sclerosis, gene networks | 10.3390/ijms17060936 |
| 366099 | Articolo in rivista | Genomic and transcriptomic comparison between Staphylococcus aureus strains associated with high and low within herd prevalence of intra-mammary infection | Capra E., Cremonesi P., Pietrelli A., Puccio S., Luini M., Stella A., Castiglioni B. | Background: Staphylococcus aureus (Staph. aureus) is one of the major pathogens causing mastitis in dairy ruminants worldwide. The chronic nature of Staph. aureus infection enhances the contagiousness risk and diffusion in herds. In order to identify the factors involved in intra-mammary infection (IMI) and diffusion in dairy cows, we investigated the molecular characteristics of two groups of Staph. aureus strains belonging to ST8 and ST398, differing in clinical properties, through comparison of whole genome and whole transcriptome sequencing. Results: The two groups of strains, one originated from high IMI prevalence herds and the other from low IMI prevalence herds, present a peculiar set of genes and polymorphisms related to phenotypic features, such as bacterial invasion of mammary epithelial cells and host adaptation. Transcriptomic analysis supports the high propensity of ST8 strain to chronicity of infection and to a higher potential cytotoxicity. Conclusions: Our data are consistent with the invasiveness and host adaptation feature for the strains GTB/ST8 associated to high within-herd prevalence of mastitis. Variation in genes coding for surface exposed proteins and those associated to virulence and defence could constitute good targets for further research. | BMC Microbiology (Online) 17 (2017): 1-16. | 2017 | PIETRELLI ALESSANDRO, CAPRA EMANUELE, PUCCIO SIMONE, CASTIGLIONI BIANCA MARIA ELISABETTA, CREMONESI PAOLA, STELLA ALESSANDRA | Genome; Mastitis; Next generation sequencing; Staphylococcus aureus; Transcriptome; Virulence | 10.1186/s12866-017-0931-8 |
| 374626 | Articolo in rivista | Retroviral Scanning: Mapping MLV Integration Sites to Define Cell-specific Regulatory Regions. | Romano, Oriana, Cifola, Ingrid, Poletti, Valentina, Severgnini, Marco, Peano, Clelia, De Bellis, Gianluca, Mavilio, Fulvio, Miccio, Annarita | Moloney murine leukemia (MLV) virus-based retroviral vectors integrate predominantly in acetylated enhancers and promoters. For this reason, mLV integration sites can be used as functional markers of active regulatory elements. Here, we present a retroviral scanning tool, which allows the genome-wide identification of cell-specific enhancers and promoters. Briefly, the target cell population is transduced with an mLV-derived vector and genomic DNA is digested with a frequently cutting restriction enzyme. After ligation of genomic fragments with a compatible DNA linker, linker-mediated polymerase chain reaction (LM-PCR) allows the amplification of the virus-host genome junctions. Massive sequencing of the amplicons is used to define the mLV integration profile genome-wide. Finally, clusters of recurrent integrations are defined to identify cell-specific regulatory regions, responsible for the activation of cell-type specific transcriptional programs. The retroviral scanning tool allows the genome-wide identification of cell-specific promoters and enhancers in prospectively isolated target cell populations. Notably, retroviral scanning represents an instrumental technique for the retrospective identification of rare populations (e.g. somatic stem cells) that lack robust markers for prospective isolation. | Journal of visualized experiments (2017). | 2017 | DE BELLIS GIANLUCA, CIFOLA INGRID, PEANO CLELIA, SEVERGNINI MARCO | * | 10.3791/55919 |
| 380048 | Articolo in rivista | High parathyroid hormone concentration in tenofovir-treated patients are due to inhibition of calcium-sensing receptor activity. | Mingione, Alessandra, Maruca, Katia, Chiappori, Federica, Pivari, Francesca, Brasacchio, Caterina, Quirino, Tiziana, Merelli, Ivan, Soldati, Laura, Bonfanti, Paolo, Mora, Stefano | Bone health impairment is a common finding in HIV-infected patients on antiretroviral treatment. High serum parathyroid hormone (PTH) concentration in patients on antiretroviral treatment containing tenofovir disoproxil fumarate (TDF) has been reported. Hyperparathyroidism was not always sustained by a reduction in vitamin D concentration. We thus hypothesized a direct inhibitory effect of TDF on the Calcium-sensing receptor (CaSR), leading to hyperparathyroidism. Human embryonic kidney cells were transfected with CASR wild-type gene or mutated in different sites (N124K, T1051G, C788T, T888M). Cells were grown in standard conditions and the activity of CaSR was assessed after stimulation with CaCl2 with and without TDF (100nM-1muM). We evaluated by western blot phospho-p44/42 ERK expression levels as a marker of CaSR activity. In silico structure models were obtained for wild-type and N124K mutant. Molecular docking with TDF was also evaluated. The stimulation by CaCl2 and TDF 100nM led to a decrease of 55% of CaSR activity (P<0.001), whereas the stimulation by CaCl2 and TDF 1muM reduced the activity by 68% (P<0.001). The decreased CaSR activity was comparable to that observed from known CASR gene inactivating mutations (T1051G, C788T), which inhibit the receptor activity by 56% and 78%, respectively. The TDF inhibits the CaSR activity carrying a gain of function mutation in the intracellular domain (T888M), but it does not influence the activity of the receptor carrying the N124K activating mutation. Our data show that TDF is able to inhibit the activity of CaSR in a dose-dependent manner. Hyperparathyroidism observed in TDF-treated patients may be therefore promoted by the direct effect of the drug on CaSR. | Biomedicine & pharmacotherapy (Online) 97 (2017): 969-974. | 2017 | CHIAPPORI FEDERICA, MERELLI IVAN | Antiretroviral therapy; Calcium-sensing receptor; Hyperparathyroidism; Parathyroid hormone; Tenofovir disoproxil fumarate | 10.1016/j.biopha.2017.11.037 |
| 380127 | Articolo in rivista | MYC-containing amplicons in acute myeloid leukemia: Genomic structures, evolution, and transcriptional consequences | A ?Abbate, D Tolomeo, I Cifola, M Severgnini, A Turchiano, B Augello, G Squeo, P D'Addabbo, D Traversa, G Daniele, A Lonoce, M Pafundi, M Carella, O Palumbo, A Dolnik, D Muehlematter, J Schoumans, N Van Roy, G De Bellis, G Martinelli, G Merla, L Bullinger, C Haferlach, C T Storlazzi | Double minutes (dmin), homogeneously staining regions, and ring chromosomes are vehicles of gene amplification in cancer. The underlying mechanism leading to their formation as well as their structure and function in acute myeloid leukemia (AML) remain mysterious. We combined a range of high-resolution genomic methods to investigate the architecture and expression pattern of amplicons involving chromosome band 8q24 in 23 cases of AML (AML-amp). This revealed that different MYC-dmin architectures can coexist within the same leukemic cell population, indicating a step-wise evolution rather than a single event origin, such as through chromothripsis. This was supported also by the analysis of the chromothripsis criteria, that poorly matched the model in our samples. Furthermore, we found that dmin could evolve toward ring chromosomes stabilized by neocentromeres. Surprisingly, amplified genes (mainly PVT1) frequently participated in fusion transcripts lacking a corresponding DNA template. We also detected a significant overexpression of the circular RNA of PVT1 (circPVT1) in AML-amp cases versus AML with a normal karyotype. Our results show that 8q24 amplicons in AML are surprisingly plastic DNA structures with an unexpected association to novel fusion transcripts and circular RNAs. | Leukemia (2017). | 2017 | DE BELLIS GIANLUCA, CIFOLA INGRID, SEVERGNINI MARCO | * | |
| 380140 | Articolo in rivista | Mutation and suppressor analysis of the essential LPS-transport protein LptA reveals strategies to overcome severe outer membrane permeability defects in . | Federica A. Falchi1, 2, Elisa A. Maccagni3, Simone Puccio4, Clelia Peano5, 6, Cristina De Castro7, Angelo Palmigiano8, Domenico Garozzo8, Alessandra M. Martorana3, Alessandra Polissi2, Gianni Deho1, Paola Sperandeo2* | In Gram-negative bacteria, lipopolysaccharide (LPS) contributes to the robust permeability barrier of the outer membrane (OM), preventing the entry of toxic molecules such as detergents and antibiotics. LPS is transported from the inner membrane (IM) to the OM by the Lpt multiprotein machinery. Defects in LPS transport compromise LPS assembly at the OM and result in increased antibiotic sensitivity. LptA is a key component of the Lpt machine that interacts with the IM protein LptC and chaperons LPS through the periplasm. We report here the construction of lptA41, a quadruple mutant in four conserved amino acids potentially involved in LPS or LptC binding. Although viable, the mutant displays increased sensitivity to several antibiotics (bacitracin, rifampicin and novobiocin) and the SDS detergent, suggesting that lptA41 affects LPS transport. Indeed, lptA41 is defective in Lpt complex assembly and its lipid A carries modifications diagnostic of LPS transport defects. We also selected and characterized two phenotypic bacitracin resistant suppressors of lptA41 One mutant, in which only bacitracin sensitivity is suppressed, harbours a small in-frame deletion in mlaA, that codes for an OM lipoprotein involved in maintaining OM asymmetry by reducing accumulation of phospholipids in the outer leaflet. The other one, in which bacitracin, rifampicin and SDS sensitivity is suppressed, harbours an additional amino acid substitution in LptA41 and a nonsense mutation in opgH, encoding a glycosyltransferase involved in periplasmic membrane-derived oligosaccharides synthesis. Characterization of the suppressor mutants highlights different strategies adopted by the cell to overcome OM defects caused by impaired LPS transport.IMPORTANCE Lipopolysaccharide (LPS) is the major constituent of the outer membrane (OM) of most Gram-negative bacteria forming a barrier against antibiotics. LPS is synthesized at the inner membrane (IM), transported across the periplasm and assembled at the OM by the multiprotein Lpt complex. LptA is the periplasmic component of the Lpt complex, which bridges IM and OM and ferries LPS across the periplasm. How the cell co-ordinates the processes involved in OM biogenesis is not completely understood. We have generated a partially defective mutant in lptA, which exhibits increased sensitivity to antibiotics and selected for suppressors of this mutant. The analysis of two independent suppressors reveals different strategies adopted by the cell to overcome defects in LPS biogenesis. | Journal of bacteriology (Print) (2017). | 2017 | PUCCIO SIMONE, GAROZZO DOMENICO, PEANO CLELIA | * | 10.1128/JB.00487-17 |
| 374176 | Articolo in rivista | DOPAL derived alpha-synuclein oligomers impair synaptic vesicles physiological function | Plotegher N, Berti G, Ferrari E, Tessari I, Zanetti M, Lunelli L, Greggio E, Bisaglia M, Veronesi M, Girotto S, Dalla Serra M, Perego C, Casella L, Bubacco L | Parkinson's disease is a neurodegenerative disorder characterized by the death of dopaminergic neurons and by accumulation of alpha-synuclein (aS) aggregates in the surviving neurons. The dopamine catabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL) is a highly reactive and toxic molecule that leads to aS oligomerization by covalent modifications to lysine residues. Here we show that DOPAL-induced aS oligomer formation in neurons is associated with damage of synaptic vesicles, and with alterations in the synaptic vesicles pools. To investigate the molecular mechanism that leads to synaptic impairment, we first aimed to characterize the biochemical and biophysical properties of the aS-DOPAL oligomers; heterogeneous ensembles of macromolecules able to permeabilise cholesterol-containing lipid membranes. aS-DOPAL oligomers can induce dopamine leak in an in vitro model of synaptic vesicles and in cellular models. The dopamine released, after conversion to DOPAL in the cytoplasm, could trigger a noxious cycle that further fuels the formation of aS-DOPAL oligomers, inducing neurodegeneration. | Scientific reports (Nature Publishing Group) 7 (2017). | 2017 | LUNELLI LORENZO, FERRARI EMANUELE, DALLA SERRA MAURO | Toxic dopamine metabolite; Parkinsons-disease; Recycling-pool; Membrane; Aldehyde; 3, 4-Dihydroxyphenylacetaldehyde; Cells; Pathogenesis; Homeostasis | 10.1038/srep40699 |
| 384796 | Articolo in rivista | Body Mass Index and Sex Affect Diverse Microbial Niches within the Gut | Borgo F 1, Garbossa S 2, Riva A 1, 3, Severgnini M 4, Luigiano C 2, Benetti A 2, Pontiroli AE 1, 2, Morace G 1, Borghi E 1. | Gut microbiota is considered a separate organ with endocrine capabilities, actively contributing to tissue homeostasis. It consists of at least two separate microbial populations, the lumen-associated (LAM) and the mucosa-associated microbiota (MAM). In the present study, we compared LAM and MAM, by collecting stools and sigmoid brush samples of forty adults without large-bowel symptoms, and through a 16S rRNA gene next-generation sequencing (NGS) approach. MAM sample analysis revealed enrichment in aerotolerant Proteobacteria, probably selected by a gradient of oxygen that decreases from tissue to lumen, and in Streptococcus and Clostridium spp., highly fermenting bacteria. On the other hand, LAM microbiota showed an increased abundance in Bacteroides, Prevotella, and Oscillospira, genera able to digest and to degrade biopolymers in the large intestine. Predicted metagenomic analysis showed LAM to be enriched in genes encoding enzymes mostly involved in energy extraction from carbohydrates and lipids, whereas MAM in amino acid and vitamin metabolism. Moreover, LAM and MAM communities seemed to be influenced by different host factors, such as diet and sex. LAM is affected by body mass index (BMI) status. Indeed, BMI negatively correlates with Faecalibacterium prausnitzii and Flavonifractor plautii abundance, putative biomarkers of healthy status. In contrast, MAM microbial population showed a significant grouping according to sex. Female MAM was enriched in Actinobacteria (with an increased trend of the genus Bifidobacterium), and a significant depletion in Veillonellaceae. Interestingly, we found the species Gemmiger formicilis to be associated with male and Bifidobacterium adolescentis, with female MAM samples. In conclusion, our results suggest that gut harbors microbial niches that differ in both composition and host factor susceptibility, and their richness and diversity may be overlooked evaluating only fecal samples. | Frontiers in microbiology 9 (2018). | 2018 | SEVERGNINI MARCO | luminal microbiota, mucosa-associated microbiota, body mass index, sex, indicative species | 10.3389/fmicb.2018.00213 |
| 386335 | Articolo in rivista | MTGO: PPI Network Analysis Via Topological and Functional Module Identification | Vella D1, 2, Marini S3, Vitali F4, 5, 6, 7, Di Silvestre D8, Mauri G2, Bellazzi R1, 4, 9. | Protein-protein interaction (PPI) networks are viable tools to understand cell functions, disease machinery, and drug design/repositioning. Interpreting a PPI, however, it is a particularly challenging task because of network complexity. Several algorithms have been proposed for an automatic PPI interpretation, at first by solely considering the network topology, and later by integrating Gene Ontology (GO) terms as node similarity attributes. Here we present MTGO - Module detection via Topological information and GO knowledge, a novel functional module identification approach. MTGO let emerge the bimolecular machinery underpinning PPI networks by leveraging on both biological knowledge and topological properties. In particular, it directly exploits GO terms during the module assembling process, and labels each module with its best fit GO term, easing its functional interpretation. MTGO shows largely better results than other state of the art algorithms (including recent GO-based ones) when searching for small or sparse functional modules, while providing comparable or better results all other cases. MTGO correctly identifies molecular complexes and literature-consistent processes in an experimentally derived PPI network of Myocardial infarction. A software version of MTGO is available freely for non-commercial purposes at https://gitlab.com/d1vella/MTGO. | Scientific reports (Nature Publishing Group) 8 (2018). | 2018 | DI SILVESTRE DARIO | * | 10.1038/s41598-018-23672-0 |
| 387485 | Articolo in rivista | Transcriptional profiling of human bronchial epithelial cell BEAS-2B exposed to diesel and biomass ultrafine particles | Grilli A., Bengalli R., Longhin E., Capasso L., Proverbio M.C., Forcato M., Bicciato S., Gualtieri M., Battaglia C., Camatini M. | Background: Emissions from diesel vehicles and biomass burning are the principal sources of primary ultrafine particles (UFP). The exposure to UFP has been associated to cardiovascular and pulmonary diseases, including lung cancer. Although many aspects of the toxicology of ambient particulate matter (PM) have been unraveled, the molecular mechanisms activated in human cells by the exposure to UFP are still poorly understood. Here, we present an RNA-seq time-course experiment (five time point after single dose exposure) used to investigate the differential and temporal changes induced in the gene expression of human bronchial epithelial cells (BEAS-2B) by the exposure to UFP generated from diesel and biomass combustion. A combination of different bioinformatics tools (EdgeR, next-maSigPro and reactome FI app-Cytoscape and prioritization strategies) facilitated the analyses the temporal transcriptional pattern, functional gene set enrichment and gene networks related to cellular response to UFP particles. Results: The bioinformatics analysis of transcriptional data reveals that the two different UFP induce, since the earliest time points, different transcriptional dynamics resulting in the activation of specific genes. The functional enrichment of differentially expressed genes indicates that the exposure to diesel UFP induces the activation of genes involved in TNF? signaling via NF-kB and inflammatory response, and hypoxia. Conversely, the exposure to ultrafine particles from biomass determines less distinct modifications of the gene expression profiles. Diesel UFP exposure induces the secretion of biomarkers associated to inflammation (CCXL2, EPGN, GREM1, IL1A, IL1B, IL6, IL24, EREG, VEGF) and transcription factors (as NFE2L2, MAFF, HES1, FOSL1, TGIF1) relevant for cardiovascular and lung disease. By means of network reconstruction, four genes (STAT3, HIF1a, NFKB1, KRAS) have emerged as major regulators of transcriptional response of bronchial epithelial cells exposed to diesel exhaust. Conclusions: Overall, this work highlights modifications of the transcriptional landscape in human bronchial cells exposed to UFP and sheds new lights on possible mechanisms by means of which UFP acts as a carcinogen and harmful factor for human health. | BMC genomics 19 (2018). | 2018 | BATTAGLIA CRISTINA | BEAS-2B, Biomass particles, Diesel particles, Environmental particles, Gene network, Human health, Lung disorders, RNA-seq, Time-course, Ultrafine particles | 10.1186/s12864-018-4679-9 |
| 388415 | Articolo in rivista | [What is real in the dream of preventing dementia?] | Massimo Musicco | Nel 2017 su Annals of Internal Medicine e su The Lancet sono apparsi articoli accompagnati da editoriali sulle possibilita e opportunita di prevenzione delle demenze. L'occasione e stata la pubblicazione di due autorevoli revisioni di letteratura, una americana promossa dalla Agency for Healthcare Research and Quality e dal National Institute on Aging, l'altra frutto del lavoro della Lancet Commission on Dementia Prevention, Intervention, and Care. | Epidemiologia e prevenzione (2018). | 2018 | MUSICCO MASSIMO | dementia | 10.19191/EP18.2.P110.035 |
| 389025 | Articolo in rivista | Dolutegravir (DTG)-containing regimens after receiving raltegravir (RAL) or elvitegravir (EVG): Durability and virological response in a large Italian HIV drug resistance network (ARCA) | Rusconi S., Adorni F., Tau P., Borghi V., Pecorari M., Maserati R., Francisci D., Monno L., Punzi G., Meraviglia P., Paolucci S., Di Biagio A., Bruzzone B., Mancon A., Micheli V., Zazzi M. | Background: Dolutegravir (DTG) is a next-generation HIV integrase inhibitor (INI) with an increased genetic barrier to resistance with respect to raltegravir (RAL) or elvitegravir (EVG). Few data are available on the durability of DTG-containing regimens. Objectives: We aimed at investigating the duration of the DTG-containing regimen, the occurrence of an HIV-1 RNA blip, and factors associated with DTG virological response. Study design: From the Antiviral Response Cohort Analysis database, we selected 89 HIV-1-positive four-class-experienced subjects who started DTG after receiving RAL or EVG. Factors associated with durability and virological response were analysed by logistic regression. Results: After a median duration of 18.8 [0.4-76.2] months, 79/89 (88.8%) subjects were still on DTG. All subjects remaining on DTG at the end of follow-up had undetectable HIV-1 RNA, compared to 5/10 subjects who discontinued DTG. DTG discontinuation was less frequent in patients who had experienced >=10 regimens (HR 0.11, p = 0.040). The probability of having an HIV-1 RNA positive value at the last follow-up significantly increased in patients with non-B HIV-1 subtype (HR 5.77, p <.001) and significantly decreased in patients with CD4 nadir >200/?L (HR 0.29, p = 0.038), with more than 10 previous regimens (HR 0.27, p = 0.040), and who harbored virus with IN mutations (HR 0.12, p = 0.023) at DTG start. Conclusions: After previous exposure to first-generation INIs, treatment with DTG showed long durability and did not show virological rebound after virological suppression. Subjects infected with a non-B HIV-1 subtype had a greater risk of having detectable HIV-1 RNA at the last observation. | Journal of clinical virology 105 (2018): 112-117. | 2018 | ADORNI FULVIO DANIELE | Dolutegravir, HIV1, Durability, Virological response, Drug resistance, Genotype | 10.1016/j.jcv.2018.06.012 |
| 389358 | Articolo in rivista | Nup153 Unlocks the Nuclear Pore Complex for HIV-1 Nuclear Translocation in Non-dividing Cells | Cindy Buffone1, Alicia Martinez-Lopez1, Thomas Fricke1, Silvana Opp1, Marco Severgnini2, Ingrid Cifola2, Luca Petiti2, Stella Frabetti3, Katarzyna Skorupka4, Kaneil K. Zadrozny4, Barbie K. Ganser-Pornillos4, Owen Pornillos4, Francesca Di Nunzio3+, Felipe Diaz-Griffero1+ | HIV-1 displays the unique ability to infect non-dividing cells. The capsid of HIV-1 is the viral determinant for viral nuclear import. To understand the cellular factors involved in the ability of HIV-1 to infect non-dividing cells, we sought to find capsid mutations that allow the virus to infect dividing but not non-dividing cells. Because the interaction of capsid with the nucleoporin protein 153 (Nup153) is important for nuclear import of HIV-1, we solved new crystal structures of hexameric HIV-1 capsid in complex with a Nup153-derived peptide containing a phenylalanine-glycine repeat (FG-repeat), which we used to guide structure-based mutagenesis of the capsid-binding interface. HIV-1 viruses with mutations in these capsid residues were tested for their ability to infect dividing and non-dividing cells. HIV-1 viruses with capsid N57 substitutions infected dividing but not non-dividing cells. Interestingly, HIV-1 viruses with N57 mutations underwent reverse transcription but not nuclear translocation. The mutant capsids also lost the ability to interact with Nup153 and CPSF6. The use of small molecules PF74 and BI-2 prevented the interaction of FG-containing nucleoporins (Nups) such as Nup153 with the HIV-1 core. Analysis of integration sites in HIV-1 viruses with N57 mutations revealed diminished integration into transcriptionally active genes, in a manner resembling that of HIV-1 in CPSF6 knockout cells, or that of HIV-1-N74D. The integration pattern of the N57 mutant HIV-1 can be explained by loss of capsid interaction with CPSF6, whereas capsid interaction with Nup153 is required for HIV-1 to infect non-dividing cells. Additionally, the observed viral integration profiles suggested that integration site-selection is a multi-parameter process that depends upon nuclear factors and the state of the cellular chromatin. IMPORTANCE One of the key advantages that distinguish lentiviruses such as HIV-1 from all other retroviruses, is its ability to infect non-dividing cells. Interaction of the HIV-1 capsid with Nup153 andCPSF6 is important for nuclear entry and integration; however, it is not clear the contribution of each of these proteins to nuclear import and integration. Using genetics, we demonstrated that these proteins contribute to different processes: Nup153 is essential for the HIV-1 nuclear import in non-dividing cells, and CPSF6 is important for HIV-1 integration. In addition, nuclear factors such as CPSF6 and the state of the chromatin are known to be important for integration site selection; nevertheless, the preferential determinant influencing integration site selection is not known. This work demonstrates that integration site-selection is a multi-parameter process that depends upon nuclear factors and the state of the cellular chromatin. | Journal of virology (Online) 92 (2018): e00648-18. | 2018 | PETITI LUCA, CIFOLA INGRID, SEVERGNINI MARCO | * | 10.1128/JVI.00648-18 |
| 389360 | Articolo in rivista | GABA-B1 Receptor-Null Schwann Cells Exhibit Compromised In Vitro Myelination | Faroni A., Melfi S., Castelnovo L.F., Bonalume V., Colleoni D., Magni P., Arauzo-Bravo M.J., Reinbold R., Magnaghi V. | GABA-B receptors are important for Schwann cell (SC) commitment to a non-myelinating phenotype during development. However, the P0-GABA-B1fl/fl conditional knockout mice, lacking the GABA-B1 receptor specifically in SCs, also presented axon modifications, suggesting SC non-autonomous effects through the neuronal compartment. In this in vitro study, we evaluated whether the specific deletion of the GABA-B1 receptor in SCs may induce autonomous or non-autonomous cross-changes in sensory dorsal root ganglia (DRG) neurons. To this end, we performed an in vitro biomolecular and transcriptomic analysis of SC and DRG neuron primary cultures from P0-GABA-B1fl/fl mice. We found that cells from conditional P0-GABA-B1fl/fl mice exhibited proliferative, migratory and myelinating alterations. Moreover, we found transcriptomic changes in novel molecules that are involved in peripheral neuron-SC interaction. | Molecular neurobiology (2018): 1-14. | 2018 | REINBOLD ROLLAND ALVONS | Conditional mice, GABA-A receptor, Gamma-aminobutyric acid, Peripheral nerve regeneration | 10.1007/s12035-018-1158-x |
| 392771 | Articolo in rivista | Characterization of multi-locus imprinting disturbances and underlying genetic defects in patients with chromosome 11p15.5 related imprinting disorders | Fontana L1, Bedeschi MF2, Maitz S3, Cereda A4, Fare C5, Motta S5, Seresini A6, 7, D'Ursi P8, Orro A8, Pecile V9, Calvello M5, Selicorni A10, Lalatta F2, Milani D11, Sirchia SM12, Miozzo M1, 5, Tabano S1. | The identification of multi-locus imprinting disturbances (MLID) appears fundamental to uncover molecular pathways underlying imprinting disorders (IDs) and to complete clinical diagnosis of patients. However, MLID genetic associated mechanisms remain largely unknown. To characterize MLID in Beckwith-Wiedemann (BWS) and Silver-Russell (SRS) syndromes, we profiled by MassARRAY the methylation of 12 imprinted differentially methylated regions (iDMRs) in 21 BWS and 7 SRS patients with chromosome 11p15.5 epimutations. MLID was identified in 50% of BWS and 29% of SRS patients as a maternal hypomethylation syndrome. By next-generation sequencing, we searched for putative MLID-causative mutations in genes involved in methylation establishment/maintenance and found two novel missense mutations possibly causative of MLID: one in NLRP2, affecting ADP binding and protein activity, and one in ZFP42, likely leading to loss of DNA binding specificity. Both variants were paternally inherited. In silico protein modelling allowed to define the functional effect of these mutations. We found that MLID is very frequent in BWS/SRS. In addition, since MLID-BWS patients in our cohort show a peculiar pattern of BWS-associated clinical signs, MLID test could be important for a comprehensive clinical assessment. Finally, we highlighted the possible involvement of ZFP42 variants in MLID development and confirmed NLRP2 as causative locus in BWS-MLID. | Epigenetics (Online) (2018). | 2018 | ORRO ALESSANDRO, D'URSI PASQUALINA | Beckwith-Wiedemann syndrome; Silver-Russell syndrome; epigenotype-phenotype correlations; multilocus methylation disturbances; targeted next-generation sequencing | 10.1080/15592294 |
| 392774 | Articolo in rivista | A Point Prevalence Study of Delirium in Italian Nursing Homes | Morichi V1, Fedecostante M1, Morandi A2,3, Di Santo SG4, Mazzone A5, Mossello E6, Bo M7, Bianchetti A8, Rozzini R9, Zanetti E10, Musicco M11,12, Ferrari A13,14, Ferrara N15,16,17, Trabucchi M2,18,19, Cherubini A1, Bellelli G2,10,20, Italian Study Group on Delirium. | Background: Delirium is a common geriatric syndrome. Few studies have been conducted in nursing home (NH) residents. The aim of this project was to perform a point prevalence study of delirium in Italian NHs. Methods: Data collected in 71 NHs are presented. Inclusion criteria were age >= 65 years and native Italian speaker. Exclusion criteria were coma, aphasia, and end-of-life status. Sociodemographic and medical data were recorded. Delirium was assessed using the Assessment Test for Delirium and Cognitive Impairment (4-AT). Patients with a 4-AT score >= 4 were considered to have delirium. Motor subtype was evaluated using the Delirium Motor Subtype Scale (DMSS). Results: A total of 1,454 patients were evaluated (mean age 84.4 +/- 7.4 years, 70.2% female), of whom 535 (36.8%) had delirium. In multivariate logistic regression analysis, variables significantly associated with delirium were education (OR 0.94, 95% CI 0.91-0.97), dementia (OR 3.12, 95% CI 2.38-4.09), functional dependence (OR 6.13, 95% CI 3.08-12.19 for ADL score 0; OR 1.99, 95% CI 1.03-3.84 for ADL score 1-5), malnutrition (OR 4.87, 95% CI 2.68-8.84), antipsychotics (OR 2.40, 95% CI 1.81-3.18), and physical restraints (OR 2.48, 95% CI 1.71-3.59). Conclusion: Delirium is common in older NH residents. Simple assessment tools might facilitate its recognition in this vulnerable population. (C) 2018 S. Karger AG, Basel | Dementia and geriatric cognitive disorders 46 (2018): 27-41. | 2018 | MUSICCO MASSIMO | Delirium, Nursing home medicine, Assessment, Prevalence | 10.1159/000490722 |
| 389515 | Articolo in rivista | Evaluation of the effects of different diets on microbiome diversity and fatty acid composition of rumen liquor in dairy goat | Cremonesi P., Conte G., Severgnini M., Turri F., Monni A., Capra E., Rapetti L., Colombini S., Chessa S., Battelli G., Alves S.P., Mele M., Castiglioni B. | Fat supplementation plays an important role in defining milk fatty acids (FA) composition of ruminant products. The use of sources rich in linoleic and ?-linolenic acid favors the accumulation of conjugated linoleic acids isomers, increasing the healthy properties of milk. Ruminal microbiota plays a pivotal role in defining milk FA composition, and its profile is affected by diet composition. The aim of this study was to investigate the responses of rumen FA production and microbial structure to hemp or linseed supplementation in diets of dairy goats. Ruminal microbiota composition was determined by 16S amplicon sequencing, whereas FA composition was obtained by gas-chromatography technique. In all, 18 pluriparous Alpine goats fed the same pre-treatment diet for 40+-7 days were, then, arranged to three dietary treatments consisting of control, linseed and hemp seeds supplemented diets. Independently from sampling time and diets, bacterial community of ruminal fluid was dominated by Bacteroidetes (about 61.2%) and Firmicutes (24.2%) with a high abundance of Prevotellaceae (41.0%) and Veillonellaceae (9.4%) and a low presence of Ruminococcaceae (5.0%) and Lachnospiraceae (4.3%). Linseed supplementation affected ruminal bacteria population, with a significant reduction of biodiversity; in particular, relative abundance of Prevotella was reduced (-12.0%), whereas that of Succinivibrio and Fibrobacter was increased (+50.0% and +75.0%, respectively). No statistically significant differences were found among the average relative abundance of archaeal genera between each dietary group. Moreover, the addition of linseed and hemp seed induced significant changes in FA concentration in the rumen, as a consequence of shift from C18 : 2n-6 to C18 : 3n-3 biohydrogenation pathway. Furthermore, dimethylacetal composition was affected by fat supplementation, as consequence of ruminal bacteria population modification. Finally, the association study between the rumen FA profile and the bacterial microbiome revealed that Fibrobacteriaceae is the bacterial family showing the highest and significant correlation with FA involved in the biohydrogenation pathway of C18 : 3n-3. | Animal (Cambridge. Print) (2018): 1-11. | 2018 | CAPRA EMANUELE, BATTELLI GIOVANNA, CASTIGLIONI BIANCA MARIA ELISABETTA, SEVERGNINI MARCO, CREMONESI PAOLA, CHESSA STEFANIA, TURRI FEDERICA | metagenome, goat, rumen, fatty acid, dimethylacetal | 10.1017/S1751731117003433 |
| 396082 | Articolo in rivista | Milk microbiome diversity and bacterial group prevalence in a comparison between healthy Holstein Friesian and Rendena cows | Cremonesi, Paola, Ceccarani, Camilla, Curone, Giulio, Severgnini, Marco, Pollera, Claudia, Bronze, Valerio, Riva, Federica, Addis, Maria Filippa, Filipe, Joel, Amadori, Massimo, Trevisi, Erminio, Vigo, Daniele, Moroni, Paolo, Castiglioni, Bianca | Dry and early lactation periods represent the most critical phases for udder health in cattle, especially in highly productive breeds, such as the Holstein Friesian (HF). On the other hand, some autochthonous cattle breeds, such as the Rendena (REN), have a lower prevalence of mastitis and other transition-related diseases. In this study, milk microbiota of 6 HF and 3 REN cows, all raised on the same farm under the same conditions, was compared. A special focus was placed on the transition period to define bacterial groups' prevalence with a plausible effect on mammary gland health. Four time points (dry-off, 1 d, 7-10 d and 30 d after calving) were considered. Through 16S rRNA sequencing, we characterized the microbiota composition for 117 out of the 144 milk samples initially collected, keeping only the healthy quarters, in order to focus on physiological microbiome changes and avoid shifts due to suspected diseases. Microbial populations were very different in the two breeds along all the time points, with REN milk showing a significantly lower microbial biodiversity. The taxonomic profiles of both cosmopolitan and local breeds were dominated by Firmicutes, mostly represented by the Streptococcus genus, although in very different proportions (HF 27.5%, REN 68.6%). Large differences in HF and REN cows were, also, evident from the metabolic predictive analysis from microbiome data. Finally, only HF milk displayed significant changes in the microbial composition along the transition period, while REN maintained a more stable microbiota. In conclusion, in addition to the influence on the final characteristics of dairy products obtained from milk of the two breeds, differences in the milk microbiome might, also, have an impact on their mammary gland health. | PloS one 13 (2018). | 2018 | CECCARANI CAMILLA, CASTIGLIONI BIANCA MARIA ELISABETTA, SEVERGNINI MARCO, CREMONESI PAOLA | microbiome, bovine, milk, mastitis | 10.1371/journal.pone.0205054 |
| 397317 | Articolo in rivista | BITS 2017: the annual meeting of the Italian Society of Bioinformatics | Armano G1, Fotia G2, Manconi A3. | This preface introduces the content of the BioMed Central journal Supplement related to the 14th annual meeting of the Bioinformatics Italian Society, held in Cagliari, Italy, from the 5th to the 7th of July, 2017. | BMC bioinformatics 19 (2018): 207-210. | 2018 | MANCONI ANDREA | BITS, Bioinformatics, Meeting of the Italian Society of Bioinformatics | 10.1186/s12859-018-2295-y |
| 397322 | Articolo in rivista | ASGAL: aligning RNA-Seq data to a splicing graph to detect novel alternative splicing events | Denti L1, Rizzi R1, Beretta S1, 2, Vedova GD1, Previtali M1, Bonizzoni P3. | BackgroundWhile the reconstruction of transcripts from a sample of RNA-Seq data is a computationally expensive and complicated task, the detection of splicing events from RNA-Seq data and a gene annotation is computationally feasible. This latter task, which is adequate for many transcriptome analyses, is usually achieved by aligning the reads to a reference genome, followed by comparing the alignments with a gene annotation, often implicitly represented by a graph: the splicing graph.ResultsWe present ASGAL (Alternative Splicing Graph ALigner): a tool for mapping RNA-Seq data to the splicing graph, with the specific goal of detecting novel splicing events, involving either annotated or unannotated splice sites. ASGAL takes as input the annotated transcripts of a gene and a RNA-Seq sample, and computes (1) the spliced alignments of each read in input, and (2) a list of novel events with respect to the gene annotation.ConclusionsAn experimental analysis shows that ASGAL allows to enrich the annotation with novel alternative splicing events even when genes in an experiment express at most one isoform. Compared with other tools which use the spliced alignment of reads against a reference genome for differential analysis, ASGAL better predicts events that use splice sites which are novel with respect to a splicing graph, showing a higher accuracy. To the best of our knowledge, ASGAL is the first tool that detects novel alternative splicing events by directly aligning reads to a splicing graph.AvailabilitySource code, documentation, and data are available for download at http://asgal.algolab.eu. | BMC bioinformatics 19 (2018). | 2018 | BERETTA STEFANO | Graph alignment, Spliced alignment, Alternative splicing events, RNA-Seq | 10.1186/s12859-018-2436-3 |
| 368314 | Articolo in rivista | Socioeconomic Position, But Not African Genomic Ancestry, Is Associated With Blood Pressure in the Bambui-Epigen (Brazil) Cohort Study of Aging | Lima-Costa, M. Fernanda, de Mello Mambrini, Juliana Vaz, Correa Leite, Maria Lea, Peixoto, Sergio Viana, Araujo Firmo, Joselia Oliveira, de Loyola Filho, Antonio Ignacio, Gouveia, Mateus H., Leal, Thiago P., Pereira, Alexandre Costa, Macinko, James, Tarazona-Santos, Eduardo | The study objective is to examine the role of African genome origin on baseline and 11-year blood pressure trajectories in community-based ethnoracially admixed older adults in Brazil. Data come from 1272 participants (aged 60 years) of the Bambui cohort study of aging during 11 years of follow-up. Outcome measures were systolic blood pressure, diastolic blood pressure, and hypertension control. Potential confounding variables were demographic characteristics, socioeconomic position (schooling and household income), and health indicators (smoking, sedentary lifestyle, high-density lipoprotein cholesterol, waist circumference, diabetes mellitus, and cardiovascular diseases), including antihypertensive drug use. We used 370 539 single-nucleotide polymorphisms to estimate each individual's African, European, and Native American trihybrid ancestry proportions. Median African, European, and Native American ancestry were 9.6%, 84.0%, and 5.3%, respectively. Among those with African ancestry, 59.4% came from East and 40.6% from West Africa. Baseline systolic and diastolic blood pressure, controlled hypertension, and their respective trajectories, were not significantly (P>0.05) associated with level (in quintiles) of African genomic ancestry. Similar results were found for West and East African subcontinental origins. Lower schooling level (<4 years versus higher) showed a significant and positive association with systolic blood pressure (Adjusted =2.92; 95% confidence interval, 0.85-4.99). Lower monthly household income per capita (| Hypertension (Dallas Tex., 1979) 67 (2016): 349-355. | 2016 | CORREA LEITE MARIA LEA | African continental ancestry group, blood pressure, cohort studies, hypertension | 10.1161/HYPERTENSIONAHA.115.06609 | |
| 368315 | Articolo in rivista | A fuzzy method for RNA-Seq differential expression analysis in presence of multireads | Consiglio, Arianna, Mencar, Corrado, Grillo, Giorgio, Marzano, Flaviana, Caratozzolo, Mariano Francesco, Liuni, Sabino | Background When the reads obtained from high-throughput RNA sequencing are mapped against a reference database, a significant proportion of them - known as multireads - can map to more than one reference sequence. These multireads originate from gene duplications, repetitive regions or overlapping genes. Removing the multireads from the mapping results, in RNA-Seq analyses, causes an underestimation of the read counts, while estimating the real read count can lead to false positives during the detection of differentially expressed sequences. Results We present an innovative approach to deal with multireads and evaluate differential expression events, entirely based on fuzzy set theory. Since multireads cause uncertainty in the estimation of read counts during gene expression computation, they can also influence the reliability of differential expression analysis results, by producing false positives. Our method manages the uncertainty in gene expression estimation by defining the fuzzy read counts and evaluates the possibility of a gene to be differentially expressed with three fuzzy concepts: over-expression, same-expression and under-expression. The output of the method is a list of differentially expressed genes enriched with information about the uncertainty of the results due to the multiread presence. We have tested the method on RNA-Seq data designed for case-control studies and we have compared the obtained results with other existing tools for read count estimation and differential expression analysis. Conclusions The management of multireads with the use of fuzzy sets allows to obtain a list of differential expression events which takes in account the uncertainty in the results caused by the presence of multireads. Such additional information can be used by the biologists when they have to select the most relevant differential expression events to validate with laboratory assays. Our method can be used to compute reliable differential expression events and to highlight possible false positives in the lists of differentially expressed genes computed with other tools. | BMC bioinformatics 17 (2016). | 2016 | CARATOZZOLO MARIANO FRANCESCO, MARZANO FLAVIA, CONSIGLIO ARIANNA, GRILLO GIORGIO, LIUNI SABINO | RNA-Seq, Differential expression, Multireads, Fuzzy sets, Possibilistic modeling | 10.1186/s12859-016-1195-2 |
| 369955 | Articolo in rivista | WoPPER: Web server for Position Related data analysis of gene Expression in Prokaryotes. | Puccio, Simone, Grillo, Giorgio, Licciulli, Flavio, Severgnini, Marco, Liuni, Sabino, Bicciato, Silvio, De Bellis, Gianluca, Ferrari, Francesco, Peano, Clelia | The structural and conformational organization of chromosomes is crucial for gene expression regulation in eukaryotes and prokaryotes as well. Up to date, gene expression data generated using either microarray or RNA-sequencing are available for many bacterial genomes. However, differential gene expression is usually investigated with methods considering each gene independently, thus not taking into account the physical localization of genes along a bacterial chromosome. Here, we present WoPPER, a web tool integrating gene expression and genomic annotations to identify differentially expressed chromosomal regions in bacteria. RNA-sequencing or microarray-based gene expression data are provided as input, along with gene annotations. The user can select genomic annotations from an internal database including 2780 bacterial strains, or provide custom genomic annotations. The analysis produces as output the lists of positionally related genes showing a coordinated trend of differential expression. Graphical representations, including a circular plot of the analyzed chromosome, allow intuitive browsing of the results. The analysis procedure is based on our previously published R-package PREDA. The release of this tool is timely and relevant for the scientific community, as WoPPER will fill an existing gap in prokaryotic gene expression data analysis and visualization tools. WoPPER is open to all users and can be reached at the following URL: https://WoPPER.ba.itb.cnr.it. | Nucleic acids research (2017). | 2017 | PUCCIO SIMONE, FERRARI FRANCESCO, DE BELLIS GIANLUCA, LICCIULLI VITO FLAVIO, GRILLO GIORGIO, PEANO CLELIA, SEVERGNINI MARCO, LIUNI SABINO | webserver, gene expression, prokaryotes, chromosomal conformation | 10.1093/nar/gkx329 |
| 378337 | Articolo in rivista | Molecular Characterization of Peripheral Extracellular Vesicles in Clinically Isolated Syndrome: Preliminary Suggestions from a Pilot Study. | Nuzziello, Nicoletta, Blonda, Maria, Licciulli, Flavio, Liuni, Sabino, Amoruso, Antonella, Valletti, Alessio, Consiglio, Arianna, Avolio, Carlo, Liguori, Maria | Extracellular vesicles (EVs), nanoparticles originated from different cell types, seem to be implicated in several cellular activities. In the Central Nervous System (CNS), glia and neurons secrete EVs and recent studies have demonstrated that the intercellular communication mediated by EVs has versatile functional impact in the cerebral homeostasis. This essential role may be due to their proteins and RNAs cargo that possibly modify the phenotypes of the targeted cells. Despite the increasing importance of EVs, little is known about their fluctuations in physiological as well as in pathological conditions. Furthermore, only few studies have investigated the contents of contemporary EVs subgroups (microvesicles, MVs and exosomes, EXOs) with the purpose of discriminating between their features and functional roles. In order to possibly shed light on these issues, we performed a pilot study in which MVs and EXOs extracted from serum samples of a little cohort of subjects (patients with the first clinical evidence of CNS demyelination, also known as Clinically Isolated Syndrome and Healthy Controls) were submitted to deep small-RNA sequencing. Data were analysed by an in-home bioinformatics platform. In line with previous reports, distinct classes of non-coding RNAs have been detected in both the EVs subsets, offering interesting suggestions on their origins and functions. We also verified the feasibility of this extensive molecular approach, thus supporting its valuable use for the analysis of circulating biomarkers (e.g., microRNAs) in order to investigate and monitor specific diseases. | Medical sciences 5 (2017). | 2017 | LIGUORI MARIA, CONSIGLIO ARIANNA, NUZZIELLO NICOLETTA, VALLETTI ALESSIO, LICCIULLI VITO FLAVIO, LIUNI SABINO | Clinically Isolated Syndrome (CIS); bioinformatics; circulating biomarkers; extracellular vesicles (EVs); small RNA sequencing | 10.3390/medsci5030019 |
| 380052 | Articolo in rivista | Combined microRNAs and mRNAs expression analysis in Pediatric Multiple Sclerosis: an integrated approach to uncover novel pathogenic mechanisms of the disease. | Liguori, Maria, Nuzziello, Nicoletta, Licciulli, Flavio, Consiglio, Arianna, Simone, Marta, Gemma Viterbo, Rosa, Creanza, Teresa Maria, Ancona, Nicola, Tortorella, Carla, Margari, Lucia, Grillo, Giorgio, Giordano, Paola, Liuni, Sabino, Trojano, Maria | Multiple Sclerosis (MS) is a complex disease of the CNS that usually affects young adults, although 3-5% of cases are diagnosed in childhood and adolescence (hence called pediatric MS, PedMS). Genetic predisposition, among other factors, seems to contribute to the risk of the onset, in pediatric as in adult ages, but few studies have investigated the genetic "environmentally naive" load of PedMS.The main goal of this study was to identify circulating markers (miRNAs), target genes (mRNAs) and functional pathways associated with PedMS; we also verified the impact of miRNAs on clinical features, i.e. disability and cognitive performances.The investigation was performed in 19 PedMS and 20 pediatric controls (PCs) using a High-Throughput Next-generation Sequencing (HT-NGS) approach followed by an integrated bioinformatics/biostatistics analysis. Twelve miRNAs were significantly upregulated (let-7a-5p, let-7b-5p, miR-25-3p, miR-125a-5p, miR-942-5p, miR-221-3p, miR-652-3p, miR-182-5p, miR-185-5p, miR-181a-5p, miR-320a, miR-99b-5p) and 1 miRNA was downregulated (miR-148b-3p) in PedMS compared to PCs. The interactions between the significant miRNAs and their targets uncovered predicted genes (i.e. TNFSF13B, TLR2, BACH2, KLF4) related to immunological functions, as well as genes involved in autophagy-related processes (i.e. ATG16L1, SORT1, LAMP2) and ATPase activity (i.e. ABCA1, GPX3). No significant molecular profiles were associated with any PedMS demographic/clinical features. Both miRNAs and mRNA expressions predicted the phenotypes (PedMS-PC) with an accuracy of 92% and 91%, respectively.In our view, this original strategy of contemporary miRNA/mRNA analysis may help to shed light in the genetic background of the disease, suggesting further molecular investigations in novel pathogenic mechanisms. | Human molecular genetics online (2017). | 2017 | CONSIGLIO ARIANNA, NUZZIELLO NICOLETTA, LICCIULLI VITO FLAVIO, GRILLO GIORGIO, LIGUORI MARIA, LIUNI SABINO | * | 10.1093/hmg/ddx385 |
| 382121 | Articolo in rivista | Combined microRNA and mRNA expression analysis in pediatric multiple sclerosis: an integrated approach to uncover novel pathogenic mechanisms of the disease. | Liguori M1, Nuzziello N1, 2, Licciulli F1, Consiglio A1, Simone M2, Viterbo RG2, Creanza TM3, Ancona N3, Tortorella C2, 4, Margari L2, Grillo G1, Giordano P5, Liuni S1, Trojano M2. | Multiple sclerosis (MS) is a complex disease of the CNS that usually affects young adults, although 3-5% of cases are diagnosed in childhood and adolescence (hence called pediatric MS, PedMS). Genetic predisposition, among other factors, seems to contribute to the risk of the onset, in pediatric as in adult ages, but few studies have investigated the genetic 'environmentally naive' load of PedMS. The main goal of this study was to identify circulating markers (miRNAs), target genes (mRNAs) and functional pathways associated with PedMS; we also verified the impact of miRNAs on clinical features, i.e. disability and cognitive performances. The investigation was performed in 19 PedMS and 20 pediatric controls (PCs) using a High-Throughput Next-generation Sequencing (HT-NGS) approach followed by an integrated bioinformatics/biostatistics analysis. Twelve miRNAs were significantly upregulated (let-7a-5p, let-7b-5p, miR-25-3p, miR-125a-5p, miR-942-5p, miR-221-3p, miR-652-3p, miR-182-5p, miR-185-5p, miR-181a-5p, miR-320a, miR-99b-5p) and 1 miRNA was downregulated (miR-148b-3p) in PedMS compared with PCs. The interactions between the significant miRNAs and their targets uncovered predicted genes (i.e. TNFSF13B, TLR2, BACH2, KLF4) related to immunological functions, as well as genes involved in autophagy-related processes (i.e. ATG16L1, SORT1, LAMP2) and ATPase activity (i.e. ABCA1, GPX3). No significant molecular profiles were associated with any PedMS demographic/clinical features. Both miRNAs and mRNA expressions predicted the phenotypes (PedMS-PC) with an accuracy of 92% and 91%, respectively. In our view, this original strategy of contemporary miRNA/mRNA analysis may help to shed light in the genetic background of the disease, suggesting further molecular investigations in novel pathogenic mechanisms. | Human molecular genetics (Print) (2018). | 2018 | CONSIGLIO ARIANNA, NUZZIELLO NICOLETTA, ANCONA NICOLA, LICCIULLI VITO FLAVIO, GRILLO GIORGIO, LIGUORI MARIA, LIUNI SABINO, CREANZA TERESA MARIA | * | |
| 382134 | Articolo in rivista | TRIM8: Making the Right Decision between the Oncogene and Tumour Suppressor Role. | Caratozzolo MF 1, Marzano F 2, Mastropasqua F 3, Sbisa E 4, Tullo A 5. | The TRIM8/GERP protein is a member of the TRIM family defined by the presence of a common domain structure composed of a tripartite motif including a RING-finger, one or two B-box domains, and a coiled-coil motif. The TRIM8 gene maps on chromosome 10 within a region frequently found deleted and rearranged in tumours and transcribes a 3.0-kB mRNA. Its expression is mostly ubiquitously in murine and human tissues, and in epithelial and lymphoid cells, it can be induced by IFNgamma. The protein spans 551 aa and is highly conserved during evolution. TRIM8 plays divergent roles in many biological processes, including important functions in inflammation and cancer through regulating various signalling pathways. In regulating cell growth, TRIM8 exerts either a tumour suppressor action, playing a prominent role in regulating p53 tumour suppressor activity, or an oncogene function, through the positive regulation of the NF-kappaB pathway. The molecular mechanisms underlying this dual role in human cancer will be discussed in depth in this review, and it will highlight the challenge and importance of developing novel therapeutic strategies specifically aimed at blocking the pro-oncogenic arm of the TRIM8 signalling pathway without affecting its tumour suppressive effects. | Genes (Basel) 8 (2017). | 2017 | MARZANO FLAVIANA, MASTROPASQUA FRANCESCA, CARATOZZOLO MARIANO FRANCESCO, TULLO APOLLONIA, SBISA' ELISABETTA | NF-?B; TRIM8; innate immunity; oncogene; p53; stemness; tumour suppressor | 10.3390/genes8120354 |
| 384540 | Articolo in rivista | G4PromFinder: an algorithm for predicting transcription promoters in GC-rich bacterial genomes based on AT-rich elements and G-quadruplex motifs | Di Salvo M1, Pinatel E2, Tala A1, Fondi M3, Peano C4, 5, Alifano P6. | BACKGROUND: Over the last few decades, computational genomics has tremendously contributed to decipher biology from genome sequences and related data. Considerable effort has been devoted to the prediction of transcription promoter and terminator sites that represent the essential "punctuation marks" for DNA transcription. Computational prediction of promoters in prokaryotes is a problem whose solution is far from being determined in computational genomics. The majority of published bacterial promoter prediction tools are based on a consensus-sequences search and they were designed specifically for vegetative ?70 promoters and, therefore, not suitable for promoter prediction in bacteria encoding a lot of ? factors, like actinomycetes. RESULTS: In this study we investigated the possibility to identify putative promoters in prokaryotes based on evolutionarily conserved motifs, and focused our attention on GC-rich bacteria in which promoter prediction with conventional, consensus-based algorithms is often not-exhaustive. Here, we introduce G4PromFinder, a novel algorithm that predicts putative promoters based on AT-rich elements and G-quadruplex DNA motifs. We tested its performances by using available genomic and transcriptomic data of the model microorganisms Streptomyces coelicolor A3(2) and Pseudomonas aeruginosa PA14. We compared our results with those obtained by three currently available promoter predicting algorithms: the ?70consensus-based PePPER, the ? factors consensus-based bTSSfinder, and PromPredict which is based on double-helix DNA stability. Our results demonstrated that G4PromFinder is more suitable than the three reference tools for both the genomes. In fact our algorithm achieved the higher accuracy (F1-scores 0.61 and 0.53 in the two genomes) as compared to the next best tool that is PromPredict (F1-scores 0.46 and 0.48). Consensus-based algorithms produced lower performances with the analyzed GC-rich genomes. CONCLUSIONS: Our analysis shows that G4PromFinder is a powerful tool for promoter search in GC-rich bacteria, especially for bacteria coding for a lot of ? factors, such as the model microorganism S. coelicolor A3(2). Moreover consensus-based tools and, in general, tools that are based on specific features of bacterial ? factors seem to be less performing for promoter prediction in these types of bacterial genomes. | BMC bioinformatics 19 (2018). | 2018 | PINATEL EVA MARIA, PEANO CLELIA | G4PromFinder, Promoters, G-Quadruplex, Motif, GC-rich genomes, Promoter elements | 10.1186/s12859-018-2049-x |
| 384799 | Articolo in rivista | HIV-1-mediated insertional activation of STAT5B and BACH2 trigger viral reservoir in T regulatory cells | Cesana, Daniela, de Sio, Francesca R. Santoni, Rudilosso, Laura, Gallina, Pierangela, Calabria, Andrea, Beretta, Stefano, Merelli, Ivan, Bruzzesi, Elena, Passerini, Laura, Nozza, Silvia, Vicenzi, Elisa, Poli, Guido, Gregori, Silvia, Tambussi, Giuseppe, Montini, Eugenio | HIV-1 insertions targeting BACH2 or MLK2 are enriched and persist for decades in hematopoietic cells from patients under combination antiretroviral therapy. However, it is unclear how these insertions provide such selective advantage to infected cell clones. Here, we show that in 30/87 (34%) patients under combination antiretroviral therapy, BACH2, and STAT5B are activated by insertions triggering the formation of mRNAs that contain viral sequences fused by splicing to their first protein-coding exon. These chimeric mRNAs, predicted to express full-length proteins, are enriched in T regulatory and T central memory cells, but not in other T lymphocyte subsets or monocytes. Overexpression of BACH2 or STAT5B in primary T regulatory cells increases their proliferation and survival without compromising their function. Hence, we provide evidence that HIV-1-mediated insertional activation of BACH2 and STAT5B favor the persistence of a viral reservoir in T regulatory cells in patients under combination antiretroviral therapy. | Nature communications 8 (2017). | 2017 | MERELLI IVAN | HIV infections, Transcriptional regulatory elements, Viral reservoirs, Virus-host interactions | 10.1038/s41467-017-00609-1 |
| 384925 | Articolo in rivista | Tay Sachs in South Italy | Patrizia Spadafora 1, Giuseppe Tagarelli 2, Nelide Romeo 1, Maria Liguori 3 | Tay Sachs disease (TSD) is an autosomal recessive neurological disorder characterized by significant deficiency of lysosomal enzyme ?-Hexosaminidase A and subsequent intralysosomal accumulation of GM2 ganglioside. Tay Sachs disease has been extensively studied in the Ashkenazy Jewish population because of an elevated incidence of cases.We have described in a recent work a young woman of 30 years old with early onset depression at around age 9, inbalance with tendency to fall and cerebellar ataxia developed at 19 years old. She was no longer able to walk without assistance at age of 25. This patient originated from an isolated village of Calabria, South Italy. Genetic tests excluded recessive spinocerebellar ataxias. In vitro determination of the ?-Hexosaminidase A activity showed a low value (< 10%) suggesting a diagnosis of TSD. Direct sequencing of HEXA gene revealed Gly269Ser mutation in compound heterozygosity with Leu127Arg. The identification of two different mutations in HEXA gene in the young woman reported by us originating from an isolated village of southern Italy, and the finding of consanguinity in the family (proband's parents were second-degree cousins), suggested the presence in this country of a founder effect of Ashkenazi Jews origin. In support of this hypothesis, historical sources indicated the presence of Jews in Calabria since eleventh century. | ISI atlas of science (2017): 1-3. | 2017 | TAGARELLI GIUSEPPE, ROMEO NELIDE, SPADAFORA PATRIZIA, LIGUORI MARIA | tay sachs, Hexa gene | |
| 385732 | Contributo in atti di convegno | Low-power storage bricks and bioinformatics on Systems-On-Chip | L. Morganti, D. Cesini, E. Corni, L. Lama, C. Pellegrino, I. Merelli, D. D'Agostino | Low-power Systems on Chip (SoCs) derived from the embedded and mobile market can be profitably used to execute scientific workloads traditionally designed for power- hungry clusters, saving energy, gaining portability and reducing infrastructural costs and sizes. We investigate the possibility of using SoCs as storage bricks of a BeeGFS filesystem in the per- spective of energy-efficient storage solutions supporting scientific computing. Then, we consider a use case from metagenomics analysis and show how the large amount of genome sequencing information streamed by portable sequencing devices could be managed by low-power SoCs making use of an underlying BeeGFS filesystem. | 26th Euromicro International Conference on Parallel, Distributed, and Network- Based Processing (PDP 2018), pp. 635-638, Cambridge, UK, 21-23/03/2018 | 2018 | D'AGOSTINO DANIELE, MERELLI IVAN | Low-power Systems-on-Chip, parallel filesystem, bioinformatics | 10.1109/PDP2018.2018.00106 |
| 385729 | Contributo in atti di convegno | Computing empirical p-values for estimating gene-gene interactions in Genome-Wide Association Studies: A parallel computing approach | V. Giansanti, D. D'Agostino, C. Maj, S. Beretta, I. Merelli | In complex phenotypes (e.g., psychiatric diseases) single locus tests, commonly performed with genome-wide association studies, have proven to be limited in discovering strong gene associations. A growing body of evidence suggests that epistatic non-linear effects may be responsible for complex phenotypes arising from the interaction of different biological factors. A major issue in epistasis analysis is the computational burden due to the huge number of statistical tests to be performed when considering all the potential genotype combinations. In this work, we developed a computational efficient approach to compute empirical p-values concerning the presence of epistasis at a genome-wide scale in bipolar disorder, which is a typical example of complex phenotype with a relevant but unexplained genetic background. By running our approach we were able to identify 13 epistasis interactions between variants located in genes potentially involved in biological processes associated with the analyzed phenotype. | 26th Euromicro International Conference on Parallel, Distributed, and Network- Based Processing PDP 2018, pp. 406-409, Cambridge, UK, 21-23/03/2018 | 2018 | BERETTA STEFANO, GIANSANTI VALENTINA, D'AGOSTINO DANIELE, MERELLI IVAN | epistasis, empirical p-value, parallel computing | 10.1109/PDP2018.2018.00071 |
| 387287 | Articolo in rivista | A lysosome-plasma membrane-sphingolipid axis linking lysosomal storage to cell growth arrest | Samarani M., Loberto N., Solda G., Straniero L., Asselta R., Duga S., Lunghi G., Zucca F.A., Mauri L., Ciampa M.G., Schiumarini D., Bassi R., Giussani P., Chiricozzi E., Prinetti A., Aureli M., Sonnino S. | Lysosomal accumulation of undegraded materials is a common feature of lysosomal storage diseases, neurodegenerative disorders, and the aging process. To better understand the role of lysosomal storage in the onset of cell damage, we used human fibroblasts loaded with sucrose as a model of lysosomal accumulation. Sucrose-loaded fibroblasts displayed increased lysosomal biogenesis followed by arrested cell proliferation. Notably, we found that reduced lysosomal catabolism and autophagy impairment led to an increase in sphingolipids (i.e., sphingomyelin, glucosylceramide, ceramide, and the gangliosides GM3 and GD3), at both intracellular and plasma membrane (PM) levels. In addition, we observed an increase in the lysosomal membrane protein Lamp-1 on the PM of sucrose-loaded fibroblasts and a greater release of the soluble lysosomal protein cathepsin D in their extracellular medium compared with controls. These results indicate increased fusion between lysosomes and the PM, as also suggested by the increased activity of lysosomal glycosphingolipid hydrolases on the PM of sucrose-loaded fibroblasts. The inhibition of ?-glucocerebrosidase and nonlysosomal glucosylceramidase, both involved in ceramide production resulting from glycosphingolipid catabolism on the PM, partially restored cell proliferation. Our findings indicate the existence of a new molecular mechanism underlying cell damage triggered by lysosomal impairment. | The FASEB journal 32 (2018): 5685-5702. | 2018 | ZUCCA FABIO ANDREA | glycosphingolipids, glycohydrolases, cell proliferation, cell surface, catabolism | 10.1096/fj.201701512RR |
| 388412 | Articolo in rivista | Implications of Placebo and Nocebo Effects for Clinical Practice: Expert Consensus | Evers AWM1, Colloca L2, Blease C3, Annoni M4, Atlas LY5, Benedetti F6, Bingel U7, Buchel C8, Carvalho C9, Colagiuri B10, Crum AJ11, Enck P12, Gaab J13, Geers AL14, Howick J15, Jensen KB16, Kirsch I17, Meissner K18, Napadow V19, Peerdeman KJ1, Raz A20, Rief W21, Vase L22, Wager TD23, Wampold BE24, 25, Weimer K26, Wiech K27, Kaptchuk TJ17, Klinger R28, Kelley JM17. | BACKGROUND: Placebo and nocebo effects occur in clinical or laboratory medical contexts after administration of an inert treatment or as part of active treatments and are due to psychobiological mechanisms such as expectancies of the patient. Placebo and nocebo studies have evolved from predominantly methodological research into a far-reaching interdisciplinary field that is unravelling the neurobiological, behavioural and clinical underpinnings of these phenomena in a broad variety of medical conditions. As a consequence, there is an increasing demand from health professionals to develop expert recommendations about evidence-based and ethical use of placebo and nocebo effects for clinical practice. METHODS: A survey and interdisciplinary expert meeting by invitation was organized as part of the 1st Society for Interdisciplinary Placebo Studies (SIPS) conference in 2017. Twenty-nine internationally recognized placebo researchers participated. RESULTS: There was consensus that maximizing placebo effects and minimizing nocebo effects should lead to better treatment outcomes with fewer side effects. Experts particularly agreed on the importance of informing patients about placebo and nocebo effects and training health professionals in patient-clinician communication to maximize placebo and minimize nocebo effects. CONCLUSIONS: The current paper forms a first step towards developing evidence-based and ethical recommendations about the implications of placebo and nocebo research for medical practice, based on the current state of evidence and the consensus of experts. Future research might focus on how to implement these recommendations, including how to optimize conditions for educating patients about placebo and nocebo effects and providing training for the implementation in clinical practice. | Psychotherapy and psychosomatics 87 (2018): 204-210. | 2018 | ANNONI MARCO ANGELO MARIA | Clinical practice; Evidence-based ethical recommendations; Nocebo effect; Patient-clinician communication; Patient's expectancies; Placebo effect | 10.1159/000490354 |
| 388413 | Articolo in rivista | The association of indwelling urinary catheter with delirium in hospitalized patients and nursing home residents: an explorative analysis from the "Delirium Day 2015" | Bo M., Porrino P., Di Santo S.G., Mazzone A., Cherubini A., Mossello E., Bianchetti A., Musicco M., Ferrari A., Ferrara N., Filippini C., Trabucchi M., Morandi A., Bellelli G. | Backround: Use of indwelling urinary catheter (IUC) in older adults has negative consequences, including delirium. Aim: This analysis, from the "Delirium Day 2015", a nationwide multicenter prevalence study, aim to evaluate the association of IUC with delirium in hospitalized and Nursing Homes (NHs) patients. Methods: Patients underwent a comprehensive geriatric assessment, including the presence of IUC; inclusion criteria were age > 65 years, being Italian speaker and providing informed consent; exclusion criteria were coma, aphasia, end-of-life status. Delirium was assessed using the 4AT test (score >= 4: possible delirium; scores 1-3: possible cognitive impairment). Results: Among 1867 hospitalized patients (mean age 82.0 +- 7.5 years, 58% female), 539 (28.9%) had IUC, 429 (22.9%) delirium and 675 (36.1%) cognitive impairment. IUC was significantly associated with cognitive impairment (OR 1.60, 95% CI 1.19-2.16) and delirium (2.45, 95% CI 1.73-3.47), this latter being significant also in the subset of patients without dementia (OR 2.28, 95% CI 1.52-3.43). Inattention and impaired alertness were also independently associated with IUC. Among 1454 NHs residents (mean age 84.4 +- 7.4 years, 70.% female), 63 (4.3%) had IUC, 535 (36.8%) a 4AT score >= 4, and 653 (44.9%) a 4AT score 1-3. The multivariate logistic regression analysis did not show a significant association between 4AT test or its specific items with IUC, neither in the subset of patients without dementia. Discussion: We confirmed a significant association between IUC and delirium in hospitalized patients but not in NHs residents. Conclusion: Environmental and clinical factors of acute setting might contribute to IUC-associated delirium occurrence. | Aging Clinical and Experimental Research (Print) (2019): 1-10. | 2019 | MUSICCO MASSIMO | 4AT test, Cognition, Delirium, Geriatric assessment | 10.1007/s40520-018-0974-1 |
| 388821 | Articolo in rivista | Pirin: a novel redox-sensitive modulator of primary and secondary metabolism in Streptomyces. | Tala A, Damiano F, Gallo G, Pinatel E, Calcagnile M, Testini M, Fico D, Rizzo D, Sutera A, Renzone G, Scaloni A, De Bellis G, Siculella L, De Benedetto GE, Puglia AM, Peano C, Alifano P. | Pirins are evolutionarily conserved iron-containing proteins that are found in all kingdoms of life, and have been implicated in diverse molecular processes, mostly associated with cellular stress. In the present study, we started from the evidence that the insertional inactivation of pirin-like gene SAM23877_RS18305 (pirA) by ?C31 Att/Int system-based vectors in spiramycin-producing strain Streptomyces ambofaciens ATCC 23877 resulted in marked effects on central carbon and energy metabolism gene expression, high sensitivity to oxidative injury and repression of polyketide antibiotic production. By using integrated transcriptomic, proteomic and metabolite profiling, together with genetic complementation, we here show that most of these effects could be traced to the inability of the pirA-defective strain to modulate beta-oxidation pathway, leading to an unbalanced supply of precursor monomers for polyketide biosynthesis. Indeed, in silico protein-protein interaction modeling and in vitro experimental validation allowed us to demonstrate that PirA is a novel redox-sensitive negative modulator of very long-chain acyl-CoA dehydrogenase, which catalyzes the first committed step of the beta-oxidation pathway. | Metabolic engineering (Print) 48 (2018): 254-268. | 2018 | SCALONI ANDREA, DE BELLIS GIANLUCA, PEANO CLELIA, RENZONE GIOVANNI, PINATEL EVA MARIA | Actinomycetes; Antibiotics; Beta-oxidation of fatty acids; Pirin; Secondary metabolism | 10.1016/j.ymben.2018.06.008. |
| 392767 | Articolo in rivista | Counting of peripheral extracellular vesicles in Multiple Sclerosis patients by an improved nanoplasmonic assay and dynamic light scattering | Mallardi A1, Nuzziello N2, Liguori M3, Avolio C4, Palazzo G5. | Extracellular vesicles (EVs) are vesicles naturally secreted by the majority of human cells. Being composed by a closed phospholipid bilayer secluding proteins and RNAs they are used to transfer molecular information to other cells, thereby influencing the recipient cell functions. Despite the increasingly recognized relevance of EVs, the clarification of their physiological role is hampered by the lack of suitable analytical tools for their quantification and characterization. In this study, we have implemented a nanoplasmonic assay, previously proposed for the purity of the EV fractions, to achieve a robust analytical protocol in order to quantify the total phospholipid concentration (CPL) and the EVs number. We show how the coupling of the nanoplasmonic assay with serial dilutions of the unknown sample allows, by simple visual inspection, to detect deviations from the physiological EVs content. The use of a response that depends on the absorbance values at three wavelengths permits to reduce the limit of detection of CPL to 5 ?M (total) and the limit of quantification to 35 ?M. We also propose a method that takes into account the spread in EV size when the concentration of phospholipids is turned into a concentration of vesicles. The proposed analytical protocol is successfully applied to a small cohort of Multiple Sclerosis patients examined in different stages of their clinical diseases. | Colloids and surfaces. B, Biointerfaces (Print) 168 (2018): 134-142. | 2018 | NUZZIELLO NICOLETTA, MALLARDI ANTONIA, LIGUORI MARIA | Extracellular vesicles, Exosomes, Nanoplasmonic assay, Gold nanoparticles, Multiple sclerosis | 10.1016/j.colsurfb.2018.02.006 |
| 397314 | Articolo in rivista | Investigating the Role of MicroRNA and Transcription Factor Co-regulatory Networks in Multiple Sclerosis Pathogenesis | Nicoletta Nuzziello 1, Laura Vilardo 2, Paride Pelucchi 2, Arianna Consiglio 1, Sabino Liuni 1, Maria Trojano 3 and Maria Liguori 1 | MicroRNAs (miRNAs) and transcription factors (TFs) play key roles in complex multifactorial diseases like multiple sclerosis (MS). Starting from the miRNomic profile previously associated with a cohort of pediatric MS (PedMS) patients, we applied a combined molecular and computational approach in order to verify published data in patients with adult-onset MS (AOMS). Six out of the 13 selected miRNAs (miR-320a, miR-125a-5p, miR-652-3p, miR-185-5p, miR-942-5p, miR-25-3p) were significantly upregulated in PedMS and AOMS patients, suggesting that they may be considered circulating biomarkers distinctive of the disease independently from age. A computational and unbiased miRNA-based screening of target genes not necessarily associated to MS was then performed in order to provide an extensive view of the genetic mechanisms underlying the disease. A comprehensive MS-specific miRNA-TF co-regulatory network was hypothesized; among others, SP1, RELA, NF-B, TP53, AR, MYC, HDAC1, and STAT3 regulated the transcription of 61 targets. Interestingly, NF-B and STAT3 cooperatively regulate the expression of immune response genes and control the cross-talk between inflammatory and immune cells. Further functional analysis will be performed on the identified critical hubs. Above all, in our view, this approach supports the need of multidisciplinary strategies for shedding light into the pathogenesis of MS. | International journal of molecular sciences (Online) 19 (2018). | 2018 | VILARDO LAURA, NUZZIELLO NICOLETTA, LIGUORI MARIA, PELUCCHI PARIDE, LIUNI SABINO, CONSIGLIO ARIANNA | Multiple Sclerosis, miRNAs, transcription factors, target genes, bioinformatics, circulating biomarkers, pathogenesis | 10.3390/ijms19113652 |
| 397320 | Articolo in rivista | Arena-Idb: a platform to build human non-coding RNA interaction networks | Bonnici V1, De Caro G2, Constantino G1, Liuni S2, D'Elia D2, Bombieri N1, Licciulli F2, Giugno R1. | BACKGROUND: High throughput technologies have provided the scientific community an unprecedented opportunity for large-scale analysis of genomes. Non-coding RNAs (ncRNAs), for a long time believed to be non-functional, are emerging as one of the most important and large family of gene regulators and key elements for genome maintenance. Functional studies have been able to assign to ncRNAs a wide spectrum of functions in primary biological processes, and for this reason they are assuming a growing importance as a potential new family of cancer therapeutic targets. Nevertheless, the number of functionally characterized ncRNAs is still too poor if compared to the number of new discovered ncRNAs. Thus platforms able to merge information from available resources addressing data integration issues are necessary and still insufficient to elucidate ncRNAs biological roles. RESULTS: In this paper, we describe a platform called Arena-Idb for the retrieval of comprehensive and non-redundant annotated ncRNAs interactions. Arena-Idb provides a framework for network reconstruction of ncRNA heterogeneous interactions (i.e., with other type of molecules) and relationships with human diseases which guide the integration of data, extracted from different sources, via mapping of entities and minimization of ambiguity. CONCLUSIONS: Arena-Idb provides a schema and a visualization system to integrate ncRNA interactions that assists in discovering ncRNA functions through the extraction of heterogeneous interaction networks. The Arena-Idb is available at http://arenaidb.ba.itb.cnr.it. | BMC bioinformatics 19 (2018): 231-244. | 2018 | D'ELIA DOMENICA, LICCIULLI VITO FLAVIO, LIUNI SABINO | Non-coding RNA, Database, Network, Data integration | 10.1186/s12859-018-2298-8 |
| 399801 | Contributo in atti di convegno | Parallel Computing in Deep Learning: bioinformatics case studies | V. Giansanti, S. Beretta, D. Cesini, D. D'Agostino, I. Merelli | In the last two decades deep learning has attracted a lot of attention internationally, solving problems in different application domains and achieving results beyond expectations. For example it has been applied in bioinformatics, game playing, imaging processing, object detection, robotic and drug discovery. One of the main reasons for the incremented use of deep learning algorithms is the need to implement approaches for the analysis of the large amount of data produces in every field, bringing researchers to dedicate their work to deep learning development. One of the main topics discussed up today is the possibility to run the training of deep models in a parallel fashion, so to reduce the time otherwise needed to find the hyperparameters and to make the achievement of the result faster. | 27th Euromicro International Conference on Parallel, Distributed and Network-Based Processing (PDP), pp. 329-333, Pavia (Italy), 13-15/02/2019 | 2019 | BERETTA STEFANO, GIANSANTI VALENTINA, D'AGOSTINO DANIELE, MERELLI IVAN | deep learning, bioinformatic, parallel computing | 10.1109/PDP.2019.00055 |
| 399961 | Articolo in rivista | The copy number variation landscape of congenital anomalies of the kidney and urinary tract | Verbitsky, Miguel, Westland, Rik, Perez, Alejandra, Kiryluk, Krzysztof, Liu, Qingxue, Krithivasan, Priya, Mitrotti, Adele, Fasel, David A., Batourina, Ekaterina, Sampson, Matthew G., Bodria, Monica, Werth, Max, Kao, Charlly, Martino, Jeremiah, Capone, Valentina P., Vivante, Asaf, Shril, Shirlee, Kil, Byum Hee, Marasa, Maddalena, Zhang, Jun Y., Na, Young-Ji, Lim, Tze Y., Ahram, Dina, Weng, Patricia L., Heinzen, Erin L., Carrea, Alba, Piaggio, Giorgio, Gesualdo, Loreto, Manca, Valeria, Masnata, Giuseppe, Gigante, Maddalena, Cusi, Daniele, Izzi, Claudia, Scolari, Francesco, van Wijk, Joanna A. E., Saraga, Marijan, Santoro, Domenico, Conti, Giovanni, Zamboli, Pasquale, White, Hope, Drozdz, Dorota, Zachwieja, Katarzyna, Miklaszewska, Monika, Tkaczyk, Marcin, Tomczyk, Daria, Krakowska, Anna, Sikora, Przemyslaw, Jarmolinski, Tomasz, Borszewska-Kornacka, Maria K., Pawluch, Robert, Szczepanska, Maria, Adamczyk, Piotr, Mizerska-Wasiak, Malgorzata, Krzemien, Grazyna, Szmigielska, Agnieszka, Zaniew, Marcin, Dobson, Mark G., Darlow, John M., Puri, Prem, Barton, David E., Furth, Susan L., Warady, Bradley A., Gucev, Zoran, Lozanovski, Vladimir J., Tasic, Velibor, Pisani, Isabella, Allegri, Landino, Rodas, Lida M., Campistol, Josep M., Jeanpierre, Cecile, Alam, Shumyle, Casale, Pasquale, Wong, Craig S., Lin, Fangming, Miranda, Debora M., Oliveira, Eduardo A., Simoes-e-Silva, Ana Cristina, Barasch, Jonathan M., Levy, Brynn, Wu, Nan, Hildebrandt, Friedhelm, Ghiggeri, Gian Marco, Latos-Bielenska, Anna, Materna-Kiryluk, Anna, Zhang, Feng, Hakonarson, Hakon, Papaioannou, Virginia E., Mendelsohn, Cathy L., Gharavi, Ali G., Sanna-Cherchi, Simone | Congenital anomalies of the kidney and urinary tract (CAKUT) are a major cause of pediatric kidney failure. We performed a genome-wide analysis of copy number variants (CNVs) in 2,824 cases and 21,498 controls. Affected individuals carried a significant burden of rare exonic (that is, affecting coding regions) CNVs and were enriched for known genomic disorders (GD). Kidney anomaly (KA) cases were most enriched for exonic CNVs, encompassing GD-CNVs and novel deletions; obstructive uropathy (OU) had a lower CNV burden and an intermediate prevalence of GD-CNVs; and vesicoureteral reflux (VUR) had the fewest GD-CNVs but was enriched for novel exonic CNVs, particularly duplications. Six loci (1q21, 4p16.1-p16.3, 16p11.2, 16p13.11, 17q12 and 22q11.2) accounted for 65% of patients with GD-CNVs. Deletions at 17q12, 4p16.1-p16.3 and 22q11.2 were specific for KA; the 16p11.2 locus showed extensive pleiotropy. Using a multidisciplinary approach, we identified TBX6 as a driver for the CAKUT subphenotypes in the 16p11.2 microdeletion syndrome. | Nature genetics (Print) 51 (2019): 117-+. | 2019 | CUSI DANIELE | * | 10.1038/s41588-018-0281-y |
| 399966 | Articolo in rivista | Association between miRNAs expression and cognitive performances of Pediatric Multiple Sclerosis patients: A pilot study | Liguori M., Nuzziello N., Simone M., Amoroso N., Viterbo R.G., Tangaro S., Consiglio A., Giordano P., Bellotti R., Trojano M. | Introduction : The Pediatric onset of Multiple Sclerosis (PedMS) occurs in up to 10% of all cases. Cognitive impairment is one of the frequent symptoms, exerting severe impact in patients' quality of life and school performances. The underlying pathogenic mechanisms are not fully understood, and molecular markers predictive of cognitive dysfunctions need to be identified. On these grounds, we searched for molecular signature/s (i.e., miRNAs and target genes) associated with cognitive impairment in a selected population of PedMS patients. Additionally, changes of their regional brain volumes associated with the miRNAs of interest were investigated. Methods: Nineteen PedMS subjects received a full cognitive evaluation; total RNA from peripheral blood samples was processed by next-generation sequencing followed by a bioinformatics/biostatistics analysis. Results: The expression of 11 miRNAs significantly correlated with the scores obtained at different cognitive tests; among the others, eight miRNAs correlated with the Trail Making Tests. The computational target prediction identified 337 genes targeted by the miRNAs of interest; a tangled network of molecular connections was hypothesized, where genes like BST1, NTNG2, SPTB, and STAB1, already associated with cognitive dysfunctions, were nodes of the net. Furthermore, the expression of some miRNAs significantly correlated with cerebral volumes, for example, four miRNAs with the cerebellum cortex. Conclusions: As far as we know, this is the first evaluation exploring miRNAs in the cognitive performances of PedMS. Although none of these results survived the multiple tests' corrections, we believe that they may represent a step forward the identification of biomarkers useful for monitoring and targeting the onset/progression of cognitive impairments in MS. | Brain and behavior (2019). | 2019 | NUZZIELLO NICOLETTA, LIGUORI MARIA, CONSIGLIO ARIANNA | HT-NGS; MRI regional volumes; bioinformatics; circulating biomarkers; cognitive dysfunctions; gene targets; miRNAs; molecular pathogenesis; networks; pediatric multiple sclerosis | 10.1002/brb3.1199 |
| 400504 | Articolo in rivista | Lying, deception, equivocation and the ethics of prescribing placebos in clinical practice | Annoni, Marco | In this paper I explore different ways in which doctors can be dishonest in clinical communications. As a case in point, I object to the idea that doctors can prescribe placebos in ways that are not transparent and yet not paternalistic. First, I briefly present evidence demonstrating that placebo effects may modulate a host of clinical outcomes. Second, I argue that doctor's duty of truth-telling in clinical contexts entails two complementary obligations: the one not to lie and deceive (i.e, the duty of truthfulness), and the one to inform patients in order to respect their autonomy (i.e, the duty to inform). Third, I distinguish different ways in which doctors may violate their duty of veracity. Specifically, I identify two ways in which doctors may fail to uphold the duty of truthfulness (by lying and deceiving), and two ways in which they can instead infringe on the duty to inform (by keeping patients in the dark and by telling half-truths). Based on these distinctions, I conclude that doctors cannot have the placebo cake and eat it too: either they prescribe placebos in a fully transparent manner, or they need to morally justify a paternalistic exception to their duty of veracity. | Rivista italiana di filosofia del linguaggio 12 (2018): 30-41. | 2018 | ANNONI MARCO ANGELO MARIA | Placebo effects, Medical Ethics, Lying, Deception, Truth-telling | 10.4396/20180601 |
| 400507 | Articolo in rivista | The Ethics of Placebo Effects in Clinical Practice and Research | Annoni, Marco | This chapter provides a synthetic overview of the contemporary debate over the ethics of placebos and placebo effects in both clinical and research contexts. Section 1 briefly reconstructs how ethical attitudes toward the use of placebos have changed during the last century following the emergence of autonomy in medical ethics. Next, Sections 2-4 chart the main ethical issues concerning the use of placebos in clinical settings, examining: the ethics of deceptive placebos; the ethics of placebos without deception; and the ethics of modulating placebo and nocebo effects without placebos. Finally, Section 5 outlines the role of placebos in research, discussing the ethics of placebos as controls in clinical experiments. | International review of neurobiology 139 (2018): 463-484. | 2018 | ANNONI MARCO ANGELO MARIA | Deception; Doctor-patient communication; Ethics; Informed consent; Placebo; Placebo effects | 10.1016/bs.irn.2018.07.031 |
| 400508 | Articolo in rivista | EDITORS' INTRODUCTION TO SPECIAL SECTION ON MEANING RESPONSE AND THE PLACEBO EFFECT | Blease, Charlotte, Annoni, Marco, Hutchinson, Phil | OVER 200 YEARS AGO, DOCTORS' most effective tools were typically not found in their medical bags. Indeed, most treatments in the history of medicine have, until relatively recently, caused more harm than good. Prior to the biomedical revolution in the late 19th century, doctors' most reliable and effective instruments of healing were their skills of communication with patients and an aptitude for a positive and supportive bedside manner. Bearing out this portrait of medicine, Thomas Jefferson, writing in 1807, noted that "one of the most successful physicians I have ever known has assured me that he used more bread pills, drops of colored water, and powers of hickory ashes, than of all other medicines put together" (qtd. in De Craen et al. 1999, 511). Jefferson referred to these skills of beneficent persuasion as a "pious fraud." Exactly one hundred years later, in 1907, Mark Twain drew similar observations: "Physicians cure many patients with a bread pill; they know that where the disease is only a fancy, the patient's confidence in the doctor will make the bread pill effective." | Perspectives in biology and medicine 61 (2018): 349-352. | 2018 | ANNONI MARCO ANGELO MARIA | MEDICINE | 10.1353/pbm.2018.0047 |
| 400510 | Articolo in rivista | A critical (And cautiously optimistic) appraisal of moerman's"meaning response" | Annoni M., Blease C. | In this article we propose a critical reassessment of Daniel Moerman's "meaning response." First, we reconstruct and criticize Moerman's original proposal of introducing the "meaning response" as a way of clarifying some terminological and conceptual issues in the placebo debate. Next we evaluate the criticisms that Moerman's proposal is epistemically moot since other existing and more empirically grounded models already account for all the phenomena that fall under the concept of the "meaning response." We conclude that Moerman's original proposal is inherently problematic and that, in order to be instrumentally useful in the future, the meaning response must be reconceived so that it may finally support, rather than oppose, other theoretical and empirical lines of research currently ongoing in the field of placebo studies. | Perspectives in biology and medicine 61 (2018): 379-387. | 2018 | ANNONI MARCO ANGELO MARIA | Medicine | 10.1353/pbm.2018.0050 |
| 400528 | Contributo in atti di convegno | Conspiracy Ideations in Healthcare: A Rhetorical and Argumentative Analysis | Roberta Martina Zagarella, Marco Annoni | Plan of the talk 1.Why it is important to study conspiracy from a rhetorical and argumentative point of view2.Our main case-study: the story of the Stamina Foundation3.Rhetorical analysis of "logos" and "ethos" in the Stamina conspiracy 2.Our main case-study: the story of the Stamina Foundation 3.Rhetorical analysis of "logos" and "ethos" in the Stamina conspiracy | Argumentation and Inference: Proceedings of the 2nd European Conference on Argumentation, Fribourg, Switzerland, 20-23 Jun 2017 | 2018 | ANNONI MARCO ANGELO MARIA, ZAGARELLA ROBERTA MARTINA | Conspiracy arguments | |
| 400530 | Contributo in volume | La consulenza etica in ambito clinico | Marco Annoni, Giovanni Boniolo | Introduzione: la consulenza etica in ambito clinico | Etiche applicate, pp. 59-70. Roma: Carocci Editore, 2018 | 2018 | ANNONI MARCO ANGELO MARIA | Etica | |
| 400532 | Articolo in rivista | Introduzione al focus la bioetica tra attualita e futuro>> | Marco Annoni e Silvia Zullo | Focus: "La bioetica tra attualita e futuro", a cura di Marco Annoni e Silvia Zullo. Marco Annoni, Silvia Zullo, Introduzione, p. 53 | Medicina & storia (Online) 2 (2018): 53. | 2018 | ANNONI MARCO ANGELO MARIA | Bioetica | |
| 400537 | Contributo in volume | Sviluppo sostenibile e benessere: il ruolo dell'ASviS e le prospettive future | Carla Collicelli | Il volume rappresenta una proposta per gli operatori socio-sanitari e per le istituzioni a impegnarsi in innovative chiavi interpretative per il futuro e nel ricercare la salute e la sostenibilita all'interno della propria organizzazione, facendo rete all'esterno. I saggi testimoniano la capacita di "resistenza" attiva di professionisti che nel mondo della scuola, della salute, del terzo settore, propongono interventi fondati sull'empowerment, sulla partecipazione, su percorsi di formazione permanente, sull'attenzione alle fasce vulnerabili e marginali di popolazione. | Crescere sostenibili e in salute. Strumenti per la promozione e lo sviluppo. Milano: FrancoAngeli, 2018 | 2018 | COLLICELLI CARLA | Sostenibilita, Sociologia della salute | |
| 400544 | Contributo in volume | La microallocazione delle risorse in oncologia: una questione anche etica | a cura di C. Collicelli, G. Beretta, D. D'Ugo, M. Di Maio, S. Sandrucci, L. Durst, F. De Lorenzo | Accesso alle cure: prospettive e criticita | , 2018 | 2018 | COLLICELLI CARLA, DURST LUDOVICA | Microallocazione Sostenibilita Dilemmi etici | |
| 400545 | Contributo in volume | Cure palliative ed assistenza domiciliare: offerta, valore generato e modelli di intervento | a cura di C. Collicelli, M. Campagna, M. Di Cesare e E. Santori, A. Di Leo, R. Pannuti e S. Varani, C. Monti e G. Casale, R. Labianca, F. De Lorenzo, L. Moroni | Aspetti politici, sociali e organizzativi in oncologia | , 2018 | 2018 | COLLICELLI CARLA, DURST LUDOVICA | Microallocazione Sostenibilita Dilemmi etici | |
| 400548 | Contributo in volume | Tempi di attesa e costi delle prestazioni nei Sistemi Sanitari Regionali | Cassa R.2, Collicelli C.3, Santurri P.2, Spandonaro F.4 | The C.R.E.A. 2017 Healthcare Survey for the CGIL Observatory on waiting lists and cost of services in the Regional Health Services was conducted in 4 Italian regions: Lombardia for the North-West; Veneto for the North-East; Lazio for Central Italy and Campania for the South. The survey highlights the concerns about the impact of waiting lists on access to the NHS and, hence, on its universal nature. The issue has two obvious "regularities": the first is that the discriminating factor is the system for paying services. In fact, those falling within the NHS scope (free of charge except for the possible prescription fee) have long waiting lists and, in some cases, very long ones: rarely they are provided within 30 days in public structures and often exceed this term even in the private accredited ones. Conversely, for the services provided not for free (both by private physicians in public structures - the so-called intramoenia regime - and for paying patients in the private structures) waiting lists are very short. The difference between these two "regimes" (paid or free of charge) is much larger than the difference in waiting lists between public and private structures. Although the waiting lists in public structures are longer - although not in a generalized way - they are not significantly longer than in private ones. Similarly, for the paid ones, the differences in waiting lists between the public and private structures are negligible. The same holds true for prices, which are not very different between the public structures (under the intramoenia regime) and the private ones (outside the NHS scope): indeed, in some cases, a higher cost is recorded under the intramoenia regime. It should also be noted that private prices are very competitive with regard to the services provided by the NHS and subject to co-payments and cost sharing. It is therefore evident that the waiting lists risk not being in line with people's expectations (the analysis was conducted on services not prescribed as urgent). Altogether, co-payments and cost sharing - in turn - risk not being in line with the market value of services, thus resulting in a severe inefficiency of the NHS, which is to be seen as a driver of the private structures' competitive positioning. In other words, timely access seems to be a condition guaranteed by the NHS only for urgent services, while it turns into a "paid service" in the remaining cases (which are certainly prevailing in number). Paradoxically, the second regularity is due to "the lack of regularity", if not in the aggregated data, at regional level. Although the average data surveyed shows some significant differences at regional level, a great variability between regions and also between structures and services is mainly recorded. Furthermore, there is no correlation between waiting lists and regional characteristics, neither at geographical level nor at service structure level. In fact, the share of private "presence" in the Regional Health Services does not correspond to a difference in waiting lists. | , pp. 320-332, 2018 | 2018 | COLLICELLI CARLA | Sistemi Sanitari Regionali | |
| 400550 | Articolo in rivista | NOTA BIBLIOGRAFICA SU GIUSEPPE LEVI | Andrea Grignolio | Bibliografia di scritti su Giuseppe Levi | Medicina nei secoli 30 (2018). | 2018 | GRIGNOLIO ANDREA | Giuseppe Levi | |
| 400551 | Contributo in volume | L'EUROPA COME ANTIDOTO CONTRO L'ANTISCIENZA | CORBELLINI G., GRIGNOLIO A. | Il presente e il futuro dei Paesi dell'Unione e quanto mai incerto e le questioni in merito sono assai complesse. Per questo motivo, Treccani ha deciso di offrire ai propri lettori un'opera divisa in tre volumi tematicamente orientati, per consentire una migliore comprensione della ricchezza e delle potenzialita del progetto europeo attraverso piu piani interpretativi. | , pp. 405-412. Roma: Istituto dell'Enciclopedia italiana Treccani, 2018 | 2018 | GRIGNOLIO ANDREA | Europa | |
| 400552 | Articolo in rivista | Understanding vaccine hesitancy as a neuro-evolutionary problem | Grignolio A. | The scientific literature offers unequivocal data that demonstrate how vaccinations today are safe and effective and in the past were the medical intervention that, together with the sanitation of the water, saved more lives than any other medical intervention. Even if they improved life expectancy in advanced countries where herd immunity has been reached, today it is in the very same countries that social resistance to vaccination is putting children at risk of harm. A recent neurocognitive approach is offering an interesting frame to understand the causes and diffusion of anti-vaccine movements. Although novaxxers are heterogeneous social groups, they show some common traits. They are generally educated and affluent people, tending to later parenthood, sensitive to conspiracy theories, unwilling to confront with different ideas, favorable to alternative medicines, and scarce in assessing risk information. Some solutions will be discussed, including the theory of "nudge" and that of "bounded rationality" which have shown some efficacy by offering citizens the right tools to orient themselves in the architecture of health choices. | Notizie di Politeia 34 (2018): 8-18. | 2018 | GRIGNOLIO ANDREA | Antiscientific movements, Post-truth, Science and society, Vaccine hesitancy | |
| 400555 | Contributo in volume | EDUCATION AND DIASPORA. THE PATH OF THREE NOBEL LAUREATE STUDENTS FROM THEIR ANATOMICAL TRAINING IN TURIN TO THE AMERICAN GENETIC-MOLECULAR MODEL (1930-1950) | Andrea Grignolio | Three students who were subsequently awarded the Nobel Prize received part of their training in the Turin laboratory of the anatomist Giuseppe Levi (1872 - 1965): Salvador E. Luria for research on bacterial genetics (1969), Renato Dulbecco on oncogenic viruses (1975) and Rita Levi Montalcini for the discovery of the nerve growth factor (1986). It is a rare case in the history of science, especially considering the different paths that his three pupils took in the US after their common internship in Levi's laboratory which focused on the microanatomy of the nervous system. Trying to reconstruct the reasons for these professional successes, in their autobiographies, all three students recognized the great merits of their master's methodology (dedication and rigor in the job, the setting up and publication of the experiment, strictness and encouragement in the evaluations), while identifying the move to US labs as the decisive factor in their careers (research policy, meritocracy and substantial funding). In this contribution, I will attempt to trace the paths that made it possible for three students from an Italian school based on histology and microscopic anatomy according to the German tradition to become three Nobel laureates in various disciplines based on a molecular approach. Understanding how this 'metamorphosis' occurred means reconstructing how individual micro-histories, coming from a local scientific and methodological context -laboratory techniques, religious backgrounds, fortuitous choices, friendships and academic relations-, merged with macro-histories involving national politics, the Second World War, and institutional and disciplinary divisions. | GIUSEPPE LEVI: A BIBLIOGRAPHY, pp. 167-209, 2018 | 2018 | GRIGNOLIO ANDREA | Giuseppe Levi | |
| 400556 | Articolo in rivista | Il concetto di "diagnosi fuzzy": una applicazione alla malattia di Anderson-Fabry | Elena Mancini & Roberta Martina Zagarella | Per garantire un'elevata affidabilita diagnostica, la classificazione tradizionale delle malattie si basa su due criteri fondamentali: la presenza di caratteristiche peculiari che identificano una malattia distinguendola dalle altre e l'individuazione delle cause o della correlazione multifattoriale. Questa concezione si basa su regole che rimandano ai principi della logica classica, la quale, tuttavia, non puo considerarsi uno strumento adeguato in medicina. Essa potrebbe rivelarsi uno strumento utile di fronte a quelle manifestazioni della malattia "prototipiche", ma non per molte patologie che si presentano come fenomeni complessi e incoerenti, ovvero caratterizzati, sul piano eziologico, da un insieme interrelato di possibili cause e fattori scatenanti e, sul piano clinico, da una elevata variabilita individuale. La diagnosi di tali malattie richiede una logica tramite la quale sia possibile categorizzare il mondo degli oggetti reali. L'articolo prende in esame la logica fuzzy come strumento per il ragionamento diagnostico, e in particolar modo i concetti di "fuzzy set" e "diagnosi fuzzy", anche al fine di verificarne il possibile impiego nella diagnosi di una patologia rara ad eziologia complessa: la malattia di Anderson-Fabry. L'analisi svolta porta a soffermarsi sulla finalita pratica (e non conoscitiva) della diagnosi, che le conferisce una valenza etica. Muovendo da questa prospettiva, l'articolo propone, nell'ultima parte, alcuni criteri etici di orientamento nel complesso bilanciamento che il clinico effettua tra il rischio inerente alla formulazione di una ipotesi diagnostica di "tipo fuzzy" e i benefici per il paziente di una diagnosi precoce, soprattutto in considerazione della disponibilita di trattamenti farmacologici innovativi. | Medicina e morale (Online) 67 (2018): 507-524. | 2018 | ZAGARELLA ROBERTA MARTINA, MANCINI ELENA | logica fuzzy, ragionamento diagnostico, malattia di Fabry, bilanciamento rischi-benefici | |
| 400557 | Articolo in rivista | Dare voce ai pazienti nella ricerca sulle malattie rare e sui famaci orfani | Elena Mancini & Roberta Martina Zagarella | L'articolo ha l'obiettivo di mettere in luce potenzialita e criticita dell'inclusione della prospettiva dei pazienti nella ricerca sulle malattie rare e sui farmaci orfani. A tal fine, nella prima parte, si propone un'analisi epistemologica dell'utilizzo dei racconti dell'esperienza individuale della malattia nella ricerca scientifica e nei trial clinici, facendo emergere, anche attraverso gli strumenti della medicina narrativa, le sfide teoriche e operative poste dall'inclusione della soggettivita del paziente e del vissuto di malattia nonche l'importanza della valorizzazione della prospettiva del paziente, sia in generale sia nella ricerca sulle malattie rare e sui farmaci orfani. Nella seconda parte, il testo analizza in particolare il ruolo degli esiti riportati dai pazienti o Patient Reported Outcomes (PROs), misure per la valutazione complessiva della salute basate sulla prospettiva dei pazienti stessi, incentrandosi sulla sperimentazione clinica nel campo delle malattie rare. In questo contesto, infatti, i racconti di malattia, raccolti e valorizzati da fonti istituzionali e associazioni di pazienti, hanno contribuito a far emergere importanti questioni critiche e difficolta nell'impiego di outcome centrati sul paziente nello sviluppo di nuovi farmaci e trattamenti, generando una serie di documenti e raccomandazioni relative al loro utilizzo per il benessere della comunita dei malati rari. | Medicina e morale (Online) 67 (2018): 25-40. | 2018 | ZAGARELLA ROBERTA MARTINA, MANCINI ELENA | prospettiva dei pazienti, vissuto di malattia, esiti riportati dai pazienti (PROs), malattie rare, trial clinici, medicina narrativa | |
| 393008 | Articolo in rivista | The continuum of aging and age-related diseases: Common mechanisms but different rates | Franceschi C., Garagnani P., Morsiani C., Conte M., Santoro A., Grignolio A., Monti D., Capri M., Salvioli S. | Geroscience, the new interdisciplinary field that aims to understand the relationship between aging and chronic age-related diseases (ARDs) and geriatric syndromes (GSs), is based on epidemiological evidence and experimental data that aging is the major risk factor for such pathologies and assumes that aging and ARDs/GSs share a common set of basic biological mechanisms. A consequence is that the primary target of medicine is to combat aging instead of any single ARD/GSs one by one, as favored by the fragmentation into hundreds of specialties and sub-specialties. If the same molecular and cellular mechanisms underpin both aging and ARDs/GSs, a major question emerges: which is the difference, if any, between aging and ARDs/GSs? The hypothesis that ARDs and GSs such as frailty can be conceptualized as accelerated aging will be discussed by analyzing in particular frailty, sarcopenia, chronic obstructive pulmonary disease, cancer, neurodegenerative diseases such as Alzheimer and Parkinson as well as Down syndrome as an example of progeroid syndrome. According to this integrated view, aging and ARDs/GSs become part of a continuum where precise boundaries do not exist and the two extremes are represented by centenarians, who largely avoided or postponed most ARDs/GSs and are characterized by decelerated aging, and patients who suffered one or more severe ARDs in their 60s, 70s, and 80s and show signs of accelerated aging, respectively. In between these two extremes, there is a continuum of intermediate trajectories representing a sort of gray area. Thus, clinically different, classical ARDs/GSs are, indeed, the result of peculiar combinations of alterations regarding the same, limited set of basic mechanisms shared with the aging process. Whether an individual will follow a trajectory of accelerated or decelerated aging will depend on his/her genetic background interacting lifelong with environmental and lifestyle factors. If ARDs and GSs are manifestations of accelerated aging, it is urgent to identify markers capable of distinguishing between biological and chronological age to identify subjects at higher risk of developing ARDs and GSs. To this aim, we propose the use of DNA methylation, N-glycans profiling, and gut microbiota composition to complement the available disease-specific markers. | Frontiers in medicine 5 (2018). | 2018 | GARAGNANI PAOLO, GRIGNOLIO ANDREA | Age-related diseases, Aging, Biomarkers, Geroscience, Inflammaging, Longevity | 10.3389/fmed.2018.00061 |
| 400595 | Articolo in rivista | La fragilita come forma di resistenza: conversazione sul biopotere con Miguel Benasayag | Clio Nicastro & Roberta Martina Zagarella | Filosofo, psicoanalista, attivista di origine argentina, tra i fondatori del Collectif Malgre tout, Miguel Benasayag vive e lavora Parigi. La sua analisi profonda del mondo occidentale contemporaneo, che tiene conto delle interconnessioni tra prospettiva psicologica, sociologica e biologica, e il frutto non solo della riflessione teorica di Benasayag ma anche e soprattutto della sua militanza politica. Tra le sue opere principali ricordiamo: L'epoca delle passioni tristi (2004), Contro il niente. L'ABC dell'impegno (2005), Elogio del conflitto (2008), La salute ad ogni costo. Medicina e biopotere (2010), Oltre le passioni tristi. Dalla solitudine contemporanea alla creazione condivisa (2016), Il cervello aumentato, l'uomo diminuito (2016), La singularite du vivant (2017). Nel contesto del volume della Rivista Italiana di Filosofia del Linguaggio dedicato ad Argomentazione e Medicina, l'intervento di Benasayag fornisce un contributo fondamentale per il dibattito sul biopotere e su come i dispositivi biopolitici contemporanei differiscano da quelli della modernita. In questo senso, abbiamo chiesto a Benasayag di soffermarsi sulle conseguenze politiche di aspetti quali l'ipermedicalizzazione della vita e il rifiuto della fragilita del corpo e della psiche, tenendo in primo piano un aspetto da sempre centrale nel suo pensiero e a cui l'autore ha dedicato il suo ultimo libro: la singolarita del vivente. | Rivista italiana di filosofia del linguaggio 1/2018 (2018): 99-108. | 2018 | ZAGARELLA ROBERTA MARTINA | Biopotere, Miguel Benasayag | 10.4396/20180610 |
| 400653 | Contributo in volume | La sostenibilita ambientale in Europa | Casonato, C., Pavone, I.R. | Contributo nel Volume Europa. Le sfide della scienza dell'Istituto della Enciclopedia Italiana | Europa. Le sfide della scienza, pp. 184-196. Roma: Istituto dell'Enciclopedia italiana Treccani, 2018 | 2018 | PAVONE ILJA RICHARD | Biodiritto, Sostenibilita ambientale | |
| 400654 | Articolo in rivista | La macellazione inconsapevole | Ilja Richard Pavone | Nota al documento del Comitato Bioetico per la Veterinaria in materia di macellazione inconsapevole | The Future of Science and Ethics (Online) 2 (2017): 164-165. | 2017 | PAVONE ILJA RICHARD | Macellazione, Benessere Animale | |
| 400655 | Articolo in rivista | The Trump Administration and the Paris Agreement: Road to Nowhere? | Ilja Richard Pavone | The unexpected election of the Republican Donald J. Trump for the US presidency generated serious concerns as to the future of the multilateral negotiations on climate change. Indeed, the President Trump is a climate skeptic who is challenging the linkage between human activity and global warming. With the long-awaited Statement of 1st June 2017 on the US withdrawal from the Paris Agreement, he claimed the prevalence of domestic economic interests over common concerns, like climate. In fact, President Trump's declaration - although void of any sort of rational, coherent explanation - constitutes the proclamation of the primacy of State sovereignty when it comes to environmental issues. In this regard, the words of President Trump are eloquent: "the withdrawal from the Paris Agreement represents a reassertion of America's sovereignty". In the present paper, the free-riding strategy that the Trump administration took regarding international climate commitments will be reviewed, focusing on the consequences of Trump's declaration, whose twofold content will be highlighted (it lies not only in the expression of the will to exit the Agreement, but also in the immediate ceasing of its implementation). Finally, the potential countermeasures to steer the US action (tit-for-tat strategy) or other incentives for and implications of the US withdrawal will be analyzed, as well as some reflections on the next steps for the US in the climate change regime, claiming that Trump's pursuit of short-term benefits would come at the risk of longer-term damages. | Journal of international studies (Kyiv) 11 (2018): 34-49. | 2018 | PAVONE ILJA RICHARD | limate regime, Paris Agreement, Trump Administration, Withdrawal, Breach | 10.14254/2071-8330.2018/11-1/3 |
| 400656 | Articolo in rivista | Race to Extinction: Shark Conservation in International and European Law and Its Limits | Ilja Richard Pavone | The purpose of this paper is to clarify the existing (global and regional) legal standards on shark conservation from over-exploitation. First, an analysis of the current international legal framework (law of the sea, sustainable fisheries management, wildlife law) applicable to shark protection is provided (Part I). Next the paper explores the evolution of the European Union (EU) policy on shark finning, since the EU - in line with the United States (Shark Conservation Act) - opted for a strict fins-attached policy, or Fins-Naturally Attached (FNA), The new policy eliminated the major pitfall of its previous regulation, based on a fin-tocarcass weight regime, that allowed separate landing of the fins detached and of the shark carcass. This paper considers whether this turn of the EU - the first intergovernmental organization to adopt a binding act on shark finning - can be considered as a breakthrough and whether FNA can be the solution to the threat of extinction of sharks, arguing for a different solution. | Ocean and coastal law journal 23 (2018): 44-86. | 2018 | PAVONE ILJA RICHARD | International and European Law | |
| 401170 | Articolo in rivista | Sussidiarieta e proporzionalita | ANTONUCCI, MARIA CRISTINA | . | Stati Uniti d'Europa (Milano) 25.03.2019 (2019): 14-17. | 2019 | ANTONUCCI MARIA CRISTINA | SUSSIDIARIETA', PROPORZIONALITA', POLITICHE EUROPEE, UE | |
| 401534 | Articolo in rivista | Precise Gene Editing Preserves Hematopoietic Stem Cell Function following Transient p53-Mediated DNA Damage Response | Schiroli G1, Conti A1, Ferrari S2, Della Volpe L2, Jacob A3, Albano L1, Beretta S4, Calabria A1, Vavassori V2, Gasparini P5, Salataj E6, Ndiaye-Lobry D6, Brombin C7, Chaumeil J6, Montini E1, Merelli I8, Genovese P9, Naldini L10, Di Micco R11. | Precise gene editing in hematopoietic stem and progenitor cells (HSPCs) holds promise for treating genetic diseases. However, responses triggered by programmable nucleases in HSPCs are poorly characterized and may negatively impact HSPC engraftment and long-term repopulation capacity. Here, we induced either one or several DNA double-stranded breaks (DSBs) with optimized zinc-finger and CRISPR/Cas9 nucleases and monitored DNA damage response (DDR) foci induction, cell-cycle progression, and transcriptional responses in HSPC subpopulations, with up to single-cell resolution. p53-mediated DDR pathway activation was the predominant response to even single-nuclease-induced DSBs across all HSPC subtypes analyzed. Excess DSB load and/or adeno-associated virus (AAV)-mediated delivery of DNA repair templates induced cumulative p53 pathway activation, constraining proliferation, yield, and engraftment of edited HSPCs. However, functional impairment was reversible when DDR burden was low and could be overcome by transient p53 inhibition. These findings provide molecular and functional evidence for feasible and seamless gene editing in HSPCs. | Cell stem cell (Print) (2019). | 2019 | MERELLI IVAN | DNA damage response; DNA double strand breaks; adeno-associated vector; genome editing; hematopoietic stem and progenitor cells; p53 pathway; programmable nucleases | 10.1016/j.stem.2019.02.019 |
| 402220 | Articolo in rivista | Phenylketonuria Diet Promotes Shifts in Firmicutes Populations | Bassanini Giulia, Ceccarani Camilla, Borgo Francesca, Severgnini Marco, Rovelli Valentina, Morace Giulia, Verduci Elvira, Borghi, Elisa | Low-phenylalanine diet, the main-stain treatment for phenylketonuria (PKU), has been shown to increase glycemic index and glycemic load, affecting the availability of substrates for microbial fermentation. Indeed, changes in the PKU gut microbiota compared with healthy controls have been previously reported. Here we compared the gut microbial communities of children with PKU and with mild hyperphenylalaninemia (MHP, unrestricted diet). For each group, we enrolled 21 children (4-18 years old), for a total dataset of 42 subjects. We assessed dietary intake and performed gut microbiota analysis by next-generation sequencing on V3-V4 hypervariable regions 16S rRNA gene. Short chain fatty acids (SCFAs) were quantified by gas chromatographic analysis. While alpha-diversity analysis showed no significant differences between PKU and MHP groups, microbial community analysis highlighted a significant separation of gut microbiota according to both unweighted (p = 0.008) and weighted Unifrac distances (p = 0.03). Major differences were seen within the Firmicutes phylum. Indeed, PKU children were depleted in Faecalibacterium spp. and enriched in Blautia spp. and Clostridium spp (family Lachnospiraceae). We found a divergent response of members of the Firmicutes phylum with respect to daily glycemic index, higher in PKU children. Faecalibacterium prausnitzii, unclassified Ruminococcaceae and, to a lesser extent Roseburia spp. negatively correlated with glycemic index, whereas unclassified Lachnospiraceae were positively associated. Indicator species analysis suggested F. prausnitzii be related to MHP status and Ruminococcus bromii to be associated with PKU. Despite PKU children have a higher vegetable and fiber intake, resembling a vegan diet, their microbial signature is far distant from the microbiota reported in the literature for such a high-fiber/low-protein intake. Indeed, beneficial microorganisms, such as F. prausnitzii, considered a biomarker for a healthy status and one of the main butyrate producers, are depleted in PKU gut microbiota. We suggest that both the quality and quantity of carbohydrates ingested participate in determining the observed Firmicutes shifts on the PKU population. | Frontiers in cellular and infection microbiology (2019). | 2019 | CECCARANI CAMILLA, SEVERGNINI MARCO | diet, microbiota, glycemic index, Faecalibacterium prausnitzii, butyrate, phenylketonuria, mild hyperphenylalaninemia | 10.3389/fcimb.2019.00101 |
| 402390 | Articolo in rivista | GenHap: A novel computational method based on genetic algorithms for haplotype assembly | Tangherloni A., Spolaor S., Rundo L., Nobile M.S., Cazzaniga P., Mauri G., Lio P., Merelli I., Besozzi D. | Background: In order to fully characterize the genome of an individual, the reconstruction of the two distinct copies of each chromosome, called haplotypes, is essential. The computational problem of inferring the full haplotype of a cell starting from read sequencing data is known as haplotype assembly, and consists in assigning all heterozygous Single Nucleotide Polymorphisms (SNPs) to exactly one of the two chromosomes. Indeed, the knowledge of complete haplotypes is generally more informative than analyzing single SNPs and plays a fundamental role in many medical applications. Results: To reconstruct the two haplotypes, we addressed the weighted Minimum Error Correction (wMEC) problem, which is a successful approach for haplotype assembly. This NP-hard problem consists in computing the two haplotypes that partition the sequencing reads into two disjoint sub-sets, with the least number of corrections to the SNP values. To this aim, we propose here GenHap, a novel computational method for haplotype assembly based on Genetic Algorithms, yielding optimal solutions by means of a global search process. In order to evaluate the effectiveness of our approach, we run GenHap on two synthetic (yet realistic) datasets, based on the Roche/454 and PacBio RS II sequencing technologies. We compared the performance of GenHap against HapCol, an efficient state-of-the-art algorithm for haplotype phasing. Our results show that GenHap always obtains high accuracy solutions (in terms of haplotype error rate), and is up to 4x faster than HapCol in the case of Roche/454 instances and up to 20x faster when compared on the PacBio RS II dataset. Finally, we assessed the performance of GenHap on two different real datasets. Conclusions: Future-generation sequencing technologies, producing longer reads with higher coverage, can highly benefit from GenHap, thanks to its capability of efficiently solving large instances of the haplotype assembly problem. Moreover, the optimization approach proposed in GenHap can be extended to the study of allele-specific genomic features, such as expression, methylation and chromatin conformation, by exploiting multi-objective optimization techniques. The source code and the full documentation are available at the following GitHub repository: https://github.com/andrea-tango/GenHap. | BMC bioinformatics 20 (2019): 172. | 2019 | RUNDO LEONARDO, MERELLI IVAN | : Haplotype assembly, Future-generation sequencing, Genetic algorithms, Combinatorial optimization, Weighted minimum error correction problem | 10.1186/s12859-019-2691-y |
| 404015 | Articolo in rivista | Microstructural characterization of corticospinal tract in subacute and chronic stroke patients with distal lesions by means of advanced diffusion MRI. | Alfonso Mastropietro 1, Giovanna Rizzo 2, Lucia Fontana 3, Matteo Figini 4, Bruno Bernardini 5, Laura Straffi 6, Simona Marcheselli 6, Sara Ghirmai 5, Nunzio Paolo Nuzzi 3, Maria Luisa Malosio 7, 8, Marco Grimaldi 3 | Purpose. The aim of the paper is to evaluate if advanced dMRI techniques, including diffusion kurtosis imaging (DKI) and neurite orientation dispersion and density imaging (NODDI), could provide novel insights into the subtle microarchitectural modifications occurring in the corticospinal tract (CST) of stroke patients in subacute and chronic phases. Methods. Seventeen subjects (age 68 +- 11 years) in the subacute phase (14 +- 3 days post-stroke), 10 of whom rescanned in the chronic phase (231 +- 36 days post-stroke), were enrolled. Images were acquired using a 3-T MRI scanner with a two-shell EPI protocol (20 gradient directions, b = 700 s/mm2, 3 b = 0; 64 gradient directions, b = 2000 s/mm2, 9 b = 0). DTI-, DKI-, and NODDI-derived parameters were calculated in the posterior limb of the internal capsule (PLIC) and in the cerebral peduncle (CP). Results. In the subacute phase, a reduction of FA, AD, and KA values was correlated with an increase of ODI, RD, and AK parameters, in both the ipsilesional PLIC and CP, suggesting that increased fiber dispersion can be the main structural factor. In the chronic phase, a reduction of FA and an increase of ODI persisted in the ipsilesional areas. This was associated with reduced Fic and increased MD, with a concomitant reduction of MK and increase of RD, suggesting that fiber reduction, possibly due to nerve degeneration, could play an important role. Conclusions This study shows that advanced dMRI approaches can help elucidate the underpinning architectural modifications occurring in the CST after stroke. Further follow-up studies on bigger cohorts are needed to evaluate if DKI- and NODDI-derived parameters might be proposed as complementary biomarkers of brain microstructural alterations. | Neuroradiology (Berl., Print) 61 (2019): 1033-1045. | 2019 | RIZZO GIOVANNA, MALOSIO MARIA LUISA, MASTROPIETRO ALFONSO | Subacute and chronic stroke . NODDI . DTI . DKI . Corticospinal tract | 10.1007/s00234-019-02249-2 |
| 405392 | Articolo in rivista | Conditioned medium of primary lung cancer cells induces EMT in A549 lung cancer cell line by TGF-ss1 and miRNA21 cooperation | Camerlingo R1, Miceli R2, Marra L1, Rea G3, D'Agnano I4, 5, Nardella M6, Montella R7, Morabito A8, Normanno N1, Tirino V7, Rocco G9 | The epithelial-mesenchymal transition (EMT) plays a key role in tumor progression, drug resistance and metastasis. Recently, numerous microRNA (miRNA) have been described to regulate EMT in tumor progression. In this study, we found that conditioned medium from the LC212 non-small-cell lung cancer (NSCLC) cell line (LC212-CM) induces morphological changes and overexpression of Vimentin, CD90, SMAD 2/3, SLUG and TWIST in A549 NSCLC cells, consistent with a mesenchymal phenotype. To identify the soluble mediators in LC212-CM involved in this phenomenon, we performed miRNA profiling and TGF-?1 quantification. We found that LC212-CM contains high levels of TGF-?1 as well as different secreted miRNAs. We focused our attention on Homo sapiens-microRNA21 (hsa-miR21), one of most relevant miRNA associated with lung cancer progression, metastasis and EMT. An hsa-miR21 antagomiR was able to prevent the LC212-CM-induced EMT phenotype in A549 cells. Furthermore, we found that TGF-?1 and hsa-miR21 cooperate in the induction of EMT in A549 cells. Intriguingly, TGF-?1 was found to induce hsa-miR21 expression in A549 cell, thus suggesting that the hsa-miR21 mediates at least in part the pro-EMT effects of TGF-?1. In conclusion, hsa-miR21 and TGF-?1 are involved in autocrine and paracrine circuits that regulate the EMT status of lung cancer cells. | PloS one (2019). | 2019 | D'AGNANO IGEA | microRNA, EMT, lung cancer, extracellular mediators | 10.1371/journal.pone.0219597 |
| 406417 | Articolo in rivista | High-throughput assessment of the antibody profile in ovarian cancer ascitic fluids | Antony, Frank, Deantonio, Cecilia, Cotella, Diego, Soluri, Maria Felicia, Tarasiuk, Olga, Raspagliesi, Francesco, Adorni, Fulvio, Piazza, Silvano, Ciani, Yari, Santoro, Claudio, Macor, Paolo, Mezzanzanica, Delia, Sblattero, Daniele | The identification of effective biomarkers for early diagnosis, prognosis, and response to treatments remains a challenge in ovarian cancer (OC) research. Here, we present an unbiased high-throughput approach to profile ascitic fluid autoantibodies in order to obtain a tumor-specific antigen signature in OC.We first reported the reactivity of immunoglobulins (Igs) purified from OC patient ascites towards two different OC cell lines. Using a discovery set of Igs, we selected tumor-specific antigens from a phage display cDNA library. After biopanning, 700 proteins were expressed as fusion protein and used in protein array to enable large-scale immunoscreening with independent sets of cancer and noncancerous control. Finally, the selected antigens were validated by ELISA.The initial screening identified eight antigenic clones: CREB3, MRPL46, EXOSC10, BCOR, HMGN2, HIP1R, OLFM4, and KIAA1755. These antigens were all validated by ELISA in a study involving ascitic Igs from 153 patients (69 with OC, 34 with other cancers and 50 without cancer), with CREB3 showing the highest sensitivity (86.95%) and specificity (98%). Notably, we were able to identify an association between the tumor-associated (TA) antibody response and the response to a first-line tumor treatment (platinum-based chemotherapy). A stronger association was found by combining three antigens (BCOR, CREB3, and MRLP46) as a single antibody signature.Measurement of an ascitic fluid antibody response to multiple TA antigens may aid in the identification of new prognostic signatures in OC patients and shift attention to new potentially relevant targets. | ONCOIMMUNOLOGY 8 (2019). | 2019 | ADORNI FULVIO DANIELE | Ovarian cancer, biomarker, tumor-associated antigen, ascite, protein microarray | 10.1080/2162402X.2019.1614856 |
| 407645 | Articolo in rivista | Recommendations for the management of pulmonary fungal infections in patients with rheumatoid arthritis | Galli, M., Antinori, S., Atzeni, F., Meroni, L., Riva, A., Scire, C., Adorni, F., Quartuccio, L., Sebastiani, M., Airo, P., Bazzichi, L., Cristini, F., Del Bono, V., Manfredi, A., Viapiana, O., De Rosa, F., Favalli, E., Petrelli, E., Salvarani, C., Govoni, M., Corcione, S., Scrivo, R., Sarmati, L., Lazzarin, A., Grassi, W., Mastroianni, C., Gaeta, G. B., Ferraccioli, G., Cutolo, M., De Vita, S., Lapadula, G., Matucci-Cerinic, M., Armignacco, O., Sarzi-Puttini, P. | Often life-threatening pulmonary fungal infections (PFIs) can occur in patients with rheumatoid arthritis (RA) receiving disease-modifying anti-rheumatic drugs (DMARDs). Most of the data concerning PFIs in RA patients come from case reports and retrospective case series. Of the five most widely described PFIs, Pneumocystis jirovecii pneumonia (PJP) has rarely been seen outside Japan, pulmonary cryptococcosis has been diagnosed in only a small number of patients worldwide, pulmonary coccidioidomycosis has almost only been observed in endemic areas, the limited number of cases of pulmonary histoplasmosis have mainly occurred in the USA, and the rare cases of invasive pulmonary aspergillosis have only been encountered in leukopenic patients. Many aspects of the prophylaxis, diagnosis and treatment of PFIs in RA patients remain to be defined, as does the role of each DMARD in increasing the risk of infection, and the possibility of resuming biological and non-biological DMARD treatment after the infection has been cured. The recommendations for the management of PFIs described in this paper are the product of a consensus procedure promoted by the Italian group for the Study and Management of Infections in Patients with Rheumatic Diseases (the ISMIR group). | Clinical and Experimental Rheumatology (Testo stamp.) 35 (2017): 1018-1028. | 2017 | ADORNI FULVIO DANIELE | rheumatoid arthritis, pneumonia, fungal infection, recommendations | |
| 408335 | Articolo in rivista | Severe Heterotopic Ossification in the Skeletal Muscle and Endothelial Cells Recruitment to Chondrogenesis Are Enhanced by Monocyte/Macrophage Depletion | Tirone, Mario, Giovenzana, Anna, Vallone, Arianna, Zordan, Paola, Sormani, Martina, Nicolosi, Pier Andrea, Meneveri, Raffaela, Gigliotti, Carmen Rosaria, Spinelli, Antonello E., Bocciardi, Renata, Ravazzolo, Roberto, Cifola, Ingrid, Brunelli, Silvia | Altered macrophage infiltration upon tissue damage results in inadequate healing due to inappropriate remodeling and stem cell recruitment and differentiation. We investigated in vivo whether cells of endothelial origin phenotypically change upon heterotopic ossification induction and whether infiltration of innate immunity cells influences their commitment and alters the ectopic bone formation. Liposome-encapsulated clodronate was used to assess macrophage impact on endothelial cells in the skeletal muscle upon acute damage in the ECs specific lineage-tracing Cdh5CreER(T2):R26REYFP/dtTomato transgenic mice. Macrophage depletion in the injured skeletal muscle partially shifts the fate of ECs toward endochondral differentiation. Upon ectopic stimulation of BMP signaling, monocyte depletion leads to an enhanced contribution of ECs chondrogenesis and to ectopic bone formation, with increased bone volume and density, that is reversed by ACVR1/SMAD pathway inhibitor dipyridamole. This suggests that macrophages contribute to preserve endothelial fate and to limit the bone lesion in a BMP/injury-induced mouse model of heterotopic ossification. Therefore, alterations of the macrophage-endothelial axis may represent a novel target for molecular intervention in heterotopic ossification. | Frontiers in immunology 10 (2019). | 2019 | CIFOLA INGRID | macrophage, endothelial cell (EC), heterotopic ossification (HO), EndoMT, endothelial progenitors cells, RNASeq and NGS data analysis, micro-computerized tomography (mu CT) analysis | 10.3389/fimmu.2019.01640 |
| 409463 | Articolo in rivista | Exploiting Transfer Learning for the Reconstruction of the Human Gene Regulatory Network | Paolo Mignone1, 3, Gianvito Pio1, 3, Domenica D'Elia2, Donato Malerba1, 3, Michelangelo Ceci1, 3 | Motivation The reconstruction of gene regulatory networks (GRNs) from gene expression data has received increasing attention in recent years, due to its usefulness in the understanding of regulatory mechanisms involved in human diseases. Most of the existing methods reconstruct the network through machine learning approaches, by analyzing known examples of interactions. However, (i) they often produce poor results when the amount of labeled examples is limited, or when no negative example is available and (ii) they are not able to exploit information extracted from GRNs of other (better studied) related organisms, when this information is available. Results In this paper, we propose a novel machine learning method that overcomes these limitations, by exploiting the knowledge about the GRN of a source organism for the reconstruction of the GRN of the target organism, by means of a novel transfer learning technique. Moreover, the proposed method is natively able to work in the positive-unlabeled setting, where no negative example is available, by fruitfully exploiting a (possibly large) set of unlabeled examples. In our experiments, we reconstructed the human GRN, by exploiting the knowledge of the GRN of Mus musculus. Results showed that the proposed method outperforms state-of-the-art approaches and identifies previously unknown functional relationships among the analyzed genes. Availability and implementation http://www.di.uniba.it/~mignone/systems/biosfer/index.html. Supplementary information Supplementary data are available at Bioinformatics online. | Bioinformatics (Oxf., Online) btz781 (2019): 1-9. | 2019 | D'ELIA DOMENICA | BIoinformatics, Transfer Learning, Gene Regulatory Network, Network Reconstruction | 10.1093/bioinformatics/btz781 |
| 409466 | Articolo in rivista | NOTCH3 and CADASIL Syndrome: A Genetic and Structural Overview | Eleni Papakonstantinou 1, 2, Flora Bacopoulou 3, Dimitrios Brouzas 4, Vasileios Megalooikonomou 5, Domenica D'Elia 6, Erik Bongcam-Rudloff 7, Dimitrios Vlachakis 1, 2, 8 | CADASIL syndrome is a rare disease that belongs to a group of disorders called leukodystrophies. It is well established that NOTCH3 gene on chromosome 19 is primarily responsible for the development of the CADASIL syndrome. Herein, an attempt is made to shed light on the actual molecular mechanism underlying CADASIL syndrome, through insights extracted from comprehensive evolutionary studies and in silico modelling on Notch3 protein. In particular, we suggest the use of optical coherence tomography angiography for the detection of early signs of small vessel diseases, which are the major precursors to a repertoire of neurodegenerative conditions, including CADASIL. | EMBnet journal 24 (2019): e921. | 2019 | D'ELIA DOMENICA | genetics; bioinformatics; NOTCH3; CADASIL; OCT-A, structural bioinformatics | 10.14806/ej.24.0.921 |
| 409491 | Contributo in atti di convegno | Standardization in Life-science Research - Making the Case for Harmonization to Improve Communication and Sharing of Data amongst Researchers | Susanne Hollmann*1, 2, Babette Regierer1, Domenica D'Elia3, Kristina Gruden4, ?pela Baebler4, Marcus Frohme5, Juliane Pfeil5, Ugur Sezerman6, Chris T Evelo7, Friederike Ehrhart7, Berthold Huppertz8, Erik Bongcam-Rudloff9, Christophe Trefois10, Aleksandra Gruca11, Deborah A. Duca12, Gianni Colotti13, Roxana Merino-Martinez14, Christos Ouzounis15, Oliver Hunewald16, Feng He16, Andreas Kremer17 | Modern, high-throughput methods for the analysis of genetic information, gene and metabolic products and their interactions offer new opportunities to gain comprehensive information on life processes. The data and knowledge generated open diverse application possibilities with enormous innovation potential. To unlock that potential skills in generating but also properly annotating the data for further data integration and analysis are needed. The data need to be made computer readable and interoperable to allow integration with existing knowledge leading to actionable biological insights. To achieve this, we need common standards and standard operating procedures as well as workflows that allow the combination of data across standards. Currently, there is a lack of experts who understand the principles and possess knowledge of the principles and relevant tools. This is a major barrier hindering the implementation of FAIR (findable, accessible, interoperable and reusable) data principles and the actual reusability of data. This is mainly due to insufficient and unequal education of the scientists and other stakeholders involved in producing and handling big data in life science that is inherently varied and complex in nature, and large in volume. Due to the interdisciplinary nature of life science research, education within this field faces numerous hurdles including institutional barriers, lack of local availability of all required expertise, as well as lack of appropriate teaching material and appropriate adaptation of curricula. | ICT Innovation Conference 2018 - Engineering and Life Sciences, pp. 149-159, Metropol Lake Resort, Ohrid, Macedonia, 17/09/2018, 19 /09/2018 | 2018 | D'ELIA DOMENICA | Education, FAIR data, Interoperability, Quality Control (QC), Quality Management (QM), Standard Operating Procedures (SOPs), standardisation | |
| 409498 | Contributo in atti di convegno | Standardization and Quality Assurance in Life-Science Research - Crucially Needed or Unnecessary and Annoying Regulation? | Hollmann S., Attwood T.K., Bongcam-Rudloff E., Duca D., D'Elia D., Endrullat C., Frohme M., Messerschmidt K., Regierer B. | Open Science describes the ongoing transitions in the way research is performed, i.e. researchers collaborate, knowledge is shared, and science is organized. It is driven by digital technologies and by the enormous growth of data, globalization, enlargement of the scientific community and the need to address societal challenges [23]. It has now widely been recognized that making research results more accessible to all societal actors contributes to better and more efficient science, as well as to innovation in the public and private sectors [1, 17]. However, the reuse of research results can only be achieved reliably and efficiently, if these data are valorized in a specific manner. Data are to be generated, formatted and stored according to Standard Operating Procedures (SOPs) and according to sophisticated Data Management Plans [23]. Hence, to generate accurate and reproducible data sets, to allow interlaboratory comparisons as well as further and future use of research data it is mandatory to work in line with good laboratory practices and well-defined and validated methodologies. Within this article, members of the Cost Action CHARME [10] will discuss aspects of quality management and standardization in context with Open Access (OA) efforts. We will address the question: Are Standardization and Quality Management measures in life-science research crucially needed or introduce further unwanted means of regulation?. | 10th International Conference, ICT Innovations 2018, , September 17-19, 2018, Proceedings, pp. 13-20, Ohrid, Macedonia, 17/09/2018, 19-09/2018 | 2018 | D'ELIA DOMENICA | FAIR data, Standardisation, Interoperability, Standard Operating Procedures (SOPs), Quality Management (QM), Quality Control (QC), Education | 10.1007/978-3-030-00825-3_2 |
| 416359 | Articolo in rivista | Extracellular Vesicles, A Possible Theranostic Platform Strategy for Hepatocellular Carcinoma-An Overview | D'Agnano I1, Berardi AC2. | Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third highest cause of mortality from cancer, largely because of delays in diagnosis. There is currently no effective therapy for advanced stage HCC, although sorafenib, the standard treatment for HCC, systemic therapy (including tyrosine kinase inhibitors and anti-angiogenesis agents), and more recently, immunotherapy, have demonstrated some survival benefit. The measurement and modification of extracellular vesicle (EVs) cargoes-composed of nucleic acids, including miRNAs, proteins, and lipids-holds great promise for future HCC diagnosis, prognosis, and treatment. This review will provide an overview of the most recent findings regarding EVs in HCC, and the possible future use of EVs as "liquid biopsy"-based biomarkers for early diagnosis and as a vehicle for targeted drug-delivery. | Cancers (Basel) 12 (2020). | 2020 | D'AGNANO IGEA | hepatocellular carcinoma; extracellular vesicles; liquid biopsy; drug delivery | 10.3390/cancers12020261 |
| 407184 | Articolo in rivista | A secure cloud-edges computing architecture for metagenomics analysis | L. Verderame, I. Merelli, L. Morganti, E. Corni, D. Cesini, D. D'Agostino, A. Merlo | Portable sequencing machines, such as the Oxford Nanopore MinION, are making the genome sequencing ubiquitous. Consequently, metagenomic studies are becoming increasingly popular, yielding important insights into microbial communities covering diverse environments from terrestrial to aquatic ecosystems. Furthermore, the adoption of low-power IoT computing devices represents a feasible way of distributing and managing those machines on the field. However, a key issue is represented by the huge amount of data produced during operations, whose management is actually challenging considering the resources required for an efficient data transfer and processing. In order to deal with such challenge, this paper put forward a novel architecture, based on the coupling of Edge and Cloud computing paradigms. The focus of the paper is the Edge layer, responsible of the dynamic management of the full analysis pipeline of IoT devices producing large datasets like the MinION ones while adopting proper security mechanisms that handle the authentication of on-field devices and the confidentiality of the transmitted data. | Future generation computer systems 111 (2020): 919-930. | 2020 | D'AGOSTINO DANIELE, MERELLI IVAN | Edge computing, Cloud computing, Trusted cloud-edges computations, Metagenomics, Internet of Things | 10.1016/j.future.2019.09.013 |
| 368303 | Articolo in rivista | Fecal metabolome of the Hadza hunter-gatherers: a host-microbiome integrative view | Turroni, Silvia, Fiori, Jessica, Rampelli, Simone, Schnorr, Stephanie L., Consolandi, Clarissa, Barone, Monica, Biagi, Elena, Fanelli, Flaminia, Mezzullo, Marco, Crittenden, Alyssa N., Henry, Amanda G., Brigidi, Patrizia, Candela, Marco | The recent characterization of the gut microbiome of traditional rural and foraging societies allowed us to appreciate the essential co-adaptive role of the microbiome in complementing our physiology, opening up significant questions on how the microbiota changes that have occurred in industrialized urban populations may have altered the microbiota-host co-metabolic network, contributing to the growing list of Western diseases. Here, we applied a targeted metabolomics approach to profile the fecal metabolome of the Hadza of Tanzania, one of the world's few remaining foraging populations, and compared them to the profiles of urban living Italians, as representative of people in the post-industrialized West. Data analysis shows that during the rainy season, when the diet is primarily plant-based, Hadza are characterized by a distinctive enrichment in hexoses, glycerophospholipids, sphingolipids, and acylcarnitines, while deplete in the most common natural amino acids and derivatives. Complementary to the documented unique metagenomic features of their gut microbiome, our findings on the Hadza metabolome lend support to the notion of an alternate microbiome configuration befitting of a nomadic forager lifestyle, which helps maintain metabolic homeostasis through an overall scarcity of inflammatory factors, which are instead highly represented in the Italian metabolome. | Scientific reports (Nature Publishing Group) 6 (2016). | 2016 | CONSOLANDI CLARISSA | Microbial ecology, Microbiome | 10.1038/srep32826 |
| 368308 | Articolo in rivista | Exposure to vehicular traffic is associated to a higher risk of hospitalization for bronchiolitis during the first year of life. | Lanari, Marcello, Vandini, Silvia, Prinelli, Federica, Adorni, Fulvio, DI Santo, Simona, Silvestri, Michela, Musicco, Massimo | BACKGROUND: The most common cause of hospitalization for children younger than age one is bronchiolitis. Several prenatal and environmental risk factors may affect the incidence of hospitalization for bronchiolitis. The aim of this study was to investigate the relation between exposure to vehicular traffic and the incidence of hospitalization for bronchiolitis in children during their first year of life in Italy. METHODS: A multicenter prospective birth cohort study, where equal numbers of newborns of 33-34, 35-37 and >=38 wGA were recruited at birth (1814 children) in 30 Italian neonatology units. Two interviewer-administered questionnaires were used to collect data. The first interview was carried out at the end of the Italian epidemic season. The second interview was carried out when the child was one year old. Data on possible prenatal, perinatal, and postnatal/environmental risk factors and on vehicular traffic density in the zone of residence were collected. On each interview, parents were also asked about any hospitalizations of the child. The outcome measure was the hospitalization for bronchiolitis (International Health Service ICD-9 code 466). RESULTS: Univariate analysis demonstrated that exposure to air pollution due to vehicular traffic, was significantly associated with an increased risk of hospitalization for bronchiolitis. The adjusted risk from logistic regression model confirmed that children exposed to air pollution due to vehicular traffic were at increased risk of hospitalization for bronchiolitis. CONCLUSIONS: Exposure to air pollution due to vehicular traffic may increase the risk of hospitalization for bronchiolitis in the first year of life. | Minerva pediatrica (Online) 68 (2016): 391-397. | 2016 | PRINELLI FEDERICA, ADORNI FULVIO DANIELE, MUSICCO MASSIMO | * | |
| 368309 | Articolo in rivista | The Importance of Mortality Risk Assessment: Validation of the Pediatric Index of Mortality 3 Score | Wolfler, Andrea, Osello, Raffaella, Gualino, Jenny, Calderini, Edoardo, Vigna, Gianluca, Santuz, Pierantonio, Amigoni, Angela, Savron, Fabio, Caramelli, Fabio, Rossetti, Emanuele, Cecchetti, Corrado, Corbari, Maurizio, Piastra, Marco, Testa, Raffaele, Coffaro, Giancarlo, Stancanelli, Giusi, Gitto, Eloisa, Amato, Roberta, Prinelli, Federica, Salvo, Ida | OBJECTIVE: To evaluate the performance of the newest version of the Pediatric Index of Mortality 3 score and compare it with the Pediatric Index of Mortality 2 in a multicenter national cohort of children admitted to PICU. DESIGN: Retrospective, prospective cohort study. SETTING: Seventeen Italian PICUs. PATIENTS: All children 0 to 15 years old admitted in PICU from January 2010 to October 2014. INTERVENTIONS: None. MEASUREMENT AND MAIN RESULTS: Eleven thousand one hundred nine children were enrolled in the study. The mean Pediatric Index of Mortality 2 and 3 values of 4.9 and 3.9, respectively, differed significantly (p < 0.05). Overall mortality rate was 3.9%, and the standardized mortality ratio was 0.80 for Pediatric Index of Mortality 2 and 0.98 for Pediatric Index of Mortality 3 (p < 0.05). The area under the curve of the receiver operating characteristic curves was similar for Pediatric Index of Mortality 2 and Pediatric Index of Mortality 3. The Hosmer-Lemeshow test was not significant for Pediatric Index of Mortality 3 (p = 0.21) but was highly significant for Pediatric Index of Mortality 2 (p < 0.001), which overestimated death mainly in high-risk categories. CONCLUSIONS: Mortality indices require validation in each country where it is used. The new Pediatric Index of Mortality 3 score performed well in an Italian population. Both calibration and discrimination were appropriate, and the score more accurately predicted the mortality risk than Pediatric Index of Mortality 2. | Pediatric critical care medicine 17 (2016): 251-256. | 2016 | PRINELLI FEDERICA | children, risk of mortality, outcome, quality measure, pediatric intensive care unit, standardized mortality ratio, validation studies | 10.1097/PCC.0000000000000657 |
| 338880 | Articolo in rivista | Porting bioinformatics applications from grid to cloud: a macromolecular surface analysis application case study | I. Merelli, P. Cozzi, E. Ronchieri, D. Cesini, D. D'Agostino | In this paper we describe our experience in exploiting different cloud-based environments for an actual use case taken from the bioinformatics domain - the molecular surfaces analysis - that identifies similarities and possible complementarities in the protein surfaces. The analysis of macromolecular surfaces is important since protein surface conformations drive many biological reactions. We developed a workflow that performs the macromolecular surfaces analysis and provides interesting results from a scientific point of view. An important issue is represented by the fact that it is highly compute-intensive, therefore it cannot be run on a single CPU system for meaningful use cases and a parallel infrastructure is required to obtain reasonable execution time. For a decade grid infrastructures have represented suitable solutions to achieve cost effective computational power for Bioinformatics applications. However, these solutions do not offer an adequate customisation of the computational environment (e.g. installing databases and configuring virtual network) due to the rigid organisation of the storage and computational sites. Running applications on customised machines obtained by user-defined images simplifies the computing model, decreases the failure rates and therefore reduces waiting times for production analysis with respect to the canonical grid computations. For these reasons a cloud-based approach is more suitable than a pure grid paradigm. We experimented using two cloud-based approaches, based on the Worker Node On Demand Service and on OpenStack, to run the molecular surfaces analysis use case and we compared the results in terms of performance, efficiency and efforts to build the computing model with respect to grid computing. | International journal of high performance computing applications (Online) 31 (2017): 182-195. | 2017 | D'AGOSTINO DANIELE, MERELLI IVAN | Cloud computing, Protein surface matching | 10.1177/1094342015588565 |
| 339175 | Articolo in rivista | Interactions of iron, dopamine and neuromelanin pathways in brain aging and Parkinson's disease | Zucca F.A., Segura-Aguilar J., Ferrari E., Munoz P., Paris I., Sulzer D., Sarna T., Casella L., Zecca L. | There are several interrelated mechanisms involving iron, dopamine, and neuromelanin in neurons. Neuromelanin accumulates during aging and is the catecholamine-derived pigment of the dopamine neurons of the substantia nigra and norepinephrine neurons of the locus coeruleus, the two neuronal populations most targeted in Parkinson's disease. Many cellular redox reactions rely on iron, however an altered distribution of reactive iron is cytotoxic. In fact, increased levels of iron in the brain of Parkinson's disease patients are present. Dopamine accumulation can induce neuronal death; however, excess dopamine can be removed by converting it into a stable compound like neuromelanin, and this process rescues the cell. Interestingly, the main iron compound in dopamine and norepinephrine neurons is the neuromelanin-iron complex, since neuromelanin is an effective metal chelator. Neuromelanin serves to trap iron and provide neuronal protection from oxidative stress. This equilibrium between iron, dopamine, and neuromelanin is crucial for cell homeostasis and in some cellular circumstances can be disrupted. Indeed, when neuromelanin-containing organelles accumulate high load of toxins and iron during aging a neurodegenerative process can be triggered. In addition, neuromelanin released by degenerating neurons activates microglia and the latter cause neurons death with further release of neuromelanin, then starting a self-propelling mechanism of neuroinflammation and neurodegeneration. Considering the above issues, age-related accumulation of neuromelanin in dopamine neurons shows an interesting link between aging and neurodegeneration. | Progress in neurobiology (Print) 155 (2017): 96-119. | 2017 | FERRARI EMANUELE, ZECCA LUIGI, ZUCCA FABIO ANDREA | iron, dopamine, melanin, human neuromelanin, Parkinson's disease | 10.1016/j.pneurobio.2015.09.012 |
| 368320 | Articolo in rivista | Targeted BMI1 inhibition impairs tumor growth in lung adenocarcinomas with low CEBPa expression | Yong K.J., Basseres D.S., Welner R.S., Zhang W.C., Yang H., Yan B., Alberich-Jorda M., Zhang J., De Figueiredo-Pontes L.L., Battelli C., Hetherington C.J., Ye M., Zhang H., Maroni G., O'Brien K., Magli M.C., Borczuk A.C., Varticovski L., Kocher O., Zhang P., Moon Y.-C., Sydorenko N., Cao L., Davis T.W., Thakkar B.M., Soo R.A., Iwama A., Lim B., Halmos B., Neuberg D., Tenen D.G., Levantini E. | Lung cancer is the most common cause of cancer deaths. The expression of the transcription factor C/EBP? (CCAAT/enhancer binding protein a) is frequently lost in non-small cell lung cancer, but the mechanisms by which C/EBP? suppresses tumor formation are not fully understood. In addition, no pharmacological therapy is available to specifically target C/EBP? expression. We discovered a subset of pulmonary adenocarcinoma patients in whom negative/low C/EBP? expression and positive expression of the oncogenic protein BMI1 (B lymphoma Mo-MLV insertion region 1 homolog) have prognostic value. We also generated a lung-specific mouse model of C/EBP? deletion that develops lung adenocarcinomas, which are prevented by Bmi1 haploinsufficiency. BMI1 activity is required for both tumor initiation and maintenance in the C/EBP?-null background, and pharmacological inhibition of BMI1 exhibits antitumor effects in both murine and human adenocarcinoma lines. Overall, we show that C/EBP? is a tumor suppressor in lung cancer and that BMI1 is required for the oncogenic process downstream of C/EBP? loss. Therefore, anti-BMI1 pharmacological inhibition may offer a therapeutic benefit for lung cancer patients with low expression of C/EBP? and high BMI1. | Science translational medicine 8 (2016): 350ra104. | 2016 | MARONI GIORGIA, LEVANTINI ELENA, MAGLI MARIA CRISTINA | cebpa tumor suppressor, knock out mice, transgenic mice, novel therapeutic treatment for lung cancer, xenograft mice, BMI1 oncogene as novel therapeutic target in lung cancer, in vivo drug treatment, preclinical murine models of disease | 10.1126/scitranslmed.aad6066 |
| 346251 | Articolo in rivista | Osteogenic differentiation of MSC through calcium signaling activation: transcriptomics and functional analysis | F. Viti, M. Landini, A. Mezzelani, L. Petecchia, L. Milanesi, S. Scaglione | The culture of progenitor mesenchymal stem cells (MSC) onto osteoconductive materials to induce a proper osteogenic differentiation and mineralized matrix regeneration represents a promising and widely diffused experimental approach for tissue-engineering (TE) applications in orthopaedics. Among modern biomaterials, calcium phosphates represent the best bone substitutes, due to their chemical features emulating the mineral phase of bone tissue. Although many studies on stem cells differentiation mechanisms have been performed involving calcium-based scaffolds, results often focus on highlighting production of in vitro bone matrix markers and in vivo tissue ingrowth, while information related to the biomolecular mechanisms involved in the early cellular calcium-mediated differentiation is not well elucidated yet. Genetic programs for osteogenesis have been just partially deciphered, and the description of the different molecules and pathways operative in these differentiations is far from complete, as well as the activity of calcium in this process. The present work aims to shed light on the involvement of extracellular calcium in MSC differentiation: a better understanding of the early stage osteogenic differentiation program of MSC seeded on calcium- based biomaterials is required in order to develop optimal strategies to promote osteogenesis through the use of new generation osteoconductive scaffolds. A wide spectrum of analysis has been performed on time-dependent series: gene expression profiles are obtained from samples (MSC seeded on calcium-based scaffolds), together with related microRNAs expression and in vivo functional validation. On this basis, and relying on literature knowledge, hypotheses are made on the biomolecular players activated by the biomaterial calcium-phosphate component. Interestingly, a key role of miR-138 was highlighted, whose inhibition markedly increases osteogenic differentiation in vitro and enhance ectopic bone formation in vivo. Moreover, there is evidence that Ca-P substrate triggers osteogenic differentiation through genes (SMAD and RAS family) that are typically regulated during dexamethasone (DEX) induced differentiation. | PloS one 11 (2016). | 2016 | LANDINI MARTINA, PETECCHIA LOREDANA, MEZZELANI ALESSANDRA MARIA, SCAGLIONE SILVIA, MILANESI LUCIANO, VITI FEDERICA | bioinformatics, bioengineering, tissue engineering | 10.1371/journal.pone.0148173 |
| 368321 | Articolo in rivista | Acetylation of C/EBPa inhibits its granulopoietic function | Bararia D., Kwok H.S., Welner R.S., Numata A., Sarosi M.B., Yang H., Wee S., Tschuri S., Ray D., Weigert O., Levantini E., Ebralidze A.K., Gunaratne J., Tenen D.G. | CCAAT/enhancer-binding protein alpha (C/EBP?) is an essential transcription factor for myeloid lineage commitment. Here we demonstrate that acetylation of C/EBP? at lysine residues K298 and K302, mediated at least in part by general control non-derepressible 5 (GCN5), impairs C/EBP? DNA-binding ability and modulates C/EBP? transcriptional activity. Acetylated C/EBPa is enriched in human myeloid leukaemia cell lines and acute myeloid leukaemia (AML) samples, and downregulated upon granulocyte-colony stimulating factor (G-CSF)- mediated granulocytic differentiation of 32Dcl3 cells. C/EBPa mutants that mimic acetylation failed to induce granulocytic differentiation in C/EBPa-dependent assays, in both cell lines and in primary hematopoietic cells. Our data uncover GCN5 as a negative regulator of C/EBPa and demonstrate the importance of C/EBPa acetylation in myeloid differentiation. | Nature communications 7 (2016). | 2016 | LEVANTINI ELENA | transcription factors, gene regulation, acetylation, myeloid differentiation, mass spec, negative regulator of gene expression, c/EBPa tumor suppressor transcription factor, myeloid leukemia models | 10.1038/ncomms10968 |
| 368322 | Articolo in rivista | Aurora kinase targeting in lung cancer reduces KRAS-induced transformation | dos Santos, Edmilson Ozorio, Carneiro-Lobo, Tatiana Correa, Aoki, Mateus Nobrega, Levantini, Elena, Basseres, Daniela Sanchez | Background Activating mutations in KRAS are prevalent in lung cancer and have been causally linked to the oncogenic process. However, therapies targeted to oncogenic RAS have been ineffective to date and identification of KRAS targets that impinge on the oncogenic phenotype is warranted. Based on published studies showing that mitotic kinases Aurora A (AURKA) and B (AURKB) cooperate with oncogenic RAS to promote malignant transformation and that AURKA phosphorylates RAS effector pathway components, the aim of this study was to investigate whether AURKA and AURKB are KRAS targets in lung cancer and whether targeting these kinases might be therapeutically beneficial. Methods In order to determine whether oncogenic KRAS induces Aurora kinase expression, we used qPCR and western blotting in three different lung cell-based models of gain- or loss-of-function of KRAS. In order to determine the functional role of these kinases in KRAS-induced transformation, we generated KRAS-positive A549 and H358 cells with stable and inducible shRNA-mediated knockdown of AURKA or AURKB and evaluated transformation in vitro and tumor growth in vivo. In order to validate AURKA and/or AURKB as therapeutically relevant KRAS targets in lung cancer, we treated A549 and H358 cells, as well as two different lung cell based models of gain-of-function of KRAS with a dual Aurora kinase inhibitor and performed functional in vitro assays. Results We determined that KRAS positively regulates AURKA and AURKB expression. Furthermore, in KRAS-positive H358 and A549 cell lines, inducible knockdown of AURKA or AURKB, as well as treatment with a dual AURKA/AURKB inhibitor, decreased growth, viability, proliferation, transformation, and induced apoptosis in vitro. In addition, inducible shRNA-mediated knockdown of AURKA in A549 cells decreased tumor growth in vivo. More importantly, dual pharmacological inhibiton of AURKA and AURKB reduced growth, viability, transformation, and induced apoptosis in vitro in an oncogenic KRAS-dependent manner, indicating that Aurora kinase inhibition therapy can specifically target KRAS-transformed cells. Conclusions Our results support our hypothesis that Aurora kinases are important KRAS targets in lung cancer and suggest Aurora kinase inhibition as a novel approach for KRAS-induced lung cancer therapy. | Molecular cancer 15 (2016). | 2016 | LEVANTINI ELENA | lung cancer, KRAS mutation, lung cancer therapy, cell growth, cell proliferation, cellular apoptosis, AURKA therapeutic targeting in lung cancer, mechanisms of lung cancer | 10.1186/s12943-016-0494-6 |
| 349994 | Articolo in rivista | Glucose availability enhances lipopolysaccharide production and immunogenicity in the opportunistic pathogen Acinetobacter baumannii. | Rossi E, Longo F, Barbagallo M, Peano C, Consolandi C, Pietrelli A, Jaillon S, Garlanda C, Landini P. | AIM: Acinetobacter baumannii can cause sepsis with high mortality rates. We investigated whether glucose sensing might play a role in A. baumannii pathogenesis. MATERIALS & METHODS: We carried out transcriptome analysis and extracellular polysaccharide determination in an A. baumannii clinical isolate grown on complex medium with or without glucose supplementation, and assessed its ability to induce production of inflammatory cytokines in human macrophages. RESULTS: Growth in glucose-supplemented medium strongly enhanced A. baumannii sugar anabolism, resulting in increasing lipopolysaccharide biosynthesis. In addition, glucose induced active shedding of lipopolysaccharide, in turn triggering a strong induction of inflammatory cytokines in human macrophages. Finally, hemolytic activity was strongly enhanced by growth in glucose-supplemented medium. CONCLUSION: We propose that sensing of exogenous glucose might trigger A. baumannii pathogenesis during sepsis. | Future microbiology (Online) (2016). | 2016 | CONSOLANDI CLARISSA, PEANO CLELIA | Acinetobacter baumannii; LPS; glucose; host-pathogen interactions; innate immune response; macrophage; sepsis; transcriptomics; virulence factors | |
| 352315 | Articolo in rivista | The bottlenose dolphin (Tursiops truncatus) fecal microbiota | Soverini M, Quercia S, Biancani B, Furlati S, Turroni S, Biagi E, Consolandi C, Peano C, Severgnini M, Rampelli S, Brigidi P, Candela M. | Cetaceans have evolved from herbivorous terrestrial artiodactyls closely related to ruminants and hippopotamuses. Delphinidae, a family included in this order, represent an extreme and successful re-adaptation of mammalian physiology to the marine habitat and piscivorous diet. The anatomical aspects of Delphinidae success are well understood, whereas some physiological aspects of their environmental fitness are less defined, such as the gut microbiota composition and its adaptation to their dietary niche. Here, we explored the fecal microbiota structure of nine adult bottlenose dolphins (Tursiops truncatus) and one breast-fed calf living in a controlled environment. According to our findings, dolphins possess a unique microbiota profile within the Mammalia class, highly resembling that of carnivorous marine fishes. The breast-fed calf showed a distinctive compositional structure of the gut microbial ecosystem, which partially overlaps with the mother's milk microbiota. Taken together, our data indicate that in dolphins the adaptation to the marine niche and piscivorous diet involved the convergence of their gut microbiota structure with that of marine fishes, overcoming the gut microbiota phylogenetic inertia previously described in terrestrial mammalians. | FEMS microbiology, ecology (print) (2016). | 2016 | CONSOLANDI CLARISSA, PEANO CLELIA, SEVERGNINI MARCO | 16S rDNA; Tursiops truncatus; cetacea; evolution; fecal microbiota; mammalia | |
| 368327 | Articolo in rivista | Osservazioni sull'utilizzo del placebo nella sperimentazione clinica | Annoni M., Pievani T., Caporale C. | * | The Future of Science and Ethics (Online) 1 (2016): 18-23. | 2016 | ANNONI MARCO ANGELO MARIA, CAPORALE CINZIA | * | |
| 354316 | Articolo in rivista | The Typhoid Toxin Promotes Host Survival and the Establishment of a Persistent Asymptomatic Infection | Del Bel Belluz L, Guidi R, Pateras IS, Levi L, Mihaljevic B, Rouf SF, Wrande M, Candela M, Turroni S, Nastasi C, Consolandi C, Peano C, Tebaldi T, Viero G, Gorgoulis VG, Krejsgaard T, Rhen M, Frisan T | Bacterial genotoxins, produced by several Gram-negative bacteria, induce DNA damage in the target cells. While the responses induced in the host cells have been extensively studied in vitro, the role of these effectors during the course of infection remains poorly characterized. To address this issue, we assessed the effects of the Salmonella enterica genotoxin, known as typhoid toxin, in in vivo models of murine infection. Immunocompetent mice were infected with isogenic S. enterica, serovar Typhimurium (S. Typhimurium) strains, encoding either a functional or an inactive typhoid toxin. The presence of the genotoxic subunit was detected 10 days post-infection in the liver of infected mice. Unexpectedly, its expression promoted the survival of the host, and was associated with a significant reduction of severe enteritis in the early phases of infection. Immunohistochemical and transcriptomic analysis confirmed the toxin-mediated suppression of the intestinal inflammatory response. The presence of a functional typhoid toxin further induced an increased frequency of asymptomatic carriers. Our data indicate that the typhoid toxin DNA damaging activity increases host survival and favours long-term colonization, highlighting a complex cross-talk between infection, DNA damage response and host immune response. These findings may contribute to understand why such effectors have been evolutionary conserved and horizontally transferred among Gram-negative bacteria. | PLOS pathogens 12 (2016): e1005528. | 2016 | CONSOLANDI CLARISSA, PEANO CLELIA, VIERO GABRIELLA | Salmonella enterica genotoxin | 10.1371/journal.ppat.1005528 |
| 355020 | Articolo in rivista | Modulation of gut microbiota dysbioses in type 2 diabetic patients by macrobiotic Ma-Pi 2 diet | Candela M., Biagi E., Soverini M., Consolandi C., Quercia S., Severgnini M., Peano C., Turroni S., Rampelli S., Pozzilli P., Pianesi M., Fallucca F., Brigidi P. | The gut microbiota exerts a role in type 2 diabetes (T2D), and deviations from a mutualistic ecosystem layout are considered a key environmental factor contributing to the disease. Thus, the possibility of improving metabolic control in T2D by correcting gut microbiome dysbioses through diet has been evaluated. Here, we explore the potential of two different energy-restricted dietary approaches - the fibre-rich macrobiotic Ma-Pi 2 diet or a control diet recommended by Italian professional societies for T2D treatment - to correct gut microbiota dysbioses in T2D patients. In a previous 21-d open-label MADIAB trial, fifty-six overweight T2D patients were randomised to the Ma-Pi 2 or the control diet. For the present study, stools were collected before and after intervention from a subset of forty MADIAB participants, allowing us to characterise the gut microbiota by 16S rRNA sequencing and imputed metagenomics. To highlight microbiota dysbioses in T2D, the gut microbiota of thirteen normal-weight healthy controls were characterised. According to our findings, both diets were effective in modulating gut microbiome dysbioses in T2D, resulting in an increase of the ecosystem diversity and supporting the recovery of a balanced community of health-promoting SCFA producers, such as Faecalibacterium, Roseburia, Lachnospira, Bacteroides and Akkermansia. The Ma-Pi 2 diet, but not the control diet, was also effective in counteracting the increase of possible pro-inflammatory groups, such as Collinsella and Streptococcus, in the gut ecosystem, showing the potential to reverse pro-inflammatory dysbioses in T2D, and possibly explaining the greater efficacy in improving the metabolic control. | British journal of nutrition (2016): 1-14. | 2016 | CONSOLANDI CLARISSA, PEANO CLELIA, SEVERGNINI MARCO | Dysbiosis, Fibre-rich diets, Gut microbiota, Macrobiotic diets, Type 2 diabetes | 10.1017/S0007114516001045 |
| 368328 | Articolo in rivista | Ripensare il sistema sanzionatorio penale | Gullo A., Caporale C., Severino Di Benedetto P. | * | The Future of Science and Ethics (Online) 1 (2016): 70-73. | 2016 | CAPORALE CINZIA | * | |
| 355024 | Articolo in rivista | Gut Microbiota and Extreme Longevity | Biagi E, Franceschi C, Rampelli S, Severgnini M, Ostan R, Turroni S, Consolandi C, Quercia S, Scurti M, Monti D, Capri M, Brigidi P, Candela M | The study of the extreme limits of human lifespan may allow a better understanding of how human beings can escape, delay, or survive the most frequent age-related causes of morbidity, a peculiarity shown by long-living individuals. Longevity is a complex trait in which genetics, environment, and stochasticity concur to determine the chance to reach 100 or more years of age [1]. Because of its impact on human metabolism and immunology, the gut microbiome has been proposed as a possible determinant of healthy aging [2, 3]. Indeed, the preservation of host-microbes homeostasis can counteract inflammaging [4], intestinal permeability [5], and decline in bone and cognitive health [6, 7]. Aiming at deepening our knowledge on the relationship between the gut microbiota and a long-living host, we provide for the first time the phylogenetic microbiota analysis of semi-supercentenarians, i.e., 105-109 years old, in comparison to adults, elderly, and centenarians, thus reconstructing the longest available human microbiota trajectory along aging. We highlighted the presence of a core microbiota of highly occurring, symbiotic bacterial taxa (mostly belonging to the dominant Ruminococcaceae, Lachnospiraceae, and Bacteroidaceae families), with a cumulative abundance decreasing along with age. Aging is characterized by an increasing abundance of subdominant species, as well as a rearrangement in their co-occurrence network. These features are maintained in longevity and extreme longevity, but peculiarities emerged, especially in semi-supercentenarians, describing changes that, even accommodating opportunistic and allochthonous bacteria, might possibly support health maintenance during aging, such as an enrichment and/or higher prevalence of health-associated groups (e.g., Akkermansia, Bifidobacterium, and Christensenellaceae). | Current biology (2016). | 2016 | CONSOLANDI CLARISSA, SEVERGNINI MARCO | health-associated gut bacteria, longevity adaptation | |
| 368332 | Articolo in rivista | Maternita surrogata: profili etici | Caporale C., Veronesi U., Mancini E., Flamigni C. | * | The Future of Science and Ethics (Online) 1 (2016): 78-84. | 2016 | CAPORALE CINZIA, MANCINI ELENA | * | |
| 368335 | Articolo in rivista | Mozione del Comitato Etico sui profili etici dell'eutanasia | Caporale C., Annoni M., Veronesi U. | * | The Future of Science and Ethics (Online) (2016): 108-110. | 2016 | ANNONI MARCO ANGELO MARIA, CAPORALE CINZIA | * | |
| 356248 | Articolo in rivista | Adipose tissue microbiota in humans: an open issue | Zulian A, Cancello R, Cesana E, Rizzi E, Consolandi C, Severgnini M, Panizzo V, Di Blasio AM, Micheletto G, Invitti C. | BackgroundA specific "adipose tissue" microbiota has been recently identified in mice and hypothesized in humans. The purpose of this study was to verify the presence of microbiota of human whole adipose tissue and isolated adipocytes by combining culture-dependent and independent methods.MethodsStandard microbiological cultural techniques and 16S ribosomal RNA (16S rRNA) gene sequencing (Illumina technology) on DNA and RNA were employed to study a) whole abdominal subcutaneous (SAT) and visceral (VAT) adipose tissue from 14 obese and 5 normal-weight subjects, b) mature adipocytes isolated from SAT and VAT after collagenase digestion or mechanical separation. To optimize the 16S rRNA gene detection we used different DNA extraction methods (lysis with proteinase K, proteinase K+lysozyme and microbeads) and amplification procedures (semi quantitative standard PCR and real time quantitative PCR).ResultsMicrobiological cultures were negative in all analyzed samples. In enzymatically isolated adipocytes, 90% of the sequenced bacterial DNA belonged to Clostridium histolyticum, the bacterium from which the collagenase enzyme was isolated. Bacterial 16S rRNA gene was not detected from DNA and RNA of whole SAT and VAT, as well as of mechanically isolated mature adipocytes, even after blocking with a specific primer the non-specific amplification of human mitochondrial 12S rRNA.ConclusionOur results do not support the presence of a human adipose tissue microbiota. In addition, they emphasized the technical problems encountered when applying metagenomic studies to human tissues with very low or absent bacterial load | International journal of obesity (Online) (2016). | 2016 | CONSOLANDI CLARISSA, SEVERGNINI MARCO | microbiota, 16S ribosomal gene, adipose tissue, sequencing | |
| 356933 | Articolo in rivista | Complexity and dynamics of the winemaking bacterial communities in berries, musts, and wines from apulian grape cultivars through time and space | Marzano M., Fosso B., Manzari C., Grieco F., Intranuovo M., Cozzi G., Mule G., Scioscia G., Valiente G., Tullo A., Sbisa E., Pesole G., Santamaria M. | Currently, there is very little information available regarding the microbiome associated with the wine production chain. Here, we used an amplicon sequencing approach based on high-throughput sequencing (HTS) to obtain a comprehensive assessment of the bacterial community associated with the production of three Apulian red wines, from grape to final product. The relationships among grape variety, the microbial community, and fermentation was investigated. Moreover, the winery microbiota was evaluated compared to the autochthonous species in vineyards that persist until the end of the winemaking process. The analysis highlighted the remarkable dynamics within the microbial communities during fermentation. A common microbial core shared among the examined wine varieties was observed, and the unique taxonomic signature of each wine appellation was revealed. New species belonging to the genus Halomonas were also reported. This study demonstrates the potential of this metagenomic approach, supported by optimized protocols, for identifying the biodiversity of the wine supply chain. The developed experimental pipeline offers new prospects for other research fields in which a comprehensive view of microbial community complexity and dynamics is desirable. | PloS one 11 (2016): 1-19. | 2016 | FOSSO BRUNO, GRIECO FRANCESCO, TULLO APOLLONIA, COZZI GIUSEPPE, PESOLE GRAZIANO, MARZANO MARINELLA, MANZARI CATERINA, SANTAMARIA MONICA, SBISA' ELISABETTA, MULE' GIUSEPPINA | Metagenomic, wine bacteria, Apulian grape | 10.1371/journal.pone.0157383 |
| 368337 | Articolo in rivista | Neuromelanin Imaging and Dopaminergic Loss in Parkinson's Disease | Isaias, Ioannis U., Trujillo, Paula, Summers, Paul, Marotta, Giorgio, Mainardi, Luca, Pezzoli, Gianni, Zecca, Luigi, Costa, Antonella | Parkinson's disease (PD) is a progressive neurodegenerative disorder in which the major pathologic substrate is a loss of dopaminergic neurons from the substantia nigra. Our main objective was to determine the correspondence between changes in the substantia nigra, evident in neuromelanin and iron sensitive magnetic resonance imaging (MRI), and dopaminergic striatal innervation loss in patients with PD. Eighteen patients and 18 healthy control subjects were included in the study. Using neuromelanin-MRI, we measured the volume of the substantia nigra and the contrast-to-noise-ratio between substantia nigra and a background region. The apparent transverse relaxation rate and magnetic susceptibility of the substantia nigra were calculated from dual-echo MRI. Striatal dopaminergic innervation was measured as density of dopamine transporter (DAT) by means of single-photon emission computed tomography and [I-123] N-omega-fluoropropy1-2b-carbomethoxy-3b-(4-iodophenyl) tropane. Patients showed a reduced volume of the substantia nigra and contrast-to-noise-ratio and both positively correlated with the corresponding striatal DAT density. The apparent transverse relaxation rate and magnetic susceptibility values of the substantia nigra did not differ between patients and healthy controls. The best predictor of DAT reduction was the volume of the substantia nigra. Clinical and imaging correlations were also investigated for the locus coeruleus. Our results suggest that neuromelanin-MRI can be used for quantifying substantia nigra pathology in PD where it closely correlates with dopaminergic striatal innervation loss. Longitudinal studies should further explore the role of Neuromelanin-MRI as an imaging biomarker of PD, especially for subjects at risk of developing the disease. | Frontiers in aging neuroscience 8 (2016). | 2016 | ZECCA LUIGI | neuromelanin, dopamine, Parkinson's disease, MRI, FP-CIT SPECT | 10.3389/fnagi.2016.00196 |
| 357962 | Articolo in rivista | Enterocyte-Associated Microbiome of the Hadza Hunter-Gatherers | Turroni, Silvia, Rampelli, Simone, Centanni, Manuela, Schnorr, Stephanie L., Consolandi, Clarissa, Severgnini, Marco, Peano, Clelia, Soverini, Matteo, Falconi, Mirella, Crittenden, Alyssa N., Henry, Amanda G., Brigidi, Patrizia, Candela, Marco | By means of a recently developed non-invasive ex vivo minimal model based on the interaction of the human enterocyte-like HT29 cell line and fecal slurries, we explored the enterocyte-associated microbiome of 21 Hadza hunter-gatherers and nine urban living Italians. Though reductionist, this model allows inferring the microbiota structural and functional arrangement as it interacts with enterocytes. Microbial suspensions obtained from Hadza or Italian stools were first evaluated for structural integrity by high resolution-scanning electron microscopy and co-incubated with HT29 cell monolayers. The enterocyte adherent microbiota fraction was then characterized by 16S rRNA gene sequencing and predictive functional profiling using PICRUSt. Compared to Italians, the Hadza enterocyte-associated microbiome was characterized by a greater amount of adhesive microorganisms with pathogenic potential, such as Proteobacteria, Erysipelotrichaceae, Enterococcus, Clostridium and Sarcina. These compositional characteristics were reflected in a functional enrichment in membrane transport, signal transduction, signaling molecules and interaction. Our results depict a new interesting mutualistic configuration of the enterocyte-associated microbiome in Hadza, stressing the importance of microbe-host interaction at the mucosal surface along the course of human evolution. | Frontiers in microbiology 7 (2016). | 2016 | CONSOLANDI CLARISSA, PEANO CLELIA, SEVERGNINI MARCO | gut microbiota, enterocyte-associated microbiome, microbiota-host interactions, Hadza hunter gatherers, human evolution | 10.3389/fmich.2016.00855 |
| 368338 | Articolo in rivista | L'integrita nella ricerca, una questione di standard | Caporale C., Fanelli D. | * | The Future of Science and Ethics (Online) (2016): 154-167. | 2016 | CAPORALE CINZIA | * | |
| 368341 | Contributo in atti di convegno | Promoting research integrity in Italy: the experience of the Research Ethics and Bioethics Advisory Committee of the Consiglio Nazionale delle Ricerche (CNR) | Caporale C., Fanelli D. | * | Proceedings of the 4th World Conference on Research Integrity, Brazil, Rio de Janeiro, 31 May - 3 June 2015 | 2016 | CAPORALE CINZIA | * | 10.1186/s41073-016-0012-9 |
| 359660 | Articolo in rivista | BioVeL: a virtual laboratory for data analysis and modelling in biodiversity science and ecology | Hardisty, Alex R., Bacall, Finn, Beard, Niall, Balc'azar-Vargas, Maria-Paula, Balech, Bachir, Barcza, Zolt'an, Bourlat, Sarah J., De Giovanni, Renato, de Jong, Yde, De Leo, Francesca, Dobor, Laura, Donvito, Giacinto, Fellows, Donal, Guerra, Antonio Fernandez, Ferreira, Nuno, Fetyukova, Yuliya, Fosso, Bruno, Giddy, Jonathan, Goble, Carole, G"untsch, Anton, Haines, Robert, Ernst, Vera Hern'andez, Hettling, Hannes, Hidy, D'ora, Horv'ath, Ferenc, Ittz'es, D'ora, Ittz'es, P'eter, Jones, Andrew, Kottmann, Renzo, Kulawik, Robert, Leidenberger, Sonja, Lyytik"ainen-Saarenmaa, P"aivi, Mathew, Cherian, Morrison, Norman, Nenadic, Aleksandra, de la Hidalga, Abraham Nieva, Obst, Matthias, Oostermeijer, Gerard, Paymal, Elisabeth, Pesole, Graziano, Pinto, Salvatore, Poign'e, Axel, Fernandez, Francisco Quevedo, Santamaria, Monica, Saarenmaa, Hannu, Sipos, Gergely, Sylla, Karl-Heinz, T"ahtinen, Marko, Vicario, Saverio, Vos, Rutger Aldo, Williams, Alan R., Yilmaz, Pelin | Making forecasts about biodiversity and giving support to policy relies increasingly on large collections of data held electronically, and on substantial computational capability and capacity to analyse, model, simulate and predict using such data. However, the physically distributed nature of data resources and of expertise in advanced analytical tools creates many challenges for the modern scientist. Across the wider biological sciences, presenting such capabilities on the Internet (as ``Web services'') and using scientific workflow systems to compose them for particular tasks is a practical way to carry out robust ``in silico'' science. However, use of this approach in biodiversity science and ecology has thus far been quite limited. | BMC ecology (Online) 16 (2016): 1-49. | 2016 | BALECH BACHIR, FOSSO BRUNO, DE LEO FRANCESCA, VICARIO SAVERIO, PESOLE GRAZIANO, SANTAMARIA MONICA | Biodiversity science, Ecology, Computing software, Informatics, Workflows, Virtual laboratory, Biodiversity virtual e-laboratory, Data processing, Analysis, Automation | 10.1186/s12898-016-0103-y |
| 361400 | Articolo in rivista | Network diffusion-based analysis of high-throughput data for the detection of differentially enriched modules | Bersanelli, Matteo, Mosca, Ettore, Remondini, Daniel, Castellani, Gastone, Milanesi, Luciano | A relation exists between network proximity of molecular entities in interaction networks, functional similarity and association with diseases. The identification of network regions associated with biological functions and pathologies is a major goal in systems biology. We describe a network diffusion-based pipeline for the interpretation of different types of omics in the context of molecular interaction networks. We introduce the network smoothing index, a network-based quantity that allows to jointly quantify the amount of omics information in genes and in their network neighbourhood, using network diffusion to define network proximity. The approach is applicable to both descriptive and inferential statistics calculated on omics data. We also show that network resampling, applied to gene lists ranked by quantities derived from the network smoothing index, indicates the presence of significantly connected genes. As a proof of principle, we identified gene modules enriched in somatic mutations and transcriptional variations observed in samples of prostate adenocarcinoma (PRAD). In line with the local hypothesis, network smoothing index and network resampling underlined the existence of a connected component of genes harbouring molecular alterations in PRAD. | Scientific reports (Nature Publishing Group) 6 (2016). | 2016 | MILANESI LUCIANO, MOSCA ETTORE | network, Bioinformatics, gene, mutations | 10.1038/srep34841 |
| 361401 | Articolo in rivista | Further Insights in the Binding Mode of Selective Inhibitors to Human PDE4D Enzyme Combining Docking and Molecular Dynamics | D'Ursi, Pasqualina, Guariento, Sara, Trombetti, Gabriele, Orro, Alessandro, Cichero, Elena, Milanesi, Luciano, Fossa, Paola, Bruno, Olga | Alzheimers disease has recently emerged as a possible field of application for PDE4D inhibitors (PDE4DIs). The great structure similarity among the various PDE4 isoforms and, furthermore, the lack of the full length crystal structure of the enzyme, impaired the rational design of new selective PDE4DIs. In this paper, with the aim of exploring new insights into the PDE4D binding, we tackled the problem by performing a computational study based on docking simulations combined with molecular dynamics (D-MD). Our work uniquely identified the binding mode and the key residues involved in the interaction with a number of in-house catechol iminoether derivatives, acting as PDE4DIs. Moreover, the new binding mode was tested using a series of analogues previously reported by us and it was used to confirm their key structural features to allow PDE4D inhibition. The binding model disclosed within the current computational study may prove to be useful to further advance the design and synthesis of novel, more potent and selective, PDE4D inhibitors. | Molecular informatics (Print) 35 (2016): 369-381. | 2016 | D'URSI PASQUALINA, ORRO ALESSANDRO, TROMBETTI GABRIELE ANTONIO, MILANESI LUCIANO | Phosphodiesterases, PDE4, PDE4D selective inhibitors, docking, molecular dynamics | 10.1002/minf.201501033 |
| 361402 | Articolo in rivista | Specific patterns of PIWI-interacting small noncoding RNA expression in dysplastic liver nodules and hepatocellular carcinoma | Rizzo, Francesca, Rinaldi, Antonio, Marchese, Giovanna, Coviello, Elena, Sellitto, Assunta, Cordella, Angela, Giurato, Giorgio, Nassa, Giovanni, Ravo, Maria, Tarallo, Roberta, Milanesi, Luciano, Destro, Anna, Torzilli, Guido, Roncalli, Massimo, Di Tommaso, Luca, Weisz, Alessandro | Hepatocellular carcinoma ( HCC) is the result of a stepwise process, often beginning with development within a cirrhotic liver of premalignant lesions, morphologically characterized by low-( LGDN) and high-grade ( HGDN) dysplastic nodules. PIWI-interacting RNAs ( piRNAs) are small noncoding RNAs ( sncRNAs), 23-35 nucleotide-long, exerting epigenetic and post-transcriptional regulation of gene expression. Recently the PIWI-piRNA pathway, best characterized in germline cells, has been identified also in somatic tissues, including stem and cancer cells, where it influences key cellular processes. | Oncotarget 7 (2016): 54650-54661. | 2016 | MILANESI LUCIANO | hepatocarcinogenesis, hepatocellular carcinoma, piRNAs, small non-coding RNA, smallRNA-seq | 10.18632/oncotarget.10567 |
| 361403 | Articolo in rivista | Exome sequencing identifies variants in two genes encoding the LIM-proteins NRAP and FHL1 in an Italian patient with BAG3 myofibrillar myopathy | D'Avila, Francesca, Meregalli, Mirella, Lupoli, Sara, Barcella, Matteo, Orro, Alessandro, De Santis, Francesca, Sitzia, Clementina, Farini, Andrea, D'Ursi, Pasqualina, Erratico, Silvia, Cristofani, Riccardo, Milanesi, Luciano, Braga, Daniele, Cusi, Daniele, Poletti, Angelo, Barlassina, Cristina, Torrente, Yvan | Myofibrillar myopathies (MFMs) are genetically heterogeneous dystrophies characterized by the disintegration of Z-disks and myofibrils and are associated with mutations in genes encoding Z-disk or Z-disk-related proteins. The c.626 C > T (p.P209L) mutation in the BAG3 gene has been described as causative of a subtype of MFM. We report a sporadic case of a 26-year-old Italian woman, affected by MFM with axonal neuropathy, cardiomyopathy, rigid spine, who carries the c.626 C > T mutation in the BAG3 gene. The patient and her non-consanguineous healthy parents and brother were studied with whole exome sequencing (WES) to further investigate the genetic basis of this complex phenotype. In the patient, we found that the BAG3 mutation is associated with variants in the NRAP and FHL1 genes that encode muscle-specific, LIM domain containing proteins. Quantitative real time PCR, immunohistochemistry and Western blot analysis of the patient's muscular biopsy showed the absence of NRAP expression and FHL1 accumulation in aggregates in the affected skeletal muscle tissue. Molecular dynamic analysis of the mutated FHL1 domain showed a modification in its surface charge, which could affect its capability to bind its target proteins. To our knowledge this is the first study reporting, in a BAG3 MFM, the simultaneous presence of genetic variants in the BAG3 and FHL1 genes (previously described as independently associated with MFMs) and linking the NRAP gene to MFM for the first time. | Journal of muscle research and cell motility 37 (2016): 101-115. | 2016 | CUSI DANIELE, ORRO ALESSANDRO, MILANESI LUCIANO | Myofibrillar myopathies, Exome sequencing, LIM proteins, BAG3 | 10.1007/s10974-016-9451-7 |
| 361404 | Articolo in rivista | Large-scale profiling of signalling pathways reveals an asthma specific signature in bronchial smooth muscle cells | Alexandrova, Elena, Nassa, Giovanni, Corleone, Giacomo, Buzdin, Anton, Aliper, Alexander M., Terekhanova, Nadezhda, Shepelin, Denis, Zhavoronkov, Alexander, Tamm, Michael, Milanesi, Luciano, Miglino, Nicola, Weisz, Alessandro, Borger, Pieter | Background: Bronchial smooth muscle (BSM) cells from asthmatic patients maintain in vitro a distinct hyper-reactive ("primed") phenotype, characterized by increased release of pro-inflammatory factors and mediators, as well as hyperplasia and/or hypertrophy. This "primed" phenotype helps to understand pathogenesis of asthma, as changes in BSM function are essential for manifestation of allergic and inflammatory responses and airway wall remodelling. | Oncotarget 7 (2016): 25150-25161. | 2016 | MILANESI LUCIANO | asthma, smooth muscle cells, signalling pathways, CAGE | 10.18632/oncotarget.7209 |
| 361405 | Articolo in rivista | Lentiviral Vectors with a Reduced Splicing Interference Potential Have a Significantly Improved Safety Profile In Vivo | Cesana, Daniela, Gallina, Pierangela, Rudilosso, Laura, Calabria, Andrea, Spinozzi, Giulio, Merelli, Ivan, Milanesi, Luciano, Montini, Eugenio | Lentiviral Vectors | Molecular therapy (Print) 24 (2016): S211-S212. | 2016 | MERELLI IVAN, MILANESI LUCIANO | Lentiviral Vectors, Gene, Teraphy | |
| 361406 | Articolo in rivista | A novel molecular dynamics approach to evaluate the effect of phosphorylation on multimeric protein interface: the alpha B-Crystallin case study | Chiappori, Federica, Mattiazzi, Luca, Milanesi, Luciano, Merelli, Ivan | Background: Phosphorylation is one of the most important post-translational modifications (PTM) employed by cells to regulate several cellular processes. Studying the effects of phosphorylations on protein structures allows to investigate the modulation mechanisms of several proteins including chaperones, like the small HSPs, which display different multimeric structures according to the phosphorylation of a few serine residues. In this context, the proposed study is aimed at finding a method to correlate different PTM patterns (in particular phosphorylations at the monomers interface of multimeric complexes) with the dynamic behaviour of the complex, using physicochemical parameters derived from molecular dynamics simulations in the timescale of nanoseconds. | BMC bioinformatics 17 (2016). | 2016 | CHIAPPORI FEDERICA, MERELLI IVAN, MILANESI LUCIANO | Post-translational modification, Phosphorylation, Molecular dynamics, PCA, Clustering, alpha B-Crystallin, Chaperone, Small HSP | 10.1186/s12859-016-0909-9 |
| 361407 | Articolo in rivista | SPIRE, a modular pipeline for eQTL analysis of RNA-Seq data, reveals a regulatory hotspot controlling miRNA expression in C. elegans | Kel, Ivan, Chang, Zisong, Galluccio, Nadia, Romeo, Margherita, Beretta, Stefano, Diomede, Luisa, Mezzelani, Alessandra, Milanesi, Luciano, Dieterich, Christoph, Merelli, Ivan | The interpretation of genome-wide association study is difficult, as it is hard to understand how polymorphisms can affect gene regulation, in particular for trans-regulatory elements located far from their controlling gene. Using RNA or protein expression data as phenotypes, it is possible to correlate their variations with specific genotypes. This technique is usually referred to as expression Quantitative Trait Loci (eQTLs) analysis and only few packages exist for the integration of genotype patterns and expression profiles. In particular, tools are needed for the analysis of next-generation sequencing (NGS) data on a genome-wide scale, which is essential to identify eQTLs able to control a large number of genes (hotspots). Here we present SPIRE (Software for Polymorphism Identification Regulating Expression), a generic, modular and functionally highly flexible pipeline for eQTL processing. SPIRE integrates different univariate and multivariate approaches for eQTL analysis, paying particular attention to the scalability of the procedure in order to support cis-as well as trans-mapping, thus allowing the identification of hotspots in NGS data. In particular, we demonstrated how SPIRE can handle big association study datasets, reproducing published results and improving the identification of trans-eQTLs. Furthermore, we employed the pipeline to analyse novel data concerning the genotypes of two different C. elegans strains (N2 and Hawaii) and related miRNA expression data, obtained using RNA-Seq. A miRNA regulatory hotspot was identified in chromosome 1, overlapping the transcription factor grh-1, known to be involved in the early phases of embryonic development of C. elegans. In a follow-up qPCR experiment we were able to verify most of the predicted eQTLs, as well as to show, for a novel miRNA, a significant difference in the sequences of the two analysed strains of C. elegans. SPIRE is publicly available as open source software at https://bitbucket.org/bereste/spire, together with some example data, a readme file, supplementary material and a short tutorial. | Molecular bioSystems (Print) 12 (2016): 3447-3458. | 2016 | GALLUCCIO NADIA, MEZZELANI ALESSANDRA MARIA, MERELLI IVAN, MILANESI LUCIANO | eQTLs, RNA-Seq, miRNA, C. elegans | 10.1039/c6mb00453a |
| 361410 | Articolo in rivista | A Machine Learning Approach for the Integration of miRNA-target Predictions | Beretta, Stefano, Castelli, Mauro, Martinez, Yuliana, Munoz, Luis, Silva, Sara, Trujillo, Leonardo, Milanesi, Luciano, Merelli, Ivan | Although several computational methods have been developed for predicting interactions between miRNA and target genes, there are substantial differences in the achieved results. For this reason, machine learning approaches are widely used for integrating the predictions obtained from different tools. | Proceedings - Euromicro Workshop on Parallel and Distributed Processing (2016): 528-534. | 2016 | MERELLI IVAN, MILANESI LUCIANO | miRNA-Target Prediction, Evolutionary Algorithm, Parallel Computing, Genetic Programming | 10.1109/PDP.2016.125 |
| 361411 | Contributo in atti di convegno | MicroRNA-target interaction: a parallel approach for computing pairing energy | E. Ronchieri, D. D'Agostino, L. Milanesi, I. Merelli | MicroRNAs (or miRNA) are key regulators of gene expression, but the precise mechanisms underlying their interaction with their mRNA-targets are still poorly understood. Since miRNA are involved in the onset of many different diseases, the study of their interaction with the genome is very important to study. Different approaches can be used to recognize miRNA-targets. These efforts have focused primarily on the quality of the sequence match between microRNA and target rather than on the role of the mRNA secondary structure in which the target is embedded. Nonetheless, it is known that the miRNA secondary structures contribute to target recognition, because there is an energetic cost to freeing base-pairing interactions within mRNA in order to make the target accessible for microRNA binding. This second approach can provide good results even when little is know about the conservation of the miRNA, but it has the drawback of being computationally very expensive. In this paper we propose a parallelization of PITA, which is one of the most popular algorithm that exploits energetic considerations for computing the miRNA-target predictions. The parallel algorithm is based on a coarse-grained subdivision of the workload, which provides good speedup figures by minimizing communications overheads. | 24th Euromicro International Conference on Parallel and Distributed, and Network-Based Processing 2016, pp. 535-540, Heraklion, Greece, February 17-19, 2016 | 2016 | D'AGOSTINO DANIELE, MERELLI IVAN, MILANESI LUCIANO | MicroRNA target identification, Binding Energy prediction, Parallel Computing, Genome-wide analysis | 10.1109/PDP.2016.117 |
| 361412 | Articolo in rivista | New insights into selective PDE4D inhibitors: 3-(Cyclopentyloxy)-4-methoxybenzaldehyde O-(2-(2,6-dimethylmorpholino)-2-oxoethyl) oxime (GEBR-7b) structural development and promising activities to restore memory impairment | Brullo, Chiara, Ricciarelli, Roberta, Prickaerts, Jos, Arancio, Ottavio, Massa, Matteo, Rotolo, Chiara, Romussi, Alessia, Rebosio, Claudia, Marengo, Barbara, Pronzato, Maria Adelaide, van Hagen, Britt T J, van Goethem, Nick P., D'Ursi, Pasqualina, Orro, Alessandro, Milanesi, Luciano, Guariento, Sara, Cichero, Elena, Fossa, Paola, Fedele, Ernesto, Fedele, Ernesto, Bruno, Olga | Phosphodiesterase type 4D (PDE4D) has been indicated as a promising target for treating neurodegenerative pathologies such as Alzheimer's Disease (AD). By preventing cAMP hydrolysis, PDE4 inhibitors (PDE4Is) increase the cAMP response element-binding protein (CREB) phosphorylation, synaptic plasticity and long-term memory formation. Pharmacological and behavioral studies on our hit GEBR-7b demonstrated that selective PDE4DIs could improve memory without causing emesis and sedation. The hit development led to new molecule series, herein reported, characterized by a catechol structure bonded to five member heterocycles. Molecular modeling studies highlighted the pivotal role of a polar alkyl chain in conferring selective enzyme interaction. Compound 8a showed PDE4D3 selective inhibition and was able to increase intracellular cAMP levels in neuronal cells, as well as in the hippocampus of freely moving rats. Furthermore, 8a was able to readily cross the blood-brain barrier and enhanced memory performance in mice without causing any emetic-like behavior. These data support the view that PDE4D is an adequate molecular target to restore memory deficits in different neuropathologies, including AD, and also indicate compound 8a as a promising candidate for further preclinical development. | European journal of medicinal chemistry 124 (2016): 82-102. | 2016 | D'URSI PASQUALINA, ORRO ALESSANDRO, MILANESI LUCIANO | cAMP enhancers, In silico ADMET properties, Memory behavior test, Molecular dynamics simulation, PDE4D inhibitors, Pharmacokinetic analyses | 10.1016/j.ejmech.2016.08.018 |
| 361413 | Articolo in rivista | BITS 2015: The annual meeting of the Italian Society of Bioinformatics | Milanesi, Luciano, Guffanti, Alessandro, Mauri, Giancarlo, Masseroli, Marco | This preface introduces the content of the BioMed Central journal Supplements related to the BITS 2015 meeting, held in Milan, Italy, from the 3th to the 5th of June, 2015. | BMC bioinformatics 17 (2016). | 2016 | MILANESI LUCIANO | Bioinformatics, BITS, Italian Society of Bioinformatics meeting | 10.1186/s12859-016-1187-2 |
| 361414 | Articolo in rivista | Removing duplicate reads using graphics processing units | Manconi, Andrea, Moscatelli, Marco, Armano, Giuliano, Gnocchi, Matteo, Orro, Alessandro, Milanesi, Luciano | Background: During library construction polymerase chain reaction is used to enrich the DNA before sequencing. Typically, this process generates duplicate read sequences. Removal of these artifacts is mandatory, as they can affect the correct interpretation of data in several analyses. Ideally, duplicate reads should be characterized by identical nucleotide sequences. However, due to sequencing errors, duplicates may also be nearly-identical. Removing nearly-identical duplicates can result in a notable computational effort. To deal with this challenge, we recently proposed a GPU method aimed at removing identical and nearly-identical duplicates generated with an Illumina platform. The method implements an approach based on prefix-suffix comparison. Read sequences with identical prefix are considered potential duplicates. Then, their suffixes are compared to identify and remove those that are actually duplicated. Although the method can be efficiently used to remove duplicates, there are some limitations that need to be overcome. In particular, it cannot to detect potential duplicates in the event that prefixes are longer than 27 bases, and it does not provide support for paired-end read libraries. Moreover, large clusters of potential duplicates are split into smaller with the aim to guarantees a reasonable computing time. This heuristic may affect the accuracy of the analysis. Results: In this work we propose GPU-DupRemoval, a new implementation of our method able to (i) cluster reads without constraints on the maximum length of the prefixes, (ii) support both single- and paired-end read libraries, and (iii) analyze large clusters of potential duplicates. Conclusions: Due to the massive parallelization obtained by exploiting graphics cards, GPU-DupRemoval removes duplicate reads faster than other cutting-edge solutions, while outperforming most of them in terms of amount of duplicates reads. | BMC bioinformatics 17 (2016). | 2016 | MANCONI ANDREA, MOSCATELLI MARCO, ORRO ALESSANDRO, MILANESI LUCIANO, GNOCCHI MATTEO | CUDA, Duplicate reads, Graphics processing units, Next generation sequencing | 10.1186/s12859-016-1192-5 |
| 361415 | Articolo in rivista | Association analysis of noncoding variants in neuroligins 3 and 4X genes with autism spectrum disorder in an Italian cohort | Landini, Martina, Merelli, Ivan, Raggi, M. Elisabetta, Galluccio, Nadia, Ciceri, Francesca, Bonfanti, Arianna, Camposeo, Serena, Massagli, Angelo, Villa, Laura, Salvi, Erika, Cusi, Daniele, Cusi, Daniele, Molteni, Massimo, Milanesi, Luciano, Marabotti, Anna, Marabotti, Anna, Mezzelani, Alessandra | Since involved in synaptic transmission and located on X-chromosome, neuroligins 3 and 4X have been studied as good positional and functional candidate genes for autism spectrum disorder pathogenesis, although contradictory results have been reported. Here, we performed a case-control study to assess the association between noncoding genetic variants in NLGN3 and NLGN4X genes and autism, in an Italian cohort of 202 autistic children analyzed by high-resolution melting. The results were first compared with data from 379 European healthy controls (1000 Genomes Project) and then with those from 1061 Italian controls genotyped by Illumina single nucleotide polymorphism (SNP) array 1M-duo. Statistical evaluations were performed using Plink v1.07, with the Omnibus multiple loci approach. According to both the European and the Italian control groups, a 6-marker haplotype on NLGN4X (rs6638575(G), rs3810688(T), rs3810687(G), rs3810686(C), rs5916269(G), rs1882260(T)) was associated with autism (odd ratio = 3.58, p-value = 2.58 ? 10-6 for the European controls; odds ratio = 2.42, p-value = 6.33 ? 10-3 for the Italian controls). Furthermore, several haplotype blocks at 5-, 4-, 3-, and 2-, including the first 5, 4, 3, and 2 SNPs, respectively, showed a similar association with autism. We provide evidence that noncoding polymorphisms on NLGN4X may be associated to autism, suggesting the key role of NLGN4X in autism pathophysiology and in its male prevalence | International journal of molecular sciences (Print) 17 (2016). | 2016 | LANDINI MARTINA, GALLUCCIO NADIA, CUSI DANIELE, MEZZELANI ALESSANDRA MARIA, MERELLI IVAN, MILANESI LUCIANO | Autism, Genetics, Haplotype analysis, Neuroligins, Noncoding regions, SNPs | 10.3390/ijms17101765 |
| 361416 | Articolo in rivista | HPC analysis of multiple binding sites communication and allosteric modulations in drug design: The HSP case study | Chiappori, Federica, Milanesi, Luciano, Merelli, Ivan | Allostery is a long-range macromolecular mechanism of internal regulation, in which the binding of a ligand in an allosteric site induces distant conformational changes in a distant portion of the protein, modifying its activity. From the drug design point of view, this mechanism can be exploited to achieve important therapeutic effects, since ligands able to bind allosteric sites may be designed to regulate target proteins. Computational tools are a valid support in this sense, since they allow the characterization of allosteric communications within proteins, which are essential to design modulator ligands. While considering long-range interactions in macromolecules, the principal drug design tool available to researcher is molecular dynamics, and related applications, since it allows the evaluation of conformational changes of a protein bound to a ligand. In particular, all-atoms molecular dynamics is suitable to verify the internal mechanisms that orchestrate allosteric communications, in order to identify key residues and internal pathways that modify the protein behaviour. The problem is that these techniques are heavily time-consuming and computationally intensive, thus high performance computing systems, including parallel computing and GPU-accelerated computations, are necessary to achieve results in a reasonable time. In this review, we will discuss how it is possible to exploit in silico approaches to characterize allosteric modulations and long-range interactions within proteins, describing the case study of the Heat Shock Proteins, a class of chaperons regulated by stress conditions, which is particularly important since it is involved in many cancers and neurodegenerative diseases. | Current drug targets (Print) 17 (2016): 1610-1625. | 2016 | CHIAPPORI FEDERICA, MERELLI IVAN, MILANESI LUCIANO | Allostery, Drug design, GPU-acceleration, Heat shock proteins, High performance computing, Molecular dynamics | 10.2174/1389450117666151209123646 |
| 362231 | Articolo in rivista | Next generation sequencing of pooled samples: Guideline for variants' filtering | Anand, Santosh, Anand, Santosh, Anand, Santosh, Mangano, Eleonora, Barizzone, Nadia, Barizzone, Nadia, Bordoni, Roberta, Sorosina, Melissa, Clarelli, Ferdinando, Corrado, Lucia, Corrado, Lucia, Boneschi, Filippo Martinelli, Boneschi, Filippo Martinelli, D'Alfonso, Sandra, D'Alfonso, Sandra, De Bellis, Gianluca | Sequencing large number of individuals, which is often needed for population genetics studies, is still economically challenging despite falling costs of Next Generation Sequencing (NGS). Pool-seq is an alternative cost- and time-effective option in which DNA from several individuals is pooled for sequencing. However, pooling of DNA creates new problems and challenges for accurate variant call and allele frequency (AF) estimation. In particular, sequencing errors confound with the alleles present at low frequency in the pools possibly giving rise to false positive variants. We sequenced 996 individuals in 83 pools (12 individuals/pool) in a targeted re-sequencing experiment. We show that Pool-seq AFs are robust and reliable by comparing them with public variant databases and in-house SNP-genotyping data of individual subjects of pools. Furthermore, we propose a simple filtering guideline for the removal of spurious variants based on the Kolmogorov-Smirnov statistical test. We experimentally validated our filters by comparing Pool-seq to individual sequencing data showing that the filters remove most of the false variants while retaining majority of true variants. The proposed guideline is fairly generic in nature and could be easily applied in other Pool-seq experiments. | Scientific reports (Nature Publishing Group) 6 (2016). | 2016 | MANGANO ELEONORA, ANAND SANTOSH, DE BELLIS GIANLUCA, BORDONI ROBERTA | NGS | 10.1038/srep33735 |
| 365034 | Articolo in rivista | Le regioni del lobbying. Come e perche alcune regioni hanno regolamentato il lobbying prima del sistema politico nazionale | Maria Cristina Antonucci | I sistemi regionali che hanno regolamentato il lobbying (Toscana, Molise, Abruzzo, Calabria e Lombardia) prima del sistema politico nazionale hanno impiegato alternativamente una ricca base associativa e partecipativa o una finestra di opportunita per la disciplina dei rapporti tra politica, economia e societa civile. | Paradoxa (Roma) 4 (2016): 74-88. | 2016 | ANTONUCCI MARIA CRISTINA | lobbying, regioni, sistema politico, gruppi di interesse, gruppi di pressione | |
| 356929 | Articolo in rivista | Systems medicine of inflammaging | Castellani G.C., Menichetti G., Garagnani P., Bacalini M.G., Pirazzini C., Franceschi C., Collino S., Sala C., Remondini D., Giampieri E., Mosca E., Bersanelli M., Vitali S., Do Valle I.F., Lio P., Milanesi L. | Systems Medicine (SM) can be defined as an extension of Systems Biology (SB) to Clinical-Epidemiological disciplines through a shifting paradigm, starting from a cellular, toward a patient centered framework. According to this vision, the three pillars of SM are Biomedical hypotheses, experimental data, mainly achieved by Omics technologies and tailored computational, statistical and modeling tools. The three SM pillars are highly interconnected, and their balancing is crucial. Despite the great technological progresses producing huge amount of data (Big Data) and impressive computational facilities, the Bio-Medical hypotheses are still of primary importance. A paradigmatic example of unifying Bio-Medical theory is the concept of Inflammaging. This complex phenotype is involved in a large number of pathologies and patho-physiological processes such as aging, age-related diseases and cancer, all sharing a common inflammatory pathogenesis. This Biomedical hypothesis can be mapped into an ecological perspective capable to describe by quantitative and predictive models some experimentally observed features, such as microenvironment, niche partitioning and phenotype propagation. In this article we show how this idea can be supported by computational methods useful to successfully integrate, analyze and model large data sets, combining cross-sectional and longitudinal information on clinical, environmental and omics data of healthy subjects and patients to provide new multidimensional biomarkers capable of distinguishing between different pathological conditions, e.g. healthy versus unhealthy state, physiological versus pathological aging. | Briefings in bioinformatics 17 (2016): 527-540. | 2016 | MILANESI LUCIANO, MOSCA ETTORE | Ecological model, Inflammation, Multi-scale, Multilayer networks, Networks, Propagation | 10.1093/bib/bbv062 |
| 367406 | Articolo in rivista | Il testamento biologico | Caporale C., Pievani T., Annoni M., De Tilla M | ** | The Future of Science and Ethics (Online) 1 (2016): 36-43. | 2016 | ANNONI MARCO ANGELO MARIA, CAPORALE CINZIA | * | |
| 367409 | Articolo in rivista | Orientamenti sull'utilizzo della randomizzazione nella sperimentazione clinica | Pievani T., Pezzotti P., Tremoli E., Caporale C. | * | The Future of Science and Ethics (Online) 1 (2016): 10-16. | 2016 | CAPORALE CINZIA | * | |
| 367437 | Articolo in rivista | The Genome Conformation As an Integrator of Multi-Omic Data: The Example of Damage Spreading in Cancer. | Tordini, Fabio, Aldinucci, Marco, Milanesi, Luciano, Lio, Pietro, Merelli, Ivan | Publicly available multi-omic databases, in particular if associated with medical annotations, are rich resources with the potential to lead a rapid transition from high-throughput molecular biology experiments to better clinical outcomes for patients. In this work, we propose a model for multi-omic data integration (i.e., genetic variations, gene expression, genome conformation, and epigenetic patterns), which exploits a multi-layer network approach to analyse, visualize, and obtain insights from such biological information, in order to use achieved results at a macroscopic level. Using this representation, we can describe how driver and passenger mutations accumulate during the development of diseases providing, for example, a tool able to characterize the evolution of cancer. Indeed, our test case concerns the MCF-7 breast cancer cell line, before and after the stimulation with estrogen, since many datasets are available for this case study. In particular, the integration of data about cancer mutations, gene functional annotations, genome conformation, epigenetic patterns, gene expression, and metabolic pathways in our multi-layer representation will allow a better interpretation of the mechanisms behind a complex disease such as cancer. Thanks to this multi-layer approach, we focus on the interplay of chromatin conformation and cancer mutations in different pathways, such as metabolic processes, that are very important for tumor development. Working on this model, a variance analysis can be implemented to identify normal variations within each omics and to characterize, by contrast, variations that can be accounted to pathological samples compared to normal ones. This integrative model can be used to identify novel biomarkers and to provide innovative omic-based guidelines for treating many diseases, improving the efficacy of decision trees currently used in clinic. | Frontiers in genetics 7 (2016): 194. | 2016 | MERELLI IVAN, MILANESI LUCIANO | * | |
| 367439 | Articolo in rivista | Phenotype microarray analysis may unravel genetic determinants of the stress response by Rhodococcus aetherivorans BCP1 and Rhodococcus opacus R7 | Cappelletti, Martina, Fedi, Stefani, Zampolli, Jessica, Di Canito, Alessandra, D'Ursi, Pasqualina, Orro, Alessandro, Viti, Carlo, Milanesi, Luciano, Zannoni, Davide, Di Gennaro, Patrizia | In the present study, the response of Rhodococcus aetherivorans BCP1 and Rhodococcus opacus R7 to various stress conditions and several antimicrobials was examined by PM in relation with genetic determinants, as revealed by annotation analysis of the two genomes. Comparison between metabolic activities and genetic features of BCP1 and R7 provided new insight into the environmental persistence of these two members of the genus Rhodococcus. (C) 2016 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved. | Research in microbiology (Paris) 167 (2016): 766-773. | 2016 | D'URSI PASQUALINA, ORRO ALESSANDRO, MILANESI LUCIANO | Rhodococcus, Rhodococcus aetherivorans BCP1, Rhodococcus opacus R7, Phenotype microarray, Toxic compounds, Stress response | 10.1016/j.resmic.2016.06.008 |
| 346351 | Articolo in rivista | Stochastic neutral modelling of the Gut Microbiota's relative species abundance from next generation sequencing data | Sala C., Vitali S., Giampieri E., do Valle I.F., Remondini D., Garagnani P., Bersanelli M., Mosca E., Milanesi L., Castellani G. | Background: Interest in understanding the mechanisms that lead to a particular composition of the Gut Microbiota is highly increasing, due to the relationship between this ecosystem and the host health state. Particularly relevant is the study of the Relative Species Abundance (RSA) distribution, that is a component of biodiversity and measures the number of species having a given number of individuals. It is the universal behaviour of RSA that induced many ecologists to look for theoretical explanations. In particular, a simple stochastic neutral model was proposed by Volkov et al. relying on population dynamics and was proved to fit the coral-reefs and rain forests RSA. Our aim is to ascertain if this model also describes the Microbiota RSA and if it can help in explaining the Microbiota plasticity. Results: We analyzed 16S rRNA sequencing data sampled from the Microbiota of three different animal species by Jeraldo et al. Through a clustering procedure (UCLUST), we built the Operational Taxonomic Units. These correspond to bacterial species considered at a given phylogenetic level defined by the similarity threshold used in the clustering procedure. The RSAs, plotted in the form of Preston plot, were fitted with Volkov's model. The model fits well the Microbiota RSA, except in the tail region, that shows a deviation from the neutrality assumption. Looking at the model parameters we were able to discriminate between different animal species, giving also a biological explanation. Moreover, the biodiversity estimator obtained by Volkov's model also differentiates the animal species and is in good agreement with the first and second order Hill's numbers, that are common evenness indexes simply based on the fraction of individuals per species. Conclusions: We conclude that the neutrality assumption is a good approximation for the Microbiota dynamics and the observation that Volkov's model works for this ecosystem is a further proof of the RSA universality. Moreover, the ability to separate different animals with the model parameters and biodiversity number are promising results if we think about future applications on human data, in which the Microbiota composition and biodiversity are in close relationships with a variety of diseases and life-styles. | BMC bioinformatics (2016). | 2016 | MILANESI LUCIANO, MOSCA ETTORE | 16S RNA, Biodiversity, Ecological modelling, Microbiota, OTU, RSA | 10.1186/s12859-015-0858-8 |
| 346349 | Articolo in rivista | Methods for the integration of multi-omics data: Mathematical aspects | Bersanelli M., Mosca E., Remondini D., Giampieri E., Sala C., Castellani G., Milanesi L. | Background: Methods for the integrative analysis of multi-omics data are required to draw a more complete and accurate picture of the dynamics of molecular systems. The complexity of biological systems, the technological limits, the large number of biological variables and the relatively low number of biological samples make the analysis of multi-omics datasets a non-trivial problem. Results and Conclusions: We review the most advanced strategies for integrating multi-omics datasets, focusing on mathematical and methodological aspects. | BMC bioinformatics (2016). | 2016 | MILANESI LUCIANO, MOSCA ETTORE | Data integration, Multi-omics, Omics | 10.1186/s12859-015-0857-9 |
| 367445 | Articolo in rivista | The Proteomic Landscape of Human Ex Vivo Regulatory and Conventional T Cells Reveals Specific Metabolic Requirements [Immunity 44, 406-421, (2016)] | Procaccini C., Carbone F., Di Silvestre D., Brambilla F., De Rosa V., Galgani M., Faicchia D., Marone G., Tramontano D., Corona M., Alviggi C., Porcellini A., La Cava A., Mauri P., Matarese G. | Human CD4(+)CD25(hi)Foxp3(+)CD127(-) Treg and CD4(+)CD25(-)Foxp3(-) Tconv cell functions are governed by their metabolic requirements. Here we report a comprehensive comparative analysis between ex vivo human Treg and Tconv cells that comprises analyses of the proteomic networks in subcellular compartments. We identified a dominant proteomic signature at the metabolic level that primarily impacted the highly-tuned balance between glucose and fatty-acid oxidation in the two cell types. Ex vivo Treg cells were highly glycolytic while Tconv cells used predominantly fatty-acid oxidation (FAO). When cultured in vitro, Treg cells engaged both glycolysis and FAO to proliferate, while Tconv cell proliferation mainly relied on glucose metabolism. Our unbiased proteomic analysis provides a molecular picture of the impact of metabolism on ex vivo human Treg versus Tconv cell functions that might be relevant for therapeutic manipulations of these cells. | Immunity (Cambridge Mass., Online) 44 (2016): 712. | 2016 | BRAMBILLA FRANCESCA, DI SILVESTRE DARIO, MAURI PIETRO LUIGI | * | 10.1016/j.immuni.2016.02.022 |
| 367447 | Articolo in rivista | Interplay of the modified nucleotide phosphoadenosine 5 '-phosphosulfate (PAPS) with global regulatory proteins in Escherichia coli: modulation of cyclic AMP (cAMP)-dependent gene expression and interaction with the HupA regulatory protein | Longo, Francesca, Motta, Sara, Mauri, Pierluigi, Landini, Paolo, Rossi, Elio | In the bacterium Escherichia coli, some intermediates of the sulfate assimilation and cysteine biosynthesis pathway can act as signal molecules and modulate gene expression. In addition to sensing and utilization of sulphur sources, these signaling mechanisms also impact more global cell processes, such as resistance to antimicrobial agents and biofilm formation. In a recent work, we have shown that inactivation of the cysH gene, encoding phosphoadenosine-phosphosulfate (PAPS) reductase, and the consequent increase in intracellular PAPS concentration, strongly affect production of several cell surface-associated structures, enhancing surface adhesion and cell aggregation. In order to identify the molecular mechanism relaying intracellular PAPS concentration to regulation of cell surface-associated structures, we looked for mutations able to suppress the effects of cysH inactivation. We found that mutations in the adenylate cyclase-encoding cyaA gene abolished the effects of PAPS accumulation; consistent with this result, cyclic AMP (cAMP)-dependent gene expression appears to be increased in the cysH mutant. Experiments aimed at the direct identification of proteins interacting with either CysC or CysH, i.e. the PAPS-related proteins APS kinase and PAPS reductase, allowed us to identify several regulators, namely, CspC, CspE, HNS and HupA. Protein-protein interaction between HupA and CysH was confirmed by a bacterial two hybrid system, and inactivation of the hupA gene enhanced the effects of the cysH mutation in terms of production of cell surface-associated factors. Our results indicate that PAPS can modulate different regulatory systems, providing evidence that this molecule acts as a global signal molecule in E. coli. (C) 2016 Elsevier Ireland Ltd. All rights reserved. | Chemico-biological interactions (Print) 259 (2016): 39-47. | 2016 | MOTTA SARA, MAURI PIETRO LUIGI | Phosphoadenosine 5 '-phosphosulphate (PAPS), Cyclic adenosine monophosphate (cAMP), Adenylate cyclase CyaA, Histone-like HU protein, Gene expression regulation, Signal molecule | 10.1016/j.cbi.2016.04.016 |
| 367448 | Articolo in rivista | Proteomics as an innovative tool to investigate frontotemporal disorders | Agresta, Anna Maria, De Palma, Antonella, Bardoni, Anna, Salvini, Roberta, Iadarola, Paolo, Mauri, Pier Luigi | Neurodegenerative diseases are characterized by slow progressive loss of one or more functions of the CNS. Worldwide, the number of people affected by neurodegeneration is dramatically high and the social impact is upsetting. While being a heterogeneous group of diseases, most of these pathologies manifest similar clinical features and illness progression, thus making their diagnosis elusive. With its ability to meet the needs of neurodegenerative research, proteomics could help facilitate the diagnosis of these disorders. This strategy, recently emerged as complementary to genomics, has led in the last years to substantial achievements in deciphering molecular mechanisms and the follow-up of neurodegenerative diseases. Specifically, aim of this review is to cover the main proteomic investigations realized in the field of familial frontotemporal dementias. This disorder is less common than Alzheimer's disease and disproportionately affects younger individuals, thus representing a major psychological and economic burden for both patients and families. Although early and accurate differential diagnosis of frontotemporal dementias is crucial because of its implications for heritability, prognosis, therapeutics, and environmental management of patients, the investigative methods currently available to clinicians are incomplete. Certainly, the development of a focused therapy cannot be separated from the investigation of biochemical pathways involved in the pathogenesis. | Proteomics. Clinical applications (Print) 10 (2016): 457-469. | 2016 | AGRESTA ANNA MARIA, DE PALMA ANTONELLA, MAURI PIETRO LUIGI | Biomarkers, Familial neurodegeneration, Frontotemporal dementia, Proteomics | 10.1002/prca.201500090 |
| 367451 | Articolo in rivista | Azithromycin Attenuates Pesudomonas-Induced Lung Inflammation by Targeting Bacterial Proteins Secreted in the Cultured Medium | Leal, Teresinha, Bergamini, Gabriella, Huaux, Francois, Panin, Nadtha, Noel, Sabrina, Dhooghe, Barbara, Haaf, Jeremy B., Mauri, Pierluigi, Motta, Sara, Di Silvestre, Dario, Melotti, Paola, Sorio, Claudio | * | Frontiers in immunology 7 (2016). | 2016 | MOTTA SARA, DI SILVESTRE DARIO, MAURI PIETRO LUIGI | azithromycin, cystic fibrosis, cytokines, inflammation, proteomics, Pseudomonas aeruginosa | 10.3389/fimmu.2016.00499 |
| 367454 | Articolo in rivista | FGF2 and EGF Are Required for Self-Renewal and Organoid Formation of Canine Normal and Tumor Breast Stem Cells | Cocola, Cinzia, Molgora, Stefano, Piscitelli, Eleonora, Veronesi, Maria Cristina, Greco, Marianna, Bragato, Cinzia, Moro, Monica, Crosti, Mariacristina, Gray, Brian, Milanesi, Luciano, Grieco, Valeria, Luvoni, Gaia Cecilia, Kehler, James, Bellipanni, Gianfranco, Reinbold, Rolland, Zucchi, Ileana, Giordano, Antonio | Recent studies suggest that human tumors are generated from cancer cells with stem cell (SC) properties. Spontaneously occurring cancers in dogs contain a diversity of cells that like for human tumors suggest that certain canine tumors are also generated from cancer stem cells (CSCs). CSCs, like normal SCs, have the capacity for self-renewal as mammospheres in suspension cultures. To understand how cells with SC properties contribute to canine mammary gland tumor development and progression, comparative analysis between normal SCs and CSCs, obtained from the same individual, is essential. We have utilized the property of sphere formation to develop culture conditions for propagating stem/progenitor cells from canine normal and tumor tissue. We show that cells from dissociated mammospheres retain sphere reformation capacity for several serial passages and have the capacity to generate organoid structures ex situ. Utilizing various culture conditions for passaging SCs and CSCs, fibroblast growth factor 2 (FGF2) and epidermal growth factor (EGF) were found to positively or negatively regulate mammosphere regeneration, organoid formation, and multi-lineage differentiation potential. The response of FGF2 and EGF on SCs and CSCs was different, with increased FGF2 and EGF self-renewal promoted in SCs and repressed in CSCs. Our protocol for propagating SCs from normal and tumor canine breast tissue will provide new opportunities in comparative mammary gland stem cell analysis between species and anticancer treatment and therapies for dogs. J. Cell. Biochem. 118: 570-584, 2017. (c) 2016 Wiley Periodicals, Inc. | Journal of cellular biochemistry (Print) 118 (2017): 570-584. | 2017 | PISCITELLI ELEONORA, COCOLA CINZIA, REINBOLD ROLLAND ALVONS, GRECO MARIANNA, MOLGORA STEFANO ANGELO ADAMO, MILANESI LUCIANO, ZUCCHI ILEANA | CANINES, CANCER, STEM, ORGANOIDS, MAMMOSPHERE, ACINI, FGF2, MAMMARY, BREAST | 10.1002/jcb.25737 |
| 367456 | Articolo in rivista | RNA-Generated and Gene-Edited Induced Pluripotent Stem Cells for Disease Modeling and Therapy. | Kehler, James, Greco, Marianna, Martino, Valentina, Pachiappan, Manickam, Yokoe, Hiroko, Chen, Alice, Yang, Miranda, Auerbach, Jonathan, Jessee, Joel, Gotte, Martin, Milanesi, Luciano, Albertini, Alberto, Bellipanni, Gianfranco, Zucchi, Ileana, Reinbold, Rolland A, Giordano, Antonio | Cellular reprogramming by epigenomic remodeling of chromatin holds great promise in the field of human regenerative medicine. As an example, human-induced Pluripotent Stem Cells (iPSCs) obtained by reprograming of patient somatic cells are sufficiently similar to embryonic stem cells (ESCs) and can generate all cell types of the human body. Clinical use of iPSCs is dependent on methods that do not utilize genome altering transgenic technologies that are potentially unsafe and ethically unacceptable. Transient delivery of exogenous RNA into cells provides a safer reprogramming system to transgenic approaches that rely on exogenous DNA or viral vectors. RNA reprogramming may prove to be more suitable for clinical applications and provide stable starting cell lines for gene-editing, isolation, and characterization of patient iPSC lines. The introduction and rapid evolution of CRISPR/Cas9 gene-editing systems has provided a readily accessible research tool to perform functional human genetic experiments. Similar to RNA reprogramming, transient delivery of mRNA encoding Cas9 in combination with guide RNA sequences to target specific points in the genome eliminates the risk of potential integration of Cas9 plasmid constructs. We present optimized RNA-based laboratory procedure for making and editing iPSCs. In the near-term these two powerful technologies are being harnessed to dissect mechanisms of human development and disease in vitro, supporting both basic, and translational research. J. Cell. Physiol. 9999: 1-8, 2016. 2016 Wiley Periodicals, Inc. | Journal of cellular physiology (Print) (2016). | 2016 | REINBOLD ROLLAND ALVONS, GRECO MARIANNA, MARTINO VALENTINA, ALBERTINI ALBERTO, MILANESI LUCIANO, ZUCCHI ILEANA | * | 10.1002/jcp.25597 |
| 367462 | Articolo in rivista | Contrast mechanisms associated with neuromelanin-MRI | Trujillo P., Summers P.E., Ferrari E., Zucca F.A., Sturini M., Mainardi L.T., Cerutti S., Smith A.K., Smith S.A., Zecca L., Costa A. | Purpose: To investigate the physical mechanisms associated with the contrast observed in neuromelanin MRI. Methods: Phantoms having different concentrations of synthetic melanins with different degrees of iron loading were examined on a 3 Tesla scanner using relaxometry and quantitative magnetization transfer (MT). Results: Concentration-dependent T1 and T2 shortening was most pronounced for the melanin pigment when combined with iron. Metal-free melanin had a negligible effect on the magnetization transfer spectra. On the contrary, the presence of iron-laden melanins resulted in a decreased magnetization transfer ratio. The presence of melanin or iron (or both) did not have a significant effect on the macromolecular content, represented by the pool size ratio. Conclusion: The primary mechanism underlying contrast in neuromelanin-MRI appears to be the T1 reduction associated with melanin-iron complexes. The macromolecular content is not significantly influenced by the presence of melanin with or without iron, and thus the MT is not directly affected. However, as T1 plays a role in determining the MT-weighted signal, the magnetization transfer ratio is reduced in the presence of melanin-iron complexes. | Magnetic resonance in medicine (Print) 78 (2017): 1790-1800. | 2017 | FERRARI EMANUELE, ZECCA LUIGI, ZUCCA FABIO ANDREA | neuromelanin, MRI, magnetization transfer, relaxation | 10.1002/mrm.26584 |
| 367481 | Articolo in rivista | Elemental mapping of Neuromelanin organelles of human Substantia Nigra: correlative ultrastructural and chemical analysis by analytical transmission electron microscopy and nano-secondary ion mass spectrometry | Biesemeier A., Eibl O., Eswara S., Audinot J.N., Wirtz T., Pezzoli G., Zucca F.A., Zecca L., Schraermeyer U. | Neuromelanin (NM) is a compound which highly accumulates mainly in catecholamine neurons of the substantia nigra (SN), and is contained in organelles (NM-containing organelles) with lipid bodies and proteins. These neurons selectively degenerate in Parkinson's disease and NM can play either a protective or toxic role. NM-containing organelles of SN were investigated by Analytical Electron Microscopy (AEM) and Nano-Secondary Ion Mass Spectrometry (NanoSIMS) within human tissue sections with respect to ultrastructure and elemental composition. Within the NM-containing organelle, the single NM granules and lipid bodies had sizes of about 200-600 nm. Energy-Dispersive X-ray microanalysis spectra of the NM granules and lipid bodies were acquired with 100 nm beam diameter in AEM, NanoSIMS yielded elemental maps with a lateral resolution of about 150 nm. AEM yielded the quantitative elemental composition of NM granules and bound metals, e.g., iron with a mole fraction of about 0.15 atomic percent. Chemical analyses by AEM and NanoSIMS were consistent at the subcellular level so that nanoSIMS measurements have been quantitated. In NM granules of SN from healthy subjects, a significant amount of S, Fe, and Cu was found. In lipid bodies an amount of P consistent with the presence of phospholipids was measured. The improved detection limits of nanoSIMS offer new possibilities for chemical mapping, high-sensitivity trace element detection, and reduced acquisition times. Variations between individual NM granules can now be investigated effectively and quantitatively by NanoSIMS mapping Cu and Fe. This should yield new insight into the changes in chemical composition of NM pigments during healthy aging and disease. | Journal of neurochemistry 138 (2016): 339-353. | 2016 | ZECCA LUIGI, ZUCCA FABIO ANDREA | analytical electron microscopy, correlative microscopy, nano-secondary ion mass spectrometry, substantia nigra neuromelanin, trace metals | 10.1111/jnc.13648 |
| 367497 | Articolo in rivista | Synthesis, Structure Characterization, and Evaluation in Microglia Cultures of Neuromelanin Analogues Suitable for Modeling Parkinson's Disease | Ferrari E., Capucciati A., Prada I., Zucca F.A., D'Arrigo G., Pontiroli D., Bridelli M.G., Sturini M., Bubacco L., Monzani E., Verderio C., Zecca L., Casella L. | In the substantia nigra of human brain, neuromelanin (NM) released by degenerating neurons can activate microglia with consequent neurodegeneration, typical of Parkinson's disease (PD). Synthetic analogues of NM were prepared to develop a PD model reproducing the neuropathological conditions of the disease. Soluble melanin-protein conjugates were obtained by melanization of fibrillated ?-lactoglobulin (fLG). The melanic portion of the conjugates contains either eumelanic (EufLG) or mixed eumelanic/pheomelanic composition (PheofLG), the latter better simulating natural NMs. In addition, the conjugates can be loaded with controlled amounts of iron. Upon melanization, PheofLG-Fe conjugates maintain the amyloid cross-? protein core as the only structurally organized element, similarly to human NMs. The similarity in composition and structural organization with the natural pigment is reflected by the ability of synthetic NMs to activate microglia, showing potential of the novel conjugates to model NM induced neuroinflammation. Thus, synthetic NM/microglia constitute a new model to develop anti-Parkinson drugs. | ACS chemical neuroscience 8 (2017): 501-512. | 2017 | FERRARI EMANUELE, PRADA ILARIA, ZECCA LUIGI, D'ARRIGO GIULIA, VERDERIO CLAUDIA, ZUCCA FABIO ANDREA | neuromelanin, iron, amyloid fibrils, synthetic melanin, microglia, Parkinson's disease | 10.1021/acschemneuro.6b00231 |
| 368135 | Contributo in atti di convegno | Low-power architectures for miRNA-target genome wide analysis | S. Beretta, L. Morganti, E. Corni, A. Ferraro, D. Cesini, D. D'Agostino, L. Milanesi, I. Merelli | In molecular biology, the interaction mechanisms between microRNAs (miRNAs) with their messenger RNA targets are poorly understood. This is the reason why many miRNAtarget prediction methods are available, but their results are often inconsistent. A lot of efforts focus on the quality of the sequence match between miRNA and target rather than on the role of the mRNA secondary structure in which the target is embedded. Nonetheless, it is known that the miRNA secondary structures contribute to target recognition, because there is an energetic cost to freeing base-pairing interactions within mRNA to make the target accessible for miRNA binding. This approach is implemented by PITA (Probability of Interaction by Target Accessibility), a very computational-intensive tool that is able to provide accurate results even when little is know about the conservation of the miRNA. In this paper we propose a new implementation of PITA, called lPITA, able to exploit a coarsegrained parallelism over low power architectures to reduce both execution times and the power consumption. | 25th Euromicro International Conference on Parallel, Distributed and Network-Based Processing, pp. 309-312, Saint Petersburg, 06-08/03, 2017 | 2017 | D'AGOSTINO DANIELE, MERELLI IVAN, MILANESI LUCIANO | low-power architecture, miRNA;, secondary structure;, genome wide | 10.1109/PDP.2017.88 |
| 369252 | Contributo in volume | Rappresentanza del Terzo Settore in Toscana | AAVV | analisi degli strumenti istituzionali e dei formati partecipativi del Terzo Settore alle politiche pubbliche della Regione Toscana | Il Terzo Settore in Toscana. Primo rapporto - anno 2017, edited by Paola Gavrin, Stefano Lomi, pp. 77-83, 2017 | 2017 | ANTONUCCI MARIA CRISTINA | terzo settore, governance, politiche regionali | |
| 369829 | Articolo in rivista | Cabozantinib Eradicates Advanced Murine Prostate Cancer by Activating Anti-Tumor Innate Immunity. | Patnaik, Akash, Swanson, Kenneth D, Csizmadia, Eva, Solanki, Aniruddh, Landon-Brace, Natalie, Gehring, Marina P, Helenius, Katja, Olson, Brian M, Pyzer, Athalia R, Wang, Lily C, Elemento, Olivier, Novak, Jesse, Thornley, Thomas B, Asara, John M, Montaser, Laleh, Timmons, Joshua J, Morgan, Todd M, Wang, Yugang, Levantini, Elena, Clohessy, John G, Kelly, Kathleen, Pandolfi, Pier Paolo, Rosenblatt, Jacalyn M, Avigan, David E, Ye, Huihui, Karp, Jeffrey M, Signoretti, Sabina, Balk, Steven P, Cantley, Lewis C | Several kinase inhibitors that target aberrant signaling pathways in tumor cells have been deployed in cancer therapy. However, their impact on the tumor immune microenvironment remains poorly understood. The tyrosine kinase inhibitor cabozantinib showed striking responses in cancer clinical trial patients across several malignancies. Here we show that cabozantinib rapidly eradicates invasive, poorly-differentiated PTEN/p53 deficient murine prostate cancer. This was associated with enhanced release of neutrophil chemotactic factors from tumor cells, including CXCL12 and HMGB1, resulting in robust infiltration of neutrophils into the tumor. Critically, cabozantinib-induced tumor clearance in mice was abolished by antibody-mediated granulocyte depletion or HMGB1 neutralization or blockade of neutrophil chemotaxis with the CXCR4 inhibitor, plerixafor. Collectively, these data demonstrate that cabozantinib triggers a neutrophil-mediated anti-cancer innate immune response, resulting in tumor clearance. | Cancer discovery (Online) (2017). | 2017 | LEVANTINI ELENA | Tumore prostata immunita' innata, immunotherapy, tumor infiltrating cells, neutrophil-mediated anti-cancer innate immune response, Preclinical murine models | 10.1158/2159-8290.CD-16-0778 |
| 369946 | Articolo in rivista | Temporal dynamics of the gut microbiota in people sharing a confined environment, a 520-day ground-based space simulation, MARS500 | Turroni, Silvia, Rampelli, Simone, Biagi, Elena, Consolandi, Clarissa, Severgnini, Marco, Peano, Clelia, Quercia, Sara, Soverini, Matteo, Carbonero, Franck G., Bianconi, Giovanna, Rettberg, Petra, Canganella, Francesco, Brigidi, Patrizia, Candela, Marco | Background The intestinal microbial communities and their temporal dynamics are gaining increasing interest due to the significant implications for human health. Recent studies have shown the dynamic behavior of the gut microbiota in free-living, healthy persons. To date, it is not known whether these dynamics are applicable during prolonged life sharing in a confined and controlled environment. Results The MARS500 project, the longest ground-based space simulation ever, provided us with a unique opportunity to trace the crew microbiota over 520 days of isolated confinement, such as that faced by astronauts in real long-term interplanetary space flights, and after returning to regular life, for a total of 2 years. According to our data, even under the strictly controlled conditions of an enclosed environment, the human gut microbiota is inherently dynamic, capable of shifting between different steady states, typically with rearrangements of autochthonous members. Notwithstanding a strong individuality in the overall gut microbiota trajectory, some key microbial components showed conserved temporal dynamics, with potential implications for the maintenance of a health-promoting, mutualistic microbiota configuration. Conclusions Sharing life in a confined habitat does not affect the resilience of the individual gut microbial ecosystem, even in the long term. However, the temporal dynamics of certain microbiota components should be monitored when programming future mission simulations and real space flights, to prevent breakdowns in the metabolic and immunological homeostasis of the crewmembers. | Mucosal immunology 5 (2017). | 2017 | CONSOLANDI CLARISSA, PEANO CLELIA, SEVERGNINI MARCO | MARS500, Gut microbiota, Temporal dynamics, Life sharing, Confined environment, Space flight, Resilience | 10.1186/s40168-017-0256-8 |
| 369947 | Articolo in rivista | TRIM8 restores p53 tumour suppressor function by blunting N-MYC activity in chemo-resistant tumours | Mastropasqua, Francesca, Marzano, Flaviana, Valletti, Alessio, Aiello, Italia, Di Tullio, Giuseppe, Morgano, Annalisa, Liuni, Sabino, Ranieri, Elena, Guerrini, Luisa, Gasparre, Giuseppe, Sbisa, Elisabetta, Pesole, Graziano, Moschetta, Antonio, Caratozzolo, Mariano Francesco, Tullo, Apollonia | Background TRIM8 plays a key role in controlling the p53 molecular switch that sustains the transcriptional activation of cell cycle arrest genes and response to chemotherapeutic drugs. The mechanisms that regulate TRIM8, especially in cancers like clear cell Renal Cell Carcinoma (ccRCC) and colorectal cancer (CRC) where it is low expressed, are still unknown. However, recent studies suggest the potential involvement of some microRNAs belonging to miR-17-92 and its paralogous clusters, which could include TRIM8 in a more complex pathway. Methods We used RCC and CRC cell models for in-vitro experiments, and ccRCC patients and xenograft transplanted mice for in vivo assessments. To measure microRNAs levels we performed RT-qPCR, while steady-states of TRIM8, p53, p21 and N-MYC were quantified at protein level by Western Blotting as well as at transcript level by RT-qPCR. Luciferase reporter assays were performed to assess the interaction between TRIM8 and specific miRNAs, and the potential effects of this interaction on TRIM8 expression. Moreover, we treated our cell models with conventional chemotherapeutic drugs or tyrosine kinase inhibitors, and measured their response in terms of cell proliferation by MTT and colony suppression assays. Results We showed that TRIM8 is a target of miR-17-5p and miR-106b-5p, whose expression is promoted by N-MYC, and that alterations of their levels affect cell proliferation, acting on the TRIM8 transcripts stability, as confirmed in ccRCC patients and cell lines. In addition, reducing the levels of miR-17-5p/miR-106b-5p, we increased the chemo-sensitivity of RCC/CRC-derived cells to anti-tumour drugs used in the clinic. Intriguingly, this occurs, on one hand, by recovering the p53 tumour suppressor activity in a TRIM8-dependent fashion and, on the other hand, by promoting the transcription of miR-34a that turns off the oncogenic action of N-MYC. This ultimately leads to cell proliferation reduction or block, observed also in colon cancer xenografts overexpressing TRIM8. Conclusions In this paper we provided evidence that TRIM8 and its regulators miR-17-5p and miR-106b-5 participate to a feedback loop controlling cell proliferation through the reciprocal modulation of p53, miR-34a and N-MYC. Our experiments pointed out that this axis is pivotal in defining drug responsiveness of cancers such ccRCC and CRC. | Molecular cancer 16 (2017). | 2017 | CARATOZZOLO MARIANO FRANCESCO, MARZANO FLAVIANA, VALLETTI ALESSIO, MASTROPASQUA FRANCESCA, TULLO APOLLONIA, PESOLE GRAZIANO, LIUNI SABINO, SBISA' ELISABETTA | TRIM8, Drug resistance, N-MYC, p53, miR-17 family | 10.1186/s12943-017-0634-7 |
| 371221 | Articolo in rivista | LAV-BPIFB4 isoform modulates eNOS signaling through Ca2+/PKC-alpha dependent mechanism. | Spinelli, Chiara Carmela, Carrizzo, Albino, Ferrario, Anna, Villa, Francesco, Damato, Antonio, Ambrosio, Mariateresa, Madonna, Michele, Frati, Giacomo, Fucile, Sergio, Sciaccalunga, Miriam, Capunzo, Mario, Cali, Gaetano, Milanesi, Luciano, Maciag, Anna, Puca, Annibale Alessandro, Vecchione, Carmine | Aims: Ageing is associated with impairment of endothelial nitric oxide synthase (eNOS) and progressive reduction in endothelial function. A genetic study on long-living individuals-who are characterized by delays in ageing and in the onset of cardiovascular disease-previously revealed I229V (rs2070325) in bactericidal/permeability-increasing fold-containing-family-B-member-4 (BPIFB4) as a longevity-associated variant (LAV); the LAV protein enhanced endothelial NO production and vasorelaxation through a protein kinase R-like endoplasmic reticulum kinase/14-3-3/heat shock protein 90 signal. Here, we further characterize the molecular mechanisms underlying LAV-BPIFB4-dependent enhancement of vascular function. Methods and results: LAV-BPIFB4 upregulated eNOS function via mobilization of Ca2+ and activation of protein kinase C alpha (PKC?). Indeed, the overexpression of LAV-BPIFB4 in human endothelial cells enhanced ATP-induced Ca2+ mobilization and the translocation of PKC? to the plasma membrane. Coherently, pharmacological inhibition of PKC? blunted the positive effect of LAV-BPIFB4 on eNOS and endothelial function. In addition, although LAV-BPIFB4 lost the ability to activate PKC? and eNOS in ex vivo vessels studied in an external Ca2+-free medium and in vessels from eNOS-/- mice, it still potentiated endothelial activity, recruiting an alternative mechanism dependent upon endothelium-derived hyperpolarizing factor (EDHF). Conclusions: We have identified novel molecular determinants of the beneficial effects of LAV-BPIFB4 on endothelial function, showing the roles of Ca2+ mobilization and PKC? in eNOS activation and of EDHF when eNOS is inhibited. These results highlight the role LAV-BPIFB4 can have in restoring signals that are lost during ageing. | Cardiovascular research (2017). | 2017 | PUCA ANNIBALE ALESSANDRO, FERRARIO ANNA, SPINELLI CHIARA CARMELA, CALI' GAETANO, VILLA MARCO FRANCESCO, MILANESI LUCIANO | BPIFB4; Endothelium; Nitric oxide; PKC?; Vascular function | 10.1093/cvr/cvx072 |
| 373531 | Articolo in rivista | From protein-protein interactions to protein co-expression networks: a new perspective to evaluate large-scale proteomic data | Vella, Danila, Zoppis, Italo, Mauri, Giancarlo, Mauri, Pierluigi, Di Silvestre, Dario | The reductionist approach of dissecting biological systems into their constituents has been successful in the first stage of the molecular biology to elucidate the chemical basis of several biological processes. This knowledge helped biologists to understand the complexity of the biological systems evidencing that most biological functions do not arise from individual molecules; thus, realizing that the emergent properties of the biological systems cannot be explained or be predicted by investigating individual molecules without taking into consideration their relations. Thanks to the improvement of the current -omics technologies and the increasing understanding of the molecular relationships, even more studies are evaluating the biological systems through approaches based on graph theory. Genomic and proteomic data are often combined with protein-protein interaction (PPI) networks whose structure is routinely analyzed by algorithms and tools to characterize hubs/bottlenecks and topological, functional, and disease modules. On the other hand, co-expression networks represent a complementary procedure that give the opportunity to evaluate at system level including organisms that lack information on PPIs. Based on these premises, we introduce the reader to the PPI and to the co-expression networks, including aspects of reconstruction and analysis. In particular, the new idea to evaluate large-scale proteomic data by means of co-expression networks will be discussed presenting some examples of application. Their use to infer biological knowledge will be shown, and a special attention will be devoted to the topological and module analysis. | EURASIP Journal on Bioinformatics and Systems Biology (Print) (2017). | 2017 | DI SILVESTRE DARIO, MAURI PIETRO LUIGI | Co-expression network, -Omics data, PPI network, Systems biology, Topological analysis, WGCNA, Pearson's correlation | 10.1186/s13637-017-0059-z |
| 373536 | Articolo in rivista | Time-Resolved Transcriptomics and Constraint-Based Modeling Identify System-Level Metabolic Features and Overexpression Targets to Increase Spiramycin Production in Streptomyces ambofaciens | Fondi, Marco, Pinatel, Eva, Tala, Adelfia, Damiano, Fabrizio, Consolandi, Clarissa, Mattorre, Benedetta, Fico, Daniela, Testini, Mariangela, De Benedetto, Giuseppe E., Siculella, Luisa, De Bellis, Gianluca, Alifano, Pietro, Peano, Clelia | In this study we have applied an integrated system biology approach to characterize the metabolic landscape of Streptomyces ambofaciens and to identify a list of potential metabolic engineering targets for the overproduction of the secondary metabolites in this microorganism. We focused on an often overlooked growth period (i.e., post-first rapid growth phase) and, by integrating constraint-based metabolic modeling with time resolved RNA-seq data, we depicted the main effects of changes in gene expression on the overall metabolic reprogramming occurring in S. ambofaciens. Moreover, through metabolic modeling, we unraveled a set of candidate overexpression gene targets hypothetically leading to spiramycin overproduction. Model predictions were experimentally validated by genetic manipulation of the recently described ethylmalonyl-CoA metabolic node, providing evidence that spiramycin productivity may be increased by enhancing the carbon flow through this pathway. The goal was achieved by over-expressing the ccr paralog srm4 in an ad hoc engineered plasmid. This work embeds the first metabolic reconstruction of S. ambofaciens and the successful experimental validation of model predictions and demonstrates the validity and the importance of in silico modeling tools for the overproduction of molecules with a biotechnological interest. Finally, the proposed metabolic reconstruction, which includes manually refined pathways for several secondary metabolites with antimicrobial activity, represents a solid platform for the future exploitation of S. ambofaciens biotechnological potential. | Frontiers in microbiology 8 (2017). | 2017 | PINATEL EVA MARIA, DE BELLIS GIANLUCA, CONSOLANDI CLARISSA, PEANO CLELIA | Streptomyces ambofaciens, antibiotic production, strain improvement, metabolic modeling, transcriptomics, systems biology | 10.3389/fmicb.2017.00835 |
| 373538 | Articolo in rivista | Proteomics-based network analysis characterizes biological processes and pathways activated by preconditioned mesenchymal stem cells in cardiac repair mechanisms. | Di Silvestre, Dario, Brambilla, Francesca, Scardoni, Giovanni, Brunetti, Pietro, Motta, Sara, Matteucci, Marco, Laudanna, Carlo, Recchia, Fabio A, Lionetti, Vincenzo, Mauri, Pierluigi | BACKGROUND: We have demonstrated that intramyocardial delivery of human mesenchymal stem cells preconditioned with a hyaluronan mixed ester of butyric and retinoic acid (MSCp+) is more effective in preventing the decay of regional myocardial contractility in a swine model of myocardial infarction (MI). However, the understanding of the role of MSCp+ in proteomic remodeling of cardiac infarcted tissue is not complete. We therefore sought to perform a comprehensive analysis of the proteome of infarct remote (RZ) and border zone (BZ) of pigs treated with MSCp+ or unconditioned stem cells. METHODS: Heart tissues were analyzed by MudPIT and differentially expressed proteins were selected by a label-free approach based on spectral counting. Protein profiles were evaluated by using PPI networks and their topological analysis. RESULTS: The proteomic remodeling was largely prevented in MSCp+ group. Extracellular proteins involved in fibrosis were down-regulated, while energetic pathways were globally up-regulated. Cardioprotectant pathways involved in the production of keto acid metabolites were also activated. Additionally, we found that new hub proteins support the cardioprotective phenotype characterizing the left ventricular BZ treated with MSCp+. In fact, the up-regulation of angiogenic proteins NCL and RAC1 can be explained by the increase of capillary density induced by MSCp+. CONCLUSIONS: Our results show that angiogenic pathways appear to be uniquely positioned to integrate signaling with energetic pathways involving cardiac repair. GENERAL SIGNIFICANCE: Our findings prompt the use of proteomics-based network analysis to optimize new approaches preventing the post-ischemic proteomic remodeling that may underlie the limited self-repair ability of adult heart. | Biochimica et biophysica acta (Print) 1861 (2017): 1190-1199. | 2017 | BRAMBILLA FRANCESCA, MOTTA SARA, DI SILVESTRE DARIO, MAURI PIETRO LUIGI | MudPIT; Myocardial infarction; PPI network; Proteomics; Stem cells; Sus scrofa | 10.1016/j.bbagen.2017.02.006 |
| 373541 | Articolo in rivista | Galectin-3: an early predictive biomarker of modulation of airway remodeling in patients with severe asthma treated with omalizumab for 36 months | Riccio, Anna Maria, Mauri, Pierluigi, De Ferrari, Laura, Rossi, Rossana, Di Silvestre, Dario, Benazzi, Louise, Chiappori, Alessandra, Dal Negro, Roberto Walter, Micheletto, Claudio, Canonica, Giorgio Walter | BACKGROUND: Bronchial asthma is a heterogeneous disease characterized by three cardinal features: chronic inflammation, variable airflow obstruction, and airway hyperresponsiveness. Asthma has traditionally been defined using nonspecific clinical and physiologic variables that encompass multiple phenotypes and are treated with nonspecific anti-inflammatory therapies. Based on the modulation of airway remodeling after 12 months of anti-immunoglobulin E (IgE) treatment, we identified two phenotypes (omalizumab responder, OR; and non-omalizumab responder, NOR) and performed morphometric analysis of bronchial biopsy specimens. We also found that these two phenotypes were correlated with the presence/absence of galectin-3 (Gal-3) at baseline (i.e., before treatment). The aims of the present study were to investigate the histological and molecular effects of long-term treatment (36 months) with anti-IgE and to analyze the behavior of OR and NOR patients. METHODS: All patients were treated with the monoclonal antibody anti-IgE omalizumab for 36 months. The bronchial biopsy specimens were evaluated using morphometric, eosinophilic, and proteomic analysis (MudPIT). New data were compared with previous data, and unsupervised cluster analysis of protein profiles was performed. RESULTS: After 36 months of treatment with omalizumab, reduction of reticular basement membrane (RBM) thickness was confirmed in OR patients (Gal-3-positive at baseline); similarly, the protein profiles (over 500 proteins identified) revealed that, in the OR group, levels of proteins specifically related to fibrosis and inflammation (e.g., smooth muscle and extracellular matrix proteins (including periostin), Gal-3, and keratins decreased by between 5- and 50-fold. Eosinophil levels were consistent with molecular data and decreased by about tenfold less in ORs and increased by twofold to tenfold more in NORs. This tendency was confirmed (p < 0.05) based on both fold change and DAVE algorithms, thus indicating a clear response to anti-IgE treatment in Gal-3-positive patients. CONCLUSIONS: Our results showed that omalizumab can be considered a disease-modifying treatment in OR. The proteomic signatures confirmed the presence of Gal-3 at baseline to be a biomarker of long-term reduction in bronchial RBM thickness, eosinophilic inflammation, and muscular and fibrotic components in omalizumab-treated patients with severe asthma. Our findings suggest a possible relationship between Gal-3 positivity and improved pulmonary function. | Clinical and translational allergy 7 (2017). | 2017 | CHIAPPORI FEDERICA, ROSSI ROSSANA, BENAZZI LOUISE, DI SILVESTRE DARIO, MAURI PIETRO LUIGI | Anti-IgE, Omalizumab, Severe asthma, Galectin-3, Biomarker, Airway remodeling, Bronchial biopsy, Proteomics, Eosinophils | 10.1186/s13601-017-0143-1 |
| 374625 | Articolo in rivista | Study on the Association among Mycotoxins and other Variables in Children with Autism. | De Santis, Barbara, Raggi, Maria Elisabetta, Moretti, Giorgio, Facchiano, Francesco, Mezzelani, Alessandra, Villa, Laura, Bonfanti, Arianna, Campioni, Alessandra, Rossi, Stefania, Camposeo, Serena, Soricelli, Sabina, Moracci, Gabriele, Debegnach, Francesca, Gregori, Emanuela, Ciceri, Francesca, Milanesi, Luciano, Marabotti, Anna, Brera, Carlo | Environmental factors and genetic susceptibility are implicated in the increased risk of autism spectrum disorder (ASD). Mycotoxins are agricultural contaminants of fungal origin that represent real risk factors for human health and especially for children. Thus, the main hypothesis of this work is that the deterioration of the clinical manifestation of autism in children may result from the exposure to mycotoxins through the consumption of contaminated food. Within a cross-sectional study, a group of autistic children (n = 172) and a group of controls (n = 61) (siblings and non-parental) were recruited in North and South Italy. All children had blood and urine samples taken, for testing some mycotoxins by a LC-MS/MS validated method. Blood samples were also tested for assessing specific IgG against food and fungal antigens and cytokines. The analyses outputs highlighted statistically significant differences comparing mycotoxins levels between (i) children groups both in urine (deoxynivalenol and de-epoxydeoxynivalenol, p = 0.0141 and p = 0.0259, respectively) and serum (aflatoxin M1, ochratoxin A and fumonisin B1, p = 0.0072, p = 0.0141 and p = 0.0061, respectively); (ii) a group of selected fungal IgGs, and IgGs against wheat and gluten and (iii) cytokines. These results suggest the need for a deeper examination of the role that mycotoxins may have on the etiology of ASD. | Toxins (Basel) 9 (2017). | 2017 | MEZZELANI ALESSANDRA MARIA, MILANESI LUCIANO | IgG; autism syndrome; cytokine/chemokine; environment; exposure; mycotoxins | 10.3390/toxins9070203 |
| 374627 | Articolo in rivista | Development and validation of a new prediction equation for energy expenditure in Mexican adults with overweight and obesity | Ximena Orozco-Ruiz1, Martha Guevara-Cruz1, Edgar Pichardo Ontiveros1, Nimbe Torres1, Isabel Medina-Vera1, Priscila Villanueva-Luna1, Claudio L Lafortuna2, Federica Prinelli3, Armando R Tovar1 | Background Accurate predictive equations of resting energy expenditure (REE) are crucial in devising nutritional strategies to fight overweight/obesity, especially in countries where these are highly prevalent. Objective To develop and validate a new equation for predicting REE in Mexican adults with overweight and obesity. A second objective was to compare the impact of the use of urea nitrogen (UN) to measure REE. Methods We conducted a cross-sectional study, including 410 men and women with overweight and obesity (age range: 20-60 yrs.). Participants were randomly assigned to the development or validation groups; the development group included 200 subjects (Body Mass Index (BMI) = 31.6 +- 5.4 kg/m2, mean +- SD) and the validation group 210 subjects (BMI = 31.7 +- 4.78 kg/m2). The new predictive equation was derived by stepwise multiple linear regression analysis in the development group and then, validated in the other group. The accuracy of the new equation was compared to several predictive existing equations. REE was measured by indirect calorimetry (IC) and body composition by bioimpedance analysis. For the second objective, 30 subjects (10 normal weight, 10 with overweight and 10 with obesity) were involved to measure UN in a 24-hour urine collection. The value of UN was used in the Weir equation to obtain REE and it was compared with the REE obtained by the simplified Weir equation. Results Two predictive equations were developed in this study. The first equation (EQ1) included LBM, weight, sex and age variables in the model (R2= 0.518, bias= 0.014 kJ/day), since lean body mass (LBM) was the best single variable to predict REE (R2= 0.440). When LBM is not an available parameter, a second equation was developed (EQ2) based on only weight, sex and age (R2= 0.513, bias= -0.025 kJ/day). Compared with others predictive equations, the new developed equations showed the lowest bias (Kj/day): EQ1= 9.92, EQ2= 25.7, Harris-Benedict= -67.4, Valencia= 130, WHO/FAO/UNU= 270, Mifflin-St Jeor= 309, Owen= -808, Carrasco= -1097. When we compared REE by Weir equations, using or not UN, there was not statistical significant differences. Conclusion The present equations had the highest predictive accuracy in subjects with overweight or obesity compared with the other equations previously derived from different populations. Also when body composition is not available, the alternative equation demonstrated a comparably predictive accuracy for its use in nutritional treatment in subjects with overweight/obesity. | The FASEB journal (2017). | 2017 | PRINELLI FEDERICA, LAFORTUNA CLAUDIO | * | |
| 375579 | Articolo in rivista | Colonization with Helicobacter is concomitant with modified gut microbiota and drastic failure of the immune control of Mycobacterium tuberculosis | Majlessi, L., Sayes, F., Bureau, J-F, Pawlik, A., Michel, V., Jouvion, G., Huerre, M., Severgnini, M., Consolandi, C., Peano, C., Brosch, R., Touati, E., Leclerc, C. | Epidemiological and experimental observations suggest that chronic microbial colonization can impact the immune control of other unrelated pathogens contracted in a concomitant or sequential manner. Possible interactions between Mycobacterium tuberculosis infection and persistence of other bacteria have scarcely been investigated. Here we demonstrated that natural colonization of the digestive tract with Helicobacter hepaticus in mice is concomitant with modification of the gut microbiota, subclinical inflammation, and drastic impairment of immune control of the growth of subsequently administered M. tuberculosis, which results in severe lung tissue injury. Our results provided insights upon the fact that this prior H. hepaticus colonization leads to failures in the mechanisms that could prevent the otherwise balanced cross-talk between M. tuberculosis and the immune system. Such disequilibrium ultimately leads to the inhibition of control of mycobacterial growth, outbreak of inflammation, and lung pathology. Among the dysregulated immune signatures, we noticed a correlation between the detrimental lung injury and the accumulation of activated T-lymphocytes. Our findings suggest that the impact of prior Helicobacter spp. colonization and subsequent M. tuberculosis parasitism might be greater than previously thought, which is a key point given that both species are among the most frequent invasive bacteria in human populations. | Mucosal immunology 10 (2017): 1178-1189. | 2017 | CONSOLANDI CLARISSA, PEANO CLELIA, SEVERGNINI MARCO | mucosal immunology | 10.1038/mi.2016.140 |
| 378343 | Articolo in rivista | The polyglutamine protein ataxin-3 enables normal growth under heat shock conditions in the methylotrophic yeast Pichia pastoris | Bonanomi, Marcella, Roffia, Valentina, De Palma, Antonella, Lombardi, Alessio, Aprile, Francesco Antonio, Visentin, Cristina, Tortora, Paolo, Mauri, Pierluigi, Regonesi, Maria Elena | The protein ataxin-3 carries a polyglutamine stretch close to the C-terminus that triggers a neurodegenerative disease in humans when its length exceeds a critical threshold. A role as a transcriptional regulator but also as a ubiquitin hydrolase has been proposed for this protein. Here, we report that, when expressed in the yeast Pichia pastoris, full-length ataxin-3 enabled almost normal growth at 37 degrees C, well above the physiological optimum of 30 degrees C. The N-terminal Josephin domain (JD) was also effective but significantly less, whereas catalytically inactive JD was completely ineffective. Based on MudPIT proteomic analysis, we observed that the strain expressing full-length, functional ataxin-3 displayed persistent upregulation of enzymes involved in mitochondrial energy metabolism during growth at 37 degrees C compared with the strain transformed with the empty vector. Concurrently, in the transformed strain intracellular ATP levels at 37 degrees C were even higher than normal ones at 30 degrees C. Elevated ATP was also paralleled by upregulation of enzymes involved in both protein biosynthesis and biosynthetic pathways, as well as of several stress-induced proteins. A similar pattern was observed when comparing a strain expressing JD with another expressing its catalytically inactive counterpart. We suggest that such effects mostly result from mechanisms of transcriptional regulation. | Scientific reports (Nature Publishing Group) 7 (2017). | 2017 | ROFFIA VALENTINA, DE PALMA ANTONELLA, MAURI PIETRO LUIGI | Biophysical chemistry; Metabolic pathways; Proteomics | 10.1038/s41598-017-13814-1 |
| 378512 | Articolo in rivista | Short-term treatment with eicosapentaenoic acid improves inflammation and affects colonic differentiation markers and microbiota in patients with ulcerative colitis | Prossomariti, Anna, Scaioli, Eleonora, Piazzi, Giulia, Fazio, Chiara, Bellanova, Matteo, Biagi, Elena, Candela, Marco, Brigidi, Patrizia, Consolandi, Clarissa, Balbi, Tiziana, Chieco, Pasquale, Munarini, Alessandra, Pariali, Milena, Minguzzi, Manuela, Bazzoli, Franco, Belluzzi, Andrea, Ricciardiello, Luigi | Patients with long-standing ulcerative colitis (UC) have an increased colorectal cancer (CRC) risk. In this pilot study we evaluated the effect of Eicosapentaenoic acid as free fatty acid (EPA-FFA) supplementation on mucosal disease activity, colonic differentiation markers and microbiota composition in UC patients. Twenty long-standing UC patients in stable clinical remission and with fecal calprotectin (FC) > 150 mu g/g were enrolled (T0) and supplemented with EPA-FFA 2 g/daily for 90 days (T3). Endoscopic and histologic disease activities were measured by Mayo and Geboes scores, respectively. HES1, KLF4, STAT3, IL-10 and SOCS3 levels were determined using western blotting and qRT-PCR, while phospho-STAT3 levels were assessed by western blotting. Goblet cells were stained by Alcian blue. Microbiota analyses were performed on both fecal and colonic samples. Nineteen patients completed the study; seventeen (89.5%) were compliant. EPA-FFA treatment reduced FC levels at T3. Patients with FC > 150 mu g/g at T3 (n = 2) were assumed as non-responders. EPA-FFA improved endoscopic and histological inflammation and induced IL-10, SOCS3, HES1 and KLF4 in compliant and responder patients. Importantly, long-term UC-driven microbiota composition was partially redressed by EPA-FFA. In conclusion, EPA-FFA supplementation reduced mucosal inflammation, promoted goblet cells differentiation and modulated intestinal microbiota composition in long-standing UC patients. | Scientific reports (Nature Publishing Group) 7 (2017). | 2017 | CONSOLANDI CLARISSA | Cancer prevention, Ulcerative colitis | 10.1038/s41598-017-07992-1 |
| 378513 | Articolo in rivista | A single amino acid substitution confers B-cell clonogenic activity to the HIV-1 matrix protein p17 | Giagulli, Cinzia, D'Ursi, Pasqualina, He, Wangxiao, Zorzan, Simone, Caccuri, Francesca, Varney, Kristen, Orro, Alessandro, Marsico, Stefania, Otjacques, Benoit, Laudanna, Carlo, Milanesi, Luciano, Dolcetti, Riccardo, Fiorentini, Simona, Lu, Wuyuan, Caruso, Arnaldo | Recent data highlight the presence, in HIV-1-seropositive patients with lymphoma, of p17 variants (vp17s) endowed with B-cell clonogenicity, suggesting a role of vp17s in lymphomagenesis. We investigated the mechanisms responsible for the functional disparity on B cells between a wild-type p17 (refp17) and a vp17 named S75X. Here, we show that a single Arginine (R) to Glycine (G) mutation at position 76 in the refp17 backbone (p17R76G), as in the S75X variant, is per se sufficient to confer a B-cell clonogenic potential to the viral protein and modulate, through activation of the PTEN/PI3K/Akt signaling pathway, different molecules involved in apoptosis inhibition (CASP-9, CASP-7, DFF-45, NPM, YWHAZ, Src, PAX2, MAPK8), cell cycle promotion and cancer progression (CDK1, CDK2, CDK8, CHEK1, CHEK2, GSK-3 beta, NPM, PAK1, PP2C-alpha). Moreover, the only R to G mutation at position 76 was found to strongly impact on protein folding and oligomerization by altering the hydrogen bond network. This generates a conformational shift in the p17 R76G mutant which enables a functional epitope(s), masked in refp17, to elicit B-cell growth-promoting signals after its interaction with a still unknown receptor(s). Our findings offer new opportunities to understand the molecular mechanisms accounting for the B-cell growth-promoting activity of vp17s. | Scientific reports (Nature Publishing Group) 7 (2017). | 2017 | D'URSI PASQUALINA, ORRO ALESSANDRO, MILANESI LUCIANO | Cellular signalling networks, Virus-host interactions | 10.1038/s41598-017-06848-y |
| 378561 | Articolo in rivista | Multiclass HCV resistance to direct-acting antiviral failure in real-life patients advocates for tailored second-line therapies | Di Maio, Velia C., Cento, Valeria, Lenci, Ilaria, Aragri, Marianna, Rossi, Piera, Barbaliscia, Silvia, Melis, Michela, Verucchi, Gabriella, Magni, Carlo F., Teti, Elisabetta, Bertoli, Ada, Antonucci, FrancescoPaolo, Bellocchi, Maria C., Micheli, Valeria, Masetti, Chiara, Landonio, Simona, Francioso, Simona, Santopaolo, Francesco, Pellicelli, Adriano M., Calvaruso, Vincenza, Gianserra, Laura, Siciliano, Massimo, Romagnoli, Dante, Cozzolongo, Raffaele, Grieco, Antonio, Vecchiet, Jacopo, Morisco, Filomena, Merli, Manuela, Brancaccio, Giuseppina, Di Biagio, Antonio, Loggi, Elisabetta, Mastroianni, Claudio M., Palitti, Valeria Pace, Tarquini, Pierluigi, Puoti, Massimo, Taliani, Gloria, Sarmati, Loredana, Picciotto, Antonino, Vullo, Vincenzo, Caporaso, Nicola, Paoloni, Maurizio, Pasquazzi, Caterina, Rizzardini, Giuliano, Parruti, Giustino, Craxi, Antonio, Babudieri, Sergio, Andreoni, Massimo, Angelico, Mario, Perno, Carlo F., Ceccherini-Silberstein, Francesca, Mariani R, Iapadre N, Grimaldi A, Cozzolongo R, Andreone P, Verucchi G, Menzaghi B, Quirino T, Pisani V, Torti C, Vecchiet J, Bruzzone B, De Maria A, Marenco S, Nicolini LA, Viscoli C, Casinelli K, Delle Monache M, Lichtner M, Aghemo A, Boccaccio V, Bruno S, Cerrone M, Colombo M, D'Arminio Monforte A, Danieli E, Donato F, Gubertini G, Lleo A, Magni CF, Mancon A, Monico S, Niero F, Russo ML, Gnocchi M, Orro A, Milanesi L, Baldelli E, Bertolotti M, Borghi V, Mussini C, Brancaccio G, Gaeta GB, Lembo V, Sangiovanni V, Di Marco V, Mazzola A, Petta S, D'Amico E, Cacciatore P, Consorte A, Pieri A, Polilli E, Sozio F, Antenucci F, Aragri M, Baiocchi L, Barbaliscia S, Biliotti E, Biolato M, Carioti L, Ceccherini-Silberstein F, Cerasari G, Cerva C, Ciotti M, D'Ambrosio C, D'Ettorre G, De Leonardis F, De Sanctis A, Di Maio VC, Di Paolo D, Furlan C, Gallo P, Gasbarrini A, Giannelli V, Grieco S, Lambiase L, Lattanzi B, Lenci I, Lula R, Malagnino V, Manuelli M, Miglioresi L, Milana M, Moretti A, Nosotti L, Palazzo D, Pellicelli A, Romano M, Sarrecchia C, Sforza D, Sorbo MC, Spaziante M, Svicher V, Tisone G, Vespasiani-Gentilucci U, D'Adamo G, Mangia A, Maida I, Mura MS, Falconi L, Di Giammartino D. | Background & Aims: Despite the excellent efficacy of direct-acting antivirals (DAA) reported in clinical trials, virological failures can occur, often associated with the development of resistance-associated substitutions (RASs). This study aimed to characterize the presence of clinically relevant RASs to all classes in real-life DAA failures. | Liver international (Print) 37 (2017): 514-528. | 2017 | ORRO ALESSANDRO, MILANESI LUCIANO, GNOCCHI MATTEO | antiviral therapy, direct-acting antivirals, hepatitis C virus, resistance-associated substitutions, resistance test | 10.1111/liv.13327 |
| 378569 | Articolo in rivista | iSmaRT: a toolkit for a comprehensive analysis of small RNA-Seq data. | Panero, Riccardo, Rinaldi, Antonio, Memoli, Domenico, Nassa, Giovanni, Ravo, Maria, Rizzo, Francesca, Tarallo, Roberta, Milanesi, Luciano, Weisz, Alessandro, Giurato, Giorgio | Summary: The interest in investigating the biological roles of small non-coding RNAs (sncRNAs) is increasing, due to the pleiotropic effects of these molecules exert in many biological contexts. While several methods and tools are available to study microRNAs (miRNAs), only few focus on novel classes of sncRNAs, in particular PIWI-interacting RNAs (piRNAs). To overcome these limitations, we implemented iSmaRT ( i ntegrative Sm all R NA T ool-kit), an automated pipeline to analyze smallRNA-Seq data. Availability and Implementation: iSmaRT is a collection of bioinformatics tools and own algorithms, interconnected through a Graphical User Interface (GUI). In addition to performing comprehensive analyses on miRNAs, it implements specific computational modules to analyze piRNAs, predicting novel ones and identifying their RNA targets. A smallRNA-Seq dataset generated from brain samples of Huntington's Disease patients was used here to illustrate iSmaRT performances, demonstrating how the pipeline can provide, in a rapid and user friendly way, a comprehensive analysis of different classes of sncRNAs. iSmaRT is freely available on the web at ftp://labmedmolge-1.unisa.it (User: iSmart - Password: password). | Bioinformatics (Oxf., Print) 33 (2017): 938-940. | 2017 | MILANESI LUCIANO | * | 10.1093/bioinformatics/btx647 |
| 378572 | Articolo in rivista | The nuclear receptor ER? engages AGO2 in regulation of gene transcription, RNA splicing and RISC loading | Tarallo R., Giurato G., Bruno G., Ravo M., Rizzo F., Salvati A., Ricciardi L., Marchese G., Cordella A., Rocco T., Gigantino V., Pierri B., Cimmino G., Milanesi L., Ambrosino C., Nyman T.A., Nassa G., Weisz A. | Background: The RNA-binding protein Argonaute 2 (AGO2) is a key effector of RNA-silencing pathways It exerts a pivotal role in microRNA maturation and activity and can modulate chromatin remodeling, transcriptional gene regulation and RNA splicing. Estrogen receptor beta (ER?) is endowed with oncosuppressive activities, antagonizing hormone-induced carcinogenesis and inhibiting growth and oncogenic functions in luminal-like breast cancers (BCs), where its expression correlates with a better prognosis of the disease. Results: Applying interaction proteomics coupled to mass spectrometry to characterize nuclear factors cooperating with ER? in gene regulation, we identify AGO2 as a novel partner of ER? in human BC cells. ER?-AGO2 association was confirmed in vitro and in vivo in both the nucleus and cytoplasm and is shown to be RNA-mediated. ChIP-Seq demonstrates AGO2 association with a large number of ER? binding sites, and total and nascent RNA-Seq in ER?+vs ER?-cells, and before and after AGO2 knock-down in ER?+cells, reveals a widespread involvement of this factor in ER?-mediated regulation of gene transcription rate and RNA splicing. Moreover, isolation and sequencing by RIP-Seq of ER?-associated long and small RNAs in the cytoplasm suggests involvement of the nuclear receptor in RISC loading, indicating that it may also be able to directly control mRNA translation efficiency and stability. Conclusions: These results demonstrate that AGO2 can act as a pleiotropic functional partner of ER?, indicating that both factors are endowed with multiple roles in the control of key cellular functions. | Genome biology (Print) 18 (2017). | 2017 | MILANESI LUCIANO | Argonaute 2, Breast cancer, Estrogen receptor beta, Interaction proteomics, RNA splicing, Transcriptional regulation | 10.1186/s13059-017-1321-0 |
| 378573 | Articolo in rivista | Network Diffusion-Based Prioritization of Autism Risk Genes Identifies Significantly Connected Gene Modules | Mosca, Ettore, Bersanelli, Matteo, Gnocchi, Matteo, Moscatelli, Marco, Castellani, Gastone, Milanesi, Luciano, Mezzelani, Alessandra | Autism spectrum disorder (ASD) is marked by a strong genetic heterogeneity, which is underlined by the low overlap between ASD risk gene lists proposed in different studies. In this context, molecular networks can be used to analyze the results of several genome-wide studies in order to underline those network regions harboring genetic variations associated with ASD, the so-called "disease modules." In this work, we used a recent network diffusion-based approach to jointly analyze multiple ASD risk gene lists. We defined genome-scale prioritizations of human genes in relation to ASD genes from multiple studies, found significantly connected gene modules associated with ASD and predicted genes functionally related to ASD risk genes. Most of them play a role in synapsis and neuronal development and function; many are related to syndromes that can be in comorbidity with ASD and the remaining are involved in epigenetics, cell cycle, cell adhesion and cancer. | Frontiers in genetics 8 (2017). | 2017 | MOSCATELLI MARCO, CASTELLANI GASTONE, MEZZELANI ALESSANDRA MARIA, MILANESI LUCIANO, GNOCCHI MATTEO, MOSCA ETTORE | autism spectrum disorder, biological networks, network diffusion, data integration, gene module | 10.3389/fgene.2017.00129 |
| 378576 | Articolo in rivista | A rare genetic variant of BPIFB4 predisposes to high blood pressure via impairment of nitric oxide signaling | Vecchione, Carmine, Villa, Francesco, Carrizzo, Albino, Spinelli, Chiara Carmela, Damato, Antonio, Ambrosio, Mariateresa, Ferrario, Anna, Madonna, Michele, Uccellatore, Annachiara, Lupini, Silvia, Maciag, Anna, Ryskalin, Larisa, Milanesi, Luciano, Frati, Giacomo, Sciarretta, Sebastiano, Bellazzi, Riccardo, Genovese, Stefano, Ceriello, Antonio, Auricchio, Alberto, Malovini, Alberto, Puca, Annibale Alessandro | BPIFB4 is associated with exceptional longevity: four single-nucleotide polymorphisms distinguish the wild-type form from a longevity-associated variant conferring positive effects on blood pressure. The effect of a rare variant (RV; allele frequency, 4%) on blood pressure is unknown. Here, we show that overexpression of RV-BPIFB4 in ex-vivo mouse vessels impairs phosphorylation of endothelial nitric oxide synthase (eNOS), blunting acetylcholine-evoked vasorelaxation; in vivo, virally mediated overexpression of RV-BPIFB4 increases blood pressure, an action absent in eNOS-deficient mice. In humans, we found RV carriers to have increased diastolic blood pressure, a finding that was more marked in subjects on anti-hypertensive medication; moreover, recombinant RV-BPIFB4 protein impaired eNOS function in ex-vivo human vessels. Thus, RV-BPIFB4 acts directly on blood pressure homeostasis and may represent a novel biomarker of vascular dysfunction and hypertension. | Scientific reports (Nature Publishing Group) 7 (2017). | 2017 | PUCA ANNIBALE ALESSANDRO, VILLA FRANCESCO, MILANESI LUCIANO | * | 10.1038/s41598-017-10341-x |
| 378580 | Articolo in rivista | Misidentification of transthyretin and immunoglobulin variants by proteomics due to methyl lysine formation in formalin-fixed paraffin-embedded amyloid tissue. | Canetti, Diana, Rendell, Nigel Brian, Di Vagno, Lucia, Gilbertson, Janet A, Rowczenio, Dorota, Rezk, Tamar, Gillmore, Julian D, Hawkins, Phillip N, Verona, Guglielmo, Mangione, Palma Patrizia, Giorgetti, Sofia, Mauri, Pierluigi, Motta, Sara, De Palma, Antonella, Bellotti, Vittorio, Taylor, Graham W | Proteomics is becoming the de facto gold standard for identifying amyloid proteins and is now used routinely in a number of centres. The technique is compound class independent and offers the added ability to identify variant and modified proteins. We re-examined proteomics results from a number of formalin-fixed paraffin-embedded amyloid samples, which were positive for transthyretin (TTR) by immunohistochemistry and proteomics, using the UniProt human protein database modified to include TTR variants. The amyloidogenic variant, V122I TTR, was incorrectly identified in 26/27 wild-type and non-V122I variant samples due to its close mass spectral similarity with the methyl lysine-modified WT peptide [126KMe]105-127 (p.[146 KMe]125-147) generated during formalin fixation. Similarly, the methyl lysine peptide, [50KMe]43-59, from immunoglobulin lambda light chain constant region was also misidentified as arising from a rare myeloma-derived lambda variant V49I. These processing-derived modifications are not present in fresh cardiac tissue, non-fixed fat nor serum and do not materially affect the identification of amyloid proteins. They could result in the incorrect assignment of a variant, and this may have consequences for the immediate family who will require genetic counselling and potentially early clinical intervention. As proteomics becomes a routine clinical test for amyloidosis, it becomes important to be aware of potentially confounding issues such as formalin-mediated lysine methylation, and how these may influence diagnosis and possibly treatment. | Amyloid (Carnforth) (2017): 1-9. | 2017 | MOTTA SARA, DE PALMA ANTONELLA, MAURI PIETRO LUIGI | Amyloidosis; formalin; immunoglobulin; proteomics; transthyretin; variant | 10.1080/13506129.2017.1385452 |
| 378635 | Articolo in rivista | Cellulose production is coupled to sensing of the pyrimidine biosynthetic pathway via c-di-GMP production by the DgcQ protein of Escherichia coli. | Rossi, Elio, Motta, Sara, Aliverti, Alessandro, Cossu, Federica, Gourlay, Louise, Mauri, Pierluigi, Landini, Paolo | Production of cellulose, a stress response-mediated process in enterobacteria, is modulated in Escherichia coli by the activity of the two pyrimidine nucleotide biosynthetic pathways, namely, the de novo biosynthetic pathway and the salvage pathway, which relies on the environmental availability of pyrimidine nitrogenous bases. We had previously reported that prevalence of the salvage over the de novo pathway triggers cellulose production via synthesis of the second messenger c-di-GMP by the DgcQ (YedQ) diguanylate cyclase. In this work, we show that DgcQ enzymatic activity is enhanced by UTP, whilst being inhibited by N-carbamoyl-aspartate, an intermediate of the de novo pathway. Thus, direct allosteric control by these ligands allows full DgcQ activity exclusively in cells actively synthesizing pyrimidine nucleotides via the salvage pathway. Inhibition of DgcQ activity by N-carbamoyl-aspartate appears to be favoured by protein-protein interaction between DgcQ and PyrB, a subunit of aspartate transcarbamylase, which synthesizes N-carbamoyl-aspartate. Our results suggest that availability of pyrimidine bases might be sensed, somehow paradoxically, as an environmental stress by E. coli. We hypothesize that this link might have evolved since stress events, leading to extensive DNA/RNA degradation or lysis of neighbouring cells, can result in increased pyrimidine concentrations and activation of the salvage pathway. | Environmental microbiology (Online) (2017). | 2017 | MOTTA SARA, MAURI PIETRO LUIGI | * | 10.1111/1462-2920.13918 |
| 378638 | Articolo in rivista | Emerging MS-based platforms for the characterization of tumor-derived exosomes isolated from human biofluids: challenges and promises of MudPIT | Ferrari, Emanuele, De Palma, Antonella, Mauri, Pierluigi | INTRODUCTION: Exosomes are small extracellular vesicles of endosomal origin that are produced and released by several type of cells. These vesicles contain different macromolecules: proteins, mRNA, miRNA, mitochondrial DNA, and lipids. Exosomes play an important role in cell-to-cell communication, also promoting cancer progression. Areas covered: Various proteomic approaches have been applied to study exosomes isolated from different human biofluids in search of possible cancer biomarkers. The results of these studies are reported, and pros and cons of each employed technique are described. Gel-free and gel-based mass spectrometry systems are discussed, giving particular emphasis on the innovative multidimensional protein identification technology (MudPIT). Expert commentary: Proteomic studies on exosomes as candidate cancer biomarkers from urine and other body fluids in cancer have shown the potential of MS-based techniques. In particular, MudPIT is a promising tool to be applied in clinical proteomics of cancer. | Expert review of proteomics (Print) 14 (2017): 757-767. | 2017 | FERRARI EMANUELE, DE PALMA ANTONELLA, MAURI PIETRO LUIGI | Cancer, exosomes, urine, plasma, proteomics, LC-MS/MS, MudPIT | 10.1080/14789450.2017.1364629 |
| 378639 | Articolo in rivista | Combination of Metabolomic and Proteomic Analysis Revealed Different Features among Lactobacillus delbrueckii Subspecies bulgaricus and lactis Strains While In Vivo Testing in the Model Organism Caenorhabditis elegans Highlighted Probiotic Properties | Zanni, Elena, Schifano, Emily, Motta, Sara, Sciubba, Fabio, Palleschi, Claudio, Mauri, Pierluigi, Perozzi, Giuditta, Uccelletti, Daniela, Devirgiliis, Chiara, Miccheli, Alfredo | Lactobacillus delbrueckii represents a technologically relevant member of lactic acid bacteria, since the two subspecies bulgaricus and lactis are widely associated with fermented dairy products. In the present work, we report the characterization of two commercial strains belonging to L. delbrueckii subspecies bulgaricus, lactis and a novel strain previously isolated from a traditional fermented fresh cheese. A phenomic approach was performed by combining metabolomic and proteomic analysis of the three strains, which were subsequently supplemented as food source to the model organism Caenorhabditis elegans, with the final aim to evaluate their possible probiotic effects. Restriction analysis of 16S ribosomal DNA revealed that the novel foodborne strain belonged to L. delbrueckii subspecies lactis. Proteomic and metabolomic approaches showed differences in folate, aminoacid and sugar metabolic pathways among the three strains. Moreover, evaluation of C. elegans lifespan, larval development, brood size, and bacterial colonization capacity demonstrated that L. delbrueckii subsp. bulgaricus diet exerted beneficial effects on nematodes. On the other hand, both L. delbrueckii subsp. lactis strains affected lifespan and larval development. We have characterized three strains belonging to L. delbrueckii subspecies bulgaricus and lactis highlighting their divergent origin. In particular, the two closely related isolates L. delbrueckii subspecies lactis display different galactose metabolic capabilities. Moreover, the L. delbrueckii subspecies bulgaricus strain demonstrated potential probiotic features. Combination of omic platforms coupled with in vivo screening in the simple model organism C. elegans is a powerful tool to characterize industrially relevant bacterial isolates. | Frontiers in microbiology 8 (2017). | 2017 | MOTTA SARA, MAURI PIETRO LUIGI | Lactobacillus delbrueckii metabolism, bacterial folate biosynthesis, bacterial galactose metabolism, tagatose pathway, lactic acid bacteria, foodborne bacteria | 10.3389/fmicb.2017.01206 |
| 378641 | Articolo in rivista | Molybdenum and iron mutually impact their homeostasis in cucumber (Cucumis sativus) plants | Vigani, Gianpiero, Di Silvestre, Dario, Agresta, Anna Maria, Donnini, Silvia, Mauri, Pierluigi, Gehl, Christian, Bittner, Florian, Murgia, Irene | Molybdenum (Mo) and iron (Fe) are essential micronutrients required for crucial enzyme activities in plant metabolism. Here we investigated the existence of a mutual control of Mo and Fe homeostasis in cucumber (Cucumis sativus). Plants were grown under single or combined Mo and Fe starvation. Physiological parameters were measured, the ionomes of tissues and the ionomes and proteomes of root mitochondria were profiled, and the activities of molybdo-enzymes and the synthesis of molybdenum cofactor (Moco) were evaluated. Fe and Mo were found to affect each other's total uptake and distribution within tissues and at the mitochondrial level, with Fe nutritional status dominating over Mo homeostasis and affecting Mo availability for molybdo-enzymes in the form of Moco. Fe starvation triggered Moco biosynthesis and affected the molybdo-enzymes, with its main impact on nitrate reductase and xanthine dehydrogenase, both being involved in nitrogen assimilation and mobilization, and on the mitochondrial amidoxime reducing component. These results, together with the identification of >100 proteins differentially expressed in root mitochondria, highlight the central role of mitochondria in the coordination of Fe and Mo homeostasis and allow us to propose the first model of the molecular interactions connecting Mo and Fe homeostasis. | New phytologist (Print) 213 (2017): 1222-1241. | 2017 | AGRESTA ANNA MARIA, DI SILVESTRE DARIO, MAURI PIETRO LUIGI | Cucumis sativus (cucumber), ionomics, iron (Fe), micronutrient homeostasis, mitochondria, molybdenum (Mo), molybdo-enzymes | 10.1111/nph.14214 |
| 378642 | Articolo in rivista | Gut microbiome response to short-term dietary interventions in reactive hypoglycemia subjects. | Quercia, Sara, Turroni, Silvia, Fiori, Jessica, Soverini, Matteo, Rampelli, Simone, Biagi, Elena, Castagnetti, Andrea, Consolandi, Clarissa, Severgnini, Marco, Pianesi, Mario, Fallucca, Francesco, Pozzilli, Paolo, Brigidi, Patrizia, Candela, Marco | BACKGROUND: Reactive hypoglycemia is a metabolic disorder that provokes severe hypoglycemic episodes after meals. Over recent years, the gut microbiota has been recognized as potential target for the control of metabolic diseases, and the possibility to correct gut microbiota dysbioses through diet, favouring the recovery of metabolic homeostasis, has been considered. METHODS: We investigate the impact of 2 short-term (3-day) nutritional interventions, based on the macrobiotic Ma-Pi 2 diet and a control Mediterranean diet, on the structure and functionality of the gut microbiota in 12 patients affected by reactive hypoglycemia. The gut microbiota composition was characterized by next-generation sequencing of the V3 to V4 region of the 16S rRNA gene, and the ecosystem functionality was addressed by measuring the faecal concentration of short-chain fatty acids (SCFAs). In order to measure the short-term physiological gut microbiota fluctuation, the microbiomes of 7 healthy people were characterized before and after 3 days of constant diet. RESULTS: While no convergence of the gut microbiota compositional profiles was observed, a significant increase in SCFA faecal levels was induced only in the Ma-Pi 2 diet group, suggesting the potential of this diet to support a short-term functional convergence of the gut microbiota, regardless of the individual compositional layout. CONCLUSIONS: The Ma-Pi 2 diet, with its high fibre load, was effective in increasing the production of SCFAs by the gut microbiota. Because these metabolites are known for their ability to counterbalance the metabolic deregulation in persons with glucose impairment disorders, their increased bioavailability could be of some relevance in reactive hypoglycemia. | Diabetes/metabolism research and reviews (Online) 33 (2017). | 2017 | CONSOLANDI CLARISSA, SEVERGNINI MARCO | gut microbiome; macrobiotic diet; reactive hypoglycemia; short-chain fatty acids; short-term response | 10.1002/dmrr.2927 |
| 378644 | Articolo in rivista | Design and validation of a DNA-microarray for phylogenetic analysis of bacterial communities in different oral samples and dental implants | Parolin, Carola, Giordani, Barbara, Palomino, Rogers Alberto Nahui, Biagi, Elena, Severgnini, Marco, Consolandi, Clarissa, Caredda, Giada, Storelli, Stefano, Strohmenger, Laura, Vitali, Beatrice | The quali-quantitative characterization of the oral microbiota is crucial for an exhaustive knowledge of the oral ecology and the modifications of the microbial composition that occur during periodontal pathologies. In this study, we designed and validated a new phylogenetic DNA-microarray (OralArray) to quickly and reliably characterize the most representative bacterial groups that colonize the oral cavity. The OralArray is based on the Ligation Detection Reaction technology associated to Universal Arrays (LDR-UA), and includes 22 probe sets targeted to bacteria belonging to the phyla Firmicutes, Proteobacteria, Actinobacteria, Bacteroidetes, Fusobacteria, and Spirochaete. The tool is characterized by high specificity, sensitivity and reproducibility. The OralArray was successfully tested and validated on different oral samples (saliva, lingual plaque, supragingival plaque, and healing cap) collected from 10 healthy subjects. For each specimen, a microbial signature was obtained, and our results established the presence of an oral microbial profile specific for each subject. Moreover, the tool was applied to evaluate the efficacy of a disinfectant treatment on the healing caps before their usage. The OralArray is, thus, suitable to study the microbiota associated with various oral sites and to monitor changes arising from therapeutic treatments. | Scientific reports (Nature Publishing Group) 7 (2017). | 2017 | CAREDDA GIADA, CONSOLANDI CLARISSA, SEVERGNINI MARCO | Biotechnology Microbial ecology | 10.1038/s41598-017-06743-6 |
| 378650 | Articolo in rivista | Genome-wide meta-analysis of 241,258 adults accounting for smoking behaviour identifies novel loci for obesity traits | Justice, Anne E., Winkler, Thomas W., Feitosa, Mary F., Graff, Misa, Fisher, Virginia A., Young, Kristin, Barata, Llilda, Deng, Xuan, Czajkowski, Jacek, Hadley, David, Ngwa, Julius S., Ahluwalia, Tarunveer S., Chu, Audrey Y., Heard-Costa, Nancy L., Lim, Elise, Perez, Jeremiah, Eicher, John D., Kutalik, Zoltan, Xue, Luting, Mahajan, Anubha, Renstrom, Frida, Wu, Joseph, Qi, Qibin, Ahmad, Shafqat, Alfred, Tamuno, Amin, Najaf, Bielak, Lawrence F., Bonnefond, Amelie, Bragg, Jennifer, Cadby, Gemma, Chittani, Martina, Coggeshall, Scott, Corre, Tanguy, Direk, Nese, Eriksson, Joel, Fischer, Krista, Gorski, Mathias, Harder, Marie Neergaard, Horikoshi, Momoko, Huang, Tao, Huffman, Jennifer E., Jackson, Anne U., Justesen, Johanne Marie, Kanoni, Stavroula, Kinnunen, Leena, Kleber, Marcus E., Komulainen, Pirjo, Kumari, Meena, Lim, Unhee, Luan, Jian'an, Lyytikainen, Leo-Pekka, Mangino, Massimo, Manichaikul, Ani, Marten, Jonathan, Middelberg, Rita P. S., Mueller-Nurasyid, Martina, Navarro, Pau, Perusse, Louis, Pervjakova, Natalia, Sarti, Cinzia, Smith, Albert Vernon, Smith, Jennifer A., Stancakova, Alena, Strawbridge, Rona J., Stringham, Heather M., Sung, Yun Ju, Tanaka, Toshiko, Teumer, Alexander, Trompet, Stella, van der Laan, Sander W., van der Most, Peter J., Van Vliet-Ostaptchouk, Jana V., Vedantam, Sailaja L., Verweij, Niek, Vink, Jacqueline M., Vitart, Veronique, Wu, Ying, Yengo, Loic, Zhang, Weihua, Zhao, Jing Hua, Zimmermann, Martina E., Zubair, Niha, Abecasis, Goncalo R., Adair, Linda S., Afaq, Saima, Afzal, Uzma, Bakker, Stephan J. L., Bartz, Traci M., Beilby, John, Bergman, Richard N., Bergmann, Sven, Biffar, Reiner, Blangero, John, Boerwinkle, Eric, Bonnycastle, Lori L., Bottinger, Erwin, Braga, Daniele, Buckley, Brendan M., Buyske, Steve, Campbell, Harry, Chambers, John C., Collins, Francis S., Curran, Joanne E., de Borst, Gert J., de Craen, Anton J. M., de Geus, Eco J. C., Dedoussis, George, Delgado, Graciela E., den Ruijter, Hester M., Eiriksdottir, Gudny, Eriksson, Anna L., Esko, Tonu, Faul, Jessica D., Ford, Ian, Forrester, Terrence, Gertow, Karl, Gigante, Bruna, Glorioso, Nicola, Gong, Jian, Grallert, Harald, Grammer, Tanja B., Grarup, Niels, Haitjema, Saskia, Hallmans, Goran, Hamsten, Anders, Hansen, Torben, Harris, Tamara B., Hartman, Catharina A., Hassinen, Maija, Hastie, Nicholas D., Heath, Andrew C., Hernandez, Dena, Hindorff, Lucia, Hocking, Lynne J., Hollensted, Mette, Holmen, Oddgeir L., Homuth, Georg, Hottenga, Jouke Jan, Huang, Jie, Hung, Joseph, Hutri-Kahonen, Nina, Ingelsson, Erik, James, Alan L., Jansson, John-Olov, Jarvelin, Marjo-Riitta, Jhun, Min A., Jorgensen, Marit E., Juonala, Markus, Kahonen, Mika, Karlsson, Magnus, Koistinen, Heikki A., Kolcic, Ivana, Kolovou, Genovefa, Kooperberg, Charles, Kramer, Bernhard K., Kuusisto, Johanna, Kvaloy, Kirsti, Lakka, Timo A., Langenberg, Claudia, Launer, Lenore J., Leander, Karin, Lee, Nanette R., Lind, Lars, Lindgren, Cecilia M., Linneberg, Allan, Lobbens, Stephane, Loh, Marie, Lorentzon, Mattias, Luben, Robert, Lubke, Gitta, Ludolph-Donislawski, Anja, Lupoli, Sara, Madden, Pamela A. F., Mannikko, Reija, Marques-Vidal, Pedro, Martin, Nicholas G., McKenzie, Colin A., McKnight, Barbara, Mellstrom, Dan, Menni, Cristina, Montgomery, Grant W., Musk, A. W. (Bill), Narisu, Narisu, Nauck, Matthias, Nolte, Ilja M., Oldehinkel, Albertine J., Olden, Matthias, Ong, Ken K., Padmanabhan, Sandosh, Peyser, Patricia A., Pisinger, Charlotta, Porteous, David J., Raitakari, Olli T., Rankinen, Tuomo, Rao, D. C., Rasmussen-Torvik, Laura J., Rawal, Rajesh, Rice, Treva, Ridker, Paul M., Rose, Lynda M., Bien, Stephanie A., Rudan, Igor, Sanna, Serena, Sarzynski, Mark A., Sattar, Naveed, Savonen, Kai, Schlessinger, David, Scholtens, Salome, Schurmann, Claudia, Scott, Robert A., Sennblad, Bengt, Siemelink, Marten A., Silbernagel, Gunther, Slagboom, P. Eline, Snieder, Harold, Staessen, Jan A., Stott, David J., Swertz, Morris A., Swift, Amy J., Taylor, Kent D., Tayo, Bamidele O., Thorand, Barbara, Thuillier, Dorothee, Tuomilehto, Jaakko, Uitterlinden, Andre G., Vandenput, Liesbeth, Vohl, Marie-Claude, Volzke, Henry, Vonk, Judith M., Waeber, Gerard, Waldenberger, Melanie, Westendorp, R. G. J., Wild, Sarah, Willemsen, Gonneke, Wolffenbuttel, Bruce H. R., Wong, Andrew, Wright, Alan F., Zhao, Wei, Zillikens, M. Carola, Baldassarre, Damiano, Balkau, Beverley, Bandinelli, Stefania, Boger, Carsten A., Boomsma, Dorret I., Bouchard, Claude, Bruinenberg, Marcel, Chasman, Daniel I., Chen, Yii-Der Ida, Chines, Peter S., Cooper, Richard S., Cucca, Francesco, Cusi, Daniele, de Faire, Ulf, Ferrucci, Luigi, Franks, Paul W., Froguel, Philippe, Gordon-Larsen, Penny, Grabe, Hans-Jorgen, Gudnason, Vilmundur, Haiman, Christopher A., Hayward, Caroline, Hveem, Kristian, Johnson, Andrew D., Jukema, Wouter, Kardia, Sharon L. R., Kivimaki, Mika, Kooner, Jaspal S., Kuh, Diana, Laakso, Markku, Lehtimaki, Terho, Le Marchand, Loic, Marz, Winfried, McCarthy, Mark I., Metspalu, Andres, Morris, Andrew P., Ohlsson, Claes, Palmer, Lyle J., Pasterkamp, Gerard, Pedersen, Oluf, Peters, Annette, Peters, Ulrike, Polasek, Ozren, Psaty, Bruce M., Qi, Lu, Rauramaa, Rainer, Smith, Blair H., Sorensen, Thorkild I. A., Strauch, Konstantin, Tiemeier, Henning, Tremoli, Elena, Van der Harst, Pim, Vestergaard, Henrik, Vollenweider, Peter, Wareham, Nicholas J., Weir, David R., Whitfield, John B., Wilson, James F., Tyrrell, Jessica, Frayling, Timothy M., Barroso, Ines, Boehnke, Michael, Deloukas, Panagiotis, Fox, Caroline S., Hirschhorn, Joel N., Hunter, David J., Spector, Tim D., Strachan, David P., van Duijn, Cornelia M., Heid, Iris M., Mohlke, Karen L., Marchini, Jonathan, Loos, Ruth J. F., Kilpelainen, Tuomas O., Liu, Ching-Ti, Borecki, Ingrid B., North, Kari E., Cupples, L. Adrienne | Few genome-wide association studies (GWAS) account for environmental exposures, like smoking, potentially impacting the overall trait variance when investigating the genetic contribution to obesity-related traits. Here, we use GWAS data from 51,080 current smokers and 190,178 nonsmokers (87% European descent) to identify loci influencing BMI and central adiposity, measured as waist circumference and waist-to-hip ratio both adjusted for BMI. We identify 23 novel genetic loci, and 9 loci with convincing evidence of gene-smoking interaction (GxSMK) on obesity-related traits. We show consistent direction of effect for all identified loci and significance for 18 novel and for 5 interaction loci in an independent study sample. These loci highlight novel biological functions, including response to oxidative stress, addictive behaviour, and regulatory functions emphasizing the importance of accounting for environment in genetic analyses. Our results suggest that tobacco smoking may alter the genetic susceptibility to overall adiposity and body fat distribution. | Nature communications 8 (2017). | 2017 | CUSI DANIELE, SANNA SERENA | * | 10.1038/ncomms14977 |
| 380046 | Articolo in rivista | Prep1 prevents premature adipogenesis of mesenchymal progenitors | Maroni, Giorgia, Tkachuk, Vsevolod A., Egorov, Alexander, Morelli, Marco J., Luongo, Raffaele, Levantini, Elena, Blasi, Francesco, Magli, Maria Cristina, Penkov, Dmitry | Transcriptional regulators are crucial in adipocyte differentiation. We now show that the homeodomain-containing transcription factor Prep1 is a repressor of adipogenic differentiation since its down-regulation (DR) in both ex vivo bone marrow-derived mesenchymal stromal cells (MSC) and in vitro 3T3-L1 preadipocytes significantly increases their adipogenic differentiation ability. Prep1 acts at a stage preceding the activation of the differentiation machinery because its DR makes cells more prone to adipogenic differentiation even in the absence of the adipogenic inducers. Prep1 DR expands the DNA binding landscape of C/EBP beta (CCAAT enhancer binding protein beta) without affecting its expression or activation. The data indicate that Prep1 normally acts by restricting DNA binding of transcription factors to adipogenic enhancers, in particular C/EBP beta. | Scientific reports (Nature Publishing Group) 7 (2017). | 2017 | MARONI GIORGIA, LEVANTINI ELENA, MAGLI MARIA CRISTINA | transcriptional regulation, bone-marrow mesenchymal stem cells, adipogenic differentiation, C/EBP beta binding to chromatin, hypomorphic mice, transgenic model, ChIP-seq, RNA-seq | 10.1038/s41598-017-15828-1 |
| 380053 | Articolo in rivista | ITSoneDB: a comprehensive collection of eukaryotic ribosomal RNA Internal Transcribed Spacer 1 (ITS1) sequences. | Santamaria, Monica, Fosso, Bruno, Licciulli, Flavio, Balech, Bachir, Larini, Ilaria, Grillo, Giorgio, De Caro, Giorgio, Liuni, Sabino, Pesole, Graziano | A holistic understanding of environmental communities is the new challenge of metagenomics. Accordingly, the amplicon-based or metabarcoding approach, largely applied to investigate bacterial microbiomes, is moving to the eukaryotic world too. Indeed, the analysis of metabarcoding data may provide a comprehensive assessment of both bacterial and eukaryotic composition in a variety of environments, including human body. In this respect, whereas hypervariable regions of the 16S rRNA are the de facto standard barcode for bacteria, the Internal Transcribed Spacer 1 (ITS1) of ribosomal RNA gene cluster has shown a high potential in discriminating eukaryotes at deep taxonomic levels. As metabarcoding data analysis rely on the availability of a well-curated barcode reference resource, a comprehensive collection of ITS1 sequences supplied with robust taxonomies, is highly needed. To address this issue, we created ITSoneDB (available at http://itsonedb.cloud.ba.infn.it/) which in its current version hosts 985 240 ITS1 sequences spanning over 134 000 eukaryotic species. Each ITS1 is mapped on the NCBI reference taxonomy with its start and end positions precisely annotated. ITSoneDB has been developed in agreement to the FAIR guidelines by enabling the users to query and download its content through a simple web-interface and access relevant metadata by cross-linking to European Nucleotide Archive. | Nucleic acids research (Online) (2017). | 2017 | LICCIULLI VITO FLAVIO, GRILLO GIORGIO, LIUNI SABINO, SANTAMARIA MONICA, BALECH BACHIR | * | 10.1093/nar/gkx855 |
| 380055 | Articolo in rivista | A compositional data perspective on studying the associations between macronutrient balances and diseases. | Leite, M L C, Prinelli, F | * | European journal of clinical nutrition (2017). | 2017 | PRINELLI FEDERICA, CORREA LEITE MARIA LEA | * | 10.1038/ejcn.2017.126 |
| 380056 | Articolo in rivista | Different Exposures to Risk Factors Do Not Explain the Inverse Relationship of Occurrence Between Cancer and Neurodegenerative Diseases: An Italian Nested Case-control Study. | Prinelli, Federica, Adorni, Fulvio, Leite, Maria Lea Correa, Pettenati, Carla, Russo, Antonio, Di Santo, Simona, Musicco, Massimo | Several studies reported that cancer is less frequent in persons with Alzheimer's and Parkinson's Diseases (AD/PD) and vice-versa. We evaluated whether a different distribution of known nongenetic risk factors for cancer and AD/PD, might explain their inverse relationship of occurrence. We nested 2 case-control studies in a subsample of a large cohort of 1,000,000 resident in Lombardy Region in Italy (n=1515), followed-up for cancer and AD/PD occurrence since 1991 until 2012. Conditional logistic regression was performed to determine the odds ratios (OR) and 95% confidence intervals (CI) of AD/PD in subjects with and without cancer and the risk of cancer in those with and without AD/PD. A total of 54 incident cases of AD/PD and 347 cancer cases were matched with 216 and 667 controls, respectively. After controlling for low education, obesity, history of hypertension, diabetes, dyslipidemia, physical activity, smoking habit, alcohol consumption, and dietary habit, cancer was found inversely associated with the risk of AD/PD (OR, 0.66; 95% CI, 0.32-1.38), and the risk of cancer in AD/PD was similarly reduced (OR, 0.42; 95% CI, 0.20-0.91). Different exposures to nongenetic risk factors of both diseases do not explain their competitive relationship of occurrence. | Alzheimer disease and associated disorders (Online) (2017). | 2017 | PRINELLI FEDERICA, ADORNI FULVIO DANIELE, CORREA LEITE MARIA LEA, MUSICCO MASSIMO | * | 10.1097/WAD.0000000000000204 |
| 380161 | Contributo in volume | Personalised guidance services for optimising lifestyle in teen-agers through awareness, motivation and engagement - PEGASO: A pilot study protocol | Adorni F., Prinelli F., Crespi C., Puigdomenech E., Gomez S.F., Mireia E.C., Conxa C.A., McKinstry B., Martin A., McCloughan L., Lang A., Condon L., Atkinson S., Rashid R. | Adolescence is a vulnerable stage in which the development of certain unhealthy behaviours can occur. The prevalence of overweight and obesity among European teenagers is rapidly increasing and may lead to both short- and long-term health complications. The fast development of the ICT, and in particular mobile technologies, together with their increasing diffusion among the EU populations offers an important opportunity for facing these issues in an innovative manner introducing the possibility of a new technological framework to re-design the healthcare system model. The PEGASO project relies on a mobile-and cloud-based ICT platform to set up a system of new healthcare services targeted to teens for obesity prevention. The present paper describes the protocol of a six-month Pilot Study that will be carried out on 525 adolescents in four different European sites (Italy, Catalonia, England, Scotland), aiming to evaluate the PEGASO system usability and effectiveness in promoting healthy lifestyles. | , pp. 45-52, 2017 | 2017 | CRESPI CHIARA, ADORNI FULVIO DANIELE, PRINELLI FEDERICA | Lifestyles, Obesity Prevention, m-Health, Study Protocol | 10.1007/978-3-319-58877-3_6 |
| 378486 | Articolo in rivista | SOS2 and ACP1 Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function | Li, Man, Li, Yong, Weeks, Olivia, Mijatovic, Vladan, Teumer, Alexander, Huffman, Jennifer E., Tromp, Gerard, Fuchsberger, Christian, Gorski, Mathias, Lyytikainen, Leo-Pekka, Nutile, Teresa, Sedaghat, Sanaz, Sorice, Rossella, Tin, Adrienne, Yang, Qiong, Ahluwalia, Tarunveer S., Arking, Dan E., Bihlmeyer, Nathan A., Boeger, Carsten A., Carroll, Robert J., Chasman, Daniel I., Comelis, Marilyn C., Dehghan, Abbas, Faul, Jessica D., Feitosa, Mary F., Gambaro, Giovanni, Gasparini, Paolo, Giulianini, Franco, Heid, Iris, Huang, Jinyan, Imboden, Medea, Jackson, Anne U., Jeff, Janina, Jhun, Min A., Katz, Ronit, Kifley, Annette, Kilpelainen, Tuomas, Kumar, Ashish, Laakso, Markku, Li-Gao, Ruifang, Lohman, Kurt, Lu, Yingchang, Maegi, Reedik, Malerba, Giovanni, Mihailov, Evelin, Mohlke, Karen L., Mook-Kanamori, Dennis O., Robino, Antonietta, Ruderfer, Douglas, Salvi, Erika, Schick, Ursula M., Schulz, Christina-Alexandra, Smith, Albert V., Smith, Jennifer A., Traglia, Michela, Yerges-Armstrong, Laura M., Zhao, Wei, Goodarzi, Mark O., Kraja, Aldi T., Liu, Chunyu, Wessel, Jennifer, Boerwinkle, Eric, Borecki, Ingrid B., Bork-Jensen, Jette, Bottinger, Erwin P., Braga, Daniele, Brandslund, Ivan, Brody, Jennifer A., Campbell, Archie, Carey, David J., Christensen, Cramer, Coresh, Josef, Crook, Errol, Curhan, Gary C., Cusi, Daniele, de Boer, Ian H., de Vries, Aiko P. J., Denny, Joshua C., Devuyst, Olivier, Dreisbach, Albert W., Endlich, Karlhans, Esko, Tonu, Franco, Oscar H., Fulop, Tibor, Gerhard, Glenn S., Gluemer, Charlotte, Gottesman, Omri, Grarup, Niels, Gudnason, Vilmundur, Hansen, Torben, Harris, Tamara B., Hayward, Caroline, Hocking, Lynne, Hofman, Albert, Hu, Frank B., Husemoen, Lise Lotte N., Jackson, Rebecca D., Jorgensen, Torben, Jorgensen, Marit E., Kaehoenen, Mika, Kardia, Sharon L. R., Koenig, Wolfgang, Kooperberg, Charles, Kriebel, Jennifer, Launer, Lenore J., Lauritzen, Torsten, Lehtimaki, Terho, Levy, Daniel, Linksted, Pamela, Linneberg, Allan, Liu, Yongmei, Loos, Ruth J. F., Lupo, Antonio, Meisinger, Christine, Melander, Olle, Metspalu, Andres, Mitchell, Paul, Nauck, Matthias, Nuernberg, Peter, Orho-Melander, Marju, Parsa, Afshin, Pedersen, Oluf, Peters, Annette, Peters, Ulrike, Polasek, Ozren, Porteous, David, Probst-Hensch, Nicole M., Psaty, Bruce M., Qi, Lu, Raitakari, Olli T., Reiner, Alex P., Rettig, Rainer, Ridker, Paul M., Rivadeneira, Fernando, Rossouw, Jacques E., Schmidt, Frank, Siscovick, David, Soranzo, Nicole, Strauch, Konstantin, Toniolo, Daniela, Turner, Stephen T., Uitterlinden, Andre G., Ulivi, Sheila, Velayutham, Dinesh, Voelker, Uwe, Volzke, Henry, Waldenberger, Melanie, Wang, Jie Jin, Weir, David R., Witte, Daniel, Kuivaniemi, Helena, Fox, Caroline S., Franceschini, Nora, Goessling, Wolfram, Koettgen, Anna, Chu, Audrey Y. | Genome-wide association studies have identified >50 common variants associated with kidney function, but these variants do not fully explain the variation in eGFR. We performed a two-stage meta-analysis of associations between genotypes from the Illumina exome array and eGFR on the basis of serum creatinine (eGFRcrea) among participants of European ancestry from the CKDGen Consortium (n(stage1);111,666;n(stage2): 48,343). In single-variant analyses, we identified single nucleotide polymorphisms at seven new loci associated with eGFRcrea (PPM1J, EDEM3, ACP1, SPEG, EYA4, CYP1A1, and ATXN2L; P-stage1<3.7 x10(-7)), of which most were common and annotated as nonsynonymous variants. Gene-based analysis identified associations of functional rare variants in three genes with eGFRcrea, including a novel association with the SOS Ras/Rho guanine nucleotide exchange factor 2 gene, SOS2 (P=5.4x 10(-8) by sequence kernel association test). Experimental follow-up in zebrafish embryos revealed changes in glomerular gene expression and renal tubule morphology in the embryonic kidney of acp1- and sos2-knockdowns. These developmental abnormalities associated with altered blood clearance rate and heightened prevalence of edema. This study expands the number of loci associated with kidney function and identifies novel genes with potential roles in kidney formation. | Journal of the American Society of Nephrology 28 (2017): 981-994. | 2017 | NUTILE TERESA | human genetics; kidney development; renal function | 10.1681/ASN.2016020131 |
| 380165 | Articolo in rivista | A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape | Ried, Janina S., Jeff, Janina M., Chu, Audrey Y., Bragg-Gresham, Jennifer L., van Dongen, Jenny, Huffman, Jennifer E., Ahluwalia, Tarunveer S., Cadby, Gemma, Eklund, Niina, Eriksson, Joel, Esko, Tonu, Feitosa, Mary F., Goel, Anuj, Gorski, Mathias, Hayward, Caroline, Heard-Costa, Nancy L., Jackson, Anne U., Jokinen, Eero, Kanoni, Stavroula, Kristiansson, Kati, Kutalik, Zoltan, Lahti, Jari, Luan, Jian'an, Maegi, Reedik, Mahajan, Anubha, Mangino, Massimo, Medina-Gomez, Carolina, Monda, Keri L., Nolte, Ilja M., Perusse, Louis, Prokopenko, Inga, Qi, Lu, Rose, Lynda M., Salvi, Erika, Smith, Megan T., Snieder, Harold, Stancakova, Alena, Sung, Yun Ju, Tachmazidou, Ioanna, Teumer, Alexander, Thorleifsson, Gudmar, van der Harst, Pim, Walker, Ryan W., Wang, Sophie R., Wild, Sarah H., Willems, Sara M., Wong, Andrew, Zhang, Weihua, Albrecht, Eva, Alves, Alexessander Couto, Bakker, Stephan J. L., Barlassina, Cristina, Bartz, Traci M., Beilby, John, Bellis, Claire, Bergman, Richard N., Bergmann, Sven, Blangero, John, Blueher, Matthias, Boerwinkle, Eric, Bonnycastle, Lori L., Bornstein, Stefan R., Bruinenberg, Marcel, Campbell, Harry, Chen, Yii-Der Ida, Chiang, Charleston W. K., Chines, Peter S., Collins, Francis S., Cucca, Fracensco, Cupples, L. Adrienne, D'Avila, Francesca, de Geus, Eco J. C., Dedoussis, George, Dimitriou, Maria, Doering, Angela, Eriksson, Johan G., Farmaki, Aliki-Eleni, Farrall, Martin, Ferreira, Teresa, Fischer, Krista, Forouhi, Nita G., Friedrich, Nele, Gjesing, Anette Prior, Glorioso, Nicola, Graff, Mariaelisa, Grallert, Harald, Grarup, Niels, Graessler, Juergen, Grewal, Jagvir, Hamsten, Anders, Harder, Marie Neergaard, Hartman, Catharina A., Hassinen, Maija, Hastie, Nicholas, Hattersley, Andrew Tym, Havulinna, Aki S., Heliovaara, Markku, Hillege, Hans, Hofman, Albert, Holmen, Oddgeir, Homuth, Georg, Hottenga, Jouke-Jan, Hui, Jennie, Husemoen, Lise Lotte, Hysi, Pirro G., Isaacs, Aaron, Ittermann, Till, Jalilzadeh, Shapour, James, Alan L., Jorgensen, Torben, Jousilahti, Pekka, Jula, Antti, Justesen, Johanne Marie, Justice, Anne E., Kahonen, Mika, Karaleftheri, Maria, Khaw, Kay Tee, Keinanen-Kiukaanniemi, Sirkka M., Kinnunen, Leena, Knekt, Paul B., Koistinen, Heikki A., Kolcic, Ivana, Kooner, Ishminder K., Koskinen, Seppo, Kovacs, Peter, Kyriakou, Theodosios, Laitinen, Tomi, Langenberg, Claudia, Lewin, Alexandra M., Lichtner, Peter, Lindgren, Cecilia M., Lindstrom, Jaana, Linneberg, Allan, Lorbeer, Roberto, Lorentzon, Mattias, Luben, Robert, Lyssenko, Valeriya, Mannisto, Satu, Manunta, Paolo, Leach, Irene Mateo, McArdle, Wendy L., Mcknight, Barbara, Mohlke, Karen L., Mihailov, Evelin, Milani, Lili, Mills, Rebecca, Montasser, May E., Morris, Andrew P., Mueller, Gabriele, Musk, Arthur W., Narisu, Narisu, Ong, Ken K., Oostra, Ben A., Osmond, Clive, Palotie, Aarno, Pankow, James S., Paternoster, Lavinia, Penninx, Brenda W., Pichler, Irene, Pilia, Maria G., Polasek, Ozren, Pramstaller, Peter P., Raitakari, Olli T., Rankinen, Tuomo, Rao, D. C., Rayner, Nigel W., Ribel-Madsen, Rasmus, Rice, Treva K., Richards, Marcus, Ridker, Paul M., Rivadeneira, Fernando, Ryan, Kathy A., Sanna, Serena, Sarzynski, Mark A., Scholtens, Salome, Scott, Robert A., Sebert, Sylvain, Southam, Lorraine, Sparso, Thomas Hempel, Steinthorsdottir, Valgerdur, Stirrups, Kathleen, Stolk, Ronald P., Strauch, Konstantin, Stringham, Heather M., Swertz, Morris A., Swift, Amy J., Toenjes, Anke, Tsafantakis, Emmanouil, van der Most, Peter J., Van Vliet-Ostaptchouk, Jana V., Vandenput, Liesbeth, Vartiainen, Erkki, Venturini, Cristina, Verweij, Niek, Viikari, Jorma S., Vitart, Veronique, Vohl, Marie-Claude, Vonk, Judith M., Waeber, Gerard, Widen, Elisabeth, Willemsen, Gonneke, Wilsgaard, Tom, Winkler, Thomas W., Wright, Alan F., Yerges-Armstrong, Laura M., Zhao, Jing Hua, Zillikens, M. Carola, Boomsma, Dorret I., Bouchard, Claude, Chambers, John C., Chasman, Daniel I., Cusi, Daniele, Gansevoort, Ron T., Gieger, Christian, Hansen, Torben, Hicks, Andrew A., Hu, Frank, Hveem, Kristian, Jarvelin, Marjo-Riitta, Kajantie, Eero, Kooner, Jaspal S., Kuh, Diana, Kuusisto, Johanna, Laakso, Markku, Lakka, Timo A., Lehtimaeki, Terho, Metspalu, Andres, Njolstad, Inger, Ohlsson, Claes, Oldehinkel, Albertine J., Palmer, Lyle J., Pedersen, Oluf, Perola, Markus, Peters, Annette, Psaty, Bruce M., Puolijoki, Hannu, Rauramaa, Rainer, Rudan, Igor, Salomaa, Veikko, Schwarz, Peter E. H., Shudiner, Alan R., Smit, Jan H., Sorensen, Thorkild I. A., Spector, Timothy D., Stefansson, Kari, Stumvoll, Michael, Tremblay, Angelo, Tuomilehto, Jaakko, Uitterlinden, Andre G., Uusitupa, Matti, Voelker, Uwe, Vollenweider, Peter, Wareham, Nicholas J., Watkins, Hugh, Wilson, James F., Zeggini, Eleftheria, Abecasis, Goncalo R., Boehnke, Michael, Borecki, Ingrid B., Deloukas, Panos, van Duijn, Cornelia M., Fox, Caroline, Groop, Leif C., Heid, Iris M., Hunter, David J., Kaplan, Robert C., McCarthy, Mark I., North, Kari E., O'Connell, Jeffrey R., Schlessinger, David, Thorsteinsdottir, Unnur, Strachan, David P., Frayling, Timothy, Hirschhorn, Joel N., Mueller-Nurasyid, Martina, Loos, Ruth J. F. | Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways. | Nature communications 7 (2016). | 2016 | CUSI DANIELE, SANNA SERENA | Genome-wide association studies Statistical methods | 10.1038/ncomms13357 |
| 379058 | Articolo in rivista | Development and validation of new predictive equation for resting energy expenditure in adults with overweight and obesity. | Ximena Orozco-Ruiz a, Edgar Pichardo-Ontiveros a, Armando R. Tovar a, Nimbe Torres a, Isabel Medina-Vera a, Federica Prinelli c, Claudio L. Lafortuna b, Martha Guevara-Cruz a | Accurate predictive equations of resting energy expenditure (REE) are crucial in devising nutritional strategies to manage overweight/obesity, especially in countries where these are highly prevalent. REE is the most common measurement used to estimate energy requirements in the nutritional context; the most accurate method of measuring REE is indirect calorimetry (IC). However, this method is costly and often rarely feasible in many clinical settings. The objective of the present study was to develop and validate a new equation for predicting REE in adults with overweight and obesity. METHODS: This was a cross-sectional study including 410 men and women with overweight and obesity (20-60 y). Participants were randomly assigned; the development group included 200 subjects and the validation group 210 subjects. The new predictive equation was derived using stepwise multiple linear regression analysis. The accuracy of the new equation was compared to several existing predictive equations (PEs). The accuracy rate was calculated as the percentage of subjects whose REE-PE was within +-10% of the REE-IC. REE was measured by IC and anthropometric measurements. RESULTS: One predictive equation was developed (NEQ) in which weight was the strongest predictor of REE. Compared with others predicted equations already using, the new designed equation showed the less mean bias (Kj/day): NEQ: 25.7, Valencia:129, WHO/FAO/United Nations University: 270, Mifflin-St Jeor: 308, Owen: -808, Carrasco: -1097, Korth: -36.4, Johnstone: -375, Livingstone: -315, De Lorenzo: -28.3, Lazzer: -123, Muller: -145, Huang: -399 and Bernstein: -1335. CONCLUSIONS: The present equation had the highest predictive accuracy in subjects with overweight or obesity compared with the previous equations derived from different populations. Thus, these new equation can be used to assist the nutritional management of these subjects. | Clinical nutrition (Edinb.) 37 (2017): 2198-2205. | 2017 | PRINELLI FEDERICA, LAFORTUNA CLAUDIO | Energy expenditure, Predicted equation, Overweight, Obesity | 10.1016/j.clnu.2017.10.022. |
| 368985 | Articolo in rivista | Exploring the under-investigated "microbial dark matter" of drinking water treatment plants | Bruno, Antonia, Sandionigi, Anna, Rizzi, Ermanno, Bernasconi, Marzia, Vicario, Saverio, Galimberti, Andrea, Cocuzza, Clementina, Labra, Massimo, Casiraghi, Maurizio | Scientists recently reported the unexpected detection of unknown or poorly studied bacterial diversity in groundwater. The ability to uncover this neglected biodiversity mainly derives from technical improvements, and the term "microbial dark matter" was used to group taxa poorly investigated and not necessarily monophyletic. We focused on such under-investigated microbial dark matter of drinking water treatment plant from groundwater, across carbon filters, to post-chlorination. We tackled this topic using an integrated approach where the efficacy of stringent water filtration (10000 MWCO) in recovering even the smallest environmental microorganisms was coupled with high-throughput DNA sequencing to depict an informative spectrum of the neglected microbial diversity. Our results revealed that the composition of bacterial communities varies across the plant system: Parcubacteria (OD1) superphylum is found mainly in treated water, while groundwater has the highest heterogeneity, encompassing non-OD1 candidate phyla (Microgenomates, Saccharibacteria, Dependentiae, OP3, OP1, BRC1, WS3). Carbon filters probably act as substrate for microorganism growth and contribute to seeding water downstream, since chlorination does not modify the incoming bacterial community. New questions arise about the role of microbial dark matter in drinking water. Indeed, our results suggest that these bacteria might play a central role in the microbial dynamics of drinking water. | Scientific reports (Nature Publishing Group) 7 (2017): 44350-44350. | 2017 | RIZZI ERMANNO, VICARIO SAVERIO | Evolution, Water, microbiology | 10.1038/srep44350 |
| 382118 | Articolo in rivista | The Hidden Genomic and Transcriptomic Plasticity of Giant Marker Chromosomes in Cancer | Gemma Macchia, Marco Severgnini, Stefania Purgato, Doron Tolomeo, Hilen Casciaro, Ingrid Cifola, Alberto L'Abbate, Anna Loverro, Orazio Palumbo, Massimo Carella, Laurence Bianchini, Giovanni Perini, Gianluca De Bellis, Fredrik Mertens, Mariano Rocchi, Clelia T. Storlazzi | Genome amplification in the form of rings or giant rod-shaped marker chromosomes is a common genetic alteration in soft tissue tumours. The mitotic stability of these structures is often rescued by perfectly functioning analphoid neocentromeres, which therefore significantly contribute to cancer progression. Here, we disentangled the genomic architecture of many neocentromeres stabilizing marker chromosomes in well-differentiated liposarcoma and lung sarcomatoid carcinoma samples. In cells carrying heavily rearranged RGMs, these structures were assembled as patchworks of multiple short amplified sequences, disclosing an extremely high level of complexity and definitely ruling out the existence of regions prone to the neocentromere seeding. Moreover, by studying two well-differentiated liposarcoma samples derived from the onset and the recurrence of the same tumor, we documented an expansion of the neocentromeric domain that occurred during tumor progression, which reflects a strong selective pressure acting toward the improvement of the neocentromeric functionality in cancer. In lung sarcomatoid carcinoma cells, extensive "centromere sliding" phenomena giving rise to multiple, closely mapping neocentromeric epialleles on separate co-existing markers occur likely due to the instability of neocentromeres arising in cancer cells. Finally, by investigating the transcriptional activity of neocentromeres, we came across a burst of chimeric transcripts, both by extremely complex genomic rearrangements, and cis/trans-splicing events. Post-transcriptional editing events have been reported to expand and variegate the genetic repertoire of higher eukaryotes, so they might have a determining role in cancer. The increased incidence of fusion transcripts, might act as a driving force for the genomic amplification process, together with the increased transcription of oncogenes. | Genetics (Austin Tex., Online) 208 (2018): 951-961. | 2018 | DE BELLIS GIANLUCA, CIFOLA INGRID, SEVERGNINI MARCO, L'ABBATE ALBERTO | neocentromere fusion transcript Liposarcoma Lung Sarcomatoid Carcinoma gene amplification LSC WDLPS | 10.1534/genetics.117.300552 |
| 382137 | Articolo in rivista | VISPA2: a scalable pipeline for high-throughput identification and annotation of vector integration sites | Spinozzi G1, Calabria A1, Brasca S1, Beretta S2, Merelli I3, Milanesi L3, Montini E4. | BACKGROUND: Bioinformatics tools designed to identify lentiviral or retroviral vector insertion sites in the genome of host cells are used to address the safety and long-term efficacy of hematopoietic stem cell gene therapy applications and to study the clonal dynamics of hematopoietic reconstitution. The increasing number of gene therapy clinical trials combined with the increasing amount of Next Generation Sequencing data, aimed at identifying integration sites, require both highly accurate and efficient computational software able to correctly process "big data" in a reasonable computational time. RESULTS: Here we present VISPA2 (Vector Integration Site Parallel Analysis, version 2), the latest optimized computational pipeline for integration site identification and analysis with the following features: (1) the sequence analysis for the integration site processing is fully compliant with paired-end reads and includes a sequence quality filter before and after the alignment on the target genome; (2) an heuristic algorithm to reduce false positive integration sites at nucleotide level to reduce the impact of Polymerase Chain Reaction or trimming/alignment artifacts; (3) a classification and annotation module for integration sites; (4) a user friendly web interface as researcher front-end to perform integration site analyses without computational skills; (5) the time speedup of all steps through parallelization (Hadoop free). CONCLUSIONS: We tested VISPA2 performances using simulated and real datasets of lentiviral vector integration sites, previously obtained from patients enrolled in a hematopoietic stem cell gene therapy clinical trial and compared the results with other preexisting tools for integration site analysis. On the computational side, VISPA2 showed a > 6-fold speedup and improved precision and recall metrics (1 and 0.97 respectively) compared to previously developed computational pipelines. These performances indicate that VISPA2 is a fast, reliable and user-friendly tool for integration site analysis, which allows gene therapy integration data to be handled in a cost and time effective fashion. Moreover, the web access of VISPA2 ( http://openserver.itb.cnr.it/vispa/ ) ensures accessibility and ease of usage to researches of a complex analytical tool. We released the source code of VISPA2 in a public repository ( https://bitbucket.org/andreacalabria/vispa2 ). | BMC bioinformatics 18 (2017). | 2017 | MERELLI IVAN, MILANESI LUCIANO | Open source software, Bioinformatics pipeline, Integration site analysis, Gene therapy, High-throughput sequencing, Next-generation sequencing, Workflow | 10.1186/s12859-017-1937-9 |
| 382193 | Contributo in volume | Alcune riflessioni etiche a partire dalla proposta di eliminare la parola "razza" dall'art.3 della Costituzione italiana | Caporale C., Annoni M. | *** | No razza, si cittadinanza. Cellula e genomi XV corso, edited by Carlo Alberto Redi, Manuela Monti, pp. 187-200. Pavia: Ibis, 2017 | 2017 | ANNONI MARCO ANGELO MARIA, CAPORALE CINZIA | *** | |
| 382451 | Articolo in rivista | Speeding Up the Identification of Cystic Fibrosis Transmembrane Conductance Regulator-Targeted Drugs: An Approach Based on Bioinformatics Strategies and Surface Plasmon Resonance. | Rusnati, Marco, Sala, Davide, Orro, Alessandro, Bugatti, Antonella, Trombetti, Gabriele, Cichero, Elena, Urbinati, Chiara, Di Somma, Margherita, Millo, Enrico, Galietta, Luis J. V., Milanesi, Luciano, Fossa, Paola, D'Ursi, Pasqualina | Cystic fibrosis (CF) is mainly caused by the deletion of Phe 508 (DeltaF508) in the cystic fibrosis transmembrane conductance regulator (CFTR) protein that is thus withheld in the endoplasmic reticulum and rapidly degraded by the ubiquitin/proteasome system. New drugs able to rescue DeltaF508-CFTR trafficking are eagerly awaited. An integrated bioinformatics and surface plasmon resonance (SPR) approach was here applied to investigate the rescue mechanism(s) of a series of CFTR-ligands including VX809, VX770 and some aminoarylthiazole derivatives (AAT). Computational studies tentatively identified a large binding pocket in the DeltaF508-CFTR nucleotide binding domain-1 (NBD1) and predicted all the tested compounds to bind to three sub-regions of this main pocket. Noticeably, the known CFTR chaperone keratin-8 (K8) seems to interact with some residues located in one of these sub-pockets, potentially interfering with the binding of some ligands. SPR results corroborated all these computational findings. Moreover, for all the considered ligands, a statistically significant correlation was determined between their binding capability to DeltaF508-NBD1 measured by SPR and the pockets availability measured by computational studies. Taken together, these results demonstrate a strong agreement between the in silico prediction and the SPR-generated binding data, suggesting a path to speed up the identification of new drugs for the treatment of cystic fibrosis. | Molecules (Basel, Online) 23 (2018). | 2018 | D'URSI PASQUALINA, ORRO ALESSANDRO, TROMBETTI GABRIELE ANTONIO, MILANESI LUCIANO | computational chemistry; cystic fibrosis; molecular dynamics; molecular modeling; surface plasmon resonance | 10.3390/molecules23010120 |
| 384539 | Articolo in rivista | Autonomous role of Wiskott-Aldrich Syndrome platelet deficiency in inducing autoimmunity and inflammation. | Sereni L1, Castiello MC2, Marangoni F3, Anselmo A4, di Silvestre D5, Motta S5, Draghici E2, Mantero S6, Thrasher AJ7, Giliani S8, Aiuti A9, Mauri P5, Notarangelo LD10, Bosticardo M2, Villa A11. | BACKGROUND: Wiskott-Aldrich Syndrome (WAS) is an X-linked immunodeficiency characterized by eczema, infections and susceptibility to develop autoimmunity and malignancies. Thrombocytopenia is a constant finding, but its pathogenesis remains elusive. OBJECTIVE: To dissect the basis of WAS platelet (PLT) defect we used a novel conditional mouse model (CoWas) lacking WASp only in the megakaryocytic lineage in presence of a normal immunological environment and in parallel we analysed samples obtained from WAS patients. METHODS: Phenotypical and functional characterization of megakaryocytes and platelets in mutant CoWas mice and WAS patients with and without autoantibodies were performed. Platelet antigen expression was examined through protein expression profile and cluster proteomic interaction network. Platelet immunogenicity was tested by ELISA assays and B and PLTs co-culture. RESULTS: CoWas displayed increased MK numbers and normal thrombopoiesis in vitro but WASp-deficient PLTs had short lifespan and high expression of activation markers. Proteomic analysis identified signatures compatible with defects in cytoskeletal reorganization and metabolism, yet surprisingly increased antigen-processing capabilities. In addition, WASp-deficient PLTs expressed high levels of surface and soluble CD40L and were capable of inducing B-cell activation in vitro. WASp-deficient PLTs were highly immunostimulatory in mice and triggered the generation of antibodies specific for WASp-deficient PLTs even in the context of a normal immune system. WAS patients also showed PLT hyperactivation and elevated plasma soluble CD40L levels correlating with the presence of auto-antibodies. CONCLUSION: Overall, these findings suggest that intrinsic defects in WASp-deficient PLTs decrease their lifespan and dysregulate immune responses, corroborating the role of PLTs as modulators of inflammation and immunity. | The journal of allergy and clinical immunology (Online) (2018). | 2018 | MOTTA SARA, DI SILVESTRE DARIO, MANTERO STEFANO, VILLA ANNA, MAURI PIETRO LUIGI | CD40 ligand; Wiskott-Aldrich syndrome; autoantibodies; autoimmunity; platelet deficiency | 10.1016/j.jaci.2017.12.1000 |
| 384798 | Articolo in rivista | Reply-Letter to the Editor-Superiority of new predictive equation for resting energy expenditure. | Orozco-Ruiz X1, Pichardo-Ontiveros E1, Tovar AR1, Torres N1, Medina-Vera I1, Prinelli F2, Lafortuna CL3, Guevara-Cruz M4. | *** | Clinical nutrition (Edinb.) (2018). | 2018 | PRINELLI FEDERICA, LAFORTUNA CLAUDIO | *** | 10.1016/j.clnu.2018.01.037 |
| 386512 | Articolo in rivista | Insights into vaginal bacterial communities and metabolic profiles of Chlamydia trachomatis infection: Positioning between eubiosis and dysbiosis | Parolin C., Foschi C., Laghi L., Zhu C., Banzola N., Gaspari V., D'Antuono A., Giordani B., Severgnini M., Consolandi C., Salvo M., Cevenini R., Vitali B., Marangoni A. | The vaginal microbiota plays a crucial role in maintaining the health and functioning of the female genital tract, preventing the colonization of urogenital pathogens and sexually transmitted infections. In this study, we characterized the vaginal bacterial communities and the metabolome associated to Chlamydia trachomatis infection (CT: 20 women), compared to healthy condition (H: 22 women) and bacterial vaginosis (BV: 19 women). A microarray-based tool (VaginArray), implemented with a real-time PCR for Gardnerella vaginalis, was used to determine the vaginal bacterial composition, whereas the metabolic profiles were assessed by a proton-based nuclear magnetic resonance (1H-NMR) spectroscopy. CT infection was characterized by bacterial and metabolic signatures similar to healthy condition, even though higher amounts of Lactobacillus iners, as well as depletion of some amino acids, biogenic amines, and succinate marked CT infection. Moreover, the frequency of Lactobacillus crispatus was higher in asymptomatic CT-positive patients than in women with CT-correlated symptoms. We also confirmed the marked differences in the microbiome and metabolome between healthy and BV-affected women. In conclusion, we highlighted microbial and metabolic peculiarities of the vaginal ecosystem in the case of CT infection, even though further studies are needed to understand if the observed alterations precede the infection onset or if the pathogen itself perturbs the vaginal environment. | Frontiers in microbiology 9 (2018). | 2018 | CONSOLANDI CLARISSA, SEVERGNINI MARCO | Bacterial vaginosis, Chlamydia trachomatis, Eubiosis, Vaginal metabolome, Vaginal microbiota | 10.3389/fmicb.2018.00600 |
| 387460 | Articolo in rivista | ChromStruct 4: a Python code to estimate the chromatin structure from Hi-C data | Caudai C., Salerno E., Zoppe M., Merelli I., Tonazzini A. | A method and a stand-alone Python(TM) code to estimate the 3D chromatin structure from chromosome conformation capture data are presented. The method is based on a multiresolution, modified-bead-chain chromatin model, evolved through quaternion operators in a Monte Carlo sampling. The solution space to be sampled is generated by a score function with a data-fit part and a constraint part where the available prior knowledge is implicitly coded. The final solution is a set of 3D configurations that are compatible with both the data and the prior knowledge. The iterative code, provided here as additional material, is equipped with a graphical user interface and stores its results in standard-format files for 3D visualization. We describe the mathematical-computational aspects of the method and explain the details of the code. Some experimental results are reported, with a demonstration of their fit to the data. | IEEE/ACM transactions on computational biology and bioinformatics (Online) 16 (2018): 1867-1878. | 2018 | CAUDAI CLAUDIA, ZOPPE' MONICA MARIA, MERELLI IVAN, SALERNO EMANUELE, TONAZZINI ANNA | Chromosome conformation capture, Chromatin configuration, Bayesian estimation | 10.1109/TCBB.2018.2838669 |
| 387484 | Articolo in rivista | Neuromelanin detection by magnetic resonance imaging (MRI) and its promise as a biomarker for Parkinson's disease | Sulzer D., Cassidy C., Horga G., Kang U.J., Fahn S., Casella L., Pezzoli G., Langley J., Hu X.P., Zucca F.A., Isaias I.U., Zecca L. | The diagnosis of Parkinson's disease (PD) occurs after pathogenesis is advanced and many substantia nigra (SN) dopamine neurons have already died. Now that therapies to block this neuronal loss are under development, it is imperative that the disease be diagnosed at earlier stages and that the response to therapies is monitored. Recent studies suggest this can be accomplished by magnetic resonance imaging (MRI) detection of neuromelanin (NM), the characteristic pigment of SN dopaminergic, and locus coeruleus (LC) noradrenergic neurons. NM is an autophagic product synthesized via oxidation of catecholamines and subsequent reactions, and in the SN and LC it increases linearly during normal aging. In PD, however, the pigment is lost when SN and LC neurons die. As shown nearly 25 years ago by Zecca and colleagues, NM's avid binding of iron provides a paramagnetic source to enable electron and nuclear magnetic resonance detection, and thus a means for safe and noninvasive measure in living human brain. Recent technical improvements now provide a means for MRI to differentiate between PD patients and age-matched healthy controls, and should be able to identify changes in SN NM with age in individuals. We discuss how MRI detects NM and how this approach might be improved. We suggest that MRI of NM can be used to confirm PD diagnosis and monitor disease progression. We recommend that for subjects at risk for PD, and perhaps generally for older people, that MRI sequences performed at regular intervals can provide a pre-clinical means to detect presymptomatic PD. | NPJ Parkinson's disease 4 (2018): 11. | 2018 | ZECCA LUIGI, ZUCCA FABIO ANDREA | neuromelanin, substantia nigra, locus coeruleus, magnetic resonance imaging, Parkinson's disease | 10.1038/s41531-018-0047-3 |
| 387486 | Articolo in rivista | A census of tandemly repeated polymorphic loci in genic regions through the comparative integration of human genome assemblies | Genovese L.M., Geraci F., Corrado L., Mangano E., D'Aurizio R., Bordoni R., Severgnini M., Manzini G., De Bellis G., D'Alfonso S., Pellegrini M. | Polymorphic Tandem Repeat (PTR) is a common form of polymorphism in the human genome. A PTR consists in a variation found in an individual (or in a population) of the number of repeating units of a Tandem Repeat (TR) locus of the genome with respect to the reference genome. Several phenotypic traits and diseases have been discovered to be strongly associated with or caused by specific PTR loci. PTR are further distinguished in two main classes: Short Tandem Repeats (STR) when the repeating unit has size up to 6 base pairs, and Variable Number Tandem Repeats (VNTR) for repeating units of size above 6 base pairs. As larger and larger populations are screened via high throughput sequencing projects, it becomes technically feasible and desirable to explore the association between PTR and a panoply of such traits and conditions. In order to facilitate these studies, we have devised a method for compiling catalogs of PTR from assembled genomes, and we have produced a catalog of PTR for genic regions (exons, introns, UTR and adjacent regions) of the human genome (GRCh38). We applied four different TR discovery software tools to uncover in the first phase 55,223,485 TR (after duplicate removal) in GRCh38, of which 373,173 were determined to be PTR in the second phase by comparison with five assembled human genomes. Of these, 263,266 are not included by state-of-the-art PTR catalogs. The new methodology is mainly based on a hierarchical and systematic application of alignment-based sequence comparisons to identify and measure the polymorphism of TR. While previous catalogs focus on the class of STR of small total size, we remove any size restrictions, aiming at the more general class of PTR, and we also target fuzzy TR by using specific detection tools. Similarly to other previous catalogs of human polymorphic loci, we focus our catalog toward applications in the discovery of disease-associated loci. Validation by cross-referencing with existing catalogs on common clinically-relevant loci shows good concordance. Overall, this proposed census of human PTR in genic regions is a shared resource (web accessible), complementary to existing catalogs, facilitating future genome-wide studies involving PTR. | Frontiers in genetics 9 (2018). | 2018 | MANZINI GIOVANNI, GENOVESE LOREDANA MARIALUISA, PELLEGRINI MARCO, DE BELLIS GIANLUCA, BORDONI ROBERTA, SEVERGNINI MARCO, GERACI FILIPPO, D'AURIZIO ROMINA, MANGANO ELEONORA | Catalog, Fuzzy tandem repeats, Genic regions, Measure of polymorphism, Polymorphic tandem repeats, Short tandem repeats, Tandem repeat detection tools, Variable number tandem repeats | 10.3389/fgene.2018.00155 |
| 387911 | Contributo in atti di convegno | Parallelizable strategy for the estimation of the 3D structure of biological macromolecules | Caudai C., Zoppe M., Salerno E., Merelli I., Tonazzini A. | We present a parallelizzable, multilevel algorithm for the study of three-dimensional structure of biological macromolecules, applied to two fundamental topics: the 3D reconstruction of Chromatin and the elaboration of motion of proteins. For Chromatin, starting from contact data obtained through Chromosome Conformation Capture techniques, our method first subdivides the data matrix in biologically relevant blocks, and then treats them separately, at several levels, depending on the initial data resolution. The result is a family of configurations for the entire fiber, each one compatible with both experimental data and prior knowledge about specific genomes. For Proteins, the method is conceived as a solution for the problem of identifying motion and alternative conformations to the deposited structures. The algorithm, using quaternions, processes the main chain and the aminoacid side chains independently; it then exploits a Monte Carlo method for selection of biologically acceptable conformations, based on energy evaluation, and finally returns a family of conformations and of trajectories at single atom resolution. | PDP 2018 - 26th Euromicro International Conference on Parallel, Distributed and Network-based Processing (PDP), pp. 134-137, Cambridge, UK, 21-23 March 2018 | 2018 | CAUDAI CLAUDIA, ZOPPE' MONICA MARIA, MERELLI IVAN, SALERNO EMANUELE, TONAZZINI ANNA | Parallel Computing, Macromolecules, Hierarchical Reconstruction, Chromatin, Protein Motion | 10.1109/PDP2018.2018.00026 |
| 388486 | Articolo in rivista | Low-power portable devices for metagenomics analysis: Fog computing makes bioinformatics ready for the Internet of Things | I. Merelli, L. Morganti, E. Corni, C. Pellegrino, D. Cesini, L. Roverelli, G. Zereik, D. D'Agostino | Portable sequencing machines, such as the Oxford Nanopore MinION, are making the genome sequencing ubiquitous. This can be particularly interesting for identifying specific bacteria in air-filters or waters and for monitoring the microbioma composition in cultivated soils or in different animal samples, using a simple and portable approach. However, a main problem of these portable sequencing devices is that they stream huge amounts of data, which management can be actually challenging. Low-power System-on-Chip architectures represent a feasible way for designing a solution, based on the Fog computing paradigm, for processing locally the raw data, considering both the base calling step and the genome alignment part, and for sending only meaningful results over Internet. Cloud services can be then used to collect and integrate results in a Internet of Things framework, in order to trigger notifications or alarms and, in perspective, for more sophisticated applications based on statistical or machine learning approaches. | Future generation computer systems 88 (2018): 467-478. | 2018 | ROVERELLI LUCA, ZEREIK GABRIELE, D'AGOSTINO DANIELE, MERELLI IVAN | Metagenomics, Environmental genomics, Fog computing, machine learning, Cloud computing, internet of things | 10.1016/j.future.2018.05.010 |
| 389364 | Articolo in rivista | Neuromelanin organelles are specialized autolysosomes that accumulate undegraded proteins and lipids in aging human brain and are likely involved in Parkinson's disease | Zucca F.A., Vanna R., Cupaioli F.A., Bellei C., De Palma A., Di Silvestre D., Mauri P., Grassi S., Prinetti A., Casella L., Sulzer D., Zecca L. | During aging, neuronal organelles filled with neuromelanin (a dark-brown pigment) and lipid bodies accumulate in the brain, particularly in the substantia nigra, a region targeted in Parkinson's disease. We have investigated protein and lipid systems involved in the formation of these organelles and in the synthesis of the neuromelanin of human substantia nigra. Membrane and matrix proteins characteristic of lysosomes were found in neuromelanin-containing organelles at a lower number than in typical lysosomes, indicating a reduced enzymatic activity and likely impaired capacity for lysosomal and autophagosomal fusion. The presence of proteins involved in lipid transport may explain the accumulation of lipid bodies in the organelle and the lipid component in neuromelanin structure. The major lipids observed in lipid bodies of the organelle are dolichols with lower amounts of other lipids. Proteins of aggregation and degradation pathways were present, suggesting a role for accumulation by this organelle when the ubiquitin-proteasome system is inadequate. The presence of proteins associated with aging and storage diseases may reflect impaired autophagic degradation or impaired function of lysosomal enzymes. The identification of typical autophagy proteins and double membranes demonstrates the organelle's autophagic nature and indicates that it has engulfed neuromelanin precursors from the cytosol. Based on these data, it appears that the neuromelanin-containing organelle has a very slow turnover during the life of a neuron and represents an intracellular compartment of final destination for numerous molecules not degraded by other systems. | NPJ Parkinson's disease 4 (2018): 17. | 2018 | CUPAIOLI FRANCESCA ANNA, VANNA RENZO, ZECCA LUIGI, ZUCCA FABIO ANDREA, DE PALMA ANTONELLA, DI SILVESTRE DARIO, BELLEI CHIARA, MAURI PIETRO LUIGI | neuromelanin pigment, neuromelanin-containing organelles, brain aging, human substantia nigra, Parkinson's disease, protein profile, lipid profile, autophagic lysosomes | 10.1038/s41531-018-0050-8 |
| 392379 | Articolo in rivista | Genome sequencing of Prototheca zopfii genotypes 1 and 2 provides evidence of a severe reduction in organellar genomes | Severgnini, Marco, Lazzari, Barbara, Lazzari, Barbara, Capra, Emanuele, Chessa, Stefania, Luini, Mario, Bordoni, Roberta, Castiglioni, Bianca, Ricchi, Matteo, Cremonesi, Paola | Prototheca zopfii (P. zopfii, class Trebouxiophyceae, order Chlorellales, family Chlorellaceae), a non-photosynthetic predominantly free-living unicellular alga, is one of the few pathogens belonging to the plant kingdom. This alga can affect many vertebrate hosts, sustaining systemic infections and diseases such as mastitis in cows. The aim of our work was to sequence and assemble the P. zopfii genotype 1 and genotype 2 mitochondrial and plastid genomes. Remarkably, the P. zopfii mitochondrial (38 Kb) and plastid (28 Kb) genomes are models of compaction and the smallest known in the Trebouxiophyceae. As expected, the P. zopfii genotype 1 and 2 plastid genomes lack all the genes involved in photosynthesis, but, surprisingly, they also lack those coding for RNA polymerases. Our results showed that plastid genes are actively transcribed in P. zopfii, which suggests that the missing RNA polymerases are substituted by nuclear-encoded paralogs. The simplified architecture and highly-reduced gene complement of the P. zopfii mitochondrial and plastid genomes are closer to those of P. stagnora and the achlorophyllous obligate parasite Helicosporidium than to those of P. wickerhamii or P. cutis. This similarity is also supported by maximum likelihood phylogenetic analyses inferences. Overall, the P. zopfii sequences reported here, which include nuclear genome drafts for both genotypes, will help provide both a deeper understanding of the evolution of Prototheca spp. and insights into the corresponding host/pathogen interactions. | Scientific reports (Nature Publishing Group) 8 (2018). | 2018 | CAPRA EMANUELE, LAZZARI BARBARA, CASTIGLIONI BIANCA MARIA ELISABETTA, BORDONI ROBERTA, SEVERGNINI MARCO, CREMONESI PAOLA, CHESSA STEFANIA | prototheca zopfii, sequencing, organelles | 10.1038/s41598-018-32992-0 |
| 392769 | Articolo in rivista | Antarctic marine ciliates under stress: superoxide dismutases from the psychrophilic Euplotes focardii are cold-active yet heat tolerant enzymes | Pischedda A, Ramasamy KP, Mangiagalli M, Chiappori F, Milanesi L, Miceli C, Pucciarelli S, Lotti M | Oxidative stress is a particularly severe threat to Antarctic marine polar organisms because they are exposed to high dissolved oxygen and to intense UV radiation. This paper reports the features of three superoxide dismutases from the Antarctic psychrophilic ciliate Euplotes focardii that faces two environmental challenges, oxidative stress and low temperature. Two out of these are Cu, Zn superoxide dismutases (named Ef-SOD1a and Ef-SOD1b) and one belongs to the Mn-containing group (Ef-SOD2). Ef-SOD1s and Ef-SOD2 differ in their evolutionary history, expression and overall structural features. Ef-SOD1 genes are expressed at different levels, with Ef-SOD1b mRNA 20-fold higher at the ciliate optimal temperature of growth (4 degrees C). All Ef-SOD enzymes are active at 4 degrees C, consistent with the definition of cold-adapted enzymes. At the same time, they display temperatures of melting in the range 50-70 degrees C and retain residual activity after incubation at 65-75 degrees C. Supported by data of molecular dynamics simulation, we conclude that the E. focardii SODs combine cold activity, local molecular flexibility and thermo tolerance. | Scientific reports (Nature Publishing Group) 8 (2018). | 2018 | CHIAPPORI FEDERICA, MILANESI LUCIANO | * | 10.1038/s41598-018-33127-1 |
| 392770 | Articolo in rivista | An active lifestyle reinforces the effect of a healthy diet on cognitive function: A population-based longitudinal study | Shakersain B., Rizzuto D., Wang H.-X., Faxen-Irving G., Prinelli F., Fratiglioni L., Xu W. | The joint effect of diet and leisure activity on cognitive function remains unknown. We aimed to verify the hypothesis that an active lifestyle reinforces the effect of the Nordic Prudent Dietary Pattern (NPDP) on cognitive function. A total of 2223 dementia-free Swedish adults aged >=60 with Mini-Mental State Examination (MMSE) scores >=27 were followed for an average of 6 years. MMSE was tested during follow-ups. Diet was assessed by food frequency questionnaire. The NPDP index was calculated and tertiled (low, moderate, and high adherence). Participation in physical, mental and social activities was trichotomised (low, moderate, and intense). An active lifestyle was defined based on the participation in each activity. Data were analyzed using mixed-effects models. Moderate-to-high adherence to NPDP was associated with a reduced decline in the MMSE score (?: 0.19, 95% Confidence Interval (CI): 0.14-0.24). This association became stronger when combined with moderate-to-intense physical (?: 0.34, 95% CI: 0.2-0.45), mental (?: 0.29, 95% CI: 0.21-0.37), or social (?: 0.27, 95% CI: 0.19-0.34) activities. An active lifestyle strengthened the effect of NPDP on cognitive function by two times, and further lowered risk of MMSE decline by 30%. Thus, an active lifestyle reinforces the effect of a healthy diet on preserved cognitive function, and further decreases the risk of cognitive decline. | Nutrients 10 (2018). | 2018 | PRINELLI FEDERICA | active life style; cognitive function; leisure activities; population-based cohort study; the Nordic Prudent Dietary Pattern | 10.3390/nu10091297 |
| 392772 | Articolo in rivista | Dysregulation of MicroRNAs and Target Genes Networks in Peripheral Blood of Patients With Sporadic Amyotrophic Lateral Sclerosis | Maria Liguori, 1, * Nicoletta Nuzziello, 1, + Alessandro Introna, 2, + Arianna Consiglio, 1 Flavio Licciulli, 1 Eustachio D'Errico, 2 Antonio Scarafino, 2 Eugenio Distaso, 2, Isabella L. Simone2 | Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease. While genetics and other factors contribute to ALS pathogenesis, critical knowledge is still missing and validated biomarkers for monitoring the disease activity have not yet been identified. To address those aspects we carried out this study with the primary aim of identifying possible miRNAs/mRNAs dysregulation associated with the sporadic form of the disease (sALS). Additionally, we explored miRNAs as modulating factors of the observed clinical features. Study included 56 sALS and 20 healthy controls (HCs). We analyzed the peripheral blood samples of sALS patients and HCs with a high-throughput next-generation sequencing followed by an integrated bioinformatics/biostatistics analysis. Results showed that 38 miRNAs (let-7a-5p, let-7d-5p, let-7f-5p, let-7g-5p, let-7i-5p, miR-103a-3p, miR-106b-3p, miR-128-3p, miR-130a-3p, miR-130b-3p, miR-144-5p, miR-148a3p, miR-148b-3p, miR-15a-5p, miR-15b-5p, miR-151a-5p, miR-151b, miR-16-5p, miR-182-5p, miR-183-5p, miR-186-5p, miR-22-3p, miR-221-3p, miR-223-3p, miR23a- 3p, miR-26a-5p, miR-26b-5p, miR-27b-3p, miR-28-3p, miR-30b-5p, miR-30c-5p, miR-342-3p, miR-425-5p, miR-451a, miR-532-5p, miR-550a-3p, miR-584-5p, miR93- 5p) were significantly downregulated in sALS. We also found that different miRNAs profiles characterized the bulbar/spinal onset and the progression rate. This observation supports the hypothesis that miRNAs may impact the phenotypic expression of the disease. Genes known to be associated with ALS (e.g., PARK7, C9orf72, ALS2, MATR3, SPG11, ATXN2) were confirmed to be dysregulated in our study. We also identified other potential candidate genes like LGALS3 (implicated in neuroinflammation) and PRKCD (activated in mitochondrial-induced apoptosis). Some of the downregulated genes are involved in molecular bindings to ions (i.e., metals, zinc, magnesium) and in ions-related functions. The genes that we found upregulated were involved in the immune response, oxidation-reduction, and apoptosis. These findings may have important implication for the monitoring, e.g., of sALS progression and therefore represent a significant advance in the elucidation of the disease's underlying molecular mechanisms. The extensive multidisciplinary approach we applied in this study was critically important for its success, especially in complex disorders such as sALS, wherein access to genetic background is a major limitation. | Frontiers in molecular neuroscience 11 (2018). | 2018 | NUZZIELLO NICOLETTA, LICCIULLI VITO FLAVIO, LIGUORI MARIA, CONSIGLIO ARIANNA | sporadic amyotrophic lateral sclerosis, microRNA, target genes, peripheral blood markers, high throughput next-generation sequencing (HT-NGS), clinical parameters, bioinformatics, pathway analysis | 10.3389/fnmol.2018.00288 |
| 392773 | Articolo in rivista | Genome-based analysis for the identification of genes involved in o-xylene degradation in Rhodococcus opacus R7 | Di Canito, Alessandra, Zampolli, Jessica, Orro, Alessandro, D'Ursi, Pasqualina, Milanesi, Luciano, Sello, Guido, Steinbuechel, Alexander, Di Gennaro, Patrizia | BACKGROUND: Bacteria belonging to the Rhodococcus genus play an important role in the degradation of many contaminants, including methylbenzenes. These bacteria, widely distributed in the environment, are known to be a powerhouse of numerous degradation functions, due to their ability to metabolize a wide range of organic molecules including aliphatic, aromatic, polycyclic aromatic compounds (PAHs), phenols, and nitriles. In accordance with their immense catabolic diversity, Rhodococcus spp. possess large and complex genomes, which contain a multiplicity of catabolic genes, a high genetic redundancy of biosynthetic pathways and a sophisticated regulatory network. The present study aimed to identify genes involved in the o-xylene degradation in R. opacus strain R7 through a genome-based approach. RESULTS: Using genome-based analysis we identified all the sequences in the R7 genome annotated as dioxygenases or monooxygenases/hydroxylases and clustered them into two different trees. The akb, phe and prm sequences were selected as genes encoding respectively for dioxygenases, phenol hydroxylases and monooxygenases and their putative involvement in o-xylene oxidation was evaluated. The involvement of the akb genes in o-xylene oxidation was demonstrated by RT-PCR/qPCR experiments after growth on o-xylene and by the selection of the R7-50 leaky mutant. Although the akb genes are specifically activated for o-xylene degradation, metabolic intermediates of the pathway suggested potential alternative oxidation steps, possibly through monooxygenation. This led us to further investigate the role of the prm and the phe genes. Results showed that these genes were transcribed in a constitutive manner, and that the activity of the Prm monooxygenase was able to transform o-xylene slowly in intermediates as 3,4-dimethylphenol and 2-methylbenzylalcohol. Moreover, the expression level of phe genes, homologous to the phe genes of Rhodococcus spp. 1CP and UPV-1 with a 90% identity, could explain their role in the further oxidation of o-xylene and R7 growth on dimethylphenols. CONCLUSIONS: These results suggest that R7 strain is able to degrade o-xylene by the Akb dioxygenase system leading to the production of the corresponding dihydrodiol. Likewise, the redundancy of sequences encoding for several monooxygenases/phenol hydroxylases, supports the involvement of other oxygenases converging in the o-xylene degradation pathway in R7 strain | BMC genomics 19 (2018). | 2018 | ORRO ALESSANDRO, MILANESI LUCIANO, D'URSI PASQUALINA | Rhodococcus, Microbial genomics, o-xylene degradation, Gene clusters, Contaminated soil | 10.1186/s12864-018-4965-6 |
| 392775 | Articolo in rivista | Pilot study on circulating miRNA signature in children with obesity born small for gestational age and appropriate for gestational age | Marzano F1, Faienza MF2, Caratozzolo MF1, Brunetti G3, Chiara M4, Horner DS4, Annese A1, D'Erchia AM1, 5, Consiglio A6, Pesole G1, Sbisa E6, Inzaghi E7, Cianfarani S7, 8, Tullo A1. | Background: Children born small for gestational age (SGA) are at increased risk of metabolic dysfunction. Dysregulation of specific microRNAs (miRNAs) contributes to aberrant gene expression patterns underlying metabolic dysfunction. Objective: We aimed to determine and compare circulating miRNA (c-miRNA) profile of SGA and appropriate for gestational age (AGA) children with obesity and with normal weight, in order to identify biomarkers for early detection of increased risk of developing metabolic dysfunction in SGA and AGA children with obesity. Methods: Small non-coding RNAs from serum of 15 SGA children with obesity (OB-SGA), 10 SGA children with normal weight (NW-SGA), 17 AGA children with obesity (OB-AGA) and 12 AGA children with normal weight (NW-AGA) (mean age 11.2 +- 2.6) have been extracted and sequenced in order to detect and quantify miRNA expression profiles. Results: RNA-seq analyses showed 28 miRNAs dysregulated in OB-SGA vs. NW-SGA and 19 miRNAs dysregulated in OB-AGA vs. NW-AGA. Among these, miR-92a-3p, miR-122-5p, miR-423-5p, miR-484, miR-486-3p and miR-532-5p were up regulated, and miR-181b-5p was down regulated in both OB-SGA and OB-AGA compared with normal weight counterparts. Pathway analysis and miRNA target prediction suggested that these miRNAs were particularly involved in insulin signalling, glucose transport, insulin resistance, cholesterol and lipid metabolism. Conclusion: We identified a specific profile of c-miRNAs in SGA and AGA children with obesity compared with SGA and AGA children with normal weight. These c-miRNAs could represent specific biomarkers for early detection of increased risk of developing metabolic dysfunction in SGA and AGA children with obesity. | pediatric obesity (2018). | 2018 | MARZANO FLAVIANA, TULLO APOLLONIA, PESOLE GRAZIANO, CARATOZZOLO MARIANO FRANCESCO, CONSIGLIO ARIANNA, SBISA' ELISABETTA | Children with obesity; SGA; metabolic disorders; miRNA | 10.1111/ijpo.12439 |
| 394635 | Articolo in rivista | Advances in distributed computing with modern drug discovery | A.J. Banegas-Luna, B. Imbernon, A. Llanes Castro, A. Perez-Garrido, J.P. Ceron-Carrasco, S. Gesing, I. Merelli, D. D'Agostino, H. Perez-Sanchez | Introduction: Computational chemistry dramatically accelerates the drug discovery process and high-performance computing (HPC) can be used to speed up the most expensive calculations. Supporting a local HPC infrastructure is both costly and time consuming and therefore many research groups are moving from in-house solutions to remote distributed computing platforms. Areas covered: The authors focus on the use of distributed technologies, solutions and infrastructures to gain access to HPC capabilities, software tools and datasets to run the complex simulations required in computational drug discovery. Expert opinion: The use of computational tools can decrease the time to market of new drugs. HPC has a crucial role in handling the complex algorithms and large volumes of data required to achieve specificity and avoid undesirable side-effects. Distributed computing environments have clear advantages over in-house solutions in terms of cost and sustainability. The use of infrastructures relying on virtualization reduces set-up costs. Distributed computing resources can be difficult to access, although web-based solutions are becoming increasingly available. There is a trade-off between cost effectiveness and accessibility in using on-demand computing resources rather than free/academic resources. Graphics processing unit computing, with its outstanding parallel computing power, is becoming increasingly important. | Expert opinion on drug discovery (Print) 14 (2019): 9-22. | 2019 | D'AGOSTINO DANIELE, MERELLI IVAN | drug discovery, distributed computing, bioinformatics, cloud computing | 10.1080/17460441.2019.1552936 |
| 395639 | Articolo in rivista | I gilet gialli e le difficolta della disintermediazione | antonucci maria cristina | repertorio sulle difficolta della disintermediazione in un sistema politico. life politics e biopolitica. | formiche.net 04.12.2018 (2018). | 2018 | ANTONUCCI MARIA CRISTINA | gilet gialli, disintermediazione, politica, francia | |
| 396312 | Articolo in rivista | An infrastructure for precision medicine through analysis of big data | Moscatelli, Marco, Manconi, Andrea, Pessina, Mauro, Fellegara, Giovanni, Rampoldi, Stefano, Milanesi, Luciano, Casasco, Andrea, Gnocchi, Matteo | Background: Nowadays, the increasing availability of omics data, due to both the advancements in the acquisition of molecular biology results and in systems biology simulation technologies, provides the bases for precision medicine. Success in precision medicine depends on the access to healthcare and biomedical data. To this end, the digitization of all clinical exams and medical records is becoming a standard in hospitals. The digitization is essential to collect, share, and aggregate large volumes of heterogeneous data to support the discovery of hidden patterns with the aim to define predictive models for biomedical purposes. Patients' data sharing is a critical process. In fact, it raises ethical, social, legal, and technological issues that must be properly addressed. Results: In this work, we present an infrastructure devised to deal with the integration of large volumes of heterogeneous biological data. The infrastructure was applied to the data collected between 2010-2016 in one of the major diagnostic analysis laboratories in Italy. Data from three different platforms were collected (i.e., laboratory exams, pathological anatomy exams, biopsy exams). The infrastructure has been designed to allow the extraction and aggregation of both unstructured and semi-structured data. Data are properly treated to ensure data security and privacy. Specialized algorithms have also been implemented to process the aggregated information with the aim to obtain a precise historical analysis of the clinical activities of one or more patients. Moreover, three Bayesian classifiers have been developed to analyze examinations reported as free text. Experimental results show that the classifiers exhibit a good accuracy when used to analyze sentences related to the sample location, diseases presence and status of the illnesses. | BMC bioinformatics 19 (2018): 257-267. | 2018 | MANCONI ANDREA, MOSCATELLI MARCO, MILANESI LUCIANO, GNOCCHI MATTEO | Big data, Machine learning, NoSQL, Clinical decision support systems, Medical record | 10.1186/s12859-018-2300-5 |
| 397301 | Articolo in rivista | Unraveling gut microbiota in Parkinson's disease and atypical parkinsonism | Barichella M1, Severgnini M2, Cilia R1, Cassani E1, Bolliri C1, Caronni S1, Ferri V1, Cancello R3, Ceccarani C2, 4, Faierman S1, Pinelli G1, 5, De Bellis G2, Zecca L2, 6, Cereda E7, Consolandi C2, Pezzoli G1. | BACKGROUND: Although several studies have suggested that abnormalities in gut microbiota may play a critical role in the pathogenesis of PD, data are still extremely heterogeneous. METHODS: 16S gene ribosomal RNA sequencing was performed on fecal samples of 350 individuals, subdivided into idiopathic PD (n = 193, of whom 39 were drug naive) stratified by disease duration, PSP (n = 22), MSA (n = 22), and healthy controls (HC; n = 113). Several confounders were taken into account, including dietary habits. RESULTS: Despite the fact that unadjusted comparison of PD and HC showed several differences in relative taxa abundances, the significant results were greatly reduced after adjusting for confounders. Although most of these differences were associated with disease duration, lower abundance in Lachnospiraceae was the only difference between de novo PD and HC (remaining lower across almost all PD duration strata). Decreased Lachnospiraceae and increased Lactobacillaceae and Christensenellaceae were associated with a worse clinical profile, including higher frequencies of cognitive impairment, gait disturbances, and postural instability. When compared with HC, MSA and PSP patients shared the changes in PD, with a few exceptions: in MSA, Lachnospiraceae were not lower, and Prevotellaceae were reduced; in PSP, Lactobacillaceae were similar, and Streptococcaceae were reduced. CONCLUSIONS: Gut microbiota may be an environmental modulator of the pathogenesis of PD and contribute to the interindividual variability of clinical features. Data are influenced by PD duration and several confounders that need to be taken into account in future studies. Prospective studies in de novo PD patients are needed to elucidate the net effect of dysbiosis on the progression of the disease. (C) 2018 International Parkinson and Movement Disorder Society. | Movement disorders 34 (2019): 396-405. | 2019 | ZECCA LUIGI, CECCARANI CAMILLA, DE BELLIS GIANLUCA, CONSOLANDI CLARISSA, SEVERGNINI MARCO | MSA; PD; PSP; Parkinson's disease; clinical features; gut-brain axis; microbiota; multiple system atrophy; progressive supranuclear palsy | 10.1002/mds.27581 |
| 396168 | Articolo in rivista | Proteome investigation of rat lungs subjected to Ex vivo perfusion (EVLP) | Roffia V., De Palma A., Lonati C., Di Silvestre D., Rossi R., Mantero M., Gatti S., Dondossola D., Valenza F., Mauri P., Blasi F. | Ex vivo lung perfusion (EVLP) is an emerging procedure that allows organ preservation, assessment and reconditioning, increasing the number of marginal donor lungs for transplantation. However, physiological and airflow measurements are unable to unveil the molecular mechanisms responsible of EVLP beneficial effects on lung graft and monitor the proper course of the treatment. Thus, it is urgent to find specific biomarkers that possess these requirements but also accurate and reliable techniques that identify them. The purpose of this study is to give an overview on the potentiality of shotgun proteomic platforms in characterizing the status and the evolution of metabolic pathways during EVLP in order to find new potential EVLP-related biomarkers. A nanoLC-MS/MS system was applied to the proteome analysis of lung tissues from an optimized rat model in three experimental groups: native, pre- and post-EVLP. Technical and biological repeatability were evaluated and, together with clustering analysis, underlined the good quality of data produced. In-house software and bioinformatics tools allowed the label-free extraction of differentially expressed proteins among the three examined conditions and the network visualization of the pathways mainly involved. These promising findings encourage further proteomic investigations of the molecular mechanisms behind EVLP procedure. | Molecules (Basel, Online) 23 (2018). | 2018 | DE PALMA ANTONELLA, DI SILVESTRE DARIO, ROSSI ROSSANA, ROFFIA VALENTINA, MAURI PIETRO LUIGI | Proteomics, Ex Vivo Lung Perfusion (EVLP), nanoLC-MS/MS, transplantation | 10.3390/molecules23123061 |
| 397316 | Articolo in rivista | Pilot Production of Mesenchymal Stem/Stromal Freeze-Dried Secretome for Cell-Free Regenerative Nanomedicine: A Validated GMP-Compliant Process | Bari E1, Perteghella S2, 3, Di Silvestre D4, Sorlini M5, 6, Catenacci L7, Sorrenti M8, Marrubini G9, Rossi R10, Tripodo G11, Mauri P12, Marazzi M13, Torre ML14, 15. | In this paper, a pilot production process for mesenchymal stem/stromal freeze-dried secretome was performed in a validated good manufacturing practice (GMP)-compliant cell factory. Secretome was purified from culture supernatants by ultrafiltration, added to cryoprotectant, lyophilized and characterized. We obtained a freeze-dried, "ready-off-the-shelf" and free soluble powder containing extracellular vesicles and proteins. In the freeze-dried product, a not-aggregated population of extracellular vesicles was detected by nanoparticle tracking analysis; Fourier transform infrared spectra showed the simultaneous presence of protein and lipids, while differential scanning calorimetry demonstrated that lyophilization process successfully occurred. A proteomic characterization allowed the identification of proteins involved in immune response, response to stress, cytoskeleton and metabolism. Moreover, the product was not cytotoxic up to concentrations of 25 mg/mL (on human fibroblasts, chondrocytes and nucleus pulposus cells by MTT assay) and was blood compatible up to 150 mg/mL. Finally, at concentrations between 5 and 50 mg/mL, freeze-dried secretome showed to in vitro counteract the oxidative stress damage induced by H2O2 on nucleus pulposus cells by MTT assay. | Cells 7 (2018). | 2018 | ROSSI ROSSANA, DI SILVESTRE DARIO, MAURI PIETRO LUIGI | exosome, microvesicles, ultrafiltration, freeze-drying, secretome, mesenchymal stem cells | 10.3390/cells7110190 |
| 390665 | Articolo in rivista | Effects of combined physical and cognitive virtual reality-based training on cognitive impairment and oxidative stress in MCI patients: a pilot study. | Mrakic-Sposta, S., Di Santo, S.G., Franchini, F., Arlati, S., Zangiacomi, A., Greci, L., Moretti, S., Marzorati, M., Rizzo, G., Sacco, M., Vezzoli, A. | There is a pressing demand for improving the quality and efficacy of health care and social support services needed by the world's growing elderly population, especially by those affected by mild cognitive impairment (MCI) and Alzheimer's disease. Exercise has been demonstrated to mitigate cognitive impairment and oxidative stress (OxS) that has been recognized as a contributing factor in the progression of multiple neurodegenerative diseases. Meeting the demand of innovative and addressed to specific needs treatment in the area of cognitive impairment mitigation and rehabilitation, the main objective of this pilot study was to evaluate the impact of a Virtual Reality-based programme combining aerobic exercise and cognitive training. 10 patients (aged 73.3 +- 5.7 ys) with MCI (Mini-Mental State Examination, MMSE: 23.0 +- 3.4) were randomly assigned to either 6 weeks physical and cognitive training (EXP) or control (CTR) group. Evaluations of cognitive profile, by a neuropsychological tests battery, and OxS, by collection of blood and urine samples, were performed before and at the end of the experimental period. Also the assessment of the patients' opinions toward the intervention was investigated through questionnaires. EXP group showed a tendency towards improvements in the MMSE, in visual-constructive test and visuo-spatial tests of attention, while the controls worsened. EXP group had a greater improvement than CTR in the executive test, memory functions and verbal fluency. None of the comparisons within and between groups reached statistical significance, reasonably due to small sample, which amplifies the effect of the slight heterogeneity in scores between subjects. Despite, a greater worsening of Activities of Daily Living (ADL) tests, all participants reported a better performance in real life thanks to the self-perceived improvement elicited. After training intervention OxS (i.e reactive oxygen species production, oxidative damage of lipids and DNA) decreased resulting significantly (range P<0.05-0.001) lower in EXP vs CTR group. Although not conclusive, the recorded effects in the present study are promising and suggest that this proposed would be an useful tool in support of cognitive training reducing oxidative stress too. Further studies on larger samples of patients are needed. | Frontiers in aging neuroscience 10 (2018). | 2018 | DI SANTO SIMONA GABRIELLA, JESUTHASAN NITHIYA, MORETTI SARAH, ARLATI SARA, SACCO MARCO, VEZZOLI ALESSANDRA, ZANGIACOMI ANDREA, RIZZO GIOVANNA, MARZORATI MAURO, GRECI LUCA, MRAKIC SPOSTA SIMONA | MCI, virtual reality, physical training, cognitive training, Oxidative Stress | 10.3389/fnagi.2018.00282 |
| 397532 | Articolo in rivista | Non solo social. La comunicazione istituzionale e politica di fine anno. | ANTONUCCI, MARIA CRISTINA | breve repertorio delle tendenze tra social e strumenti tradizionali della comunicazione politica ed istituzionale della fine del 2018. | Formiche (Conversano) 2.1.2019 (2019). | 2019 | ANTONUCCI MARIA CRISTINA | comunicazione, politica, discorso politico, sistema politico, social network | |
| 398780 | Articolo in rivista | Le ministre del governo Conte e i social. | antonucci maria cristina | sintetica analisi della presenza e dei canali mediatici impiegati dalle ministre del governo Conte. | Formiche (Conversano) 20.01.2019 (2019). | 2019 | ANTONUCCI MARIA CRISTINA | comunicazione politica, questioni di genere, sistema politico italiano | |
| 399490 | Articolo in rivista | Il referendum propositivo e la democrazia partecipativa oggi. Istruzioni per l'uso | Antonucci, Maria Cristina | . | formiche.net (2019). | 2019 | ANTONUCCI MARIA CRISTINA | democrazia, partecipazione, referendum propositivo, consultazioni pubbliche, dibattito pubblico | |
| 399521 | Articolo in rivista | Mutation and Suppressor Analysis of the Essential Lipopolysaccharide Transport Protein LptA Reveals Strategies To Overcome Severe Outer Membrane Permeability Defects in Escherichia col | Federica A. Falchi, Elisa A. Maccagni, Simone Puccio, Clelia Peano, Cristina De Castro, Angelo Palmigiano, Domenico Garozzo, Alessandra M. Martorana, Alessandra Polissi, Gianni Deho, Paola Sperandeo | In Gram-negative bacteria, lipopolysaccharide (LPS) contributes to the ro- bust permeability barrier of the outer membrane (OM), preventing the entry of toxic molecules, such as detergents and antibiotics. LPS is transported from the inner mem- brane (IM) to the OM by the Lpt multiprotein machinery. Defects in LPS transport com- promise LPS assembly at the OM and result in increased antibiotic sensitivity. LptA is a key component of the Lpt machine that interacts with the IM protein LptC and chaper- ones LPS through the periplasm. We report here the construction of lptA41, a quadruple mutant in four conserved amino acids potentially involved in LPS or LptC binding. Al- though viable, the mutant displays increased sensitivity to several antibiotics (bacitracin, rifampin, and novobiocin) and the detergent SDS, suggesting that lptA41 affects LPS transport. Indeed, lptA41 is defective in Lpt complex assembly, and its lipid A carries modifications diagnostic of LPS transport defects. We also selected and characterized two phenotypic bacitracin-resistant suppressors of lptA41. One mutant, in which only bacitracin sensitivity is suppressed, harbors a small in-frame deletion in mlaA, which codes for an OM lipoprotein involved in maintaining OM asymmetry by reducing accu- mulation of phospholipids in the outer leaflet. The other mutant, in which bacitracin, ri- fampin, and SDS sensitivity is suppressed, harbors an additional amino acid substitution in LptA41 and a nonsense mutation in opgH, encoding a glycosyltransferase involved in periplasmic membrane-derived oligosaccharide synthesis. Characterization of the sup- pressor mutants highlights different strategies adopted by the cell to overcome OM de- fects caused by impaired LPS transport. | Journal of bacteriology (Online) 200 (2018): 1-25. | 2018 | PUCCIO SIMONE, GAROZZO DOMENICO, PEANO CLELIA, PALMIGIANO ANGELO | suppressor analysis, outer membrane biogenesis, OpgH, lipopolysaccharide transport | 10.1128/JB.00487-17 |
| 399608 | Articolo in rivista | SoC-based computing infrastructures for scientific applications and commercial services: Performance and economic evaluations | D. D'Agostino, A. Quarati, A. Clematis, L. Morganti, E. Corni, V. Giansanti, D. Cesini, I. Merelli | Energy consumption represents one of the most relevant issues by now in operating computing infrastructures, from traditional High Performance Computing Centers to Cloud Data Centers. Low power System-on-Chip (SoC) architectures, originally developed in the context of mobile and embedded technologies, are becoming attractive also for scientific and industrial applications given their increasing computing performances, coupled with relatively low costs and power demands. In this paper, we investigate the performance of the most representative SoCs for a computational intensive N-body benchmark, a simple deep learning based application and a real-life application taken from the field of molecular biology. The goal is to assess the trade-off among time-to-solution, energy-to-solution and economical aspects for both scientific and commercial purposes they are able to achieve in comparison to traditional server-grade architectures adopted in present infrastructures. | Future generation computer systems 96 (2019): 11-22. | 2019 | GIANSANTI VALENTINA, QUARATI ALFONSO, D'AGOSTINO DANIELE, MERELLI IVAN, CLEMATIS ANDREA | Low power Systems-on-Chip, N-body benchmark, Deep learning, Next-Generation Sequencing, Performance and economic evaluations | 10.1016/j.future.2019.01.024 |
| 399964 | Articolo in rivista | A diethylpyrocarbonate-based derivatization method for the LC-MS/MS measurement of plasma arginine and its chemically related metabolites and analogs | Sotgia S., Zinellu A., Paliogiannis P., Pinna G.A., Mangoni A.A., Milanesi L., Carru C. | BACKGROUND: Changes in NO metabolism correlate with cardiovascular risk factors and are associated with endothelial dysfunction. NO availability is regulated by nitric oxide synthase (NOS) and arginine and some chemically related metabolites and analogs have the capacity to alter NOS activity. Hence the need for analytical methods for the simultaneous assessment of these analytes. METHODS: Analytes (L-arginine (Arg), NG-monomethyl-L-arginine (MMA), L-homoarginine (hArg), asymmetric dimethyl-L-arginine (ADMA), symmetric dimethyl-L-arginine (SDMA), and L-citrulline (CIT)) were isolated from human plasma by thermal coagulation of plasma followed by a derivatization with diethylpyrocarbonate. Carbetoxy derivatives were separated on a C18 reversed-phase column in <10 min using an aqueous solution of 0.4% v/v formic acid and acetonitrile (95:5, v/v) mixture as a mobile phase. Positive electrospray ionization and tandem mass spectrometry in combination with specific multiple reaction monitoring transitions were used for detection of analytes and three deuterated forms of the analytes used as internal standards. RESULTS: Intra- and inter-day precision %RSD values ranged between 3 and 5.5% and percentage recoveries were close to 100% for all analytes. Plasma concentrations in 20 healthy male volunteers were 58.62 +- 8.81 ?mol/L for Arg, 105.08 +- 21.66 nmol/L for MMA, 1.88 +- 0.57 ?mol/L for hArg, 0.612 +- 0.140 ?mol/L for ADMA, 0.581 +- 0.172 ?mol/L for SDMA, and 28.62 +- 11.60 ?mol/L for Cit, respectively. CONCLUSION: This LC-MS/MS method provides the capacity to quantify the plasma concentrations of arginine and some of its chemically related metabolites. Sample preparation was simple, inexpensive and effortless. Overall, given the short sample preparation and chromatographic run time, the method may be suitable for the fast and reproducible quantitative determination of the analytes in large clinical trials and routine analysis. | Clinica chimica acta (Print) 492 (2019): 29-36. | 2019 | MILANESI LUCIANO | Arginine methylation; Cardiovascular disease; Diethylpyrocarbonate; Nitric oxide; Tandem mass spectrometry | 10.1016/j.cca.2019.02.004 |
| 399969 | Articolo in rivista | The impact of nutrient-based dietary patterns on cognitive decline in older adults | Prinelli F., Fratiglioni L., Musicco M., Johansson I., Adorni F., Shakersain B., Rizzuto D., Xu W. | Background & aims: The impact of nutrient patterns on cognitive decline is complex and findings are still inconclusive. We aimed to identify major nutrient patterns and to explore their association with cognitive decline over time among older adults. Methods: In a population-based cohort, 2250 cognitively healthy people aged >=60 years were identified at baseline (2001-2004), and followed-up to 9 years. Global cognitive function was tested with the Mini-Mental State Examination (MMSE) at baseline and follow-ups. Nutrients intake was assessed on the basis of food intake using a 98-semi-quantitative food frequency questionnaire at baseline, and nutrient-based patterns were identified by principal components analysis based on 30 nutrients. Mixed-effects linear regression models were used to determine their association with change in cognitive function taking into account potential confounders. Results: Four major patterns (the plant-, animal-, dairy-derived nutrients and animal/plants-derived fats) were identified. Over the follow-up time, each one unit increment in plant- (? = 0.081, P = 0.002) and animal-derived nutrients pattern scores (? = 0.098, P < 0.001) was associated with slower decline in MMSE score. On the other hand, one-unit higher in dairy-derived nutrients pattern was related to a faster decline in global cognitive function (? = -0.064, P = 0.014). No significant association between animal/plants fats pattern and cognitive decline was observed. In stratified analyses, the association of high scores of plants- and animal-derived nutrient pattern with slower cognitive decline was stronger in APOE ?4 carriers than in ?4 non-carriers. Conclusions: Plant- and animal -derived nutrients are associated with preserved cognitive function, especially among the APOE ?4 carriers, whereas nutrients derived from dairy products may accelerate cognitive decline in older adults. | Clinical nutrition (Edinb.) (2018). | 2018 | PRINELLI FEDERICA, ADORNI FULVIO DANIELE, MUSICCO MASSIMO | Nutrient-based dietary patterns Cognitive decline Older adults Population-based cohort study | 10.1016/j.clnu.2018.12.012 |
| 399971 | Articolo in rivista | Dachshund Depletion Disrupts Mammary Gland Development and Diverts the Composition of the Mammary Gland Progenitor Pool | Jiao X1, Li Z1, Wang M1, Katiyar S2, Di Sante G1, Farshchian M3, South AP3, Cocola C4, Colombo D4, Reinbold R4, Zucchi I4, Wu K5, Tabas I6, Spike BT7, Pestell RG8. | DACH1 abundance is reduced in human malignancies, including breast cancer. Herein DACH1 was detected among multipotent fetal mammary stem cells in the embryo, among mixed lineage precursors, and in adult basal cells and (ER alpha(+)) luminal progenitors. Dachl gene deletion at 6 weeks in transgenic mice reduced ductal branching, reduced the proportion of mammary basal cells (Lin(-) CD24(med) CD29(high)) and reduced abundance of basal cytokeratin 5, whereas DACH1 overexpression induced ductal branching, increased Gata3 and Notchl, and expanded mammosphere formation in LA-7 breast cells. Mammary gland-transforming growth factor beta (TGF-beta) activity, known to reduce ductal branching and to reduce the basal cell population, increased upon Dachl deletion, associated with increased SMAD phosphorylation. Association of the scaffold protein Smad anchor for receptor activation with Smad2/3, which facilitates TGF-beta activation, was reduced by endogenous DACH1. DACH1 increases basal cells, enhances ductal formation and restrains TGF-beta activity in vivo. | Stem Cell Reports 12 (2019): 135-151. | 2019 | COCOLA CINZIA, COLOMBO DANIELE, ZUCCHI ILEANA, REINBOLD ROLLAND ALVONS | DACH; SARA; TGF-?; breast cancer; mammary gland; stem cells | 10.1016/j.stemcr.2018.11.010 |
| 400152 | Articolo in rivista | Inhibition of histone methyltransferase DOT1L silences ER? gene and blocks proliferation of antiestrogen-resistant breast cancer cells | Nassa G1, Salvati A1, Tarallo R1, Gigantino V1, Alexandrova E1, 2, Memoli D1, Sellitto A1, Rizzo F1, Malanga D3, Mirante T3, Morelli E3, Nees M4, Akerfelt M4, Kangaspeska S5, Nyman TA6, Milanesi L7, Giurato G1, 2, Weisz A1. | Breast cancer (BC) resistance to endocrine therapy results from constitutively active or aberrant estrogen receptor ? (ER?) signaling, and ways to block ER? pathway in these tumors are sought after. We identified the H3K79 methyltransferase DOT1L as a novel cofactor of ER? in BC cell chromatin, where the two proteins colocalize to regulate estrogen target gene transcription. DOT1L blockade reduces proliferation of hormone-responsive BC cells in vivo and in vitro, consequent to cell cycle arrest and apoptotic cell death, with widespread effects on ER-dependent gene transcription, including ER? and FOXA1 gene silencing. Antiestrogen-resistant BC cells respond to DOT1L inhibition also in mouse xenografts, with reduction in ER? levels, H3K79 methylation, and tumor growth. These results indicate that DOT1L is an exploitable epigenetic target for treatment of endocrine therapy-resistant ER?-positive BCs | Science Advances (2019). | 2019 | MILANESI LUCIANO | * | 10.1126/sciadv.aav5590 |
| 400535 | Articolo in rivista | Le 5 soluzioni del Libro bianco sul futuro dell'Europa | Maria Cristina Antonucci | Prima del 9 maggio 2019, giorno delle consultazioni elettorali europee, si terra un vertice europeo a Sibiu, in Romania, dove verra adottata una delle posizioni di scenario previste dal Libro bianco sul futuro dell'Europa | formiche.net 16/12/2018 (2018). | 2018 | ANTONUCCI MARIA CRISTINA | Europa | |
| 400622 | Contributo in volume | L'UE e i gruppi di interesse nelle politiche per l'innovazione | Liborio Mattina, Maria Cristina Antonucci | Contributo realizzato da Liborio Mattina e Maria Cristina Antonucci per il II volume Europa dell'Istituto dell'Enciclopedia Italiana | , pp. 589-597. Roma: Istituto dell'Enciclopedia italiana Treccani, 2018 | 2018 | ANTONUCCI MARIA CRISTINA | Europa, gruppi di interesse | |
| 400638 | Articolo in rivista | Osservazioni sull'utilizzo dei placebo nella sperimentazione clinica | Marco Annoni1, Telmo Pievani2, Cinzia Caporale1 | Con il termine "placebo" si definisce nel presente documento qualsiasi procedura o trattamento medico che, pur essendo considerato "inefficace" o "inattivo", viene comunque somministrato da un medico o da un ricercatore come se fosse una procedura o un trattamento "efficace" o "attivo". In linea di principio, qualsiasi terapia puo essere usata come un "placebo" se utilizzata per condizioni cliniche e/o secondo modalita di somministrazione per le quali e ritenuta essere inefficace (ad es. un medicinale somministrato a un dosaggio troppo basso per essere efficace). A seconda del contesto, un "placebo" puo quindi essere una pillola, un'iniezione, un esame diagnostico, o anche una procedura chirurgica2. Nell'ambito della sperimentazione clinica i placebo sono utilizzati prin- cipalmente in alcuni tipi di studi spe- rimentali denominati "studi rando- mizzati in doppio cieco con controllo placebo" (o RCTs, dall'inglese ran- domized double-blind placebo-con- trolled trials). In questi esperimenti i ricercatori determinano l'efficacia di una terapia medica comparando- ne gli effetti con quelli di un placebo somministrato nelle stesse condi- zioni sperimentali. L'uso di controlli placebo nella ricerca clinica solleva pero importanti questioni bioetiche perche implica che una parte dei soggetti coinvolti nelle sperimenta- zioni cliniche riceve un placebo al posto di una terapia potenzialmente efficace in almeno una delle fasi del- lo studio sperimentale. | The Future of Science and Ethics (Online) 1 (2016): 18-25. | 2016 | ANNONI MARCO ANGELO MARIA, CAPORALE CINZIA | Placebo, Sperimentazione clinica | |
| 400639 | Articolo in rivista | Orientamenti sull'utilizzo della randomizzazione della sperimentazione clinica | Telmo Pievani1, Patrizio Pezzotti2, Elena Tremoli3, Cinzia Caporale4 | Nell'ambito della sperimentazione clinica, la randomizzazione consiste nella assegnazione di trattamenti terapeutici ai partecipanti operata con un metodo casuale (random). In presenza di un trattamento gia riconosciuto come efficace dalla comunita scientifica (possibilmente quello ritenuto piu efficace tra quelli gia sperimentati in passato e utilizzato ordinariamente nella pratica clinica, ovvero il cosiddetto 'trattamento standard'), usualmente i partecipanti vengono assegnati in modo casuale (tirando a sorte) a due gruppi distinti: quello a cui verra somministrato il trattamento la cui efficacia e sicurezza devono ancora essere valutate e quello a cui viene somministrato il trattamento standard. Viceversa, in assenza di un trattamento standard ritenuto efficace, l'assegnazione casuale sara tra il nuovo trattamento da valutare e un placebo oppure nessun trat- tamento. Nella gran parte dei casi, l'assegnazione casuale e 'bilanciata' e cioe ciascun paziente ha una pro- babilita del 50% di essere assegna- to a uno dei due gruppi che si vuole porre a confronto. | The Future of Science and Ethics (Online) 1 (2016): 10-16. | 2016 | CAPORALE CINZIA | Randomizzazione, Sperimentazione clinica | |
| 400640 | Articolo in rivista | L'integrita nella ricerca, una questione di standard | Cinzia Caporale1, Daniele Fanelli2 | Il contributo introduce e contestualizza le Linee guida per l'integrita nella ricerca, elaborate nell'ambito delle attivita della Commissione per l'Etica della Ricerca e la Bioetica del Consiglio Nazionale delle Ricerche (CNR) e qui pubblicate per la prima volta in una rivista scientifica. I due autori - rispettivamente, Coordinatore della Commissione e Relatore del gruppo di lavoro tematico, nonche estensori delle successive versioni del documento - delineano il fenomeno delle condotte scorrette e delle frodi nella ricerca scientifica, sottolineando l'impatto sulla reputazione della scienza presso l'opinione pubblica. Pur non essendo un fenomeno in crescita, le sue dimensioni rendono necessaria una azione di prevenzione e contenimento a livello globale. | The Future of Science and Ethics (Online) 1 (2016): 154-157. | 2016 | CAPORALE CINZIA | Integrita nella ricerca, Frode scientifica, Condotte scorrette, Condotte irresponsabili nella scienza, Condotte discutibili nella scienza, Etica della ricerca | |
| 400642 | Articolo in rivista | Medicina genomica e ricerca clinica: profili etici | Carlo Alberto Redi1, Telmo Pievani2, Alberto Piazza3, Giuseppe Testa4, Marco Annoni5, Cinzia Caporale6 | A partire dalla scoperta della struttura del DNA, avvenuta nel 1953, l'indagine a livello molecolare dei fenomeni viventi ha determinato un'autentica rivoluzione scientifica e tecnologica che e coincisa con la nascita della genomica, cioe di quella branca della biologia che studia la totalita del materiale genetico di un organismo - il suo genoma. Tra le molte applicazioni che la genomica prospetta per il futuro dell'uomo, alcune delle piu importanti riguardano il settore biomedico. La "Medicina Genomica", e cioe la medicina basata su dati che riguardano i genomi e in particolare il genoma umano, permette gia oggi di immaginare un futuro in cui le tecniche di prevenzione, diagnosi e cura saranno perfettamente calibrate sulle caratteristiche biologiche di ciascun individuo, aprendo cosi la via a una nuova medicina sempre piu "personalizzata" e "di precisione". Nel corso degli ultimi anni si e assistito alla proliferazione esponenziale di nuove tecniche diagnostiche e terapeutiche mirate a rendere visibili, e dunque disponibili a eventuali interventi e manipolazioni, le relazioni che intercorrono tra il genoma di un individuo (il suo genotipo) e quei tratti osservabili che possono poi essere di potenziale interesse medico-clinico (il fenotipo). Grazie alla disponibilita di questo nuovo tipo di dati, oggi e gia possibile ricorrere a tecniche di medicina genomica per intervenire pressoche lungo tutto l'arco di sviluppo di un individuo, dalle fasi precedenti alla nascita - con la possibilita, ad esempio, di condurre diagnosi pre-impianto e pre-natali per accertare la presenza di patologie ereditarie quali la fibrosi cistica e la sindrome di Down -, per arrivare poi a tutte le successive fasi della vita - con la possibilita, ad esempio, di effettuare test genetici per determinare la propria suscettibilita a sviluppare determinate patologie o per selezionare delle terapie antitumorali mirate negli individui colpiti da particolari tumori.... | The Future of Science and Ethics (Online) 1 (2016): 142-153. | 2016 | ANNONI MARCO ANGELO MARIA, CAPORALE CINZIA | Medicina genomica | |
| 400645 | Articolo in rivista | Mozione del Comitato Etico sui profili etici dell'eutanasia | Cinzia Caporale1, Marco Annoni2, Umberto Veronesi3 | Mozione del Comitato Etico della Fondazione Umberto Veronesi sui profili etici dell'eutanasia | The Future of Science and Ethics (Online) 1 (2016): 108-110. | 2016 | ANNONI MARCO ANGELO MARIA, CAPORALE CINZIA | Eutanasia | |
| 400647 | Articolo in rivista | Ethical toolkit, codici di condotta e linee guida per la ricerca scientifica. Significato e potenzialita del consenso informato | Cinzia Caporale, Elena Mancini | La comunita dei ricercatori necessita di strumenti di orientamento che nascano dal suo interno, si basino sull'esperienza del lavoro di ricerca, siano consolidati attraverso una discussione partecipata e revisionabili in modo effciente via via che avanzano le conoscenze e mutano le circostanze, e che abbiano una chiara valenza applicativa. | The Future of Science and Ethics (Online) 2 (2017): 170-172. | 2017 | CAPORALE CINZIA, MANCINI ELENA | Ricerca scientifica | |
| 400649 | Contributo in atti di convegno | Introducing an unbiased software procedure for image checking in a large research institution | Bucci E.M.1-2, Adamo G.3, Frandi A.3, Caporale C.3 | Communication in Fifth World Conference on Research Integrity | Fifth World Conference on Research Integrity, Amsterdam, May 28-31, 2017 | 2017 | CAPORALE CINZIA, FRANDI ALESSANDRO, ADAMO GIORGIA | Reserach Integrity, Research Misconduct | |
| 400650 | Contributo in volume | Alcune riflessioni etiche a partire dalla proposta di eliminare la parola "razza" dall'art.3 della Costituzione italiana | Cinzia Caporale e Marco Annoni | Il sequenziamento del genoma umano e molte altre prove scientifiche negano in termini definitivi l'esistenza di razze geneticamente distinte nell'ambito della specie umana. Questi dati smascherano le ideologie razziste e ne rivelano, lasciandola nuda, la vera natura del razzismo che e quella della discriminazione per fini politici, sociali, economici, etc. attuata da sottogruppi nell'ambito di una popolazione, o tra popolazioni diverse, per instaurare o mantenere privilegi. Prende cosi forza il lavoro di storici, filosofi, sociologi, giuristi, etc, al fine di tracciare gli eventi che hanno portato a formulare e mantenere in vita un concetto che ormai non ha piu alcun valore scientifico: "razza" e "razzismo" sono costrutti sociali. L'aver provato scientificamente che non esistono razze non mette al riparo dal vedere quotidianamente accadere ripugnanti fenomeni di razzismo, l'impiego di volgarita e stupide posizioni razziste a fini di conquista di consensi elettorali e l'adagiarsi supinamente su posizioni lassiste di convivenza con fenomeni di razzismo, ed ancora mille altre forme di discriminazione. L'iniziativa pavese su "No razza, si cittadinanza" vuole essere un contributo al necessario dibattito per giungere ad una raccolta di firme utile per una iniziativa di legge popolare che abbia come fine la cancellazione della parola "razza" dall'art. 3 della nostra Costituzione. | No razza, si cittadinanza. Cellula e genomi XV corso, edited by Carlo Alberto Redi, Manuela Monti, pp. 189-202. Pavia: Ibis, 2017 | 2017 | ANNONI MARCO ANGELO MARIA, CAPORALE CINZIA | Razza, Costituzione | |
| 400651 | Articolo in rivista | A recap on Italian neurolaw: epistemological and ethical issues | 1. Elisabetta Sirgiovanni, 1. Gilberto Corbellini, 2. Cinzia Caporale | Italy is in the forefront of forensic neuroscience practice among European nations. In recent years, the country presented two major criminal cases, the Trieste Case in 2009 and the Como Case in 2011, which were the first cases employing neurogenetic and functional neuroimaging methods in European courts. In these paper we will discuss the consequences that an understanding of the neural and genetic determinants of human (mis)behavior will have on law, especially on the Italian legal context. Some claim that such consequences will actually be revolutionary, while others argue that legal doctrine assumptions won't be undermined by neuroscientific findings. In the first section of the paper, we introduce the general debate and follow with a section devoted to the two Italian cases. In the third and final section, we discuss epistemological and ethical issues regarding Italian neurolaw. We defend a position which diverges from those prevailing in the debate. While negative outcomes and concerns were usually evidenced, we focus on positive changes coming with the new paradigm of interaction between neuroscience and the law. Our view is that these cases are clearly pioneering ones, anticipating what will happen in the courtrooms of the European Union in the whole, in the near future. | Mind & society 16 (2016): 17-35. | 2016 | CAPORALE CINZIA | Neurogenetics Neuroscience Neurolaw Neuroethics Bioethics | |
| 401535 | Articolo in rivista | Cryo-EM structure of cardiac amyloid fibrils from an immunoglobulin light chain AL amyloidosis patient | Swuec, Paolo, Lavatelli, Francesca, Tasaki, Masayoshi, Paissonil, Cristina, Rognoni, Paola, Maritanl, Martina, Brambilla, Francesca, Milani, Paolo, Mauri, Pierluigi, Camilloni, Carlo, Palladini, Giovanni, Merlini, Giampaolo, Ricagno, Stefano, Bolognesi, Martino | Systemic light chain amyloidosis (AL) is a life-threatening disease caused by aggregation and deposition of monoclonal immunoglobulin light chains (LC) in target organs. Severity of heart involvement is the most important factor determining prognosis. Here, we report the 4.0 angstrom resolution cryo-electron microscopy map and molecular model of amyloid fibrils extracted from the heart of an AL amyloidosis patient with severe amyloid cardiomyopathy. The helical fibrils are composed of a single protofilament, showing typical 4.9 angstrom stacking and cross-beta architecture. Two distinct polypeptide stretches (total of 77 residues) from the LC variable domain (V-l) fit the fibril density. Despite Vl high sequence variability, residues stabilizing the fibril core are conserved through different cardiotoxic V-l, highlighting structural motifs that may be common to misfolding-prone LCs. Our data shed light on the architecture of LC amyloids, correlate amino acid sequences with fibril assembly, providing the grounds for development of innovative medicines. | Nature communications 10 (2019). | 2019 | BRAMBILLA FRANCESCA, MAURI PIETRO LUIGI | *** | 10.1038/s41467-019-09133-w |
| 401915 | Articolo in rivista | Durum wheat genome highlights past domestication signatures and future improvement targets | Maccaferri M, Harris NS, Twardziok SO, Pasam RK, Gundlach H, Spannagl M, Ormanbekova D, Lux T, Prade VM, Milner SG, Himmelbach A, Mascher M, Bagnaresi P, Faccioli P, Cozzi P, Lauria M, Lazzari B, Stella A, Manconi A, Gnocchi M, Moscatelli M, Avni R, Deek J, Biyiklioglu S, Frascaroli E, Corneti S, Salvi S, Sonnante G, Desiderio F, Mare C, Crosatti C, Mica E, Ozkan H, Kilian B, De Vita P, Marone D, Joukhadar R, Mazzucotelli E, Nigro D, Gadaleta A, Chao S, Faris JD, Melo ATO, Pumphrey M, Pecchioni N, Milanesi L, Wiebe K, Ens J, MacLachlan RP, Clarke JM, Sharpe AG, Koh CS, Liang KYH, Taylor GJ, Knox R, Budak H, Mastrangelo AM, Xu SS, Stein N, Hale I, Distelfeld A, Hayden MJ, Tuberosa R, Walkowiak S, Mayer KFX, Ceriotti A, Pozniak CJ, Cattivelli L | The domestication of wild emmer wheat led to the selection of modern durum wheat, grown mainly for pasta production. We describe the 10.45 gigabase (Gb) assembly of the genome of durum wheat cultivar Svevo. The assembly enabled genome-wide genetic diversity analyses revealing the changes imposed by thousands of years of empirical selection and breeding. Regions exhibiting strong signatures of genetic divergence associated with domestication and breeding were widespread in the genome with several major diversity losses in the pericentromeric regions. A locus on chromosome 5B carries a gene encoding a metal transporter (TdHMA3-B1) with a non-functional variant causing high accumulation of cadmium in grain. The high-cadmium allele, widespread among durum cultivars but undetected in wild emmer accessions, increased in frequency from domesticated emmer to modern durum wheat. The rapid cloning of TdHMA3-B1 rescues a wild beneficial allele and demonstrates the practical use of the Svevo genome for wheat improvement. | Nature genetics (Print) (2019). | 2019 | MANCONI ANDREA, COZZI PAOLO ALESSANDRO, SONNANTE GABRIELLA, LAZZARI BARBARA, LAURIA MASSIMILIANO, STELLA ALESSANDRA, MILANESI LUCIANO, GNOCCHI MATTEO, MOSCATELLI MARCO, CERIOTTI ALDO | Triticum turgidum ssp. durum, domesticatio, genome sequencing, cadmium accumulation | 10.1038/s41588-019-0381 |
| 402101 | Articolo in rivista | Luci e ombre della campagna elettorale per le europee 2019 | ANTONUCCI, MARIA CRISTINA | E possibile pensare ad una campagna elettorale centrata su tutela delle identita e sul modello del "law and order", piuttosto che una comunicazione elettorale fondata sull'idea di Europa e sul modello di europeismo da costruire nei prossimi anni. | Formiche (Conversano) (2019). | 2019 | ANTONUCCI MARIA CRISTINA | UE, elezioni europee, opinione pubblica | |
| 402174 | Articolo in rivista | Targeting Chemoresistant Tumors: Could TRIM Proteins-p53 Axis Be a Possible Answer? | Alessio Valletti 1, Flaviana Marzano 2, Graziano Pesole 2, 3, Elisabetta Sbisa 4, Apollonia Tullo 2 | Chemosensitivity is a crucial feature for all tumours so that they can be successfully treated, but the huge heterogeneity of these diseases, to be intended both inter- and intra-tumour, makes it a hard-to-win battle. Indeed, this genotypic and phenotypic variety, together with the adaptability of tumours, results in a plethora of chemoresistance acquisition mechanisms strongly affecting the effectiveness of treatments at different levels. Tripartite motif (TRIM) proteins are shown to be involved in some of these mechanisms thanks to their E3-ubiquitin ligase activity, but also to other activities they can exert in several cellular pathways. Undoubtedly, the ability to regulate the stability and activity of the p53 tumour suppressor protein, shared by many of the TRIMs, represents the preeminent link between this protein family and chemoresistance. Indeed, they can modulate p53 degradation, localization and subset of transactivated target genes, shifting the cellular response towards a cytoprotective or cytotoxic reaction to whatever damage induced by therapy, sometimes in a cellular-dependent way. The involvement in other chemoresistance acquisition mechanisms, independent by p53, is known, affecting pivotal processes like PI3K/Akt/NF-?B signalling transduction or Wnt/beta catenin pathway, to name a few. Hence, the inhibition or the enhancement of TRIM proteins functionality could be worth investigating to better understand chemoresistance and as a strategy to increase effectiveness of anticancer therapies | International journal of molecular sciences (Online) (2019). | 2019 | MARZANO FLAVIANA, TULLO APOLLONIA, PESOLE GRAZIANO, SBISA' ELISABETTA | chemoresistance; TRIM proteins; p53 | |
| 402175 | Articolo in rivista | isma: an R package for the integrative analysis of mutations detected by multiple pipelines | Di Nanni, Noemi, Moscatelli, Marco, Gnocchi, Matteo, Milanesi, Luciano, Mosca, Ettore | BackgroundRecent comparative studies have brought to our attention how somatic mutation detection from next-generation sequencing data is still an open issue in bioinformatics, because different pipelines result in a low consensus. In this context, it is suggested to integrate results from multiple calling tools, but this operation is not trivial and the burden of merging, comparing, filtering and explaining the results demands appropriate software.ResultsWe developed isma (integrative somatic mutation analysis), an R package for the integrative analysis of somatic mutations detected by multiple pipelines for matched tumor-normal samples. The package provides a series of functions to quantify the consensus, estimate the variability, underline outliers, integrate evidences from publicly available mutation catalogues and filter sites. We illustrate the capabilities of isma analysing breast cancer somatic mutations generated by The Cancer Genome Atlas (TCGA) using four pipelines.ConclusionsComparing different points of view on the same data, isma generates a unique mutation catalogue and a series of reports that underline common patterns, variability, as well as sites already catalogued by other studies (e.g. TCGA), so as to design and apply filtering strategies to screen more reliable sites. The package is available for non-commercial users at the URL https://www.itb.cnr.it/isma. | BMC bioinformatics 20 (2019). | 2019 | DI NANNI NOEMI, MILANESI LUCIANO, GNOCCHI MATTEO, MOSCA ETTORE, MOSCATELLI MARCO | Somatic mutations, Next-generation sequencing, Cancer, Data integration | 10.1186/s12859-019-2701-0 |
| 402219 | Articolo in rivista | Gut resistome plasticity in pediatric patients undergoing hematopoietic stem cell transplantation | D'Amico, Federica, Soverini, Matteo, Zama, Daniele, Consolandi, Clarissa, Severgnini, Marco, Prete, Arcangelo, Pession, Andrea, Barone, Monica, Turroni, Silvia, Biagi, Elena, Brigidi, Patrizia, Masetti, Riccardo, Rampelli, Simone, Candela, Marco | The gut microbiome of pediatric patients undergoing allo-hematopoietic stem cell transplantation (HSCT) has recently been considered as a potential reservoir of antimicrobial resistance, with important implications in terms of patient mortality rate. By means of shotgun metagenomics, here we explored the dynamics of the gut resistome - i.e. the pattern of antibiotic resistance genes provided by the gut microbiome - in eight pediatric patients undergoing HSCT, half of whom developed acute Graft-versusHost Disease (aGvHD). According to our findings, the patients developing aGvHD are characterized by post-HSCT expansion of their gut resistome, involving the acquisition of new resistances, as well as the consolidation of those already present before HSCT. Interestingly, the aGvHD-associated bloom in resistome diversity is not limited to genes coding for resistance to the antibiotics administered along the therapeutic course, but rather involves a broad pattern of different resistance classes, including multidrug resistance, as well as resistance to macrolides, aminoglycosides, tetracyclines and beta-lactams. Our data stress the relevance of mapping the gut resistome in HSCT pediatric patients to define the most appropriate anti-infective treatment post HSCT. | Scientific reports (Nature Publishing Group) 9 (2019). | 2019 | CONSOLANDI CLARISSA, SEVERGNINI MARCO | resistome, gut microbiome, NGS, HSCT, antibiotic-resistant bacteria | 10.1038/s41598-019-42222-w |
| 402800 | Articolo in rivista | Neuromelanin-sensitive MRI as a noninvasive proxy measure of dopamine function in the human brain | Cassidy C.M., Zucca F.A., Girgis R.R., Baker S.C., Weinstein J.J., Sharp M.E., Bellei C., Valmadre A., Vanegas N., Kegeles L.S., Brucato G., Kang U. J., Sulzer D., Zecca L., Abi-Dargham A., Horga G. | Neuromelanin-sensitive MRI (NM-MRI) purports to detect the content of neuromelanin (NM), a product of dopamine metabolism that accumulates in the substantia nigra (SN). Prior work has shown that NM-MRI provides a marker of SN integrity in Parkinson's disease. Here, we show that it may additionally provide a marker of dopamine function in the human nigrostriatal pathway. Supporting this, we found that NM-MRI signal correlated with NM concentration, dopamine levels in the striatum, SN blood flow, and severity of psychosis in schizophrenia, all in the absence of neurodegeneration. Thus, noninvasive NM-MRI is a promising tool that could have diverse research and clinical applications to investigate in vivo the role of dopamine in neuropsychiatric illness. | Proceedings of the National Academy of Sciences of the United States of America 116 (2019): 5108-5117. | 2019 | VALMADRE ALICE, ZECCA LUIGI, ZUCCA FABIO ANDREA, BELLEI CHIARA | magnetic resonance imaging, dopamine, neuromelanin, schizophrenia, Parkinson's disease | 10.1073/pnas.1807983116 |
| 404017 | Articolo in rivista | New On-Water Test for the Assessment of Blood Lactate Response to Exercise in Elite Kayakers | Pilotto AM 1, 2, Rasica L 3, 4, Scalise G 1, Annoni S 1, La Torre A 4, 5, Marzorati M 1, Porcelli S 1. | PURPOSE: Lactate thresholds are physiological parameters used to train athletes and monitor performance or training. Currently, the assessment of lactate thresholds in kayakers is performed in a laboratory setting utilizing specific ergometers; however, laboratory tests differ from on-water evaluation for several reasons. The aim of this study was to assess reliability and validity of a new on-water incremental test for the assessment of blood lactate response to exercise in flat-water kayakers. Maximal lactate steady state test (MLSS) was used as criterion measurement. METHODS: Eleven junior (16.5+-1.9yr) elite flat-water kayakers performed: i) an incremental cardiopulmonary test up to voluntary exhaustion on a stationary kayak ergometer to determine peak oxygen uptake; ii) an on-water 1000m distance trial (T1000) to record best performance time and average speed (S1000); iii) two repetitions of on-water incremental kayaking test (WIK-test); iv) several repetitions of on-water constant speed tests to determine MLSS. Speed, heart rate and blood lactate concentrations were determined during on-water tests. RESULTS: The best performance time in T1000 was 262+-13s, corresponding to an S1000 of 3.82+-0.19m.s. Lactate threshold determined by modified Dmax method (LTDmod) during WIK-test was 2.78+-1.02mmol.L and the corresponding speed (SLT) was 3.34+-0.16m.s. Test-retest reliability, calculated on SLT, was strong (ICC=0.95 and r=0.93). MLSS corresponded to 3.06+-0.68mmol.L and was reached at a speed (SMLSS) of 3.36+-0.14m.s. Correlation coefficient between SLT and SMLSS was 0.90 (p=0.0001). Interestingly, a significant correlation (r=0.96, p<0.0001) was observed between SLT and S1000. CONCLUSIONS: WIK-test showed good reliability and validity for the assessment of speed corresponding to LTDmod in flat-water kayakers and it could be a useful tool to monitor athletic performance. The speed value at LTDmod nicely predicted performance on 1000m. | Medicine and science in sports and exercise (Online) 51 (2019): 2595-2602. | 2019 | RASICA LETIZIA, MARZORATI MAURO, PORCELLI SIMONE | - | 10.1249/MSS.0000000000002077 |
| 404763 | Articolo in rivista | Locus coeruleus imaging as a biomarker for noradrenergic dysfunction in neurodegenerative diseases. | Betts M.J., Kirilina E., Otaduy M.C.G., Ivanov D., Acosta-Cabronero J., Callaghan M.F., Lambert C., Cardenas-Blanco A., Pine K., Passamonti L., Loane C., Keuken M.C., Trujillo P., Lusebrink F., Mattern H., Liu K.Y., Priovoulos N., Fliessbach K., Dahl M.J., Maass A., Madelung C.F., Meder D., Ehrenberg A.J., Speck O., Weiskopf N., Dolan R., Inglis B., Tosun D., Morawski M., Zucca F.A., Siebner H.R., Mather M., Uludag K., Heinsen H., Poser B.A., Howard R., Zecca L., Rowe J.B., Grinberg L.T., Jacobs H.I.L., Duzel E., Hammerer D. | Pathological alterations to the locus coeruleus, the major source of noradrenaline in the brain, are histologically evident in early stages of neurodegenerative diseases. Novel MRI approaches now provide an opportunity to quantify structural features of the locus coeruleus in vivo during disease progression. In combination with neuropathological biomarkers, in vivo locus coeruleus imaging could help to understand the contribution of locus coeruleus neurodegeneration to clinical and pathological manifestations in Alzheimer's disease, atypical neurodegenerative dementias and Parkinson's disease. Moreover, as the functional sensitivity of the noradrenergic system is likely to change with disease progression, in vivo measures of locus coeruleus integrity could provide new pathophysiological insights into cognitive and behavioural symptoms. Locus coeruleus imaging also holds the promise to stratify patients into clinical trials according to noradrenergic dysfunction. In this article, we present a consensus on how non-invasive in vivo assessment of locus coeruleus integrity can be used for clinical research in neurodegenerative diseases. We outline the next steps for in vivo, post-mortem and clinical studies that can lay the groundwork to evaluate the potential of locus coeruleus imaging as a biomarker for neurodegenerative diseases. | Brain (Online) 142 (2019): 2558-2571.. | 2019 | ZECCA LUIGI, ZUCCA FABIO ANDREA, PASSAMONTI LUCA | Locus coeruleus (LC); magnetic resonance imaging (MRI); neurodegeneration; noradrenaline (NA), biomarker | 10.1093/brain/awz193 |
| 405952 | Articolo in rivista | Exploiting Docker containers over Grid computing for a comprehensive study of chromatin conformation in different cell types | I. Merelli, F. Fornari, F. Tordini, D. D'Agostino, M. Aldinucci, D. Cesini | Many bioinformatic applications require to exploit the capabilities of several computational resources to effectively access and process large and distributed datasets. In this context, Grid computing has been largely used to face unprecedented challenges in Computational Biology, at the cost of complex workarounds needed to make applications successfully running. The Grid computing paradigm, in fact, has always suffered from a lack of flexibility. Although this has been partially solved by Cloud computing, the on-demand approach is way distant from the original idea of volunteering computing that boosted the Grid paradigm. A solution to outpace the impossibility of creating custom environments for running applications in Grid is represented by the containerization technology. In this paper, we describe our experience in exploiting a Docker-based approach to run in a Grid environment a novel, computationally intensive, bioinformatic application, which models the DNA spatial conformation inside the nucleus of eukaryotic cells. Results assess the feasibility of this approach in terms of performance and efforts to run large experiments. | Journal of parallel and distributed computing (Print) 134 (2019): 116-127. | 2019 | D'AGOSTINO DANIELE, MERELLI IVAN | Grid computing, Docker containers, Data modelling, Chromatin conformation, Computational Biology | 10.1016/j.jpdc.2019.08.002 |
| 406415 | Articolo in rivista | A novel homozygous mutation in the TRDN gene causes a severe form of pediatric malignant ventricular arrhythmia | Rossi D1, Gigli L2, Gamberucci A1, Bordoni R3, Pietrelli A3, Lorenzini S1, Pierantozzi E1, Peretto G2, De Bellis G3, Della Bella P2, Ferrari M4, Sorrentino V1, Benedetti S5, Sala S2, Di Resta C6. | BACKGROUND: Triadin is a protein expressed in cardiac and skeletal muscle with an essential role in the structure and functional regulation of calcium release units and excitation-contraction coupling. Mutations in the triadin gene (TRDN) have been described in different forms of human arrhythmia syndromes with early onset and severe arrhythmogenic phenotype, among which the triadin knockout syndrome. OBJECTIVE: To characterize the pathogenetic mechanism underlying a case of severe pediatric malignant arrhythmia associated with defect in the TRDN gene. METHODS: We exploited trio whole exome sequencing approach to identify the genetic defect in a 2-years old boy with a resuscitated sudden cardiac arrest, frequent ventricular fibrillations and positive family history for sudden death. Then we performed in vitro functional analysis to investigate possible pathogenic mechanisms underlying this severe phenotype. RESULTS: We identified a novel homozygous missense variant (p.L56P) in the TRDN gene in the proband, inherited by the heterozygous unaffected parents. Expression of a GFP-tagged mutant human cardiac triadin isoform (TRISK32-L56P-GFP) in heterologous systems revealed that the mutation alters protein dynamics. Furthermore, when co-expressed with the type 2 ryanodine receptor, the caffeine-induced calcium release from TRISK32-L56P-GFP was relatively lower compared to that observed with wild type construct. CONCLUSIONS: These evidences allowed to hypothesize a pathogenic mechanism underlying this rare arrhythmogenic recessive form, suggesting that the mutant protein can potentially trigger arrhythmias by altering calcium homeostasis. | Heart rhythm (2019). | 2019 | PIETRELLI ALESSANDRO, DE BELLIS GIANLUCA, BORDONI ROBERTA | Long QT; Triadin; Whole-exome sequencing; novel mutation; ventricular fibrillation | |
| 407621 | Articolo in rivista | Candidate Genes and MiRNAs Linked to the Inverse Relationship Between Cancer and Alzheimer's Disease: Insights From Data Mining and Enrichment Analysis | Battaglia, Cristina, Venturin, Marco, Sojic, Aleksandra, Jesuthasan, Nithiya, Orro, Alessandro, Spinelli, Roberta, Musicco, Massimo, De Bellis, Gianluca, Adorni, Fulvio | The incidence of cancer and Alzheimer's disease (AD) increases exponentially with age. A growing body of epidemiological evidence and molecular investigations inspired the hypothesis of an inverse relationship between these two pathologies. It has been proposed that the two diseases might utilize the same proteins and pathways that are, however, modulated differently and sometimes in opposite directions. Investigation of the common processes underlying these diseases may enhance the understanding of their pathogenesis and may also guide novel therapeutic strategies. Starting from a text-mining approach, our in silico study integrated the dispersed biological evidence by combining data mining, gene set enrichment, and protein-protein interaction (PPI) analyses while searching for common biological hallmarks linked to AD and cancer. We retrieved 138 genes (ALZCAN gene set), computed a significant number of enriched gene ontology clusters, and identified four PPI modules. The investigation confirmed the relevance of autophagy, ubiquitin proteasome system, and cell death as common biological hallmarks shared by cancer and AD. Then, from a closer investigation of the PPI modules and of the miRNAs enrichment data, several genes (SQSTM1, UCHL1, STUB1, BECN1, CDKN2A, TP53, EGFR, GSK3B, and HSPA9) and miRNAs (miR-146a-5p, MiR-34a-5p, miR-21-5p, miR-9-5p, and miR-16-5p) emerged as promising candidates. The integrative approach uncovered novel miRNA-gene networks (e.g., miR-146 and miR-34 regulating p62 and Beclin1 in autophagy) that might give new insights into the complex regulatory mechanisms of gene expression in AD and cancer. | Frontiers in genetics 10 (2019). | 2019 | JESUTHASAN NITHIYA, BATTAGLIA CRISTINA, SOJIC ALEKSANDRA, DE BELLIS GIANLUCA, ORRO ALESSANDRO, ADORNI FULVIO DANIELE, MUSICCO MASSIMO | genes, miRNAs, cancer, Alzheimer, inverse relationship, data mining, enrichment analysis, protein-protein interaction network | 10.3389/fgene.2019.00846 |
| 407622 | Articolo in rivista | Specific nutrient patterns are associated with higher structural brain integrity in dementia-free older adults | Prinelli, Federica, Fratiglioni, Laura, Kalpouzos, Gregoria, Musicco, Massimo, Adorni, Fulvio, Johansson, Ingegerd, Marseglia, Anna, Xu, Weili | Optimal nutrition may play a beneficial role in maintaining a healthy brain. However, the relationship between nutrient intake and brain integrity is largely unknown. We investigated the association of specific nutrient dietary patterns with structural characteristics of the brain. Within the population-based Swedish National study on Aging and Care-Kungsholmen (SNAC-K), a cross-sectional study of 417 dementia-free participants aged >=60 years who underwent structural magnetic resonance imaging (MRI) scans during 2001-2003, was carried-out. Data on dietary intake were collected using a food frequency questionnaire, from which intake of 21 nutrients was estimated. By principal component analysis, five nutrient patterns were extracted: (1) NP1 was characterized by fiber, vitamin C, E, ?-carotene, and folate [Fiber&Antioxidants], (2) NP2 by eicosapentaenoic (EPA, 20:5 ?-3) and docosahexaenoic (DHA, 22:6 ?-3) polyunsaturated fatty acids (PUFAs), proteins, cholesterol, vitamin B3, B12, and D [long chain (LC) ?-3PUFAs&Proteins], (3) NP3 by ?-linoleic (18:2 ?-6) and ?-linolenic (18:3 ?-3) PUFAs, monounsaturated fatty acids (MUFAs), and vitamin E [MUFAs&?-3,6PUFAs], (4) NP4 by saturated fatty acids (SFAs), trans fats, MUFAs, and cholesterol [SFAs&Trans fats], (5) NP5 by B-vitamins, retinol, and proteins [B-Vitamins&Retinol]. Nutrient patterns scores were tertiled with the lowest tertile as reference, and were related to total brain volume (TBV) and white matter hyperintensities volume (WMHV) using linear regression models adjusting for potential confounders. In the multi-adjusted model, compared to the lowest intake for each pattern, the highest intake of NP1 (? = 11.11, P = 0.009), NP2 (? = 7.47, P = 0.052), and NP3 (? = 10.54, P = 0.005) was associated with larger TBV whereas NP5 was related to smaller TBV (? = -12.82, P = 0.001). The highest intake of NP1 was associated with lower WMHV (? = -0.32, P = 0.049), whereas NP4 was associated with greater WMHV (? = 0.31, P = 0.036). In sum, our results suggest that the identified brain-health specific nutrient combinations characterized by higher intake of fruit, vegetables, legumes, olive and seed oils, fish, lean red meat, poultry and low in milk and dairy products, cream, butter, processed meat and offal, were strongly associated with greater brain integrity among older adults. | NeuroImage (Orlando Fla., Print) 199 (2019): 281-288. | 2019 | ADORNI FULVIO DANIELE, PRINELLI FEDERICA, MUSICCO MASSIMO | Brain integrity, Cross-sectional study, Nutrient patterns, Total brain volume, White matter hyper intensity volume | 10.1016/j.neuroimage.2019.05.066 |
| 407646 | Articolo in rivista | Exposure to vehicular traffic is associated to a higher risk of hospitalization for bronchiolitis during the first year of life | Lanari, Marcello, Vandini, Silvia, Prinelli, Federica, Adorni, Fulvio, Di Santo, Simona, Silvestri, Michela, Musicco, Massimo | BACK GROUND: The most common cause of hospitalization for children younger than age one is bronchiolitis. Several prenatal and environmental risk factors may affect the incidence of hospitalization for bronchiolitis. The aim of this study was tninvestigate the relation between exposure to vehicular traffic and the incidence of hospitalization for bronchiolitis in children during their first year of life in Italy. | Minerva pediatrica (Testo stamp.) 68 (2016): 391-397. | 2016 | ADORNI FULVIO DANIELE, PRINELLI FEDERICA, MUSICCO MASSIMO | Air pollution, Hospitalization, Bronchiolitis, Respiratory syncytial viruses, Child, Risk factors. | |
| 407707 | Articolo in rivista | Diversity of vaginal microbiome and metabolome during genital infections | Ceccarani, Camilla, Foschi, Claudio, Parolin, Carola, D'Antuono, Antonietta, Gaspari, Valeria, Consolandi, Clarissa, Laghi, Luca, Camboni, Tania, Vitali, Beatrice, Severgnini, Marco, Marangoni, Antonella | We characterized the vaginal ecosystem during common infections of the female genital tract, as vulvovaginal candidiasis (VVC, n = 18) and Chlamydia trachomatis infection (CT, n = 20), recruiting healthy (HC, n = 21) and bacterial vaginosis-affected (BV, n = 20) women as references of eubiosis and dysbiosis. The profiles of the vaginal microbiome and metabolome were studied in 79 reproductive-aged women, by means of next generation sequencing and proton based-nuclear magnetic resonance spectroscopy. Lactobacillus genus was profoundly depleted in all the genital infections herein considered, and species-level analysis revealed that healthy vaginal microbiome was dominated by L. crispatus. In the shift from HC to CT, VVC, and BV, L. crispatus was progressively replaced by L. iners. CT infection and VVC, as well as BV condition, were mainly characterised by anaerobe genera, e.g. Gardnerella, Prevotella, Megasphaera, Roseburia and Atopobium. The changes in the bacterial communities occurring during the genital infections resulted in significant alterations in the vaginal metabolites composition, being the decrease of lactate a common marker of all the pathological conditions. In conclusion, according to the taxonomic and metabolomics analysis, we found that each of the four conditions is characterized by a peculiar vaginal microbiome/metabolome fingerprint. | Scientific reports (Nature Publishing Group) 9 (2019): 14095. | 2019 | CECCARANI CAMILLA, CAMBONI TANIA, CONSOLANDI CLARISSA, SEVERGNINI MARCO | vaginal microbiota, metabolome, chlamydia, bacterial vaginosis, candididiasis | 10.1038/s41598-019-50410-x |
| 408351 | Articolo in rivista | The role of extracellular matrix in mouse and human corneal neovascularization | Barbariga M., Vallone F., Mosca E., Bignami F., Magagnotti C., Fonteyne P., Chiappori F., Milanesi L., Rama P., Andolfo A., Ferrari G. | Corneal neo-vascularization (CNV) is a highly prevalent medical condition which impairs visual acuity. The role of specific proteins in modulating CNV has been extensively reported, although no studies have described the entire human proteome in CNV corneas. In this paper, we performed a proteomic analysis of vascularized vs healthy corneal stroma, in a CNV mouse model and in CNV-affected patients, with a specific focus on extracellular matrix (ECM) proteins. We identified and quantified 2315 murine proteins, 691 human proteins and validated 5 proteins which are differentially expressed in vascularized samples and conserved in mice and humans: tenascin-C and fibronectin-1 were upregulated, while decorin, lumican and collagen-VI were downregulated in CNV samples. Interestingly, among CNV patients, those affected with Acanthamoeba keratitis showed the highest levels of fibronectin-1 and tenascin-C, suggesting a specific role of these two proteins in Acanthamoeba driven corneal CNV. On a broader picture, our findings support the hypothesis that the corneal stroma in CNV samples is disorganized and less compact. We are confident that the dissection of the human corneal proteome may shed new light on the complex pathophysiology of human CNV, and finally lead to improved treatments. | Scientific reports (Nature Publishing Group) 9 (2019): 14272. | 2019 | CHIAPPORI FEDERICA, MILANESI LUCIANO, MOSCA ETTORE | corneal neovascularization, Proteomics | 10.1038/s41598-019-50718-8 |
| 405667 | Articolo in rivista | Network-Based Integrative Analysis of Genomics, Epigenomics and Transcriptomics in Autism Spectrum Disorders | Di Nanni, Noemi, Bersanelli, Matteo, Cupaioli, Francesca Anna, Milanesi, Luciano, Mezzelani, Alessandra, Mosca, Ettore | Current studies suggest that autism spectrum disorders (ASDs) may be caused by many genetic factors. In fact, collectively considering multiple studies aimed at characterizing the basic pathophysiology of ASDs, a large number of genes has been proposed. Addressing the problem of molecular data interpretation using gene networks helps to explain genetic heterogeneity in terms of shared pathways. Besides, the integrative analysis of multiple omics has emerged as an approach to provide a more comprehensive view of a disease. In this work, we carry out a network-based meta-analysis of the genes reported as associated with ASDs by studies that involved genomics, epigenomics, and transcriptomics. Collectively, our analysis provides a prioritization of the large number of genes proposed to be associated with ASDs, based on genes' relevance within the intracellular circuits, the strength of the supporting evidence of association with ASDs, and the number of different molecular alterations affecting genes. We discuss the presence of the prioritized genes in the SFARI (Simons Foundation Autism Research Initiative) database and in gene networks associated with ASDs by other investigations. Lastly, we provide the full results of our analyses to encourage further studies on common targets amenable to therapy. | International journal of molecular sciences (Online) 20 (2019). | 2019 | CUPAIOLI FRANCESCA ANNA, DI NANNI NOEMI, MEZZELANI ALESSANDRA MARIA, MILANESI LUCIANO, MOSCA ETTORE | autism spectrum disorders, biological networks, genomics, multi-omics, network diffusion, data integration | 10.3390/ijms20133363 |
| 408355 | Articolo in rivista | A rare genetic variant of BPIFB4 predisposes to high blood pressure via impairment of nitric oxide signaling | Vecchione, Carmine, Villa, Francesco, Carrizzo, Albino, Spinelli, Chiara Carmela, Damato, Antonio, Ambrosio, Mariateresa, Ferrario, Anna, Madonna, Michele, Uccellatore, Annachiara, Lupini, Silvia, Maciag, Anna, Ryskalin, Larisa, Milanesi, Luciano, Frati, Giacomo, Sciarretta, Sebastiano, Bellazzi, Riccardo, Genovese, Stefano, Ceriello, Antonio, Auricchio, Alberto, Malovini, Alberto, Puca, Annibale Alessandro | BPIFB4 is associated with exceptional longevity: four single-nucleotide polymorphisms distinguish the wild-type form from a longevity-associated variant conferring positive effects on blood pressure. The effect of a rare variant (RV; allele frequency, 4%) on blood pressure is unknown. Here, we show that overexpression of RV-BPIFB4 in ex-vivo mouse vessels impairs phosphorylation of endothelial nitric oxide synthase (eNOS), blunting acetylcholine-evoked vasorelaxation; in vivo, virally mediated overexpression of RV-BPIFB4 increases blood pressure, an action absent in eNOS-deficient mice. In humans, we found RV carriers to have increased diastolic blood pressure, a finding that was more marked in subjects on anti-hypertensive medication; moreover, recombinant RV-BPIFB4 protein impaired eNOS function in ex-vivo human vessels. Thus, RV-BPIFB4 acts directly on blood pressure homeostasis and may represent a novel biomarker of vascular dysfunction and hypertension. | Scientific reports (Nature Publishing Group) 9 (2019). | 2019 | MILANESI LUCIANO | rare genetic variant | 10.1038/s41598-019-45691-1 |
| 408373 | Articolo in rivista | Exploitation of a novel biosensor based on the full-length human F508de1-CFTR with computational studies, biochemical and biological assays for the characterization of a new Lumacaftor/Tezacaftor analogue | D'Ursi, Pasqualina, Uggeri, Matteo, Urbinati, Chiara, Millo, Enrico, Paiardi, Giulia, Milanesi, Luciano, Ford, Robert C., Clews, Jack, Meng, Xin, Bergese, Paolo, Ridolfi, Andrea, Pedemonte, Nicoletta, Fossa, Paola, Orro, Alessandro, Rusnati, Marco | Cystic fibrosis (CF) is mainly caused by the mutation F508del of the cystic fibrosis transmembrane conductance regulator (CFTR) that is thus retained in the endoplasmic reticulum and degraded. New drugs able to rescue F508del-CFTR trafficking and activity are eagerly awaited, a goal that requires the availability of computational and experimental models closely resembling the F508del-CFTR structure and environment in vivo. | Sensors and actuators. B, Chemical (Print) 301 (2019). | 2019 | D'URSI PASQUALINA, UGGERI MATTEO, ORRO ALESSANDRO, MILANESI LUCIANO | Biosensor, Surface plasmon resonance, Cystic fibrosis, CFTR, Computational chemistry, Molecular dynamics | 10.1016/j.snb.2019.127131 |
| 408375 | Articolo in rivista | Durum wheat genome highlights past domestication signatures and future improvement targets | Maccaferri, Marco, Harris, Neil S., Twardziok, Sven O., Pasam, Raj K., Gundlach, Heidrun, Spannagl, Manuel, Ormanbekova, Danara, Lux, Thomas, Prade, Verena M., Milner, Sara G., Himmelbach, Axel, Mascher, Martin, Bagnaresi, Paolo, Faccioli, Primetta, Cozzi, Paolo, Lauria, Massimiliano, Lazzari, Barbara, Stella, Alessandra, Manconi, Andrea, Gnocchi, Matteo, Moscatelli, Marco, Avni, Raz, Deek, Jasline, Biyiklioglu, Sezgi, Frascaroli, Elisabetta, Corneti, Simona, Salvi, Silvio, Sonnante, Gabriella, Desiderio, Francesca, Mare, Caterina, Crosatti, Cristina, Mica, Erica, Ozkan, Hakan, Kilian, Benjamin, De Vita, Pasquale, Marone, Daniela, Joukhadar, Reem, Mazzucotelli, Elisabetta, Nigro, Domenica, Gadaleta, Agata, Chao, Shiaoman, Faris, Justin D., Melo, Arthur T. O., Pumphrey, Mike, Pecchioni, Nicola, Milanesi, Luciano, Wiebe, Krystalee, Ens, Jennifer, MacLachlan, Ron P., Clarke, John M., Sharpe, Andrew G., Koh, Chu Shin, Liang, Kevin Y. H., Taylor, Gregory J., Knox, Ron, Budak, Hikmet, Mastrangelo, Anna M., Xu, Steven S., Stein, Nils, Hale, Iago, Distelfeld, Assaf, Hayden, Matthew J., Tuberosa, Roberto, Walkowiak, Sean, Mayer, Klaus F. X., Ceriotti, Aldo, Pozniak, Curtis J., Cattivelli, Luigi | The domestication of wild emmer wheat led to the selection of modern durum wheat, grown mainly for pasta production. We describe the 10.45 gigabase (Gb) assembly of the genome of durum wheat cultivar Svevo. The assembly enabled genome-wide genetic diversity analyses revealing the changes imposed by thousands of years of empirical selection and breeding. Regions exhibiting strong signatures of genetic divergence associated with domestication and breeding were widespread in the genome with several major diversity losses in the pericentromeric regions. A locus on chromosome 5B carries a gene encoding a metal transporter (TdHMA3-B1) with a non-functional variant causing high accumulation of cadmium in grain. The high-cadmium allele, widespread among durum cultivars but undetected in wild emmer accessions, increased in frequency from domesticated emmer to modern durum wheat. The rapid cloning of TdHMA3-B1 rescues a wild beneficial allele and demonstrates the practical use of the Svevo genome for wheat improvement. | Nature genetics (Print) 51 (2019): 885-+. | 2019 | COZZI PAOLO ALESSANDRO, SONNANTE GABRIELLA, STELLA ALESSANDRA, MILANESI LUCIANO, GNOCCHI MATTEO, MANCONI ANDREA, MOSCATELLI MARCO, CERIOTTI ALDO | Durum wheat genome | 10.1038/s41588-019-0381-3 |
| 408381 | Articolo in rivista | A Scalable Genetic Programming Approach to Integrate miRNA-Target Predictions: Comparing Different Parallel Implementations of M3GP | Beretta, Stefano, Castelli, Mauro, Munoz, Luis, Trujillo, Leonardo, Martinez, Yuliana, Popovic, Ales, Milanesi, Luciano, Merelli, Ivan | There are many molecular biology approaches to the analysis of microRNA (miRNA) and target interactions, but the experiments are complex and expensive. For this reason, in silico computational approaches able to model these molecular interactions are highly desirable. Although several computational methods have been developed for predicting the interactions between miRNA and target genes, there are substantial differences in the results achieved since most algorithms provide a large number of false positives. Accordingly, machine learning approaches are widely used to integrate predictions obtained from different tools. In this work, we adopt a method called multidimensional multiclass GP with multidimensional populations (M3GP), which relies on a genetic programming approach, to integrate and classify results from different miRNA-target prediction tools. The results are compared with those obtained with other classifiers, showing competitive accuracy. Since we aim to provide genome-wide predictions with M3GP and, considering the high number of miRNA-target interactions to test (also in different species), a parallel implementation of this algorithm is recommended. In this paper, we discuss the theoretical aspects of this algorithm and propose three different parallel implementations. We show that M3GP is highly parallelizable, it can be used to achieve genome-wide predictions, and its adoption provides great advantages when handling big datasets. | Complexity (N.Y.N.Y.) (2018). | 2018 | BERETTA STEFANO, MERELLI IVAN, MILANESI LUCIANO | microRNA, target interactions, bioinformatics | 10.1155/2018/4963139 |
| 408383 | Articolo in rivista | NuChart-II: The road to a fast and scalable tool for Hi-C data analysis | Tordini, Fabio, Drocco, Maurizio, Misale, Claudia, Milanesi, Luciano, Lio, Pietro, Merelli, Ivan, Torquati, Massimo, Aldinucci, Marco | Recent advances in molecular biology and bioinformatic techniques have brought about an explosion of information about the spatial organisation of the DNA in the nucleus of a cell. High-throughput molecular biology techniques provide a genome-wide capture of the spatial organisation of chromosomes at unprecedented scales, which permit one to identify physical interactions between genetic elements located throughout a genome. This important information is, however, hampered by the lack of biologist-friendly analysis and visualisation software: these disciplines are literally caught in a flood of data and are now facing many of the scale-out issues that high-performance computing has been addressing for years. Data must be managed, analysed and integrated, with substantial requirements of speed (in terms of execution time), application scalability and data representation. In this work, we present NuChart-II, an efficient and highly optimised tool for genomic data analysis that provides a gene-centric, graph-based representation of genomic information and which proposes an ex-post normalisation technique for Hi-C data. While designing NuChart-II, we addressed several common issues in the parallelisation of memory-bound algorithms for shared-memory systems. | The international journal of high performance computing applications 31 (2017): 196-211. | 2017 | MERELLI IVAN, MILANESI LUCIANO | High-performance computing, bioinformatics, Hi-C data analysis, parallel computing, memory-bound algorithms | 10.1177/1094342016668567 |
| 408386 | Articolo in rivista | The Genome Conformation As an Integrator of Multi-Omic Data: Thie Example of Damage Spreading in Cancer | Tordini, Fabio, Aldinucci, Marco, Milanesi, Luciano, Lio, Pietro, Merelli, Ivan | Publicly available multi-omic databases, in particular if associated with medical annotations, are rich resources with the potential to lead a rapid transition from high-throughput molecular biology experiments to better clinical outcomes for patients. In this work, we propose a model for multi-omic data integration (i.e., genetic variations, gene expression, genome conformation, and epigenetic patterns), which exploits a multi-layer network approach to analyse, visualize, and obtain insights from such biological information, in order to use achieved results at a macroscopic level. Using this representation, we can describe how driver and passenger mutations accumulate during the development of diseases providing, for example, a tool able to characterize the evolution of cancer. Indeed, our test case concerns the MCF-7 breast cancer cell line, before and after the stimulation with estrogen, since many datasets are available for this case study. In particular, the integration of data about cancer mutations, gene functional annotations, genome conformation, epigenetic patterns, gene expression, and metabolic pathways in our multi-layer representation will allow a better interpretation of the mechanisms behind a complex disease such as cancer. Thanks to this multi-layer approach, we focus on the interplay of chromatin conformation and cancer mutations in different pathways, such as metabolic processes, that are very important for tumor development. Working on this model, a variance analysis can be implemented to identify normal variations within each omics and to characterize, by contrast, variations that can be accounted to pathological samples compared to normal ones. This integrative model can be used to identify novel biomarkers and to provide innovative omic-based guidelines for treating many diseases, improving the efficacy of decision trees currently used in clinic. | Frontiers in genetics 7 (2016). | 2016 | MERELLI IVAN, MILANESI LUCIANO | gene functional annotations, chromosome conformation capture, metabolic pathways, epigenetic patterns, gene expression, cancer mutations, multi-layer networks, damage spreading | 10.3389/fgene.2016.00194 |
| 408387 | Articolo in rivista | HCV NS3 sequencing as a reliable and clinically useful tool for the assessment of genotype and resistance mutations for clinical samples with different HCV-RNA levels | Di Maio, V. C., Cento, V., Di Paolo, D., Aragri, M., De Leonardis, F., Tontodonati, M., Micheli, V., Bellocchi, M. C., Antonucci, F. P., Bertoli, A., Lenci, I., Milana, M., Gianserra, L., Melis, M., Di Biagio, A., Sarrecchia, C., Sarmati, L., Landonio, S., Francioso, S., Lambiase, L., Nicolini, L. A., Marenco, S., Nosotti, L., Giannelli, V., Siciliano, M., Romagnoli, D., Pellicelli, A., Vecchiet, J., Magni, C. F., Babudieri, S., Mura, M. S., Taliani, G., Mastroianni, C., Vespasiani-Gentilucci, U., Romano, M., Morisco, F., Gasbarrini, A., Vullo, V., Bruno, S., Baiguera, C., Pasquazzi, C., Tisone, G., Picciotto, A., Andreoni, M., Parruti, G., Rizzardini, G., Angelico, M., Perno, C. F., Ceccherini-Silberstein, F.Mariani R, Paoloni M, Iapadre N, Grimaldi A, Menzaghi B, Quirino T, Vecchiet J, Bruzzone B, De Maria A, Di Biagio A, Marenco S, Nicolini LA, Picciotto A, Viscoli C, Casinelli K, Monache MD, Lichtner M, Mastroianni C, Aghemo A, Bruno S, Cerrone M, Colombo M, Monforte AD, Danieli E, Donato F, Gubertini G, Landonio S, Magni CF, Mancon A, Micheli V, Monico S, Niero F, Puoti M, Rizzardini G, Russo ML, Alfieri R, Gnocchi M, Orro A, Milanesi L, Baldelli E, Bertolotti M, Borghi V, Mussini C, Romagnoli D, Brancaccio G, Caporaso N, Gaeta GB, Lembo V, Morisco F, Calvaruso V, Craxi A, Di Marco V, Mazzola A, Petta S, D'Amico E, Cacciatore P, Consorte A, Palitti VP, Parruti G, Pieri A, Polilli E, Tontodonati M, Andreoni M, Angelico M, Antenucci F, Antonucci FP, Aragri M, Armenia D, Baiocchi L, Bellocchi M, Bertoli A, Biliotti E, Biolato M, Carioti L, Ceccherini-Silberstein F, Cento V, Cerasari G, Cerva C, Ciotti M, D'Ambrosio C, D'Ettorre G, De Leonardis F, De Sanctis A, Di Maio VC, Di Paolo D, Francioso S, Furlan C, Gallo P, Gasbarrini A, Giannelli V, Gianserra L, Grieco A, Grieco S, Lambiase L, Lattanzi B, Lenci I, Malagnino V, Manuelli M, Merli M, Miglioresi L, Milana M, Nosotti L, Palazzo D, Pasquazzi C, Pellicelli A, Perno CF, Romano M, Santopaolo F, Santoro MM, Sarmati L, Sarrecchia C, Sforza D, Siciliano M, Sorbo MC, Spaziante M, Svicher V, Taliani G, Teti E, Tisone G, Vespasiani-Gentilucci U, Vullo V, Mangia A, Babudieri S, Maida I, Melis M, Mura MS, Falconi L, Di Giammartino D, Tarquini P. | This study aims to evaluate the reliability and clinical utility of NS3 sequencing in hepatitis C virus (HCV) 1-infected patients who were candidates to start a PI-containing regimen. | Journal of antimicrobial chemotherapy (Print) 71 (2016): 739-750. | 2016 | ORRO ALESSANDRO, MILANESI LUCIANO, GNOCCHI MATTEO, ALFIERI ROBERTA | hcv, ns3, HCV-RNA | 10.1093/jac/dkv403 |
| 408454 | Articolo in rivista | Translational Medicine: Exercise Physiology Applied to Metabolic Myopathies. | Bruno Grassi 1, 2, Simone Porcelli 2, 3, Mauro Marzorati 2, 3 | The relevance of translational medicine (bringing basic science methods "to the bed of patients") is universally recognized. Too often, however, the tools to be applied translationally are thought to derive only from the "-omics" (genomics, proteomics, transcriptomics, metabolomics, etc.) world. The failures of this "reductionist" approach are widely recognized. In the review, we discuss studies demonstrating that scientifically sound mechanistic insights into diseases, relevant both in terms of basic science and clinically, and very well suited to be utilized within a translational medicine approach, can be obtained from the established field of exercise physiology. Methods originally aimed toward basic physiological mechanisms, and applied for the functional evaluation of athletes and sport performance, can have a valuable translational application in patients with metabolic myopathies; such as myophosphorylase deficiency (McArdle disease) or mitochondrial myopathies, diseases which share the common denominator of an impaired skeletal muscle oxidative metabolism. Several variables can yield pathophysiological insights, can identify and quantify the metabolic impairment and the effects on exercise tolerance (one of the main determinants of the patients' clinical picture and quality of life), and can offer diagnostic clues: the impaired capacity of O2 extraction by skeletal muscle, evaluated by near-infrared spectroscopy; the "exaggerated" cardiovascular response to exercise; the slower speed of adjustment of oxidative metabolism during metabolic transitions; the "slow component" of pulmonary O2 uptake kinetics and the associated reduced efficiency and fatigue; the impaired intramuscular matching between O2 delivery and O2 utilization. The proposed methods are noninvasive, and therefore facilitate repeated or serial evaluations. They provide support for a simple message: physiology and physiological research remain the essential link between genes, molecules, and clinical care. | Medicine and science in sports and exercise (Online) 51 (2019): 2183-2192. | 2019 | GRASSI BRUNO, MARZORATI MAURO, PORCELLI SIMONE | - | 10.1249/MSS.0000000000002056 |
| 409564 | Articolo in rivista | Rectal Microbiota Associated With Chlamydia trachomatis and Neisseria gonorrhoeae Infections in Men Having Sex With Other Men | Ceccarani, Camilla, Marangoni, Antonella, Severgnini, Marco, Camboni, Tania, Laghi, Luca, Gaspari, Valeria, D'Antuono, Antonietta, Foschi, Claudio, Re, Maria Carla, Consolandi, Clarissa | Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) represent the most common agents of sexually transmitted rectal infections among men having sex with other men (MSM). In this study, we assessed the bacterial composition of the rectal microbiota associated with CT and/or NG infections in a cohort of men reporting unsafe rectal intercourse. A total of 125 rectal swabs were collected and four groups were compared: non-infected subjects (n = 53), patients with CT (n = 37), or NG rectal infection (n = 17) and patients with contemporary positivity for CT/NG (n = 18). CT and NG infections were detected by a real-time commercial test and the rectal microbiota composition was analyzed from rectal swabs through sequencing of the hypervariable V3-V4 regions of the 16S rRNA gene. The rectal microbiota of all subgroups was dominated by Prevotellaceae, Enterobacteriaceae, and Ruminococcaceae families. Irrespective of the analyzed subgroup, we found that the rectal environment of all the enrolled MSM was rich in Prevotella and Escherichia genera. Moreover, a shift in the bacterial composition between patients with sexually transmitted rectal infections and controls was noticed: infected patients were characterized by a depletion of Escherichia species, associated with an increase of anaerobic genera, including Peptoniphilus, Peptostreptococcus, and Parvimonas. Overall, the presence of rectal symptoms did not significantly modify the rectal microbiota profiles among the four groups of analyzed patients. We confirmed that HIV-positive patients are characterized by a lower bacterial richness than HIV-negative subjects. However, we found that the presence of HIV has a different impact on bacterial rectal communities compared to CT and NG infections, modifying the relative abundance of several genera, including Gardnerella, Lactobacillus, Corynebacterium, and Sutterella. Information about the rectal microbiota composition in CT and NG infections could shed light on the pathogenesis of these conditions and could contribute to the onset of new strategies for their control. | Frontiers in cellular and infection microbiology 9 (2019): 358. | 2019 | CECCARANI CAMILLA, CAMBONI TANIA, CONSOLANDI CLARISSA, SEVERGNINI MARCO | Chlamydia trachomatis, HIV, microbiota, MSM, Neisseria gonorrhoeae, rectal microbiome | 10.3389/fcimb.2019.00358 |
| 409701 | Articolo in rivista | Dopamine, Oxidative Stress and Protein-Quinone Modifications in Parkinson's and Other Neurodegenerative Diseases | Monzani E., Nicolis S., Dell'Acqua S., Capucciati A., Bacchella C., Zucca F.A., Mosharov E.V., Sulzer D., Zecca L., Casella L. | Dopamine (DA) is the most important catecholamine in the brain, as it is the most abundant and the precursor of other neurotransmitters. Degeneration of nigrostriatal neurons of substantia nigra pars compacta in Parkinson's disease represents the best-studied link between DA neurotransmission and neuropathology. Catecholamines are reactive molecules that are handled through complex control and transport systems. Under normal conditions, small amounts of cytosolic DA are converted to neuromelanin in a stepwise process involving melanization of peptides and proteins. However, excessive cytosolic or extraneuronal DA can give rise to nonselective protein modifications. These reactions involve DA oxidation to quinone species and depend on the presence of redox-active transition metal ions such as iron and copper. Other oxidized DA metabolites likely participate in post-translational protein modification. Thus, protein-quinone modification is a heterogeneous process involving multiple DA-derived residues that produce structural and conformational changes of proteins and can lead to aggregation and inactivation of the modified proteins. | Angewandte Chemie (Int. ed., Print) 58 (2019): 6512-6527. | 2019 | ZECCA LUIGI, ZUCCA FABIO ANDREA | dopamine, neurodegeneration, neuromelanin, oxidative stress, Parkinson's disease | 10.1002/anie.201811122 |
| 409703 | Articolo in rivista | Iron, Myelin, and the Brain: Neuroimaging Meets Neurobiology | Moller H.E., Bossoni L., Connor J.R., Crichton R.R., Does M.D., Ward R.J., Zecca L., Zucca F.A., Ronen I. | Although iron is crucial for neuronal functioning, many aspects of cerebral iron biology await clarification. The ability to quantify specific iron forms in the living brain would open new avenues for diagnosis, therapeutic monitoring, and understanding pathogenesis of diseases. A modality that allows assessment of brain tissue composition in vivo, in particular of iron deposits or myelin content on a submillimeter spatial scale, is magnetic resonance imaging (MRI). Multimodal strategies combining MRI with complementary analytical techniques ex vivo have emerged, which may lead to improved specificity. Interdisciplinary collaborations will be key to advance beyond simple correlative analyses in the biological interpretation of MRI data and to gain deeper insights into key factors leading to iron accumulation and/or redistribution associated with neurodegeneration. | Trends in neurosciences (Regul. ed.) 42 (2019): 384-401. | 2019 | ZECCA LUIGI, ZUCCA FABIO ANDREA | aging and neurodegeneration, iron biology, magnetic resonance imaging, magnetic susceptibility, myelin, water proton relaxation | 10.1016/j.tins.2019.03.009 |
| 414766 | Contributo in atti di convegno | Preliminary vastus lateralis characterization with time domain near infrared spectroscopy during incremental cycle exercise | Pirovano, I., Porcelli, S., Azzarello, F., Re, R., Spinelli, L., Contini, D., Marzorati, M., Torricelli, A. | Functional near infrared spectroscopy (NIRS) is a widespread non-invasive technique to monitor skeletal muscle metabolism. However, only variation of oxygenated (HHb), deoxygenated (O2Hb), total (tHb) hemoglobin and saturation (SO2) are usually reported. In this study, Time Domain (TD) NIRS approach was exploited to perform a preliminary quantitative characterization of vastus lateralis muscle during incremental exercise. A population of 11 healthy young male subjects performed on a mechanical cycle ergometer an incremental exercise (initial work rate range = 60-96 W, increment = 12-18 W/min) until exhaustion. TD NIRS, heart rate, pulmonary ventilation (VE), O2 uptake (VO2), CO2 output (VCO2), blood lactate concentration ([La]b) and Borg scale were measured during the exercise. From TD NIRS, muscles absolute values of absorption and scattering coefficients were obtained with a homogeneous approach and hemoglobin concentrations and saturation levels were calculated. The time courses of HHb, O2Hb, tHb and SO2 were consistent with previous literature results. A high inter-subject variability was found for both optical properties and hemodynamic concentrations. Further statistical group analysis will be required in order to highlight significant behavior within the population and correlation with physiological parameters. | Diffuse Optical Spectroscopy and Imaging VII 2019, pp. 1107424-1-1107424-3, Munich; Germany | 2019 | TORRICELLI ALESSANDRO, RE REBECCA, SPINELLI LORENZO CLEMENTE, MARZORATI MAURO, PORCELLI SIMONE | cycling exercise, muscle oxidative metabolism, optical properties, TD NIRS, vastus lateralis | 10.1117/12.2527068 |
| 414881 | Articolo in rivista | A novel bayesian approach with conditional autoregressive specification for intravoxel incoherent motion diffusion-weighted MRI | Lanzarone, Ettore, Mastropietro, Alfonso, Scalco, Elisa, Vidiri, Antonello, Rizzo, Giovanna | The Intra-Voxel Incoherent Motion (IVIM) model is largely adopted to estimate slow and fast diffusion coefficients of water molecules in biological tissues, which are used in cancer applications. The most reported fitting approach is a voxel-wise segmented non-linear least square, whereas Bayesian approaches with a direct fit, also considering spatial regularization, were proposed too. In this work a novel segmented Bayesian method was proposed, also in combination with a spatial regularization through a Conditional Autoregressive (CAR) prior specification. The two segmented Bayesian approaches, with and without CAR specification, were compared with two standard least-square and a direct Bayesian fitting methods. All approaches were tested on simulated images and real data of patients with head-and-neck and rectal cancer. Estimation accuracy and maps noisiness were quantified on simulated images, whereas the coefficient of variation and the goodness of fit were evaluated for real data. Both versions of the segmented Bayesian approach outperformed the standard methods on simulated images for pseudo-diffusion (D*) and perfusion fraction (f), whilst the segmented least-square fitting remained the less biased for the diffusion coefficient (D). On real data, Bayesian approaches provided the less noisy maps, and the two Bayesian methods without CAR generally estimated lower values for f and D* coefficients with respect to the other approaches. The proposed segmented Bayesian approaches were superior, in terms of estimation accuracy and maps quality, to the direct Bayesian model and the least-square fittings. The CAR method improved the estimation accuracy, especially for D*. | NMR in biomedicine 33 (2020): e4201. | 2020 | RIZZO GIOVANNA, LANZARONE ETTORE, SCALCO ELISA, MASTROPIETRO ALFONSO | Bayesian Segmented Approach, Conditional Autoregressive Model, Diffusion-Weighted MRI, IVIM | 10.1002/nbm.4201 |
| 415392 | Articolo in rivista | Genotyping by Sequencing of Cultivated Lentil (Lens culinaris Medik.) Highlights Population Structure in the Mediterranean Gene Pool Associated With Geographic Patterns and Phenotypic Variables | Pavan, Stefano, Bardaro, Nicoletta, Fanelli, Valentina, Marcotrigiano, Angelo Raffaele, Mangini, Giacomo, Taranto, Francesca, Catalano, Domenico, Montemurro, Cinzia, De Giovanni, Claudio, Lotti, Concetta, Ricciardi, Luigi | Cultivated lentil (Lens culinaris Medik.) is one of the oldest domesticated crops and one of the most important grain legumes worldwide. The Mediterranean Basin holds large part of lentil biodiversity; however, no genetic structure was defined within the Mediterranean gene pool. In this study, we used high-throughput genotyping by sequencing to resolve the genetic structure of the Mediterranean ex situ lentil collection held at the Italian National Research Council. Sequencing of a 188-plex genotyping-by-sequencing library and bioinformatics treatment of data yielded 6,693 single nucleotide polymorphisms. Analysis of nonredundant genotypes with nonparametric and parametric methods highlighted the occurrence of five highly differentiated genetic clusters. Clustering could be related to geographic patterns and phenotypic traits, indicating that post-domestication routes introducing cultivation in Mediterranean countries and selection were major forces shaping lentil population structure. The estimation of the fixation index F-ST at individual single nucleotide polymorphism loci allowed the identification of distinctive alleles across clusters, suggesting the possibility to set up molecular keys for the assignment of lentil germplasm to specific genetic groups. Finally, significant associations between markers and phenotypic data were identified. Overall, the results of this study are of major importance for lentil conservation genetics and breeding and provide insights on the lentil evolutionary history. | Frontiers in genetics 10 (2019). | 2019 | CATALANO DOMENICO, TARANTO FRANCESCA | breeding, conservation genetics, genetic structure, genotyping-by-sequencing, lentil | 10.3389/fgene.2019.00872 |
| 393317 | Articolo in rivista | Identification and classification of meteorites using a handheld LIBS instrument coupled with a fuzzy logic-based method | Senesi G.S.1, Manzari P.2, Consiglio A.3, De Pascale O.1 | A handheld laser-induced breakdown spectroscopy (LIBS) instrument is proposed as a novel tool that is able to provide information on the nature of meteorites and discriminate among iron, stone, stony-iron meteorites and meteor-wrongs. Further, a novel fuzzy logic-based inference algorithm is applied to broadband LIBS spectra for the identification of meteorites and their classification according to their origin and nature. The identification of meteorites is a decision-making problem based on a compromise among human experience, visual evidence and analytical data, which fuzzy logic is proved to be able to solve. The final model is able to correctly classify 25 out of 26 samples and provides a set of IF-THEN rules that describe how some selected wavelengths are involved in the classification task. | Journal of analytical atomic spectrometry (Print) 33 (2018): 1664-1675. | 2018 | DE PASCALE OLGA, SENESI GIORGIO SAVERIO, CONSIGLIO ARIANNA | Laserinduced breakdown spectroscopy, Meteorites, Fuzzy logic | 10.1039/c8ja00224j |
| 416083 | Articolo in rivista | T2w-MRI signal normalization affects radiomics features reproducibility. | Elisa Scalco 1, 2, * Antonella Belfatto 2, Alfonso Mastropietro 1, 2 Tiziana Rancati 3, Barbara Avuzzi 4, Antonella Messina 5, Riccardo Valdagni 3, 4, 6, Giovanna Rizzo 1, 2 | PURPOSE: Despite its increasing application, radiomics has not yet demonstrated a solid reliability, due to the difficulty in replicating analyses. The extraction of radiomic features from clinical MRI (T1w/T2w) presents even more challenges because of the absence of well-defined units (e.g. HU). Some pre-processing steps are required before the estimation of radiomic features and one of this is the intensity normalization, that can be performed using different methods. The aim of this work is to evaluate the effect of three different normalization techniques, applied on T2w-MRI images of the pelvic region, on radiomic features reproducibility. METHODS: T2w-MRI acquired before (MRI1) and 12 months after radiotherapy (MRI2) on 14 patients treated for prostate cancer were considered. Four different conditions were analyzed: 1) the original MRI (No_Norm); 2) MRI normalized by the mean image value (Norm_Mean); 3) MRI normalized by the mean value of the urine in the bladder (Norm_ROI); 4) MRI normalized by the histogram-matching method (Norm_HM). 91 radiomic features were extracted in three organs of interest (prostate, internal obturator muscles and bulb) on both time-points and on each image discretized using a fixed-bin width approach and the difference between the two time-points was calculated (?feature). To estimate the effect of normalization methods on the reproducibility of radiomic features, ICC was calculated in three analyses: 1) considering the features extracted on MRI2 in the four conditions together and considering the influence of each method separately, with respect to No_Norm; 2) considering the features extracted on MRI2 in the four conditions with respect to the inter-observer variability in ROI contouring, considering also the effect of the discretization approach; 3) considering ?feature to evaluate if some indices can recover some consistency when differences are calculated. RESULTS: Nearly 60% of the features have shown poor reproducibility (ICC<0.5) on MRI2 and the method that most affected features reliability was Norm_ROI (average ICC of 0.45). The other two methods were similar, except for first order features, where Norm_HM outperformed Norm_Mean (average ICC = 0.33 and 0.76 for Norm_Mean and Norm_HM, respectively). In the inter-observer setting, the number of reproducible features varied in the three structures, being higher in the prostate than in the penile bulb and in the obturators. The analysis on ?feature highlighted that more than 60% of the features were not consistent with respect to the normalization method and confirmed the high reproducibility of the features between Norm_Mean and Norm_HM, whereas Norm_ROI was the less reproducible method. CONCLUSIONS: The normalization process impacts the reproducibility of radiomic features, both in terms of changes in the image information content and in the inter-observer setting. Among the considered methods, Norm_Mean and Norm_HM seem to provide the most reproducible features with respect to the original image and also between themselves, whereas Norm_ROI generates the less reproducible. Only a very small subset of feature remained reproducible and independent in any tested condition, regardless the ROI and the adopted algorithm: skewness or kurtosis, correlation and one among Imc2, Idmn and Idn from GLCM group. | Medical physics (Lanc.) 47 (2020): 1680-1691. | 2020 | BELFATTO ANTONELLA, RIZZO GIOVANNA, SCALCO ELISA, MASTROPIETRO ALFONSO | MRI intensity normalization; prostate cancer; radiomics; reproducibility assessment | 10.1002/mp.14038 |
| 416471 | Articolo in rivista | Promoting healthy teenage behaviour across three European countries through the use of a novel smartphone technology platform, PEGASO fit for future: Study protocol of a quasi-experimental, controlled, multi-Centre trial | Puigdomenech, Elisa, Martin, Anne, Lang, Alexandra, Adorni, Fulvio, Gomez, Santiago Felipe, McKinstry, Brian, Prinelli, Federica, Condon, Laura, Rashid, Rajeeb, Caon, Maurizio, Atkinson, Sarah, Lafortuna, Claudio L., Ciociola, Valentina, Hanley, Janet, McCloughan, Lucy, Castell, Conxa, Espallargues, Mireia | Background: Behaviour change interventions targeting physical activity, diet, sleep and sedentary behaviour of teenagers show promise when delivered through smartphones. However, to date there is no evidence of effectiveness of multicomponent smartphone-based interventions. Utilising a user-centred design approach, we developed a theory-based, multi-dimensional system, PEGASO Fit For Future (PEGASO F4F), which exploits sophisticated game mechanics involving smartphone applications, a smartphone game and activity sensors to motivate teenagers to take an active role in adopting and maintaining a healthy lifestyle. This paper describes the study protocol to assess the feasibility, usability and effectiveness (knowledge/awareness and behavioural change in lifestyle) of the PEGASO system. Methods: We are conducting a quasi-experimental controlled cluster trial in 4 sites in Spain, Italy, and UK (England, Scotland) over 6 months. We plan to recruit 525, in a 2:1 basis, teenagers aged 13-16 years from secondary schools. The intervention group is provided with the PEGASO system whereas the comparison group continues their usual educational routine. Outcomes include feasibility, acceptance, and usability of the PEGASO system as well as between and within group changes in motivation, self-reported diet, physical activity, sedentary and sleeping behaviour, anthropometric measures and knowledge about a healthy lifestyle. Discussion: PEGASO F4F will provide evidence into the cross-cultural similarities and differences in the feasibility, acceptability and usability of a multi-dimensional smartphone based behaviour change intervention for teenagers. The study will explore facilitating factors, challenges and barriers of engaging teenagers to adapt and maintain a healthy lifestyle when using smartphone technology. Positive results from this ICT based multi component intervention may have significant implications both at clinical level, improving teenagers health and at public health level since it can present an influential tool against the development of chronic disease during adulthood. Trial registration: https://clinicaltrials.gov Registration number: NCT02930148, registered 4 October 2016. | BMC medical informatics and decision making (Online) 19 (2019). | 2019 | CARAMENTI MARTINA, TABOZZI SARAH ANTONELLA, CIOCIOLA VALENTINA, ADORNI FULVIO DANIELE, PRINELLI FEDERICA | Adolescents, Behaviour change, Diet, eHealth, Health promotion, mHealth, Mobile health, Obesity prevention, Physical activity, Sedentary behaviour, Serious game, Sleep, Smartphone application | 10.1186/s12911-019-0958-x |
| 417129 | Articolo in rivista | Gene relevance based on multiple evidences in complex networks | Di Nanni N., Gnocchi M., Moscatelli M., Milanesi L., Mosca E. | MOTIVATION: Multi-omics approaches offer the opportunity to reconstruct a more complete picture of the molecular events associated with human diseases, but pose challenges in data analysis. Network-based methods for the analysis of multi-omics leverage the complex web of macromolecular interactions occurring within cells to extract significant patterns of molecular alterations. Existing network-based approaches typically address specific combinations of omics and are limited in terms of the number of layers that can be jointly analysed. In this study, we investigate the application of network diffusion to quantify gene relevance on the basis of multiple evidences (layers). RESULTS: We introduce a gene score (mND) that quantifies the relevance of a gene in a biological process taking into account the network proximity of the gene and its first neighbours to other altered genes. We show that mND has a better performance over existing methods in finding altered genes in network proximity in one or more layers. We also report good performances in recovering known cancer genes. The pipeline described in this article is broadly applicable, because it can handle different types of inputs: in addition to multi-omics datasets, datasets that are stratified in many classes (e.g., cell clusters emerging from single cell analyses) or a combination of the two scenarios. AVAILABILITY AND IMPLEMENTATION: The R package 'mND' is available at URL: https://www.itb.cnr.it/mnd. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. | Bioinformatics (Oxf., Online) 36 (2020): 865-871. | 2020 | DI NANNI NOEMI, MILANESI LUCIANO, GNOCCHI MATTEO, MOSCA ETTORE, MOSCATELLI MARCO | multi-omics, biological networks | 10.1093/bioinformatics/btz652 |
| 417684 | Articolo in rivista | Prediction of new associations between ncRNAs and diseases exploiting multi-type hierarchical clustering | Emanuele Pio Barracchia1, Gianvito Pio1*, Domenica D'Elia3, Michelangelo Ceci1, 2, 4 | Background: The study of functional associations between ncRNAs and human diseases is a pivotal task of modern research to develop new and more effective therapeutic approaches. Nevertheless, it is not a trivial task since it involves entities of different types, such as microRNAs, lncRNAs or target genes whose expression also depends on endogenous or exogenous factors. Such complexity can be faced by representing the involved biological entities and their relationships as a network and by exploiting network-based computational approaches able to identify new associations. However, existing methods are limited to homogeneous networks (i.e., consisting of only one type of objects and relationships) or can exploit only a small subset of the features of biological entities, such as the presence of a particular binding domain, enzymatic properties or their involvement in specific diseases. Results: To overcome the limitations of existing approaches, we propose the system LP-HCLUS, which exploits a multi-type hierarchical clustering method to predict possibly unknown ncRNA-disease relationships. In particular, LP-HCLUS analyzes heterogeneous networks consisting of several types of objects and relationships, each possibly described by a set of features, and extracts multi-type clusters that are subsequently exploited to predict new ncRNA-disease associations. The extracted clusters are overlapping, hierarchically organized, involving entities of different types, and allow LP-HCLUS to catch multiple roles of ncRNAs in diseases at different levels of granularity. Our experimental evaluation, performed on heterogeneous attributed networks consisting of microRNAs, lncRNAs, diseases, genes and their known relationships, shows that LP-HCLUS is able to obtain better results with respect to existing approaches. The biological relevance of the obtained results was evaluated according to both quantitative (i.e., TPR@k, Areas Under the TPR@k, ROC and Precision-Recall curves) and qualitative (i.e., according to the consultation of the existing literature) criteria. Conclusions: The obtained results prove the utility of LP-HCLUS to conduct robust predictive studies on the biological role of ncRNAs in human diseases. The produced predictions can, therefore, be reliably considered as new, previously unknown, relationships among ncRNAs and diseases. | BMC bioinformatics 21 (2020): 1-24. | 2020 | D'ELIA DOMENICA | Non-coding RNA (ncRNAs), Diseases, Cancer, Heterogeneous network, Clustering, Link prediction | 10.1186/s12859-020-3392-2 |
| 417687 | Articolo in rivista | Gene expression signature induced by grape intake in healthy subjects reveals wide-spread beneficial effects on peripheral blood mononuclear cells | Milella, Rosa Anna, Gasparro, Marica, Alagna, Fiammetta, Cardone, Maria Francesca, Rotunno, Silvia, Ammollo, Concetta Tiziana, Semeraro, Fabrizio, Tullo, Apollonia, Marzano, Flaviana, Catalano, Domenico, Antonacci, Donato, Colucci, Mario, D'Elia, Domenica | Using a transcriptomic approach, we performed a pilot study in healthy subjects to evaluate the changes in gene expression induced by grape consumption. Blood from twenty subjects was collected at baseline (T0), after 21 days of grape-rich diet (T1) and after one-month washout (T2). Gene expression profiling of peripheral blood mononuclear cells from six subjects identified 930 differentially expressed transcripts. Gene functional analysis revealed changes (at T1 and/or T2) suggestive of antithrombotic and anti-inflammatory effects, confirming and extending previous finding on the same subjects. Moreover, we observed several other favourable changes in the transcription of genes involved in crucial processes such as immune response, DNA and protein repair, autophagy and mitochondrial biogenesis. Finally, we detected significant changes in many long non-coding RNAs genes, whose regulatory functions are being increasingly appreciated. Altogether, our data suggest that a grape diet may exert its beneficial effects by targeting different strategic pathways. | Journal of Functional Foods 64 (2020): 105278-105278. | 2020 | MARZANO FLAVIANA, TULLO APOLLONIA, D'ELIA DOMENICA, CATALANO DOMENICO | Grape, Diet, Polyphenols, Nutrigenomics, Cell homeostasis, Long non-coding RNAs | 10.1016/j.jff.2019.103705 |
| 417688 | Articolo in rivista | Microarray data and pathway analyses of peripheral blood mononuclear cells from healthy subjects after a three weeks grape-rich diet | Rosa Anna Milella a, **, Marica Gasparro a, Fiammetta Alagna a, 1, Maria Francesca Cardone a, Silvia Rotunno a, 2, Concetta Tiziana Ammollo b, Fabrizio Semeraro b, Apollonia Tullo c, Flaviana Marzano c, Domenico Catalano d, Donato Antonacci a, Mario Colucci b, Domenica D'Elia d, * | Using Human Gene Expression Microarrays (Agilent) technologies, we investigated changes of the level of gene expression in peripheral blood mononuclear cells of healthy subjects after 21 days of fresh table grape-rich diet and after an additional 28-day washout. Several hundreds of genes were differentially expressed after grape intake or after washout. The functional analysis of these genes detected significant changes in key processes such as inflammation and immunity, thrombosis, DNA and protein repair, autophagy and mitochondrial biogenesis. Moreover, fresh grape intake was found to influence the expression of many long non-coding RNA genes. The data can be valuable for researchers interested in nutrigenetics and nutrigenomics studies and are related to the research article "Gene expression signature induced by grape intake in healthy subjects reveals wide-spread beneficial effects on PBMCs" [1]. | Data in brief 29 (2020): 105278-105278. | 2020 | MARZANO FLAVIANA, TULLO APOLLONIA, D'ELIA DOMENICA, CATALANO DOMENICO | Peripheral blood mononuclear cells, Microarray data, Pathway analyses, Biological processes, Grape intake, Diets, Human health, Health benefits | 10.1016/j.dib.2020.105278 |
| 417795 | Articolo in rivista | Single-Cell Transcriptomics of Human and Mouse Lung Cancers Reveals Conserved Myeloid Populations across Individuals and Species | Zilionis R, Engblom C, Pfirschke C, Savova V, Zemmour D, Saatcioglu HD, Krishnan I, Maroni G, Meyerovitz CV, Kerwin CM, Choi S, Richards WG, De Rienzo A, Tenen DG, Bueno R, Levantini E, Pittet MJ, Klein AM | Tumor-infiltrating myeloid cells (TIMs) comprise monocytes, macrophages, dendritic cells, and neutrophils, and have emerged as key regulators of cancer growth. These cells can diversify into a spectrum of states, which might promote or limit tumor outgrowth but remain poorly understood. Here, we used single-cell RNA sequencing (scRNA-seq) to map TIMs in non-small-cell lung cancer patients. We uncovered 25 TIM states, most of which were reproducibly found across patients. To facilitate translational research of these populations, we also profiled TIMs in mice. In comparing TIMs across species, we identified a near-complete congruence of population structures among dendritic cells and monocytes; conserved neutrophil subsets; and species differences among macrophages. By contrast, myeloid cell population structures in patients' blood showed limited overlap with those of TIMs. This study determines the lung TIM landscape and sets the stage for future investigations into the potential of TIMs as immunotherapy targets. | Immunity (Camb. Mass.) 50 (2019): 1317-+. | 2019 | MARONI GIORGIA, LEVANTINI ELENA | single cell transcriptomics, InDrop technology, lung cancer tumor infiltrating myeloid cells, patient samples, murine model of lung cancer, identification of 25 novel myeloid signatures, tumor microenvironment landscape defined at the single cell level, scRNAseq | 10.1016/j.immuni.2019.03.009 |
| 417796 | Articolo in rivista | Protein synthesis rates and ribosome occupancies reveal determinants of translation elongation rates | Andrea Ribaa, a) Noemi Di Nanni, b, c) Nitish Mittal, d) Erik Arhne, d) Alexander Schmidt, d), Mihaela Zavolan, d) | Although protein synthesis dynamics has been studied both with theoretical models and by profiling ribosome footprints, the determinants of ribosome flux along open reading frames (ORFs) are not fully understood. Combining measurements of protein synthesis rate with ribosome footprinting data, we here inferred translation initiation and elongation rates for over a 1,000 ORFs in exponentially growing wild-type yeast cells. We found that the amino acid composition of synthesized proteins is as important a determinant of translation elongation rate as parameters related to codon and transfer RNA (tRNA) adaptation. We did not find evidence of ribosome collisions curbing the protein output of yeast transcripts, either in high translation conditions associated with exponential growth, or in strains in which deletion of individual ribosomal protein (RP) genes leads to globally increased or decreased translation. Slow translation elongation is characteristic of RP-encoding transcripts, which have markedly lower protein output compared with other transcripts with equally high ribosome densities. | Proceedings of the National Academy of Sciences of the United States of America 116 (2019): 15023-15032. | 2019 | DI NANNI NOEMI | translation, yeast, protein charge, TASEP, ribosomal proteins | 10.1073/pnas.1817299116 |
| 417797 | Articolo in rivista | Lentiviral gene therapy corrects platelet phenotype and function in patients with Wiskott-Aldrich syndrome | Sereni L1, Castiello MC1, Di Silvestre D2, Della Valle P3, Brombin C4, Ferrua F5, Cicalese MP6, Pozzi L3, Migliavacca M6, Bernardo ME6, Pignata C7, Farah R8, Notarangelo LD9, Marcus N10, Cattaneo L11, Spinelli M12, Giannelli S1, Bosticardo M1, van Rossem K13, D'Angelo A3, Aiuti A5, Mauri P2, Villa A14. | BACKGROUND: Thrombocytopenia is a serious issue for all patients with classical Wiskott-Aldrich syndrome (WAS) and X-linked thrombocytopenia (XLT) because it causes severe and life-threatening bleeding. Lentiviral gene therapy (GT) for WAS has shown promising results in terms of immune reconstitution. However, despite the reduced severity and frequency of bleeding events, platelet counts remain low in GT-treated patients. OBJECTIVE: We carefully investigated platelet defects in terms of phenotype and function in untreated patients with WAS and assessed the effect of GT treatment on platelet dysfunction. METHODS: We analyzed a cohort of 20 patients with WAS/XLT, 15 of them receiving GT. Platelet phenotype and function were analyzed by using electron microscopy, flow cytometry, and an aggregation assay. Platelet protein composition was assessed before and after GT by means of proteomic profile analysis. RESULTS: We show that platelets from untreated patients with WAS have reduced size, abnormal ultrastructure, and a hyperactivated phenotype at steady state, whereas activation and aggregation responses to agonists are decreased. GT restores platelet size and function early after treatment and reduces the hyperactivated phenotype proportionally to WAS protein expression and length of follow-up. CONCLUSIONS: Our study highlights the coexistence of morphologic and multiple functional defects in platelets lacking WAS protein and demonstrates that GT normalizes the platelet proteomic profile with consequent restoration of platelet ultrastructure and phenotype, which might explain the observed reduction of bleeding episodes after GT. These results are instrumental also from the perspective of a future clinical trial in patients with XLT only presenting with microthrombocytopenia. | Journal of allergy and clinical immunology 144 (2019): 825-838. | 2019 | DI SILVESTRE DARIO, VILLA ANNA, MAURI PIETRO LUIGI | Wiskott-Aldrich syndrome, X-linked thrombocytopenia, gene therapy, platelets | 10.1016/j.jaci.2019.03.012 |
| 417799 | Articolo in rivista | Methionine oxidation in ?-synuclein inhibits its propensity for ordered secondary structure | Erika Ponzini1, Antonella De Palma2, Lucilla Cerboni1, Antonino Natalello3, Rossana Rossi4, Rani Moons5, Albert Konijnenberg5, Joanna Narkiewicz6, Giuseppe Antonio Legname7, Frank Sobott8, Pierluigi Mauri4, Carlo Santambrogio1*, Rita Grandori9 | ?-Synuclein (AS) is an intrinsically disordered protein highly expressed in dopaminergic neurons. Its amyloid aggregates are the major component of Lewy bodies, a hallmark of Parkinson's disease (PD). AS is particularly exposed to oxidation of its methionine residues, both in vivo and in vitro. Oxidative stress has been implicated in PD and oxidized ?-synuclein has been shown to assemble into soluble, toxic oligomers, rather than amyloid fibrils. However, the structural effects of methionine oxidation are still poorly understood. In this work, oxidized AS was obtained by prolonged incubations with dopamine (DA) or epigallocatechin-3-gallate (EGCG), two inhibitors of AS aggregation, indicating that EGCG promotes the same final oxidation product as DA. The conformational transitions of the oxidized and non-oxidized protein were monitored by complementary biophysical techniques, including MS, ion mobility (IM), CD and FTIR spectroscopy assays. Although the two variants displayed very similar structures under conditions that stabilize highly disordered or highly ordered states, differences emerged in the intermediate points of transitions induced by organic solvents, such as trifluoroethanol (TFE) and methanol (MeOH), indicating a lower propensity of the oxidized protein for forming either ?- or ?-type secondary structure. Furthermore, oxidized AS displayed restricted secondary-structure transitions in response to dehydration and slightly amplified tertiary-structure transitions induced by ligand binding. This difference in susceptibility to induced folding could explain the loss of fibrillation potential observed for oxidized AS. | The Journal of biological chemistry (Print) Apr 5;294(14) (2019): 5657-5665. | 2019 | ROSSI ROSSANA, DE PALMA ANTONELLA, MAURI PIETRO LUIGI | epigallocatechin-3-gallate methionine oxidation ion mobility (IM) amyloid mass spectrometry (MS) dopamine alpha-synuclein (a-synuclein) Fourier transform IR (FTIR) neurodegenerative disease circular dichroism (CD) | 10.1074/jbc.RA118.001907 |
| 417800 | Articolo in rivista | Mutation of a bHLH transcription factor allowed almond domestication | R. Sanchez-Perez1, 2, 3, *, +, S. Pavan4, 5, *, +, R. Mazzeo2, 3, 4, C. Moldovan2, 3, R. Aiese Cigliano6, J. Del Cueto1, 2, 3, 7, F. Ricciardi2, 3, 8, C. Lotti8, L. Ricciardi4, F. Dicenta1, R. L. Lopez-Marques9, B. Lindberg Moller2, 3 | Wild almond species accumulate the bitter and toxic cyanogenic diglucoside amygdalin. Almond domestication was enabled by the selection of genotypes harboring sweet kernels. We report the completion of the almond reference genome. Map-based cloning using an F-1 population segregating for kernel taste led to the identification of a 46-kilobase gene cluster encoding five basic helix-loop-helix transcription factors, bHLH1 to bHLH5. Functional characterization demonstrated that bHLH2 controls transcription of the P450 monooxygenase-encoding genes PdCYP79D16 and PdCYP71AN24, which are involved in the amygdalin biosynthetic pathway. A nonsynonymous point mutation (Leu to Phe) in the dimerization domain of bHLH2 prevents transcription of the two cytochrome P450 genes, resulting in the sweet kernel trait. | Science (N. Y., N.Y.) 364 (2019): 1095-+. | 2019 | PAVAN STEFANO | * | 10.1126/science.aav8197 |
| 417801 | Articolo in rivista | The LIBRA Index in Relation to Cognitive Function, Functional Independence, and Psycho-Behavioral Symptoms in a Sample of Non-Institutionalized Seniors at Risk of Dementia | Franchini F1, 2, Musicco M3, Ratto F1, Storti G4, Shofany J1, Caltagirone C1, 2, Di Santo SG1, 2. | BACKGROUND: Alzheimer's disease is the principal cause of dementia and is determined, in at least one third cases, by modifiable risk factors (MRF). The "Lifestyle for Brain Health (LIBRA)" index was recently developed to quantify the individual risk of progression to dementia ascribable to MRF. OBJECTIVE: The aim of this study was to investigate the association between LIBRA scores and markers of cognitive performance, functional independence, and psycho-behavioral symptoms in a community-based sample of Italian elders. METHODS: 308 senior participants with mild cognitive impairment (MCI) or subjective cognitive decline (SCD) were evaluated with a complete neuropsychological battery and semi-structured interviews for the assessment of depression, apathy, and functional autonomy. All the 12 LIBRA MRF were available for the calculation of LIBRA scores. A modified version of the index (LIBRA-2) was calculated by removing depression weight from the LIBRA index. Partial correlation analyses, controlling for age and education, assessed the association between LIBRA indices and cognitive, functional, and behavioral outcomes. Separate analyses were repeated in the MCI and SCD subgroups. RESULTS: In participants with SCD (SCDp), significant correlations existed between LIBRA and markers of impairment in global cognition, visuo-spatial attention, and semantic fluency. LIBRA-2 associated with psycho-behavioral symptoms in the whole sample and in SCDp. LIBRA-2 only associated with apathy in the MCI subgroup. CONCLUSIONS: The LIBRA index might be useful to determine the lifestyle-attributable risk of cognitive and psycho-behavioral decline in Italian seniors at risk, while in those with overt cognitive impairment, these outcomes are presumably mainly associated with non-modifiable factors. | Journal of Alzheimer's disease 72 (2019): 717-731. | 2019 | MUSICCO MASSIMO | Alzheimer's disease, apathy, depression, LIBRA Index, modifiable risk factors, mild cognitive impairment, neuropsychological tests, subjective cognitive decline | 10.3233/JAD-190495 |
| 417802 | Articolo in rivista | Adipose Mesenchymal Extracellular Vesicles as Alpha-1-Antitrypsin Physiological Delivery Systems for Lung Regeneration | Bari E1, Ferrarotti I2, Di Silvestre D3, Grisoli P1, Barzon V2, Balderacchi A2, Torre ML4, 5, Rossi R3, Mauri P3, Corsico AG2, 6, Perteghella S1, 6. | Accumulating evidence shows that Mesenchymal Stem/Stromal Cells (MSCs) exert their therapeutic effects by the release of secretome, made of both soluble proteins and nano/microstructured extracellular vesicles (EVs). In this work, for the first time, we proved by a proteomic investigation that adipose-derived (AD)-MSC-secretome contains alpha-1-antitrypsin (AAT), the main elastase inhibitor in the lung, 72 other proteins involved in protease/antiprotease balance, and 46 proteins involved in the response to bacteria. By secretome fractionation, we proved that AAT is present both in the soluble fraction of secretome and aggregated and/or adsorbed on the surface of EVs, that can act as natural carriers promoting AAT in vivo stability and activity. To modulate secretome composition, AD-MSCs were cultured in different stimulating conditions, such as serum starvation or chemicals (IL-1 beta and/or dexamethasone) and the expression of the gene encoding for AAT was increased. By testing in vitro the anti-elastase activity of MSC-secretome, a dose-dependent effect was observed; chemical stimulation of AD-MSCs did not increase their secretome anti-elastase activity. Finally, MSC-secretome showed anti-bacterial activity on Gram-negative bacteria, especially for Klebsiella pneumoniae. These preliminary results, in addition to the already demonstrated immunomodulation, pave the way for the use of MSC-secretome in the treatment of AAT-deficiency lung diseases. | Cells 8 (2019). | 2019 | ROSSI ROSSANA, DI SILVESTRE DARIO, MAURI PIETRO LUIGI | mesenchymal secretome, mesenchymal extracellular vesicles, mesenchymal exosomes, mesenchymal microvesicles, alpha-1-antitrypsin, lung diseases, anti-elastase | 10.3390/cells8090965 |
| 405195 | Articolo in rivista | Human induced pluripotent stem cell-derived extracellular vesicles reduce hepatic stellate cell activation and liver fibrosis. | Davide Povero, 1 Eva M. Pinatel, 2 Aleksandra Leszczynska, 1 Nidhi P. Goyal, 1 Takahiro Nishio, 3 Jihoon Kim, 4 David Kneiber, 1 Lucas de Araujo Horcel, 1, 5 Akiko Eguchi, 1 Paulina M. Ordonez, 1 Tatiana Kisseleva, 3, Ariel E. Feldstein1 | Progression of fibrosis and the development of cirrhosis are responsible for the liver related morbidity and mortality associated with chronic liver diseases. There is currently a great unmet need for effective anti-fibrotic strategies. Stem cells play a central role in wound healing responses to restore liver homeostasis following injury. Here we tested the hypothesis that extracellular vesicles (EVs) isolated from induced pluripotent stem cells (iPSC) modulate hepatic stellate cell (HSCs) activation and may have anti-fibrotic effects. Human iPSCs were generated by reprogramming primary skin fibroblasts. EVs were isolated by differential centrifugation, quantified by flow cytometry (FACS) and characterized by dynamic light scattering (DLS) and electron microscopy (TEM). Primary human HSCs were activated with TGF? (10 ng/mL) and exposed to iPSC-EVs. Efficacy of iPSC-EVs was tested on HSC in vitro and in two murine models of liver injury (CCl4 and bile duct ligation). Characterization of iPSC-derived EVs by flow cytometry identified a large population of EVs released by iPSC, primarily with a diameter of 300 nm and that could be visualized by TEM as round, cup-shaped objects. Fluorescent tracing assays detected iPSC-EVs in HSC cytosol after a short incubation and EV uptake by HSCs resulted in both decrease of pro-fibrogenic markers ?SMA, CollagenI?1, Fibronectin and TIMP-1 and HSC pro-fibrogenic responses such as chemotaxis and proliferation. Genomics analyses of iPSC-EV miRNA cargo revealed 22 highly expressed miRNAs, among which miR-92a-3p resulted the most abundant. Transcriptome analysis identified 60 genes down-modulated and 235 up-regulated in TGF-?-primed HSC in presence or absence of iPSC-EVs. Intravenous injection of iPSC-EVs in CCl4 and bile duct ligation-induced liver fibrosis resulted in anti-fibrotic effects at protein and gene levels. Results of this study identify iPSC-EVs as a novel anti-fibrotic approach that may reduce or reverse liver fibrosis in patients with chronic liver disease. | The journal of clinical investigation (Online) (2019). | 2019 | PINATEL EVA MARIA | miRNA vesicles | 10.1172/jci.insight.125652 |
| 417803 | Articolo in rivista | Neuronal Proteins as Targets of 3-Hydroxykynurenine: Implications in Neurodegenerative Diseases | Andrea Capucciati Monica Galliano Luigi Bubacco Luigi Zecca Luigi* Casella Enrico Monzani Stefania Nicolis | The neurotoxic activity of the tryptophan metabolite 3-hydroxykynurenine (3OHKyn) in neurodegenerative disorders, such as Parkinson's and Alzheimer's diseases, is related to oxidative stress and 3OHKyn interaction with cellular proteins. The pattern of protein modification induced by 3OHKyn involves the nucleophilic side chains of Cys, His, and Lys residues, similarly to the one promoted by dopamine and other catecholamines. In the present work, we have analyzed the reactivity of 3OHKyn toward the neuronal targets alpha-synuclein (and its N-terminal fragments 1-6 and 1-15) and amyloid-beta peptides (1-16 and 1-28) and characterized the resulting conjugates through spectrometric (LCMS/MS) and spectroscopic (UV-vis, fluorescence, NMR) techniques. The amino acid residues of alpha-synuclein and amyloid-beta peptides involved in derivatizations by 3OHKyn and its autoxidation products (belonging to the xanthommatin family) are Lys and His, respectively. The pattern of protein modification is expanded in the conjugates obtained in the presence of the metal ions copper(II) or iron(III), reflecting a more oxidizing environment that in addition to adducts with protein/peptide residues also favors the fragmentation of the protein. These results open the perspective to using the 3OHKyn-protein/peptide synthetic conjugates to explore their competence to activate microglia cell cultures as well as to unravel their role in neuroinflammatory conditions. | ACS chemical neuroscience 10 (2019): 3731-3739. | 2019 | ZECCA LUIGI | Autoxidation, 3-hydroxykynurenine, metal ions, neurodegeneration, protein modifications, xanthommatin | 10.1021/acschemneuro.9b00265 |
| 417805 | Articolo in rivista | Data on the chemical composition, bioactive compounds, fatty acid composition, physico-chemical and functional properties of a global chickpea collection | CarmineSummo a Davide De Angelis a Luigi Ricciardi a Francesco Caponio a Concetta Lotti b Stefano Pavan a c Antonella Pasqualone a | The data article refers to the paper "Nutritional, physico-chemical and functional characterization of a global chickpea collection" [1]. The data are referred to a germplasm collection of 57 chickpea accessions from the ex situ repositories of the United States Department of Agriculture (USDA), the Department of Plant, Soil and Food Science of the University of Bari, Italy (DiSSPA), and the Institute of Biosciences and Bioresources of the Italian National Research Council (CNR-IBBR). Thirty-six accessions, belonging to desi and kabuli types, were representative of the geographic distribution of chickpea global cultivation, whereas twenty-one accessions, referable to the Apulian black type, derived from different area of the Apulian region, south of Italy. All the accessions were grown at the experimental farm "P. Martucci" of the University of Bari "Aldo Moro" (41 degrees 01'22.1 '' N 16 degrees 54'21.0 '' E) during the growing season 2017-2018, according to a randomized block design with two replicates, each replicate formed by 30 individual plants. This article reports the data of the proximate composition, the total bioactive compounds content, the fatty acid composition and the physico-chemical and functional properties of chickpea flour. Information provided in this article can be used by food industry to develop chickpea-based foods and by geneticists for studies of association mapping aimed at the identification of genomic regions controlling the nutritional and technological traits. (c) 2019 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). | Data in brief 27 (2019). | 2019 | PAVAN STEFANO | Chickpea collection, Chickpea flour, Nutritional composition, Functional properties, Bioactive compounds, Germplasm collection | 10.1016/j.dib.2019.104612 |
| 417806 | Articolo in rivista | Helicobacter pylori Stress-Response: Definition of the HrcA Regulon | Roncarati D1, Pinatel E2, Fiore E3, Peano C4, 5, Loibman S6, Scarlato V7. | Bacteria respond to different environmental stresses by reprogramming the transcription of specific genes whose proper expression is critical for their survival. In this regard, the heat-shock response, a widespread protective mechanism, triggers a sudden increase in the cellular concentration of different proteins, including molecular chaperones and proteases, to preserve protein folding and maintain cellular homeostasis. In the medically important gastric pathogen Helicobacter pylori the regulation of the principal heat-shock genes is under the transcriptional control of two repressor proteins named HspR and HrcA. To define the HrcA regulon, we carried out whole transcriptome analysis through RNA-sequencing, comparing the transcriptome of the H. pylori G27 wild type strain to that of the isogenic hrcA-knockout strain. Overall, differential gene expression analysis outlined 49 genes to be deregulated upon hrcA gene inactivation. Interestingly, besides controlling the transcription of genes coding for molecular chaperones and stress-related mediators, HrcA is involved in regulating the expression of proteins whose function is linked to several cellular processes crucial for bacterial survival and virulence. These include cell motility, membrane transporters, Lipopolysaccharide modifiers and adhesins. The role of HrcA as a central regulator of H. pylori transcriptome, as well as its interconnections with the HspR regulon are here analyzed and discussed. As the HrcA protein acts as a pleiotropic regulator, influencing the expression of several stress-unrelated genes, it may be considered a promising target for the design of new antimicrobial strategies. | Microorganisms 7 (2019). | 2019 | PEANO CLELIA, PINATEL EVA MARIA | heat-shock response, stress conditions, HrcA repressor, Helicobacter pylori, RNA-sequencing, transcriptome | 10.3390/microorganisms7100436 |
| 417807 | Articolo in rivista | y-TRIS: a graph-algorithm for comprehensive identification of vector genomic insertion sites | Andrea Calabria, Stefano Beretta*, Ivan Merelli*, Giulio Spinozzi, Stefano Brasca, Yuri Pirola, Fabrizio Benedicenti, Erika Tenderini, Paola Bonizzoni, Luciano Milanesi*, Eugenio Montini | Retroviruses and their vector derivatives integrate semi-randomly in the genome of host cells and are inherited by their progeny as stable genetic marks. The retrieval and mapping of the sequences flanking the virus-host DNA junctions allows the identification of insertion sites in gene therapy or virally infected patients, essential for monitoring the evolution of genetically modified cells in vivo. However, since ~30% of insertions land in low complexity or repetitive regions of the host cell genome, they cannot be correctly assigned and are currently discarded, limiting the accuracy and predictive power of clonal tracking studies. Here, we present ?-TRIS, a new graph-based genome-free alignment tool for identifying insertion sites even if embedded in low complexity regions. By using ?-TRIS to reanalyze clinical studies, we observed improvements in clonal quantification and tracking. | Bioinformatics (Oxf., Print) (2019). | 2019 | BERETTA STEFANO, MERELLI IVAN, MILANESI LUCIANO | * | 10.1093/bioinformatics/btz747 |
| 417813 | Articolo in rivista | Antenatal Microbial Colonization of Mammalian Gut | Elisa Borghi, PhD, 1 Valentina Massa, PhD, 1 Marco Severgnini, PhD, 2 Grazia Fazio, PhD, 3 Laura Avagliano, MD, 1 Elena Menegola, PhD, 4 Gaetano Pietro Bulfamante, MD, 1 Giulia Morace, PhD, 1, Francesca Borgo, PhD1 | The widely accepted dogma of intrauterine sterility and initial colonization of the newborn during birth has been blurred by recent observations of microbial presence in meconium, placenta, and amniotic fluid. Given the importance of a maternal-derived in utero infant seeding, it is crucial to exclude potential environmental or procedural contaminations and to assess fetal colonization before parturition. To this end, we analyzed sterilely collected intestinal tissues, placenta, and amniotic fluid from rodent fetuses and tissues from autoptic human fetuses. Total bacterial DNA was extracted from collected samples and analyzed by Next Generation Sequencing (NGS) techniques using hypervariable 16S ribosomal RNA (rRNA) regions (V3-V4). Colonizing microbes were visualized in situ, using labeled probes targeting 16S ribosomal DNA by fluorescent in situ hybridization. The NGS analysis showed the presence of pioneer microbes in both rat and human intestines as well as in rodent placentas and amniotic fluids. Microbial communities showed fetus- and dam-dependent clustering, confirming the high interindividual variability of commensal microbiota even in the antenatal period. Fluorescent in situ hybridization analysis confirmed the microbes' presence in the lumen of the developing gut. These findings suggest a possible antenatal colonization of the developing mammalian gut. | Reproductive sciences (Thousand Oaks, Calif.) 26 (2019): 1045-1053. | 2019 | SEVERGNINI MARCO | mammalian gut, embryonic development, microbiota, 16S rRNA gene sequencing | 10.1177/1933719118804411 |
| 408685 | Articolo in rivista | P2X7 activation enhances skeletal muscle metabolism and regeneration in SOD1G93A mouse model of amyotrophic lateral sclerosis. | Fabbrizio P1, Apolloni S2, Bianchi A2, Salvatori I2, Valle C2, 3, Lanzuolo C2, 4, Bendotti C1, Nardo G1, Volonte C2, 5. | Muscle weakness plays an important role in neuromuscular disorders comprising amyotrophic lateral sclerosis (ALS). However, it is not established whether muscle denervation originates from the motor neurons, the muscles or more likely both. Previous studies have shown that the expression of the SOD1G93A mutation in skeletal muscles causes denervation of the neuromuscular junctions, inability to regenerate and consequent atrophy, all clear symptoms of ALS. In this work, we used SOD1G93A mice, a model that best mimics some pathological features of both familial and sporadic ALS, and we investigated some biological effects induced by the activation of the P2X7 receptor in the skeletal muscles. The P2X7, belonging to the ionotropic family of purinergic receptors for extracellular ATP, is abundantly expressed in the healthy skeletal muscles, where it controls cell duplication, differentiation, regeneration or death. In particular, we evaluated whether an in vivo treatment in SOD1G93A mice with the P2X7 specific agonist 2?(3?)-O-(4-Benzoylbenzoyl) adenosine5?-triphosphate (BzATP) just before the onset of a pathological neuromuscular phenotype could exert beneficial effects in the skeletal muscles. Our findings indicate that stimulation of P2X7 improves the innervation and metabolism of myofibers, moreover elicits the proliferation/differentiation of satellite cells, thus preventing the denervation atrophy of skeletal muscles in SOD1G93A mice. Overall, this study suggests that a P2X7-targeted and site-specific modulation might be a strategy to interfere with the complex multifactorial and multisystem nature of ALS. | Brain pathology (2020). | 2020 | VALLE CRISTIANA, LANZUOLO CHIARA, VOLONTE' CINZIA | amyotrophic lateral sclerosis, purinergic receptors, skeletal muscle, SOD1G93A mice. | 10.1111/bpa.12774 |
| 408134 | Articolo in rivista | Integrated analysis of microRNA and mRNA expression profiles reveals a complex interaction network in Attention Deficit Hyperactivity Disorder | Nicoletta Nuzziello, Francesco Craig, Marta Simone, Arianna Consiglio, Flavio Licciulli, Lucia Margari, Giorgio Grillo, Sabino Liuni, Maria Liguori | Attention Deficit Hyperactivity Disorder (ADHD) is a childhood-onset neurodevelopmental disorder, whose etiology and pathogenesis are still largely unknown. In order to uncover novel regulatory networks and molecular pathways possibly related to ADHD, we performed an integrated miRNA and mRNA expression profiling analysis in peripheral blood samples of children with ADHD and age-matched typically developing (TD) children. The expression levels of 13 miRNAs were evaluated with microfluidic qPCR, and differentially expressed (DE) mRNAs were detected on an Illumina HiSeq 2500 genome analyzer. The miRNA targetome was identified using an integrated approach of validated and predicted interaction data extracted from seven different bioinformatic tools. Gene ontology and pathway enrichment analyses were carried out. Results showed that six miRNAs (miR-652-3p, miR-942-5p, let-7b-5p, miR-181a-5p, miR-320a, and miR-148b-3p) and 560 genes were significantly DE in children with ADHD compared to TD subjects. After correction for multiple testing, only three miRNAs (miR-652-3p, miR-148b, and miR-942-5p) remained significant. Genes known to be associated with ADHD (e.g., B4GALT2, SLC6A9 TLE1, ANK3, TRIO, TAF1, and SYNE1) were confirmed to be significantly DE in our study. Integrated miRNA and mRNA expression data identified critical key hubs involved in ADHD. Finally, the GO and pathway enrichment analyses of all DE genes showed their deep involvement in immune functions, reinforcing the hypothesis that an immune imbalance might contribute to the ADHD etiology. Despite the relatively small sample size, in this study we were able to build a complex miRNA-target interaction network in children with ADHD that might help in deciphering the disease pathogenesis. Validation in larger samples should be performed in order to possibly suggest novel therapeutic strategies for treating this complex disease. | Brain sciences (2019). | 2019 | NUZZIELLO NICOLETTA, LICCIULLI VITO FLAVIO, GRILLO GIORGIO, LIGUORI MARIA, LIUNI SABINO, CONSIGLIO ARIANNA | circulating biomarkers; microRNA; transcriptome; targetome; bioinformatics; high throughput next-generation sequencing (HT-NGS) | 10.3390/brainsci9100288 |
| 417814 | Articolo in rivista | TRIM8 Blunts the Pro-proliferative Action of ?Np63? in a p53 Wild-Type Background | Mariano Francesco Caratozzolo, 1, + Flaviana Marzano, 1, + Daniela Isabel Abbrescia, 2 Francesca Mastropasqua, 1 Vittoria Petruzzella, 3 Viola Calabro, 4 Graziano Pesole, 1, 5 Elisabetta Sbisa, 2 Luisa Guerrini, 6, *, Apollonia Tullo1, * | The p53 gene family network plays a pivotal role in the control of many biological processes and therefore the right balance between the pro-apoptotic and pro-survival isoforms is key to maintain cellular homeostasis. The stability of the p53 tumor suppressor protein and that of oncogenic ?Np63?, is crucial to control cell proliferation. The aberrant expression of p53 tumor suppressor protein and oncogenic ?Np63? contributes to tumorigenesis and significantly affects anticancer drug response. Recently, we demonstrated that TRIM8 increases p53 stability, potentiating its tumor suppressor activity. In this paper, we show that TRIM8 simultaneously reduces the level of the pro-proliferative ?Np63? protein, in both a proteasomal and caspase-1 dependent way, thereby playing a critical role in the cellular response to DNA damaging agents. Moreover, we provided evidence that ?Np63? in turn, suppresses TRIM8 gene expression by preventing p53-mediated transactivation of TRIM8, therefore suggesting the existence of a negative feedback loop. These findings indicate that TRIM8 exerts its anticancer power through a joint action that provides on one hand, the activation of the p53 tumor suppressor role, and on the other the quenching of the oncogenic ?Np63? protein activity. The enhancement of TRIM8 activity may offer therapeutic benefits and improve the management of chemoresistant tumors. | Frontiers in oncology 9 (2019). | 2019 | ABBRESCIA DANIELA ISABEL, PESOLE GRAZIANO, TULLO APOLLONIA, MARZANO MARINELLA, CARATOZZOLO MARIANO FRANCESCO, SBISA' ELISABETTA | [object Object], [object Object], [object Object], [object Object], [object Object], [object Object] | 10.3389/fonc.2019.01154 |
| 417815 | Articolo in rivista | The Role of Prep1 in the Regulation of Mesenchymal Stromal Cells | Giorgia Maroni, Daniele Panetta, Raffaele Luongo, Indira Krishnan, Federica La Rosa, Daniela Campani, Piero Salvadori, Patricia Iozzo, Francesco Blasi, Dmitry Penkov, Elena Levantini, Maria Cristina Magli. | Molecular mechanisms governing cell fate decision events in bone marrow mesenchymal stromal cells (MSC) are still poorly understood. Herein, we investigated the homeobox gene Prep1 as a candidate regulatory molecule, by adopting Prep1 hypomorphic mice as a model to investigate the effects of Prep1 downregulation, using in vitro and in vivo assays, including the innovative single cell RNA sequencing technology. Taken together, our findings indicate that low levels of Prep1 are associated to enhanced adipogenesis and a concomitant reduced osteogenesis in the bone marrow, suggesting Prep1 as a potential regulator of the adipo-osteogenic differentiation of mesenchymal stromal cells. Furthermore, our data suggest that in vivo decreased Prep1 gene dosage favors a pro-adipogenic phenotype and induces a browning effect in all fat tissues. | International journal of molecular sciences (Print) 20 (2019). | 2019 | MARONI GIORGIA, LA ROSA FEDERICA, IOZZO PATRICIA, PANETTA DANIELE, LEVANTINI ELENA, SALVADORI PIERO, MAGLI MARIA CRISTINA | mesenchymal stromal cells (MSC), homeobox gene, single cell RNA sequencing, gene regulation, hypomorphic mice, murine models, micro CT imaging, osteogenic differentiation | 10.3390/ijms20153639 |
| 417816 | Articolo in rivista | Italian Study Group on Delirium (ISGoD). The association of indwelling urinary catheter with delirium in hospitalized patients and nursing home residents: an explorative analysis from the "Delirium Day 2015" | Bo M1, Porrino P2, Di Santo SG3, Mazzone A4, Cherubini A5, Mossello E6, Bianchetti A7, Musicco M8,9, Ferrari A10, Ferrara N11, Filippini C12, Trabucchi M13,14, Morandi A15, Bellelli G16,17, Italian Study Group on Delirium (ISGoD). | BACKROUND: Use of indwelling urinary catheter (IUC) in older adults has negative consequences, including delirium. AIM: This analysis, from the "Delirium Day 2015", a nationwide multicenter prevalence study, aim to evaluate the association of IUC with delirium in hospitalized and Nursing Homes (NHs) patients. METHODS: Patients underwent a comprehensive geriatric assessment, including the presence of IUC; inclusion criteria were age > 65 years, being Italian speaker and providing informed consent; exclusion criteria were coma, aphasia, end-of-life status. Delirium was assessed using the 4AT test (score >= 4: possible delirium; scores 1-3: possible cognitive impairment). RESULTS: Among 1867 hospitalized patients (mean age 82.0 +- 7.5 years, 58% female), 539 (28.9%) had IUC, 429 (22.9%) delirium and 675 (36.1%) cognitive impairment. IUC was significantly associated with cognitive impairment (OR 1.60, 95% CI 1.19-2.16) and delirium (2.45, 95% CI 1.73-3.47), this latter being significant also in the subset of patients without dementia (OR 2.28, 95% CI 1.52-3.43). Inattention and impaired alertness were also independently associated with IUC. Among 1454 NHs residents (mean age 84.4 +- 7.4 years, 70.% female), 63 (4.3%) had IUC, 535 (36.8%) a 4AT score >= 4, and 653 (44.9%) a 4AT score 1-3. The multivariate logistic regression analysis did not show a significant association between 4AT test or its specific items with IUC, neither in the subset of patients without dementia. DISCUSSION: We confirmed a significant association between IUC and delirium in hospitalized patients but not in NHs residents. CONCLUSION: Environmental and clinical factors of acute setting might contribute to IUC-associated delirium occurrence. | Aging Clinical and Experimental Research (Print) (2019). | 2019 | MUSICCO MASSIMO | 4AT test; Cognition; Delirium; Geriatric assessment | |
| 405539 | Articolo in rivista | Fluorescence imaging of biochemical relationship between ubiquitinated histone 2A and Polycomb complex protein BMI1 | Barbara Storti, Simone Civita, Paolo Faraci, Giorgia Maroni, Indira Krishnan, Elena Levantini, Ranieri Bizzarri | Several in vitro experiments have highlighted that the Polycomb group protein BMI1 plays a pivotal role in determining the biological functions of the Polycomb Repressor Complex 1 (PRC1), including its E3-ligase activity towards the Lys119 of histone H2A to yield ubiquitinated uH2A. The role of BMI1 in the epigenetic activity of PRC1 is particularly relevant in several cancers, particularly Non-Small Cell Lung Cancer (NSCLC). In this study, using indirect immunofluorescence protocols implemented on a confocal microscopy apparatus, we investigated the relationship between BMI1 and uH2A at different resolutions, in cultured (A549) and clinical NSCLC tissues, at the single cell level. In both cases, we observed a linear dependence of uH2A concentration upon BMI1 expression at the single nucleus level, indicating that the association of BMI1 to PRC1, which is needed for E3-ligase activity, occurs linearly in the physiological BMI1 concentration range. Additionally, in the NSCLC cell line model, a minor pool of uH2A may exist in absence of concurrent BMI1 expression, indicating non-exclusive, although predominant, role of BMI1 in the amplification of the E3-ligase activity of PRC1. A pharmacological downregulator of BMI1, PTC-209, was also tested in this context. Finally, the absence of significant colocalization (as measured by the Pearson's coefficient) between BMI1 and uH2A submicron clusters hints to a dynamic model where PRC1 resides transiently at ubiquitination sites. Beside unveiling subtle functional relationships between BMI1 and uH2A, these results also validate the use of uH2A as downstream "reporter" for BMI1 activity at the nuclear level in NSCLC contexts. | Biophysical chemistry (Print) 253 (2019). | 2019 | MARONI GIORGIA, BIZZARRI RANIERI, LEVANTINI ELENA, STORTI BARBARA | ubiquitinated histone, Polycomb complex, epigenetic, non-small cell lung cancer, anti-BMI1 pharmacological treatment (PTC209), submicron cluster organization of BMI1 within the nucleus, Single-cell analysis of BMI1-uH2A correlation by fluorescent imaging | 10.1016/j.bpc.2019.106225 |
| 417817 | Articolo in rivista | CAV1-GLUT3 signaling is important for cellular energy and can be targeted by Atorvastatin in Non-Small Cell Lung Cancer | Ali A, Levantini E, Fhu CW, Teo JT, Clohessy JG, Goggi JL, Wu CS, Chen L, Chin TM, Tenen DG1. | Background: The development of molecular targeted therapies, such as EGFR-TKIs, has positively impacted the management of EGFR mutated NSCLC. However, patients with innate and acquired resistance to EGFR-TKIs still face limited effective therapeutic options. Statins are the most frequently prescribed anti-cholesterol agents and have been reported to inhibit the progression of various malignancies, including in lung. However, the mechanism by which statin exerts its anti-cancer effects is unclear. This study is designed to investigate the anti-proliferative effects and identify the mechanism-of-action of statins in NSCLC. Methods: In this study, the anti-tumoral properties of Atorvastatin were investigated in NSCLC utilizing cell culture system and in vivo models. Results: We demonstrate a link between elevated cellular cholesterol and TKI-resistance in NSCLC, which is independent of EGFR mutation status. Atorvastatin suppresses growth by inhibiting Cav1 expression in tumors in cell culture system and in in vivo models. Subsequent interrogations demonstrate an oncogenic physical interaction between Cav1 and GLUT3, and glucose uptake found distinctly in TKI-resistant NSCLC and this may be due to changes in the physical properties of Cav1 favoring GLUT3 binding in which significantly stronger Cav1 and GLUT3 physical interactions were observed in TKI-resistant than in TKI-sensitive NSCLC cells. Further, the differential effects of atorvastatin observed between EGFR-TKI resistant and sensitive cells suggest that EGFR mutation status may influence its actions. Conclusions: This study reveals the inhibition of oncogenic role of Cav1 in GLUT3-mediated glucose uptake by statins and highlights its potential impact to overcome NSCLC with EGFR-TKI resistance. | Theranostics 9 (2019): 6157-6174. | 2019 | LEVANTINI ELENA | molecular targeted tehrapy, non small cell lung cancer, EGFR mutant resistant lung cancer, Magnetic Resonance Imaging, Atorvastatin therapy, tyrosine kinase inhibitor-resistance, xenograft mice, EGFR mutant transgenic mice, murine models of lung cancer, proliferation, apoptosis, glucose metabolism | 10.7150/thno.35805 |
| 417818 | Articolo in rivista | Evolutionary conservation of MLO gene promoter signatures | Andolfo, Giuseppe, Iovieno, Paolo, Ricciardi, Luigi, Lotti, Concetta, Filippone, Edgardo, Pavan, Stefano*, Ercolano, Maria Raffaella | BackgroundPowdery mildew (PM) is a widespread fungal disease of plants in temperate climates, causing significant economic losses in agricultural settings. Specific homologs of the MLO gene family are PM susceptibility factors, as their loss-of function results in durable PM resistance (mlo resistance) in several plant species. The role of MLO susceptibility genes in plant-pathogen interactions is still elusive, however it is known that they are strongly upregulated following PM infection.ResultsIn this study, we investigated the structure of 414 Putative Promoter Regions (PPRs) of MLO genes and highlighted motif and regulatory element patterns related to genomic relationships among species and phylogenetic distance among homologs. A TC box-like motif and a thymine-rich motif were found to be overrepresented in MLO genes transcriptionally upregulated upon infection with PM fungi. As proof of concept, we showed that the expression of a melon (Cucumis melo L.) gene enriched for the motifs above mentioned was strongly upregulated upon infection with the PM fungus Podosphaera xanthii.ConclusionWhile identifying a candidate MLO susceptibility gene in melon, this study provides insight on the transcriptional control of MLO genes and indicates diagnostic features useful to identify MLO susceptibility genes across species affected by the PM disease. | BMC plant biology (Online) 19 (2019). | 2019 | PAVAN STEFANO | Cis-acting regulatory element, Motif, MLO, Powdery mildew resistance, Transcription | 10.1186/s12870-019-1749-3 |
| 408573 | Articolo in rivista | Compositional data analysis as an alternative paradigm for nutritional studies | Leite, Maria Lea Correa | Background & aim: Although the compositional nature of dietary data is well recognized, little attention has been given to the methods specifically developed for the statistical analysis of compositional data. The use of standard statistical procedures that ignore the relative nature of compositional elements can lead to spurious results when applied to crude data. This note proposes using a compositional data approach for the statistical analysis of nutritional data. | Clinical nutrition ESPEN Online 33 (2019): 207-212. | 2019 | CORREA LEITE MARIA LEA | Nutrient balances, Compositional data, Log-ratio transformation, Energy adjustment, Obesity | 10.1016/j.clnesp.2019.05.011 |
| 417819 | Articolo in rivista | Dementia Research Fit for the Planet: Reflections on Population Studies of Dementia for Researchers and Policy Makers Alike | Brayne CE1, Barnes LE2, Breteler MMB3, 4, Brooks RL2, Dufouil C5, Fox C6, Fratiglioni L7, Ikram MA8, Kenny RA9, Kivipelto M7, Lobo A10, Musicco M11, Qiu C7, Richard E12, 13, Riedel-Heller SG14, Ritchie C15, Skoog I16, Stephan BCM17, Venneri A18, Matthews FE19. | In recent years, a rapidly increasing collection of investigative methods in addition to changes in diagnostic criteria for dementia have followed "high-tech" trends in medicine, with the aim to better define the dementia syndrome and its biological substrates, mainly in order to predict risk prior to clinical expression. These approaches are not without challenge. A set of guidelines have been developed by a group of European experts in population-based cohort research through a series of workshops, funded by the Joint Program for Neurodegenerative Disorders (JPND). The aims of the guidelines are to assist policy makers and researchers to understand (1) What population studies for ageing populations should encompass and (2) How to interpret the findings from population studies. Such studies are essential to provide evidence relevant to the understanding of healthy and frail brain ageing, including the dementia syndrome for contemporary and future societies by drawing on the past. | Neuroepidemiology (2019). | 2019 | MUSICCO MASSIMO | Cohorts; Dementia; Guidelines; Population-based studies | |
| 417820 | Articolo in rivista | Moderate Intensity Resistive Training Reduces Oxidative Stress and Improves Muscle Mass and Function in Older Individuals | Vezzoli A1, Mrakic-Sposta S2, Montorsi M3, Porcelli S4, Vago P5, Cereda F6, Longo S7, Maggio M8, Narici M9. | An innovative moderate-intensity resistive exercise-training (RT) program was tested in thirty-five sarcopenic elders (SAR). The subjects were randomized into two groups: SAR training (SAR-RT), n = 20, 73.0 +/- 5.5 years, or SAR non-training (SAR-NT), n = 15, 71.7 +/- 3.4 years. The training consisted of 12-week progressive RT, thrice/week, at 60% one-repetition maximum (1RM), 3 sets, 14-16 repetitions for both upper and lower limbs. The pre and post intervention measurements included: the skeletal muscle index (SMI%); strength (1RM); stair-climbing power (SCP); muscle thickness (MT) of vastus lateralis (VL) and elbow flexors (EF), VL pennation angle (PA), rectus femoris (RF) anatomical cross-sectional area (ACSA); reactive oxygen species (ROS), total antioxidant capacity (TAC), protein carbonyls (PC), thiobarbituric acid-reactive substances (TBARS), 8-isoprostane (8-iso-PGF2-alpha), 8-OH-2-deoxyguanosine (8-OH-dG), as markers of oxidative stress/damage (OxS). In SAR-RT, SCP increased by 7.7% (P < 0.01), MT increased by 5.5% for VL, 10.4% for EF and PA increased by 13.4% for VL (P < 0.001 for all). The RF ACSA increased by 14.5% (P < 0.001). 1RM significantly increased by at least 67% for all muscles tested. Notably muscle strength (1RM) positively correlated (P < 0.001) with TAC and negatively with PC (P < 0.001). In conclusion, moderate intensity RT is an effective strategy to increase muscle mass and strength in SAR, while minimizing OxS. | Antioxidants 8 (2019). | 2019 | VEZZOLI ALESSANDRA, PORCELLI SIMONE, MRAKIC SPOSTA SIMONA | resistive training, muscle mass, muscle strength, oxidative stress | 10.3390/antiox8100431 |
| 417926 | Articolo in rivista | Metabolic profiles of six African cultivars of cassava (Manihot esculenta Crantz) highlight bottlenecks of root yield | Toshihiro Obata Patrick A.W. Klemens Laise Rosado-Souza Armin Schlereth Andreas Gisel* Livia Stavolone* Wolfgang Zierer Nicolas Morales Lukas A. Mueller Samuel C. Zeeman Frank Ludewig Mark Stitt Uwe Sonnewald H. Ekkehard Neuhaus Alisdair R. Fernie | Cassava is an important staple crop in sub-Saharan Africa, due to its high productivity even on nutrient poor soils. The metabolic characteristics underlying this high productivity are poorly understood including the mode of photosynthesis, reasons for the high rate of photosynthesis, the extent of source/sink limitation, the impact of environment, and the extent of variation between cultivars. Six commercial African cassava cultivars were grown in the greenhouse in Erlangen, Germany and the field in Ibadan, Nigeria. Source leaves, sink leaves, stems and storage roots were harvested during storage root bulking and analyzed for sugars, organic acids, amino acids, phosphorylated intermediates, minerals, starch, protein, activities of enzymes in central metabolism and yield traits. High ratios of Rubisco:phosphoenolpyruvate carboxylase activity support a C3 mode of photosynthesis. The high rate of photosynthesis is likely attributed to high activities of enzymes in the Calvin-Benson cycle and pathways for sucrose and starch synthesis. Nevertheless, source limitation is indicated because root yield traits correlated with metabolic traits in leaves rather than in the stem or storage roots. This was especially so in greenhouse-grown plants, where irradiance will have been low. In the field, plants produced more storage roots. This was associated with higher AGPase activity and lower sucrose in the roots, indicating that feedforward loops enhance sink capacity in the high light and low nitrogen environment in the field. Overall, the results indicate that carbon assimilation rate, the K battery, root starch synthesis, trehalose, and chlorogenic acid accumulation are potential target traits for genetic improvement. | Plant journal (Online) (2019). | 2019 | STAVOLONE LIVIA, GISEL ANDREAS | Cassava, root yield, source/sink limitation, photosynthesis, carbon fixation, enzyme activity, nitrogen metabolism, starch synthesis, K battery, chlorogenic acidAccepte | |
| 417928 | Articolo in rivista | MTGO-SC, A Tool to Explore Gene Modules in Single-Cell RNA Sequencing Data | Nelson Nazzicari, 1 Danila Vella, 2, 3 Claudia Coronnello, 4 Dario Di Silvestre, 5 Riccardo Bellazzi, 3, 6, Simone Marini 6, 7 | The identification of functional modules in gene interaction networks is a key step in understanding biological processes. Network interpretation is essential for unveiling biological mechanisms, candidate biomarkers, or potential targets for drug discovery/repositioning. Plenty of biological module identification algorithms are available, although none is explicitly designed to perform the task on single-cell RNA sequencing (scRNAseq) data. Here, we introduce MTGO-SC, an adaptation for scRNA-seq of our biological network module detection algorithm MTGO. MTGO-SC isolates gene functional modules by leveraging on both the network topological structure and the annotations characterizing the nodes (genes). These annotations are provided by an external source, such as databases and literature repositories (e.g., the Gene Ontology, Reactome). Thanks to the depth of single-cell data, it is possible to define one network for each cell cluster (typically, cell type or state) composing each sample, as opposed to traditional bulk RNA-seq, where the emerging gene network is averaged over the whole sample. MTGO-SC provides two complexity levels for interpretation: the gene-gene interaction and the intermodule interaction networks. MTGO-SC is versatile in letting the users define the rules to extract the gene network and integrated with the Seurat scRNA-seq analysis pipeline. MTGO-SC is available at https://github.com/ne1s0n/MTGOsc. | Frontiers in genetics 10 (2019). | 2019 | DI SILVESTRE DARIO | single cell, RNA-seq, enrichment, gene network, clustering, gene module, annotation, scRNA-seq | 10.3389/fgene.2019.00953 |
| 417930 | Articolo in rivista | Extracellular Vesicles, A Possible Theranostic Platform Strategy for Hepatocellular Carcinoma | Igea D'Agnano 1 and Anna Concetta Berardi 2 | Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third highest cause of mortality from cancer, largely because of delays in diagnosis. There is currently no effective therapy for advanced stage HCC, although sorafenib, the standard treatment for HCC, systemic therapy (including tyrosine kinase inhibitors and anti-angiogenesis agents), and more recently, immunotherapy, have demonstrated some survival benefit. The measurement and modification of extracellular vesicle (EVs) cargoes--composed of nucleic acids, including miRNAs, proteins, and lipids--holds great promise for future HCC diagnosis, prognosis, and treatment. This review will provide an overview of the most recent findings regarding EVs in HCC, and the possible future use of EVs as "liquid biopsy"-based biomarkers for early diagnosis and as a vehicle for targeted drug-delivery. | Cancers (Basel) (2019). | 2019 | D'AGNANO IGEA | hepatocellular carcinoma; extracellular vesicles; liquid biopsy; drug delivery | |
| 412886 | Articolo in rivista | Serum cholesterol elasticities in relation to macro- and micronutrient balances | Correa Leite, Maria Lea, Prinelli, Federica | The application of the isometric log-ratio (ilr) transformation to dietary data leads to the definition of nutrient balances that represent new variables which can be included in regression models as covariates. However, their effects on the response variable are not easy to quantify. We then propose borrowing the concept of elasticity from econometrics as an appealing means of improving the interpretability of the ilr-related coefficients. Using data from an Italian population-based study, a multiple linear regression model of the serum total-/HDL-cholesterol ratio on nutrient balances was fitted and the estimated coefficients were used to derive elasticities. The elasticities measure the relative changes in the cholesterol ratio in response to the relative changes in specific nutrient ratios, while keeping unchanged the proportional relationships between the other dietary elements. In a comprehensive overview of the diet, this alternative approach to dietary data analysis allows isocaloric analysis and may provide interesting new insights. | European journal of clinical nutrition (2019). | 2019 | PRINELLI FEDERICA, CORREA LEITE MARIA LEA | nutrition, compositional data | 10.1038/s41430-019-0506-x |
| 417931 | Articolo in rivista | Integration of Machine Learning Methods to Dissect Genetically Imputed Transcriptomic Profiles in Alzheimer's Disease | Carlo Maj1*+, Tiago Azevedo2+, Valentina Giansanti3+, Oleg Borisov1, Giovanna Maria Dimitri2, Simeon Spasov2, Alzheimer's Disease Neuroimaging Initiative, Pietro Lio2*, Ivan Merelli3* | The genetic component of many common traits is associated with the gene expression and several variants act as expression quantitative loci, regulating the gene expression in a tissue specific manner. In this work, we applied tissue-specific cis-eQTL gene expression prediction models on the genotype of 808 samples including controls, subjects with mild cognitive impairment, and patients with Alzheimer's Disease. We then dissected the imputed transcriptomic profiles by means of different unsupervised and supervised machine learning approaches to identify potential biological associations. Our analysis suggests that unsupervised and supervised methods can provide complementary information, which can be integrated for a better characterization of the underlying biological system. In particular, a variational autoencoder representation of the transcriptomic profiles, followed by a support vector machine classification, has been used for tissue-specific gene prioritizations. Interestingly, the achieved gene prioritizations can be efficiently integrated as a feature selection step for improving the accuracy of deep learning classifier networks. The identified gene-tissue information suggests a potential role for inflammatory and regulatory processes in gut-brain axis related tissues. In line with the expected low heritability that can be apportioned to eQTL variants, we were able to achieve only relatively low prediction capability with deep learning classification models. However, our analysis revealed that the classification power strongly depends on the network structure, with recurrent neural networks being the best performing network class. Interestingly, cross-tissue analysis suggests a potentially greater role of models trained in brain tissues also by considering dementia-related endophenotypes. Overall, the present analysis suggests that the combination of supervised and unsupervised machine learning techniques can be used for the evaluation of high dimensional omics data. | Frontiers in genetics 10 (2019). | 2019 | GIANSANTI VALENTINA, MERELLI IVAN | eQTL, gene expression imputation, GTEx, variational autoencoder, support vector machine, deep learning, recurrent neural networks, Alzheimer's | 10.3389/fgene.2019.00726 |
| 409129 | Articolo in rivista | Heparin and heparan sulfate proteoglycans promote HIV-1 p17 matrix protein oligomerization: computational, biochemical and biological implications | Bugatti A., Paiardi G., Urbinati C., Chiodelli P., Orro A., Uggeri M., Milanesi L., Caruso A., Caccuri F., D'Ursi P., Rusnati M. | p17 matrix protein released by HIV+ cells interacts with leukocytes heparan sulfate proteoglycans (HSPGs), CXCR1 and CXCR2 exerting different cytokine-like activities that contribute to AIDS pathogenesis. Since the bioactive form of several cytokines is represented by dimers/oligomers and oligomerization is promoted by binding to heparin or HSPGs, here we evaluated if heparin/HSPGs also promote p17 oligomerization. Heparin favours p17 dimer, trimer and tetramer assembly, in a time- and biphasic dose-dependent way. Heparin-induced p17 oligomerization is of electrostatic nature, being it prevented by NaCl, by removing negative sulfated groups of heparin and by neutralizing positive lysine residues in the p17 N-terminus. A new computational protocol has been implemented to study heparin chains up to 24-mer accommodating a p17 dimer. Molecular dynamics show that, in the presence of heparin, two p17 molecules undergo conformational modifications creating a continuous "electropositive channel" in which heparin sulfated groups interact with p17 basic amino acids, promoting its dimerization. At the cell surface, HSPGs induce p17 oligomerization, as demonstrated by using B-lymphoblastoid Namalwa cells overexpressing the HSPG Syndecan-1. Also, HSPGs on the surface of BJAB and Raji human B-lymphoblastoid cells are required to p17 to induce ERK activation, suggesting that HS-induced oligomerization plays a role in p17-induced lymphoid dysregulation during AIDS. | Scientific reports (Nature Publishing Group) 9 (2019). | 2019 | UGGERI MATTEO, ORRO ALESSANDRO, MILANESI LUCIANO, D'URSI PASQUALINA | docking | 10.1038/s41598-019-52201-w |
| 417932 | Articolo in rivista | IKKbeta targeting reduces KRAS-induced lung cancer angiogenesis in vitro and in vivo: A potential anti-angiogenic therapeutic target | Carneiro-Lobo T.C., Scalabrini L.C., Magalhaes L.D.S., Cardeal L.B., Rodrigues F.S., dos Santos E.O., Baldwin A.S., Levantini E., Giordano R.J., Basseres D.S. | Objectives: The ability of tumor cells to drive angiogenesis is an important cancer hallmark that positively correlates with metastatic potential and poor prognosis. Therefore, targeting angiogenesis is a rational therapeutic approach and dissecting proangiogenic pathways is important, particularly for malignancies driven by oncogenic KRAS, which are widespread and lack effective targeted therapies. Based on published studies showing that oncogenic RAS promotes angiogenesis by upregulating the proangiogenic NF-?B target genes IL-8 and VEGF, that NF-?B activation by KRAS requires the IKK? kinase, and that targeting IKK? reduces KRAS-induced lung tumor growth in vivo, but has limited effects on cell growth in vitro, we hypothesized that IKK? targeting would reduce lung tumor growth by inhibiting KRAS-induced angiogenesis. Materials and methods: To test this hypothesis, we targeted IKK? in KRAS-mutant lung cancer cell lines either by siRNA-mediated transfection or by treatment with Compound A (CmpdA), a highly specific IKK? inhibitor, and used in vitro and in vivo assays to evaluate angiogenesis. Results and conclusions: Both pharmacological and siRNA-mediated IKK? targeting in lung cells reduced expression and secretion of NF-?B-regulated proangiogenic factors IL-8 and VEGF. Moreover, conditioned media from IKK?-targeted lung cells reduced human umbilical vein endothelial cell (HUVEC) migration, invasion and tube formation in vitro. Furthermore, siRNA-mediated IKK? inhibition reduced xenograft tumor growth and vascularity in vivo. Finally, IKK? inhibition also affects endothelial cell function in a cancer-independent manner, as IKK? inhibition reduced pathological retinal angiogenesis in a mouse model of oxygen-induced retinopathy. Taken together, these results provide a novel mechanistic understanding of how the IKK? pathway affects human lung tumorigenesis, indicating that IKK? promotes KRAS-induced angiogenesis both by cancer cell-intrinsic and cancer cell-independent mechanisms, which strongly suggests IKK? inhibition as a promising antiangiogenic approach to be explored for KRAS-induced lung cancer therapy. | Lung cancer 130 (2019): 169-178. | 2019 | LEVANTINI ELENA | K-RAS-induced lung cancer, Ikk beta therapeutic targeting, anti-angiogenic therapy, cytokine cascade, growth factors signaling, IL-8, VEGF | 10.1016/j.lungcan.2019.02.027 |
| 417941 | Articolo in rivista | Pharyngeal microbiome alterations during Neisseria gonorrhoeae infection | Marangoni A, Ceccarani C, Camboni T, Consolandi C, Foschi C, Salvo M, Gaspari V, D'Antuono A, Belletti M, Re MC, Severgnini M. | Pharyngeal gonorrhoea is a common sexually transmitted infection among 'men having sex with other men' (MSM). Neisseria gonorrhoeae (NG) pharyngeal infections are usually characterized by the absence of symptoms, acting as an important reservoir for their further spread. To the best of our knowledge, no information about the composition of the pharyngeal microbiome during an ongoing NG infection is currently available. Therefore, in this study, we characterized the pharyngeal bacterial community profiles associated with NG infection in a well-selected cohort of HIV-negative MSM reporting unsafe oral intercourse. A total of 70 pharyngeal swabs were considered, comparing non-infected subjects (n = 45) versus patients with pharyngeal gonorrhoea (n = 25) whose microbiota composition was analyzed from pharyngeal swabs through sequencing of hypervariable V3-V4 regions of the 16S rRNA gene. The pharyngeal microbiome of all subjects was dominated by Prevotellaceae, Veillonellaceae and Streptococcaceae families. Patients with pharyngeal gonorrhoea harboured a pharyngeal microbiome quite similar to negative subjects. Nevertheless, when looking to less-represented bacterial species (relative abundance approximately 1% or less), an imbalance between aerobe and anaerobe microorganisms was observed in NG-infected patients. In particular, the pharyngeal microbiome of NG-positive individuals was richer in several anaerobes (e.g. Treponema, Parvimonas, Peptococcus, Catonella, Filifactor) and poorer in various aerobe genera (i.e. Pseudomonas, Escherichia), compared to non-infected controls. No significant differences were noticed in the distribution of commensal Neisseria species of the oropharynx between NG-positive and negative subjects. Metabolic variations induced by changes in the microbiome abundance were assessed by a functional prediction of the bacterial metabolic pathways: a more abundant involvement of D-glutamine and D-glutamate metabolism, carbohydrate metabolism, as well as a greater activation of the energy metabolism was observed in patients with pharyngeal gonorrhoea compared to non-infected individuals. Information about the bacterial composition of the pharyngeal microbiome in case of gonorrhoea could shed light on the pathogenesis of the infection and open new perspectives for the prevention and control of this condition. | PloS one 15 (2020). | 2020 | CECCARANI CAMILLA, CAMBONI TANIA, CONSOLANDI CLARISSA, SEVERGNINI MARCO | * | 10.1371/journal.pone.0227985 |
| 417943 | Articolo in rivista | Expanded circulating hematopoietic stem/progenitor cells as novel cell source for the treatment of TCIRG1 osteopetrosis | Valentina Capo1, Sara Penna1, Ivan Merelli2, Matteo Barcella1, Serena Scala1, Luca Basso-Ricci1, Elena Draghici1, Eleonora Palagano3, Erika Zonari1, Giacomo Desantis1, Paolo Uva4, Roberto Cusano4, Lucia Sergi Sergi1, Laura Crisafulli3, Despina Moshous5, Polina Stepensky6, Katarzyna Drabko7, Zuhre Kaya8, Ekrem Unal9, Alper Gezdirici10, Giuseppe Menna11, Marta Serafini12, Alessandro Aiuti1, Silvia Laura Locatelli13, Carmelo Carlo-Stella13, Ansgar S. Schulz14, Francesca Ficara3, Cristina Sobacchi3, Bernhard Gentner1, Anna Villa1 | Allogeneic hematopoietic stem cell transplantation is the treatment of choice for autosomal recessive osteopetrosis caused by defects in the TCIRG1 gene. Despite recent progress in conditioning, a relevant number of patients are not eligible for allogeneic stem cell transplantation because of the severity of the disease and significant transplant-related morbidity. We exploited peripheral CD34+ cells, known to circulate at high frequency in the peripheral blood of TCIRG1-deficient patients, as a novel cell source for autologous transplantation of gene corrected cells. Detailed phenotypical analysis showed that circulating CD34+ cells have a cellular composition that resembles bone marrow, supporting their use in gene therapy protocols. Transcriptomic profile revealed enrichment in genes expressed by hematopoietic stem and progenitor cells (HSPCs). To overcome the limit of bone marrow harvest/ HSPC mobilization and serial blood drawings in TCIRG1 patients, we applied UM171-based ex-vivo expansion of HSPCs coupled with lentiviral gene transfer. Circulating CD34+ cells from TCIRG1-defective patients were transduced with a clinically-optimized lentiviral vector (LV) expressing TCIRG1 under the control of phosphoglycerate promoter and expanded ex vivo. Expanded cells maintained long-term engraftment capacity and multi-lineage repopulating potential when transplanted in vivo both in primary and secondary NSG recipients. Moreover, when CD34+ cells were differentiated in vitro, genetically corrected osteoclasts resorbed the bone efficiently. Overall, we provide evidence that expansion of circulating HSPCs coupled to gene therapy can overcome the limit of stem cell harvest in osteopetrotic patients, thus opening the way to future gene-based treatment of skeletal diseases caused by bone marrow fibrosis. | Haematologica (Roma) (2020). | 2020 | CRISAFULLI LAURA, PALAGANO ELEONORA, SOBACCHI CRISTINA, MERELLI IVAN, FICARA FRANCESCA, VILLA ANNA | hematopoietic stem cell bone marrow failure stem cell transplantation Gene Therapy and Transfer HSPC expansion | |
| 417945 | Articolo in rivista | Frailness and resilience of gene networks predicted by detection of co-occurring mutations via a stochastic perturbative approach | Bersanelli M., Mosca E., Milanesi L., Bazzani A., Castellani G. | In recent years complex networks have been identified as powerful mathematical frameworks for the adequate modeling of many applied problems in disparate research fields. Assuming a Master Equation (ME) modeling the exchange of information within the network, we set up a perturbative approach in order to investigate how node alterations impact on the network information flow. The main assumption of the perturbed ME (pME) model is that the simultaneous presence of multiple node alterations causes more or less intense network frailties depending on the specific features of the perturbation. In this perspective the collective behavior of a set of molecular alterations on a gene network is a particularly adapt scenario for a first application of the proposed method, since most diseases are neither related to a single mutation nor to an established set of molecular alterations. Therefore, after characterizing the method numerically, we applied as a proof of principle the pME approach to breast cancer (BC) somatic mutation data downloaded from Cancer Genome Atlas (TCGA) database. For each patient we measured the network frailness of over 90 significant subnetworks of the protein-protein interaction network, where each perturbation was defined by patient-specific somatic mutations. Interestingly the frailness measures depend on the position of the alterations on the gene network more than on their amount, unlike most traditional enrichment scores. In particular low-degree mutations play an important role in causing high frailness measures. The potential applicability of the proposed method is wide and suggests future development in the control theory context. | Scientific reports (Nature Publishing Group) 10 (2020). | 2020 | MILANESI LUCIANO, MOSCA ETTORE | Breast cancer Stochastic modelling | 10.1038/s41598-020-59036-w |
| 417950 | Articolo in rivista | Inhibition of histone methyltransferase DOT1L silences ER? gene and blocks proliferation of antiestrogen-resistant breast cancer cells | Nassa G1, Salvati A1, Tarallo R1, Gigantino V1, Alexandrova E1, 2, Memoli D1, Sellitto A1, Rizzo F1, Malanga D3, Mirante T3, Morelli E3, Nees M4, Akerfelt M4, Kangaspeska S5, Nyman TA6, Milanesi L7, Giurato G1, 2, Weisz A1. | Breast cancer (BC) resistance to endocrine therapy results from constitutively active or aberrant estrogen receptor ? (ER?) signaling, and ways to block ER? pathway in these tumors are sought after. We identified the H3K79 methyltransferase DOT1L as a novel cofactor of ER? in BC cell chromatin, where the two proteins colocalize to regulate estrogen target gene transcription. DOT1L blockade reduces proliferation of hormone-responsive BC cells in vivo and in vitro, consequent to cell cycle arrest and apoptotic cell death, with widespread effects on ER-dependent gene transcription, including ER? and FOXA1 gene silencing. Antiestrogen-resistant BC cells respond to DOT1L inhibition also in mouse xenografts, with reduction in ER? levels, H3K79 methylation, and tumor growth. These results indicate that DOT1L is an exploitable epigenetic target for treatment of endocrine therapy-resistant ER?-positive BCs. | Science Advances (2019). | 2019 | MILANESI LUCIANO | * | |
| 408179 | Articolo in rivista | Urinary proteomics profiles are useful for detection of cancer biomarkers and changes induced by therapeutic procedures | Ferrari E., Wittig A., Basilico F., Rossi R., De Palma A., Di Silvestre D., Sauerwein W.A.G., Mauri P.L. | Boron neutron capture therapy (BNCT) is a binary cancer treatment modality where two different agents (B and thermal neutrons) have to be present to produce an effect. A dedicated trial design is necessary for early clinical trials. The concentration of B in tissues is an accepted surrogate to predict BNCT effects on tissues. Tissue, blood, and urines were sampled after infusion of two different boron carriers, namely BSH and BPA in the frame of the European Organisation for Research and Treatment of Cancer (EORTC) trial 11001. In this study, urine samples were used to identify protein profiles prior and after drug infusion during surgery. Here, an approach that is based on the mass spectrometry (MS)-based proteomic analysis of urine samples from head and neck squamous cell carcinoma (HNSCC) and thyroid cancer patients is presented. This method allowed the identification of several inflammation- and cancer-related proteins, which could serve as tumor biomarkers. In addition, changes in the urinary proteome during and after therapeutic interventions were detected. In particular, a reduction of three proteins that were involved in inflammation has been observed: Galectin-3 Binding Protein, CD44, and osteopontin. The present work represents a proof of principle to follow proteasome changes during complex treatments based on urine samples. | Molecules (Basel, Online) 24 (2019). | 2019 | ROSSI ROSSANA, FERRARI EMANUELE, BASILICO FABRIZIO, DE PALMA ANTONELLA, DI SILVESTRE DARIO, MAURI PIETRO LUIGI | BNCT; LC-MS; MudPIT; boron; proteomics; squamous cell cancer of head and neck; thyroid cancer; urine | 10.3390/molecules24040794 |
| 419578 | Contributo in atti di convegno | Radiomics to predict prostate cancer aggressiveness: a preliminary study | Germanese D., Mercatelli L., Colantonio S., Miele V., Pascali M.A., Caudai C., Zoppetti N., Carpi R., Barucci A., Bertelli E., Agostini S. | Radiomics is encouraging a paradigm shift in oncological diagnostics towards the symbiosis of radiology and Artificial Intelligence (AI) techniques. The aim is to exploit very accurate, robust image processing algorithms and provide quantitative information about the phenotypic differences of cancer traits. By exploring the association between this quantitative information and patients' prognosis, AI algorithms are boosting the power of radiomics in the perspective of precision oncology. However, the choice of the most suitable AI method can determine the success of a radiomic application. The current state-of-the art methods in radiomics aim at extracting statistical features from biomedical images and, then, process them with Machine Learning (ML) techniques. Many works have been reported in the literature presenting various combinations of radiomic features and ML methods. In this preliminary study, we aim to analyse the performance of a radiomic approach to predict prostate cancer (PCa) aggressiveness from multiarametric Magnetic Resonance Imaging (mp-MRI). Clinical mp-MRI data were collected from patients with histology-confirmed PCa and labelled by a team of expert radiologists. Such data were used to extract and select two sets of radiomic features; hence, the classification performances of five classifiers were assessed. This analysis is meant as a preliminary step towards the overall goal of investigating the potential of radiomic-based analyses. | BIBE 2019: 19th annual IEEE International Conference on Bioinformatics and Bioengineering, pp. 972-976, Athens, Greece, 28-30 October 2019 | 2019 | GERMANESE DANILA, COLANTONIO SARA, ZOPPETTI NICOLA, BARUCCI ANDREA, PASCALI MARIA ANTONIETTA, CAUDAI CLAUDIA | Radiomics, Machine learning, Artificial Intelligence, Medical Imaging, Prostate Cancer | 10.1109/BIBE.2019.00181 |
| 421490 | Articolo in rivista | A mobile phone intervention to improve obesity-related health behaviors of adolescents across Europe: Iterative co-design and feasibility study | Martin, Anne, Caon, Maurizio, Adorni, Fulvio, Andreoni, Giuseppe, Ascolese, Antonio, Atkinson, Sarah, Bul, Kim, Carrion, Carme, Castell, Conxa, Ciociola, Valentina, Condon, Laura, Espallargues, Mireia, Hanley, Janet, Jesuthasan, Nithiya, Lafortuna, Claudio L., Lang, Alexandra, Prinelli, Federica, Puidomenech Puig, Elisa, Tabozzi, Sarah A., McKinstry, Brian | Background: Promotion of physical activity, healthy eating, adequate sleep, and reduced sedentary behavior in adolescents is a major priority globally given the current increase in population health challenges of noncommunicable diseases and risk factors such as obesity. Adolescents are highly engaged with mobile technology, but the challenge is to engage them with mobile health (mHealth) technology. Recent innovations in mobile technology provide opportunities to promote a healthy lifestyle in adolescents. An increasingly utilized approach to facilitate increased engagement with mHealth technology is to involve potential users in the creation of the technology. Objective: This study aimed to describe the process of and findings from co-designing and prototyping components of the PEGASO Fit for Future (F4F) mHealth intervention for adolescents from different cultural backgrounds. Methods: A total of 74 adolescents aged 13 to 16 years from Spain, Italy, and the United Kingdom participated in the co-design of the PEGASO F4F technology. In 3 iterative cycles over 12 months, participants were involved in the co-design, refinement, and feasibility testing of a system consisting of diverse mobile apps with a variety of functions and facilities to encourage healthy weight-promoting behaviors. In the first iteration, participants attended a single workshop session and were presented with mock-ups or early-version prototypes of different apps for user requirements assessment and review. During the second iteration, prototypes of all apps were tested by participants for 1 week at home or school. In the third iteration, further developed prototypes were tested for 2 weeks. Participants' user experience feedback and development ideas were collected through focus groups and completion of questionnaires. Results: For the PEGASO F4F technology to be motivating and engaging, participants suggested that it should (1) allow personalization of the interface, (2) have age-appropriate and easy-to-understand language (of icons, labels, instructions, and notifications), (3) provide easily accessible tutorials on how to use the app or navigate through a game, (4) present a clear purpose and end goal, (5) have an appealing and self-explanatory reward system, (6) offer variation in gamified activities within apps and the serious game, and (7) allow to seek peer support and connect with peers for competitive activities within the technology. Conclusions: Incorporating adolescents' preferences, the PEGASO F4F technology combines the functions of a self-monitoring, entertainment, advisory, and social support tool. This was the first study demonstrating that it is possible to develop a complex mobile phone-based technological system applying the principles of co-design to mHealth technology with adolescents across 3 countries. The findings from this study informed the development of an mHealth system for healthy weight promotion to be tested in a controlled multinational pilot trial. | JMIR mhealth and uhealth 8 (2020): e14118. | 2020 | TABOZZI SARAH ANTONELLA, JESUTHASAN NITHIYA, CIOCIOLA VALENTINA, ADORNI FULVIO DANIELE, LAFORTUNA CLAUDIO | adolescents; co-design; focus groups; health behavior; mHealth; mobile app; mobile phone; obesity; youth | 10.2196/14118 |
| 421678 | Articolo in rivista | Assessment of haptoglobin alleles in autism spectrum disorders | Francesca Anna Cupaioli1, Ettore Mosca 1, Chiara Magri 2, Massimo Gennarelli2, 3, Marco Moscatelli1, Maria elisabetta Raggi4, Martina Landini1, Nadia Galluccio 1, Laura Villa4, Arianna Bonfanti4, Alessandra Renieri5, 6, Chiara fallerini5, Alessandra Minelli2, Anna Marabotti 7, Luciano Milanesi 1, Alessio fasano 8, 9, Alessandra Mezzelani 1 ? | Gene-environment interactions, by means of abnormal macromolecular intestinal adsorption, is one of the possible causes of autism spectrum disorders (ASD) predominantly in patients with gastrointestinal disorders. Pre-haptoglobin-2 (zonulin), encoded by the Haptoglobin (HP) allele-2 gene, enhances the intestinal permeability by modulation of intercellular tight junctions. the two alleles of HP, HP1 and HP2, di er for 2 extra exons in HP2 that result in exon duplication undetectable by classic genome- wide association studies. to evaluate the role of HP2 in ASD pathogenesis and to set up a method to discriminate HP alleles, italian subjects with ASD (n = 398) and healthy controls (n = 379) were genotyped by pcR analysis; subsequently, the pcR results were integrated with microarray genotypes (Illumina Human Omni 1S-8), obtained using a subset from the same subjects, and then we developed a computational method to predict HP alleles. On the contrary to our expectations, there was no association between HP2 and ASD (p > 0.05), and there was no signi cant allele association in subjects with ASD with or without gastrointestinal disorders (p > 0.05). With the aid of bioinformatics analysis, from a window frame of ~2 Mb containing 314 SNPs, we obtain imputation accuracy (r2) between 0.4 and 0.9 (median 0.7) and correct predictions were between 70% and 100% (median 90%). The conclusions endorse that enhanced intestinal permeability in subjects with ASD should not be imputed to HP2 but to other members of the zonulin family and/or to environmental factors. | Scientific report (Camb. Res. Inst. (G.B.)) 10 (2020). | 2020 | MEZZELANI ALESSANDRA MARIA, MOSCA ETTORE, MOSCATELLI MARCO, CUPAIOLI FRANCESCA ANNA | autism, haptoglobin, risk factor, intestinal permeability | 10.1038/s41598-020-64679-w |
| 424282 | Articolo in rivista | Expression profiling of microRNAs and isomiRs in conventional central chondrosarcoma | Parafioriti A., Cifola I., Gissi C., Pinatel E., Vilardo L., Armiraglio E., Di Bernardo A., Daolio P.A., Felsani A., D'Agnano I., Berardi A.C. | Conventional central chondrosarcoma (CCC) is a malignant bone tumor that is characterized by the production of chondroid tissue. Since radiation therapy and chemotherapy have limited effects on CCC, treatment of most patients depends on surgical resection. This study aimed to identify the expression profiles of microRNAs (miRNAs) and isomiRs in CCC tissues to highlight their possible participation to the regulation of pathways critical for the formation and growth of this type of tumor. Our study analyzed miRNAs and isomiRs from Grade I (GI), Grade II (GII), and Grade III (GIII) histologically validated CCC tissue samples. While the different histological grades shared a similar expression profile for the top abundant miRNAs, we found several microRNAs and isomiRs showing a strong different modulation in GII + GIII vs GI grade samples and their involvement in tumor biology could be consistently hypothesized. We then in silico validated these differently expressed miRNAs in a larger chondrosarcoma public dataset and confirmed the expression trend for 17 out of 34 miRNAs. Our results clearly suggests that the contribution of miRNA deregulation, and their targeted pathways, to the progression of CCC could be relevant and strongly indicates that when studying miRNA deregulation in tumors, not only the canonical miRNAs, but the whole set of corresponding isomiRs should be taken in account. Improving understanding of the precise roles of miRNAs and isomiRs over the course of central chondrosarcoma progression could help identifying possible targets for precision medicine therapeutic intervention. | Cell Death Discovery 6 (2020). | 2020 | CIFOLA INGRID, PINATEL EVA MARIA, D'AGNANO IGEA | Conventional central chondrosarcoma, miRNA, isomiR, small RNA next-generation sequencing | 10.1038/s41420-020-0282-3 |
| 424284 | Articolo in rivista | Circulating miRNAs in Small Extracellular Vesicles Secreted by a Human Melanoma Xenograft in Mouse Brains | Loredana Guglielmi 1, +, Marta Nardella 2, +, Carla Musa 3, +, Ingrid Cifola 1, +, Manuela Porru 4, Beatrice Cardinali 3, Ilaria Iannetti 3, Chiara Di Pietro 3, Giulia Bolasco 5, Valentina Palmieri 6, 7, Laura Vilardo 1, Nicolo Panini 8, Fabrizio Bonaventura 3, Massimiliano Papi 6, 7, Ferdinando Scavizzi 3, Marcello Raspa 3, Carlo Leonetti 4, ?, Germana Falcone 3, ?, Armando Felsani 9, ? and Igea D'Agnano 1, *, ? | The identification of liquid biomarkers remains a major challenge to improve the diagnosis of melanoma patients with brain metastases. Circulating miRNAs packaged into tumorsecreted small extracellular vesicles (sEVs) contribute to tumor progression. To investigate the release of tumor-secreted miRNAs by brain metastasis, we developed a xenograft model where human metastatic melanoma cells were injected intracranially in nude mice. The comprehensive profiles of both free miRNAs and those packaged in sEVs secreted by the melanoma cells in the plasma demonstrated that most (80%) of the sEV-associated miRNAs were also present in serum EVs from a cohort of metastatic melanomas, included in a publicly available dataset. Remarkably, among them, we found three miRNAs (miR-224-5p, miR-130a-3p and miR-21-5p) in sEVs showing a trend of upregulation during melanoma progression. Our model is proven to be valuable for identifying miRNAs in EVs that are unequivocally secreted by melanoma cells in the brain and could be associated to disease progression | Cancers (Basel) (2020). | 2020 | CARDINALI BEATRICE, RASPA MARCELLO, FALCONE GERMANA, CIFOLA INGRID, DI PIETRO CHIARA, VILARDO LAURA, D'AGNANO IGEA, SCAVIZZI FERDINANDO | melanoma; circulating miRNAs; small extracellular vesicles | |
| 425539 | Articolo in rivista | Behcet's Disease Under Microbiotic Surveillance? A Combined Analysis of Two Cohorts of Behcet's Disease Patients | van der Houwen, Tim B., van Laar, Jan A. M., Kappen, Jasper H., van Hagen, Petrus M., de Zoete, Marcel R., van Muijlwijk, Guus H., Berbers, Roos-Marijn, Fluit, Ad C., Rogers, Malbert, Groot, James, Hazelbag, C. Marijn, Consolandi, Clarissa, Severgnini, Marco, Peano, Clelia, D'Elios, Mario M., Emmi, Giacomo, Leavis, Helen L. | Background:In Behcet's disease (BD), an auto-inflammatory vasculitis, an unbalanced gut microbiota can contribute to pro-inflammatory reactions. In separate studies, distinct pro- and anti-inflammatory bacteria associated with BD have been identified. Methods:To establish disease-associated determinants, we performed gut microbiome profiling in BD patients from the Netherlands (n= 19) and Italy (n= 13), matched healthy controls (HC) from the Netherlands (n= 17) and Italy (n= 15) and oral microbiome profiling in Dutch BD patients (n= 18) and HC (n= 15) by 16S rRNA gene sequencing. In addition, we used fecal IgA-SEQ analysis to identify specific IgA coated bacterial taxa in Dutch BD patients (n= 13) and HC (n= 8). Results:In BD stool samples alpha-diversity was conserved, whereas beta-diversity analysis showed no clustering based on disease, but a significant segregation by country of origin. Yet, a significant decrease of unclassifiedBarnesiellaceaeandLachnospiragenera was associated with BD patients compared to HC. Subdivided by country, the Italian cohort displays a significant decrease of unclassifiedBarnesiellaceaeandLachnospiragenera, in the Dutch cohort this decrease is only a trend. Increased IgA-coating ofBifidobacteriumspp.,Doreaspp. andRuminococcus bromiispecies was found in stool from BD patients. Moreover, oral Dutch BD microbiome displayed increased abundance ofSpirochaetaceaeandDethiosulfovibrionaceaefamilies. Conclusions:BD patients show decreased fecal abundance ofBarnesiellaceaeandLachnospiraand increased oral abundance ofSpirochaetaceaeandDethiosulfovibrionaceae. In addition, increased fecal IgA coating ofBifidobacterium, Ruminococcus bromiiandDoreamay reflect retention of anti-inflammatory species and neutralization of pathosymbionts in BD, respectively. Additional studies are warranted to relate intestinal microbes with the significance of ethnicity, diet, medication and response with distinct pro- and inflammatory pathways in BD patients. | Frontiers in immunology 11 (2020). | 2020 | CONSOLANDI CLARISSA, PEANO CLELIA, SEVERGNINI MARCO | Behcet's disease, microbiota, intestinal, oral, IgA-SEQ | 10.3389/fimmu.2020.01192 |
| 425541 | Articolo in rivista | Esophageal microbiome signature in patients with Barrett's esophagus and esophageal adenocarcinoma | Lopetuso, Loris Riccardo, Severgnini, Marco, Pecere, Silvia, Ponziani, Francesca Romana, Boskoski, Ivo, Larghi, Alberto, Quaranta, Gianluca, Masucci, Luca, Ianiro, Gianluca, Camboni, Tania, Gasbarrini, Antonio, Costamagna, Guido, Consolandi, Clarissa, Cammarota, Giovanni | Preliminary studies suggested a possible correlation of microbiota with Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC), where the need for tools to ameliorate its poor prognosis is mandatory. We explored the potential signature of esophageal microbiota and its predicted functional profile along the continuous spectrum from BE to EAC. We analyzed through 16S-based amplicon sequencing the mucosal microbiota and the microbiota-related functional predictions in 10 BE and 6 EAC patients compared with 10 controls, exploring also potential differences between the metaplastic mucosa (BEM) and the adjacent normal areas of BE patients (BEU). BEM and EAC showed a higher level of alpha and beta-diversity. BEM evidenced a decrease of Streptococcus and an increase of Prevotella, Actinobacillus, Veillonella, and Leptotrichia. EAC displayed a striking reduction of Streptococcus, with an increase of Prevotella, Veillonella and Leptotrichia. LefSe analysis identified Leptotrichia as the main taxa distinguishing EAC. BEM showed a decreased a-diversity compared with BEU and a reduction of Bacteroidetes, Prevotella and Fusobacterium. Functional predictions identified peculiar profiles for each group with a high potential for replication and repair in BEM; an upregulated energy, replication and signaling metabolisms, with the fatty-acids biosynthesis and nitrogen and D-alanine pathways down-regulated in EAC. Our pilot study identifies a unique microbial structure and function profile for BE and EAC, as well as for metaplastic and near-normal areas. It proposes a new concept for BE, which could be intended not only as the histological, but, also, as the microbial closest precursor of EAC. This requires further larger follow-up studies, but opens intriguing horizons towards innovative diagnostic and therapeutic options for EAC. | PloS one 15 (2020): e0231789. | 2020 | CAMBONI TANIA, CONSOLANDI CLARISSA, SEVERGNINI MARCO | Barrett's esophagus, esophageal adenocarcinoma, microbiota, next-generation sequencing | 10.1371/journal.pone.0231789 |
| 425569 | Articolo in rivista | InteractomeSeq: a web server for the identification and profiling of domains and epitopes from phage display and next generation sequencing data | Puccio S., Grillo G., Consiglio A., Soluri M.F., Sblattero D., Cotella D., Santoro C., Liuni S., Bellis G., Lugli E., Peano C., Licciulli F. | High-Throughput Sequencing technologies are transforming many research fields, including the analysis of phage display libraries. The phage display technology coupled with deep sequencing was introduced more than a decade ago and holds the potential to circumvent the traditional laborious picking and testing of individual phage rescued clones. However, from a bioinformatics point of view, the analysis of this kind of data was always performed by adapting tools designed for other purposes, thus not considering the noise background typical of the 'interactome sequencing' approach and the heterogeneity of the data. InteractomeSeq is a web server allowing data analysis of protein domains ('domainome') or epitopes ('epitome') from either Eukaryotic or Prokaryotic genomic phage libraries generated and selected by following an Interactome sequencing approach. InteractomeSeq allows users to upload raw sequencing data and to obtain an accurate characterization of domainome/epitome profiles after setting the parameters required to tune the analysis. The release of this tool is relevant for the scientific and clinical community, because InteractomeSeq will fill an existing gap in the field of large-scale biomarkers profiling, reverse vaccinology, and structural/functional studies, thus contributing essential information for gene annotation or antigen identification. InteractomeSeq is freely available at https://InteractomeSeq.ba.itb.cnr.it/. | Nucleic acids research (Online) 48 (2020): W200-W207. | 2020 | DE BELLIS GIANLUCA, LICCIULLI VITO FLAVIO, GRILLO GIORGIO, PEANO CLELIA, LIUNI SABINO, CONSIGLIO ARIANNA | interactome sequencing web tool | 10.1093/nar/gkaa363 |
| 425427 | Articolo in rivista | Aurora A kinase and its activator TPX2 are potential therapeutic targets in KRAS-induced pancreatic cancer | Gomes-Filho, Sandro Mascena, dos Santos, Edmilson Ozorio, Matos Bertoldi, Ester Riserio, Scalabrini, Luiza Coimbra, Heidrich, Vitor, Dazzani, Bianca, Levantini, Elena, Reis, Eduardo Moraes, Basseres, Daniela Sanchez | Purpose Oncogenic KRAS mutations are found in over 90% of pancreatic ductal adenocarcinomas (PDACs). As yet, however, no effective therapies are available for KRAS-induced malignancies. Therefore, research aimed at the identification of KRAS targets with therapeutic potential is warranted. Our goal was to investigate Aurora A (AURKA) and targeting protein for Xklp2 (TPX2) as potential therapeutic targets in PDAC. Methods AURKA and TPX2 expression was assessed using RNAseq and qRT-PCR in PDAC patient samples and matched non-tumor pancreatic tissues. Publicly available PDAC datasets were used to investigate associations of AURKA and TPX2 expression levels with patient survival and the presence of KRAS mutations. Next, we used an Aurora kinase inhibitor, or KRAS, AURKA and TPX2 targeting using RNA interference in KRAS-mutant PDAC cells and, subsequently, analyzed their clonogenic and anchorage-independent growth and migration. Results We found that relative to matched non-tumor tissues, PDAC tumors displayed significantly higher expression levels of AURKA and TPX2. In addition, we found that AURKA and TPX2 were co-expressed in PDAC datasets, and that high expression levels of AURKA and TPX2 were associated with a shorter patient survival and with the presence of oncogenic KRAS mutations. In addition, we found that siRNA-mediated KRAS targeting in KRAS-mutant PDAC cells reduced AURKA and TPX2 expression. Furthermore, targeting AURKA or TPX2 in KRAS-mutant PDAC cells reduced their clonogenic and anchorage-independent growth, as well their migration. Conclusions From our data we conclude that AURKA and TPX2 may act as KRAS biomarkers in PDAC that can predict a worse prognosis, and that AURKA or TPX2 targeting in PDAC cells may reduce their transformed phenotype. These results indicate that AURKA and TPX2 may serve as promising targets to be explored for KRAS-mutant PDAC therapy. | Cellulair oncology (2011. Print) 43 (2020): 445-460. | 2020 | LEVANTINI ELENA | Pancreatic cancer, KRAS, Therapeutic target, mechanisms of tumorigenesis, AURKA or TPX2 as new targets | 10.1007/s13402-020-00498-5 |
| 425428 | Articolo in rivista | Targeting microtubules sensitizes drug resistant lung cancer cells to lysosomal pathway inhibitors | Chin T.-M., Boopathy G.T.K., Man E.P.S., Clohessy J.G., Csizmadia E., Quinlan M.P., Putti T., Wan S.-C., Xie C., Ali A., Wai F.C., Ong Y.S., Goh B.-C., Settleman J., Hong W., Levantini E., Tenen D.G. | Oncogene-addicted cancers are predominantly driven by specific oncogenic pathways and display initial exquisite sensitivity to designer therapies, but eventually become refractory to treatments. Clear understanding of lung tumorigenic mechanisms is essential for improved therapies. Methods: Lysosomes were analyzed in EGFR-WT and mutant cells and corresponding patient samples using immunofluorescence or immunohistochemistry and immunoblotting. Microtubule organization and dynamics were studied using immunofluorescence analyses. Also, we have validated our findings in a transgenic mouse model that contain EGFR-TKI resistant mutations. Results: We herein describe a novel mechanism that a mutated kinase disrupts the microtubule organization and results in a defective endosomal/lysosomal pathway. This prevents the efficient degradation of phosphorylated proteins that become trapped within the endosomes and continue to signal, therefore amplifying downstream proliferative and survival pathways. Phenotypically, a distinctive subcellular appearance of LAMP1 secondary to microtubule dysfunction in cells expressing EGFR kinase mutants is seen, and this may have potential diagnostic applications for the detection of such mutants. We demonstrate that lysosomal-inhibitors re-sensitize resistant cells to EGFR tyrosine-kinase inhibitors (TKIs). Identifying the endosome-lysosome pathway and microtubule dysfunction as a mechanism of resistance allows to pharmacologically intervene on this pathway. Conclusions: We find that the combination of microtubule stabilizing agent and lysosome inhibitor could reduce the tumor progression in EGFR TKI resistant mouse models of lung cancer. | Theranostics 10 (2020): 2727-2743. | 2020 | LEVANTINI ELENA | Magnetic resonance Imaging, Preclinical murine model of lung cancer, Molecular pathogenesis of lung cancer, EGFR mutant lung cancer therapy, Drug treatment | 10.7150/thno.38729 |
| 425426 | Articolo in rivista | Fatty acid synthase mediates EGFR palmitoylation in EGFR mutated non-small cell lung cancer | Ali, Azhar, Levantini, Elena, Teo, Jun Ting, Goggi, Julian, Clohessy, John G., Wu, Chan Shuo, Chen, Leilei, Yang, Henry, Krishnan, Indira, Kocher, Olivier, Zhang, Junyan, Soo, Ross A., Bhakoo, Kishore, Chin, Tan Min, Tenen, Daniel G. | Metabolic reprogramming is widely known as a hallmark of cancer cells to allow adaptation of cells to sustain survival signals. In this report, we describe a novel oncogenic signaling pathway exclusively acting in mutated epidermal growth factor receptor (EGFR) non-small cell lung cancer (NSCLC) with acquired tyrosine kinase inhibitor (TKI) resistance. Mutated EGFR mediates TKI resistance through regulation of the fatty acid synthase (FASN), which produces 16-C saturated fatty acid palmitate. Our work shows that the persistent signaling by mutated EGFR in TKI-resistant tumor cells relies on EGFR palmitoylation and can be targeted by Orlistat, an FDA-approved anti-obesity drug. Inhibition of FASN with Orlistat induces EGFR ubiquitination and abrogates EGFR mutant signaling, and reduces tumor growths both in culture systems and invivo. Together, our data provide compelling evidence on the functional interrelationship between mutated EGFR and FASN and that the fatty acid metabolism pathway is a candidate target for acquired TKI-resistant EGFR mutant NSCLC patients. | EMBO molecular medicine (Print) 10 (2018). | 2018 | LEVANTINI ELENA | Lung cancer pathogenesis, Preclinical murine model of lung cancer, Drug treatment, New therapeutic targets, fatty acid synthase (FASN) targeting, EGFR ubiquitination, Magnetic Resonance Imaging, Resistance to therapy | 10.15252/emmm.201708313 |
| 369828 | Contributo in volume | Runx1 structure and function in blood cell development | Bonifer C., Levantini E., Kouskoff V., Lacaud G. | Capitolo su Libro | , pp. 65-81, 2017 | 2017 | LEVANTINI ELENA | cellule staminali ematopoietiche, fattori di trascrizione, fattori di trascrizione della famiglia RUNX, modelli murini (studi preclinici per leucemie e tumore al polmone), studio espressione genica, studi di conformazione della cromatina per la regolazione genica | 10.1007/978-981-10-3233-2_5 |
| 425425 | Articolo in rivista | ZNF143 protein is an important regulator of the myeloid transcription factor C/EBPa | Gonzalez, David, Luyten, Annouck, Bartholdy, Boris, Zhou, Qiling, Kardosova, Miroslava, Ebralidze, Alex, Swanson, Kenneth D., Radomska, Hanna S., Zhang, Pu, Kobayashi, Susumu S., Welner, Robert S., Levantini, Elena, Steidl, Ulrich, Chong, Gilbert, Collombet, Samuel, Choi, Min Hee, Friedman, Alan D., Scott, Linda M., Alberich-Jorda, Meritxell, Tenen, Daniel G. | The transcription factor C/EBPa is essential for myeloid differentiation and is frequently dysregulated in acute myeloid leukemia. Although studied extensively, the precise regulation of its gene by upstream factors has remained largely elusive. Here, we investigated its transcriptional activation during myeloid differentiation. We identified an evolutionarily conserved octameric sequence, CCCAGCAG, approximate to 100 bases upstream of the CEBPA transcription start site, and demonstrated through mutational analysis that this sequence is crucial for C/EBPa expression. This sequence is present in the genes encoding C/EBPa in humans, rodents, chickens, and frogs and is also present in the promoters of other C/EBP family members. We identified that ZNF143, the human homolog of the Xenopus transcriptional activator STAF, specifically binds to this 8-bp sequence to activate C/EBPa expression in myeloid cells through a mechanism that is distinct from that observed in liver cells and adipocytes. Altogether, our data suggest that ZNF143 plays an important role in the expression of C/EBPa in myeloid cells. | Journal of biological chemistry (Online) 292 (2017): 18924-18936. | 2017 | LEVANTINI ELENA | CCAAT-enhancer-binding protein (C, gene regulation, hematopoiesis, promoter, transcription factor, ZNF143, gene regulation during myeloid differentiation, basic research on transcription factors involved in leukemia | 10.1074/jbc.M117.811109 |
| 419850 | Articolo in rivista | Listening to the neurological teams for multiple sclerosis: the SMART project | Chesi, P., Marini, M. G., Mancardi, G. L., Patti, F., Alivernini, L., Bisecco, A., Borriello, G., Bucello, S., Caleri, F., Cavalla, P., Cocco, E., Cordioli, C., Di Giuseppe, M., Fantozzi, R., Gattuso, M., Granella, F., Liguori, M., Locatelli, L., Lugaresi, A., Marangoni, S., Moiola, L., Mutta, E., Neri, W., Pasto, L., Perini, P., Petruzzo, M., Plewnia, K., Repice, A. M., Rezzonico, M., Romano, S., Rovaris, M., Sessa, E., Tortorella, C., Totaro, R., Valentino, P. | Objective Aim of the research was to define the quality of life of Italian neurologists and nurses' professional caring for multiple sclerosis, to understand their living the clinical practice and identify possible signals of compassion fatigue. Material and methods One hundred five neurologists and nurses from 30 Italian multiple sclerosis centres were involved in an online quali-quantitative survey on the organization of care, combined with the Satisfaction and Compassion Fatigue Test and a collection of narratives. Descriptive statistics of the quantitative data were integrated with the results obtained by the narrative medicine methods of analysis. Results Most of the practitioners were neurologists, 46 average years old, 69% women, 43% part time dedicated to multiple sclerosis. An increased number of patients in the last 3 years were referred in 29 centres. Differences were found between neurologists and nurses. Physicians showed higher risks of burnout, reporting intensive working paces, lack of medical personnel, and anxiety caused by the precarious employment conditions. Nurses appeared more satisfied, although the reference to the lack of spaces, and the cross professional roles risk of compassion fatigue. Both positive and negative relationships of care were depicted as influencing the professional quality of life. Conclusion The interviewed neurological teams need to limit the risk of compassion fatigue, which appeared from the first years of the career. The prevalence of the risk among neurologists suggests more awareness among scientific societies and health care managers on the risk for this category, as first step to prevent it. | Neurological sciences (Testo stamp.) (2020). | 2020 | LIGUORI MARIA | Burnout, Compassion fatigue, Narrative medicine | 10.1007/s10072-020-04301-z |
| 426233 | Articolo in rivista | 96-week results of a dual therapy with darunavir/ritonavir plus rilpivirine once a day vs triple therapy in patients with suppressed viraemia: virological success and non-HIV related morbidity evaluation | Di Cristo, Valentina, Adorni, Fulvio, Maserati, Renato, Annovazzi Lodi, Marco, Bruno, Giuseppe, Maggi, Paolo, Volpe, Anna, Vitiello, Paola, Abeli, Clara, Bonora, Stefano, Ferrara, Micol, Cossu, Maria Vittoria, Oreni, Maria Letizia, Colella, Elisa, Rusconi, Stefano | Antiretroviral therapies have been tested with the goal of maintaining virological suppression with a particular attention in limiting drug-related toxicity. With this aim we designed the DUAL study: a randomized, open-label, multicenter, 96 weeks-long pilot exploratory study in virologically suppressed HIV-1+ patients with the aim of evaluating the immunovirological success and the impact on non-HIV related morbidity of switching to a dual therapy with darunavir-ritonavir (DRV/r) and rilpivirine (RPV). We recruited patients who received a PI/r-containing HAART for >=6 months, HIV-RNA < 50 cp/mL for >=3 months, eGFR > 60 mL/min/1,73m2, without DRV or RPV RAMs. We randomized patients in arm A: RPV + DRV/r QD or arm B: ongoing triple therapy. The primary endpoint has been defined as the percentage of patients with HIV-RNA < 50 cp/mL at week 48 (ITT). VACS index, Framingham CVD risk (FRS) and urinary RBP (uRBP) were calculated. We used Chi-square or Fisher statistics for categorical variables and Mann-Whitney U for continuous ones. Forty-one patients were enrolled (22 in arm A, 14 in arm B, plus 5 screening failures): 30 patients reached 96 weeks: 100% had HIV-RNA < 50 cp/mL in arm A versus 91.7% in arm B. Similar changes were observed in median CD4/mL between baseline and week 96 (+59 versus - 31, p: n.s.). Thirty-one in arm A and 23 in arm B adverse events took place, whereas only 1 was serious (arm A: turbinate hypertrophy, unrelated to HAART). Among the 6 discontinuations (3 in A, 3 in B), only 1 was related to adverse event (arm A: G3 depression, insomnia, weakness). VACS index, median FRS and median uRBP values did not vary from baseline to week 96. At 96-weeks all patients switched to a QD 2-drug regimen based on DRV/r + RPV maintained HIV-RNA suppression, but a single patient who showed a virological failure at week 4. CD4 counts increased overtime without significant differences between the two arms. The novel dual regimen was well tolerated with the same amount of discontinuation as the control arm. VACS index, FRS and uRBP did not differ between arms at week 96. | HIV Research & Clinical Practice (Online) 21 (2020): 34-43. | 2020 | ADORNI FULVIO DANIELE | Darunavir, Dual therapy, HIV-1, Immunovirological success, Rilpivirine, Safety | 10.1080/25787489.2020.1734752 |
| 426243 | Articolo in rivista | Integrating microstructured electrospun scaffolds in an open microfluidic system for in vitro studies of human patient-derived primary cells | Guida P., Piscitelli E., Marrese M., Martino V., Cirillo V., Guarino V., Angeli E., Cocola C., Pelucchi P., Repetto L., Firpo G., Karnavas T., Gotte M., Gritzapis A., D'Albore M., Repetto D., Pezzuoli D., Missitzis I., Porta G., Bertalot G., Bellipanni G., Zucchi I., Ambrosio L., Valbusa U., Reinbold R.A. | Recent studies have suggested that microenvironmental stimuli play a significant role in regulating cellular proliferation and migration, as well as in modulating self-renewal and differentiation processes of mammary cells with stem cell (SCs) properties. Recent advances in micro/nanotechnology and biomaterial synthesis/engineering currently enable the fabrication of innovative tissue culture platforms suitable for maintenance and differentiation of SCs in vitro. Here, we report the design and fabrication of an open microfluidic device (OMD) integrating removable poly(?-caprolactone) (PCL) based electrospun scaffolds, and we demonstrate that the OMD allows investigation of the behavior of human cells during in vitro culture in real time. Electrospun scaffolds with modified surface topography and chemistry can influence attachment, proliferation, and differentiation of mammary SCs and epigenetic mechanisms that maintain luminal cell identity as a function of specific morphological or biochemical cues imparted by tailor-made fiber post-treatments. Meanwhile, the OMD architecture allows control of cell seeding and culture conditions to collect more accurate and informative in vitro assays. In perspective, integrated systems could be tailor-made to mimic specific physiological conditions of the local microenvironment and then analyze the response from screening specific drugs for more effective diagnostics, long-term prognostics, and disease intervention in personalized medicine. | ACS biomaterials science & engineering 6 (2020): 3649-3663. | 2020 | PISCITELLI ELEONORA, COCOLA CINZIA, CIRILLO VALENTINA, MARTINO VALENTINA, D'ALBORE MARIETTA, MARRESE MARICA, AMBROSIO LUIGI, GUARINO VINCENZO, PELUCCHI PARIDE, REINBOLD ROLLAND ALVONS, ZUCCHI ILEANA | polydimethylsiloxane, surface treatments, electrospun scaffolds, mammary luminal cells, preclinical screening | 10.1021/acsbiomaterials.0c00352 |
| 426267 | Articolo in rivista | Syndecan-1-Dependent Regulation of Heparanase Affects Invasiveness, Stem Cell Properties, and Therapeutic Resistance of Caco2 Colon Cancer Cells | Katakam, Sampath Kumar, Pelucchi, Paride, Cocola, Cinzia, Reinbold, Rolland, Vlodaysky, Israel, Greve, Burkhard, Goette, Martin | The heparan sulfate proteoglycan Syndecan-1 binds cytokines, morphogens and extracellular matrix components, regulating cancer stem cell properties and invasiveness. Syndecan-1 is modulated by the heparan sulfate-degrading enzyme heparanase, but the underlying regulatory mechanisms are only poorly understood. In colon cancer pathogenesis, complex changes occur in the expression pattern of Syndecan-1 and heparanase during progression from well-differentiated to undifferentiated tumors. Loss of Syndecan-1 and increased expression of heparanase are associated with a change in phenotypic plasticity and an increase in invasiveness, metastasis and dedifferentiation. Here we investigated the regulatory and functional interplay of Syndecan-1 and heparanase employing siRNA-mediated silencing and plasmid-based overexpression approaches in the human colon cancer cell line Caco2. Heparanase expression and activity were upregulated in Syndecan-1 depleted cells. This increase was linked to an upregulation of the transcription factor Egr1, which regulates heparanase at the promoter level. Inhibitor experiments demonstrated an impact of focal adhesion kinase, Wnt and ROCK-dependent signaling on this process. siRNA-depletion of Syndecan-1, and upregulation of heparanase increased the colon cancer stem cell phenotype based on sphere formation assays and phenotypic marker analysis (Side-population, NANOG, KLF4, NOTCH, Wnt, and TCF4 expression). Syndecan-1 depletion increased invasiveness of Caco2 cells in vitro in a heparanase-dependent manner. Finally, upregulated expression of heparanase resulted in increased resistance to radiotherapy, whereas high expression of enzymatically inactive heparanase promoted chemoresistance to paclitaxel and cisplatin. Our findings provide a new avenue to target a stemness-associated signaling axis as a therapeutic strategy to reduce metastatic spread and cancer recurrence. | Frontiers in oncology 10 (2020). | 2020 | REINBOLD ROLLAND ALVONS | heparanase, syndecan, colon cancer, cancer stem cells, heparan sulfate, proteoglycan | 10.3389/fonc.2020.00774 |
| 426269 | Articolo in rivista | The heparan sulfate proteoglycan syndecan-1 regulates colon cancer stem cell function via a focal adhesion kinase-Wnt signaling axis | Katakam, Sampath Kumar, Tria, Valeria, Sim, Wey-Cheng, Yip, George W., Molgora, Stefano, Karnavas, Theodoros, Elghonaimy, Eslam A., Pelucchi, Paride, Piscitelli, Eleonora, Ibrahim, Sherif Abdelaziz, Zucchi, Ileana, Reinbold, Rolland, Greve, Burkhard, Goette, Martin | In colon cancer, downregulation of the transmembrane heparan sulfate proteoglycan syndecan-1 (Sdc-1) is associated with increased invasiveness, metastasis, and dedifferentiation. As Sdc-1 modulates signaling pathways relevant to stem cell function, we tested the hypothesis that it may regulate a tumor-initiating cell phenotype. Sdc-1 small-interfering RNA knockdown in the human colon cancer cell lines Caco2 and HT-29 resulted in an increased side population (SP), enhanced aldehyde dehydrogenase 1 activity, and higher expression of CD133, LGR5, EPCAM, NANOG, SRY (sex-determining region Y)-box 2, KLF2, and TCF4/TCF7L2. Sdc-1 knockdown enhanced sphere formation, cell viability, Matrigel invasiveness, and epithelial-to-mesenchymal transition-related gene expression. Sdc-1-depleted HT-29 xenograft growth was increased compared to controls. Decreased Sdc-1 expression was associated with an increased activation of beta 1-integrins, focal adhesion kinase (FAK), and wingless-type (Wnt) signaling. Pharmacological FAK and Wnt inhibition blocked the enhanced stem cell phenotype and invasive growth. Sequential flow cytometric SP enrichment substantially enhanced the stem cell phenotype of Sdc-1-depleted cells, which showed increased resistance to doxorubicin chemotherapy and irradiation. In conclusion, Sdc-1 depletion cooperatively enhances activation of integrins and FAK, which then generates signals for increased invasiveness and cancer stem cell properties. Our findings may provide a novel concept to target a stemness-associated signaling axis as a therapeutic strategy to reduce metastatic spread and cancer recurrence. | The FEBS journal (Print) (2020). | 2020 | PISCITELLI ELEONORA, TRIA VALERIA, REINBOLD ROLLAND ALVONS, MOLGORA STEFANO ANGELO ADAMO, PELUCCHI PARIDE, ZUCCHI ILEANA | extracellular matrix, glycosaminoglycan, syndecans, tumor-initiating cells, xenograft | 10.1111/febs.15356 |
| 407711 | Articolo in rivista | Development and validation of new predictive equation for resting energy expenditure in adults with overweight and obesity | Orozco-Ruiz, Ximena, Pichardo-Ontiveros, Edgar, Tovar, Armando R., Torres, Nimbe, Medina-Vera, Isabel, Prinelli, Federica, Lafortuna, Claudio L., Guevara-Cruz, Martha | Background & aims: Accurate predictive equations of resting energy expenditure (REE) are crucial in devising nutritional strategies to manage overweight/obesity, especially in countries where these are highly prevalent. REE is the most common measurement used to estimate energy requirements in the nutritional context; the most accurate method of measuring REE is indirect calorimetry (IC). However, this method is costly and often rarely feasible in many clinical settings. The objective of the present study was to develop and validate a new equation for predicting REE in adults with overweight and obesity. | Clinical nutrition (Edinb.) 37 (2018): 2198-2205. | 2018 | PRINELLI FEDERICA | Energy expenditure, Predicted equation, Overweight, Obesity | 10.1016/j.clnu.2017.10.022 |
| 426353 | Articolo in rivista | Exploring the relationship between Nutrition, gUT microbiota, and BRain AgINg in community-dwelling seniors: the Italian NutBrain population-based cohort study protocol | Federica Prinelli, Nithiya Jesuthasan, Marco Severgnini, Massimo Musicco, Fulvio Adorni, Maria Lea Correa Leite, Chiara Crespi, Sara Bernini. | Background: Epidemiological evidence suggests that healthy diet is associated with a slowdown of cognitive decline leading to dementia, but the underlying mechanisms are still partially unexplored. Diet is the main determinant of gut microbiota composition, which in turn impacts on brain structures and functions, however to date no studies on this topic are available. The goal of the present paper is to describe the design and methodology of the NutBrain Study aimed at investigating the association of dietary habits with cognitive function and their role in modulating the gut microbiota composition, and brain measures as well. Methods/Design: This is a population-based cohort study of community-dwelling adults aged 65 years or more living in Northern Milan, Italy. At the point of presentation people are screened for cognitive functions. Socio-demographic characteristics along with lifestyles and dietary habits, medical history, drugs, functional status, and anthropometric measurements are also recorded. Individuals suspected to have cognitive impairment at the screening phase undergo a clinical evaluation including a neurological examination and a Magnetic Resonance Imaging (MRI) scanning (both structural and functional). Stool and blood samples for the gut microbiota analysis and for the evaluation of putative biological markers are also collected. For each subject with a confirmed diagnosis of Mild Cognitive Impairment (MCI), two cognitively intact controls of the same sex and age are visited. We intend to enrol at least 683 individuals for the screening phase and 240 persons for the clinical assessment. Discussion: The NutBrain is an innovative study that incorporates modern and advanced technologies (i.e. microbiome and neuroimaging) into traditional epidemiologic design. The study represents a unique opportunity to address key questions about the role of modifiable risk factors on cognitive impairment, with a particular focus on dietary habits and their association with gut microbiota and markers of the brain-aging process. These findings will help to encourage and plan lifestyle interventions, for both prevention and treatment, aiming at promoting healthy cognitive ageing. Trial Registration: Trial registration number NCT04461951, date of registration July 7, 2020 (retrospectively registered, ClinicalTrials.gov). | BMC geriatrics (Online) (2020). | 2020 | JESUTHASAN NITHIYA, SEVERGNINI MARCO, ADORNI FULVIO DANIELE, PRINELLI FEDERICA, CORREA LEITE MARIA LEA, MUSICCO MASSIMO | Cognitive Impairments, Dietary habits, Observational Study, Gut Microbiota, Brain measures, Gut-brain axis | 10.1186/s12877-020-01652-2 |
| 426737 | Articolo in rivista | The neurobiology of human aggressive behavior: Neuroimaging, genetic, and neurochemical aspects | Cupaioli F.A., Zucca F.A., Caporale C., Lesch K.P., Passamonti L., Zecca L. | In modern societies, there is a strive to improve the quality of life related to risk of crimes which inevitably requires a better understanding of brain determinants and mediators of aggression. Neurobiology provides powerful tools to achieve this end. Pre-clinical and clinical studies show that changes in regional volumes, metabolism-function and connectivity within specific neural networks are related to aggression. Subregions of prefrontal cortex, insula, amygdala, basal ganglia and hippocampus play a major role within these circuits and have been consistently implicated in biology of aggression. Genetic variations in proteins regulating the synthesis, degradation, and transport of serotonin and dopamine as well as their signal transduction have been found to mediate behavioral variability observed in aggression. Gene-gene and gene-environment interactions represent additional important risk factors for aggressiveness. Considering the social burden of pathological forms of aggression, more basic and translational studies should be conducted to accelerate applications to clinical practice, justice courts, and policy making. | Progress in neuro-psychopharmacology & biological psychiatry 106 (2021): 110059. | 2021 | ZECCA LUIGI, ZUCCA FABIO ANDREA, PASSAMONTI LUCA, CAPORALE CINZIA, CUPAIOLI FRANCESCA ANNA | aggression, imaging of aggressive brain, brain regions of aggression, dopamine and serotonin in aggression, genetics of aggression | 10.1016/j.pnpbp.2020.110059 |
| 425975 | Articolo in rivista | Identification of genetic polymorphisms modulating nausea and vomiting in two series of opioid-treated cancer patients | Colombo, Francesca, Pintarelli, Giulia, Galvan, Antonella, Noci, Sara, Corli, Oscar, Skorpen, Frank, Klepstad, Pal, Kaasa, Stein, Pigni, Alessandra, Brunelli, Cinzia, Roberto, Anna, Piazza, Rocco, Pirola, Alessandra, Gambacorti-Passerini, Carlo, Caraceni, Augusto Tommaso | Nausea and vomiting are often associated with opioid analgesia in cancer patients; however, only a subset of patients develop such side effects. Here, we tested the hypothesis that the occurrence of nausea and vomiting is modulated by the genetic background of the patients. Whole exome sequencing of DNA pools from patients with either low (n = 937) or high (n = 557) nausea and vomiting intensity, recruited in the European Pharmacogenetic Opioid Study, revealed a preliminary association of 53 polymorphisms. PCR-based genotyping of 45 of these polymorphisms in the individual patients of the same series confirmed the association for six SNPs in AIM1L, CLCC1, MUC16, PDE3A, POM121L2, and ZNF165 genes. Genotyping of the same 45 polymorphisms in 264 patients of the Italian CERP study, also treated with opioids for cancer pain, instead confirmed the association for two SNPs in ZNF568 and PDE3A genes. Only one SNP, rs12305038 in PDE3A, was confirmed in both series, although with opposite effects of the minor allele on the investigated phenotype. Overall, our findings suggest that genetic factors are indeed associated with nausea and vomiting in opioid-treated cancer patients, but the role of individual polymorphisms may be weak. | Scientific reports (Nature Publishing Group) 10 (2020). | 2020 | COLOMBO FRANCESCA | Pharmacogenomics, opioids, cancer pain | 10.1038/s41598-019-57358-y |
| 426822 | Articolo in rivista | Read-through transcripts in lung: germline genetic regulation and correlation with the expression of other genes | Maspero, Davide, Dassano, Alice, Pintarelli, Giulia, Noci, Sara, De Cecco, Loris, Incarbone, Matteo, Tosi, Davide, Santambrogio, Luigi, Dragani, Tommaso A., Colombo, Francesca | Transcripts originating from the transcriptional read through of two adjacent, similarly oriented genes have been identified in normal and neoplastic tissues, but their functional role and the mechanisms that regulate their expression are mostly unknown. Here, we investigated whether the expression of read-through transcripts previously identified in the non-involved lung tissue of lung adenocarcinoma patients was genetically regulated. Data on genome-wide single nucleotide variant genotypes and expression levels of 10 read-through transcripts in 201 samples of lung tissue were combined to identify expression quantitative trait loci (eQTLs). Then, to identify genes whose expression levels correlated with the 10 read-through transcripts, we used whole transcriptome profiles available for 154 patients. For 8 read-though transcripts, we identified 60 eQTLs (false discovery rate <0.05), including 17 cis-eQTLs and 43 trans-eQTLs. These eQTLs did not maintain their behavior on the 'parental' genes involved in the read-through transcriptional event. The expression levels of 7 read-through transcripts were found to correlate with the expression of other genes: CHIA-PIFO and CTSC-RAB38 correlated with CHIA and RAB38, respectively, while 5 other read-through transcripts correlated with 43 unique non-parental transcripts; thus offering indications about the molecular processes in which these chimeric transcripts may be involved. We confirmed 9 eQTLs (for 4 transcripts) in the non-involved lung tissue from an independent series of 188 lung adenocarcinoma patients. Therefore, this study indicates that the expression of four read-through transcripts in normal lung tissue is under germline genetic regulation, and that this regulation is independent of that of the genes involved in the read-through event. | Carcinogenesis (N.Y., Print) 41 (2020): 918-926. | 2020 | MASPERO DAVIDE, COLOMBO FRANCESCA | Conjoned genes, Lung adenocarcinoma, gene expression regulation, quantitative trait loci | 10.1093/carcin/bgaa020 |
| 426837 | Articolo in rivista | Cigarette smoke alters the transcriptome of non-involved lung tissue in lung adenocarcinoma patients | Pintarelli, Giulia, Noci, Sara, Maspero, Davide, Pettinicchio, Angela, Dugo, Matteo, De Cecco, Loris, Incarbone, Matteo, Tosi, Davide, Santambrogio, Luigi, Dragani, Tommaso A., Colombo, Francesca | Alterations in the gene expression of organs in contact with the environment may signal exposure to toxins. To identify genes in lung tissue whose expression levels are altered by cigarette smoking, we compared the transcriptomes of lung tissue between 118 ever smokers and 58 never smokers. In all cases, the tissue studied was non-involved lung tissue obtained at lobectomy from patients with lung adenocarcinoma. Of the 17,097 genes analyzed, 357 were differentially expressed between ever smokers and never smokers (FDR < 0.05), including 290 genes that were up-regulated and 67 down-regulated in ever smokers. For 85 genes, the absolute value of the fold change was >=2. The gene with the smallest FDR was MYO1A (FDR = 6.9 x 10) while the gene with the largest difference between groups was FGG (fold change = 31.60). Overall, 100 of the genes identified in this study (38.6%) had previously been found to associate with smoking in at least one of four previously reported datasets of non-involved lung tissue. Seven genes (KMO, CD1A, SPINK5, TREM2, CYBB, DNASE2B, FGG) were differentially expressed between ever and never smokers in all five datasets, with concordant higher expression in ever smokers. Smoking-induced up-regulation of six of these genes was also observed in a transcription dataset from lung tissue of non-cancer patients. Among the three most significant gene networks, two are involved in immunity and inflammation and one in cell death. Overall, this study shows that the lung parenchyma transcriptome of smokers has altered gene expression and that these alterations are reproducible in different series of smokers across countries. Moreover, this study identified a seven-gene panel that reflects lung tissue exposure to cigarette smoke. | Scientific reports (Nature Publishing Group) 9 (2019). | 2019 | MASPERO DAVIDE, COLOMBO FRANCESCA | gene expression, tobacco, lung parenchyma, inflammation | 10.1038/s41598-019-49648-2 |
| 426876 | Articolo in rivista | Malignant mesothelioma diagnosed at a younger age is associated with heavier asbestos exposure | Dragani, Tommaso A., Colombo, Francesca, Pavlisko, Elizabeth N., Roggli, Victor L. | Asbestos exposure is the main etiology of malignant mesothelioma, but there are conflicting data on whether the intensity of exposure modulates the development of this disease. This study considered 594 patients with malignant mesothelioma for whom count data on asbestos bodies and fibers (per gram of wet lung tissue) were available. The relationships between age at diagnosis (a time-to-event outcome variable) and these two measures of internal asbestos exposure, along with other possible modulating factors (sex, tumor location, histological subtype and childhood exposure), were assessed on multivariable Cox proportional hazard models, stratifying by decade of birth year. For both measures of asbestos in lung tissue, younger age at diagnosis was associated with higher internal measures of exposure to asbestos. Stratified Cox analyses showed that for each doubling in asbestos body count patients were 1.07 times more likely to be diagnosed at a younger age [hazard ratio (HR) = 1.07; 95% confidence interval (CI), 1.04-1.09; P = 2.2 x 10 ] and for each doubling in asbestos fiber count patients were 1.13 times more likely to be diagnosed at a younger age (HR = 1.13; 95% CI, 1.09-1.17; P = 8.6 x 10 ). None of the other variables considered were associated with age at diagnosis. Our finding that tumors become clinically apparent at a younger age in heavily exposed subjects suggests that asbestos is involved not only in the malignant mesothelioma tumor initiation but, somehow, also in the progression of the disease. | Carcinogenesis (N.Y., Print) 39 (2018): 1151-1156. | 2018 | COLOMBO FRANCESCA | age at diagnosis, pleural malignant mesothelioma, asbestos exposure | 10.1093/carcin/bgy089 |
| 426885 | Articolo in rivista | Pharmacogenetic study of seven polymorphisms in three nicotinic acetylcholine receptor subunits in smoking-cessation therapies | Pintarelli, Giulia, Galvan, Antonella, Pozzi, Paolo, Noci, Sara, Pasetti, Giovanna, Sala, Francesca, Pastorino, Ugo, Boffi, Roberto, Colombo, Francesca | Smoking-cessation therapy reduces the risk of smoking-related diseases, but is successful only in a fraction of smokers. There is growing evidence that genetic variations in nicotinic acetylcholine receptor (nAChR) subunits influence the risk of nicotine dependence and the ability to quit smoking. To investigate the role of polymorphisms in nAChR genes on smoking quantity and the outcome of smoking-cessation therapies, we carried out an association study on 337 smokers who underwent pharmacotherapy with varenicline, bupropion, nicotine replacement therapy (NRT) alone, or NRT plus bupropion. Smoking habit and abstention were assessed from the number of cigarettes smoked per day (CPD) and the exhaled CO (eCO), at baseline and up to 12 months. We genotyped seven polymorphisms in genes encoding the nAChR subunits CHRNA4, CHRNA5, and CHRNB2. At baseline, both CPD and eCO were associated with polymorphisms in the CHRNA5 locus (rs503464, rs55853698, rs55781567 and rs16969968; P < 0.01). rs503464, a variant in the 5?-UTR of CHRNA5, was also associated with short-, mid- A nd long-term responses to therapy (P = 0.011, P = 0.0043, P = 0.020, respectively), although after correction for multiple testing only the association at the mid-term assessment remained significant (FDR = 0.03). These data support the role of individual genetic makeup in the ability to quit smoking. | Scientific reports (Nature Publishing Group) 7 (2017). | 2017 | COLOMBO FRANCESCA | nicotinic acetylcholine receptors, SNP, varenicline, bupropion, nicotine replacement therapy, cigarette smoke, therapy response, genetics | 10.1038/s41598-017-16946-6 |
| 426886 | Articolo in rivista | Complex genetic control of lung tumorigenesis in resistant mice strains | Dassano, Alice, Pintarelli, Giulia, Cotroneo, Chiara E., Pettinicchio, Angela, Forcati, Elena, De Cecco, Loris, Borrego, Andrea, Colombo, Francesca, Dragani, Tommaso A., Manenti, Giacomo | The SM/J mouse strain is resistant to chemically-induced lung tumorigenesis despite having a haplotype, in the pulmonary adenoma susceptibility locus (Pas1) locus, that confers tumor susceptibility in other strains. To clarify this inconsistent genotype-phenotype correlation, we crossed SM/J mice with another resistant strain and conducted genome-wide linkage analysis in the (C57BL/6J x SM/J)F2 progeny exposed to urethane to induce lung tumors. Overall, >80% of F2 mice of both sexes developed from 1 to 20 lung tumors. Genotyping of 372 F2 mice for 744 informative non-redundant SNPs dispersed over all autosomal chromosomes revealed four quantitative trait loci (QTLs) affecting lung tumor multiplicity, on chromosomes 3 (near rs13477379), 15 (rs6285067), 17 (rs33373629) and 18 (rs3706601), all with logarithm of the odds (LOD) scores >5. Four QTLs modulated total lung tumor volume, on chromosome 3 (rs13477379), 10 (rs13480702), 15 (rs6285067) and 17 (rs3682923), all with LOD scores >4. No QTL modulating lung tumor multiplicity or total volume was detected in Pas1 on chromosome 6. The present study demonstrates that the SM/J strain carries, at the Pas1 locus, the resistance allele: a finding that will facilitate identification of the Pas1 causal element. More generally, it demonstrates that lung tumorigenesis is under complex polygenic control even in a pedigree with low susceptibility to this neoplasia, suggesting that the genetics of lung tumorigenesis is much more complex than evidenced by the pulmonary adenoma susceptibility and resistance loci that have, so far, been mapped in a small number of crosses between a few inbred strains. | Cancer science 108 (2017): 2281-2286. | 2017 | COLOMBO FRANCESCA | Genetic linkage, genetic loci, lung cancer, Pas1, quantitative trait loci | 10.1111/cas.13349 |
| 426888 | Articolo in rivista | Association of an aurora kinase a (AURKA) gene polymorphism with progression-free survival in patients with advanced urothelial carcinoma treated with the selective aurora kinase a inhibitor alisertib | Necchi, Andrea, Pintarelli, Giulia, Raggi, Daniele, Giannatempo, Patrizia, Colombo, Francesca | Background and purpose Salvage therapies for urothelial carcinoma are needed. A single-arm trial in patients with advanced or metastatic urothelial carcinoma refractive to other therapies found that alisertib, a selective inhibitor of aurora kinase A, maintained stable disease in a few cases, despite a low objective response rate. To better understand why some patients benefited from alisertib, we genotyped the 22 patients of this pilot trial for two single nucleotide polymorphisms (rs2273535 and rs1047972) in AURKA, the gene encoding aurora kinase A, and looked for associations with survival and treatment response. Results Carrier status for the minor allele of rs2273535 (T91A, p. F31I) was a favorable prognostic factor for progression-free survival (HR = 0.18; 95% CI, 0.039-0.81; P = 0.026) but not for overall survival (HR = 0.88; 95% CI, 0.26-2.9; P = 0.83). These results were confirmed in multivariable analyses, adjusting for sex, age and hemoglobin, for both progression-free survival (HR = 0.11; 95% CI, 0.018-0.69; P = 0.018) and overall survival. No association was found between rs1047972 and survival. Moreover, neither SNP was associated with treatment response. Conclusion In patients who received alisertib for advanced or metastatic urothelial carcinoma, longer progression-free survival was observed in carriers of the minor allele A of rs2273535 in AURKA than in patients who were homozygous for the major allele T. This finding, based on a small pilot trial, warrants further investigation. | Investigational new drugs (Print) 35 (2017): 524-528. | 2017 | COLOMBO FRANCESCA | Bladder cancer, MLN8237, NCT02109328, Serine/threonine kinase | 10.1007/s10637-017-0440-5 |
| 426891 | Articolo in rivista | Genetic susceptibility variants for lung cancer: Replication study and assessment as expression quantitative trait loci | Pintarelli, Giulia, Cotroneo, Chiara Elisabetta, Noci, Sara, Dugo, Matteo, Galvan, Antonella, Delli Carpini, Simona, Citterio, Lorena, Manunta, Paolo, Incarbone, Matteo, Tosi, Davide, Santambrogio, Luigi, Dragani, Tommaso A., Colombo, Francesca | Many single nucleotide polymorphisms (SNPs) have been associated with lung cancer but lack confirmation and functional characterization. We retested the association of 56 candidate SNPs with lung adenocarcinoma risk and overall survival in a cohort of 823 Italian patients and 779 healthy controls, and assessed their function as expression quantitative trait loci (eQTLs). In the replication study, eight SNPs (rs401681, rs3019885, rs732765, rs2568494, rs16969968, rs6495309, rs11634351, and rs4105144) associated with lung adenocarcinoma risk and three (rs9557635, rs4105144, and rs735482) associated with survival. Five of these SNPs acted as cis-eQTLs, being associated with the transcription of IREB2 (rs2568494, rs16969968, rs11634351, rs6495309), PSMA4 (rs6495309) and ERCC1 (rs735482), out of 10,821 genes analyzed in lung. For these three genes, we obtained experimental evidence of differential allelic expression in lung tissue, pointing to the existence of in-cis genomic variants that regulate their transcription. These results suggest that these SNPs exert their effects on cancer risk/outcome through the modulation of mRNA levels of their target genes. | Scientific reports (Nature Publishing Group) 7 (2017). | 2017 | COLOMBO FRANCESCA | lung adenocarcinoma risk, survival, SNP, differential allelic expression | 10.1038/srep42185 |
| 426893 | Articolo in rivista | Human lung tissue transcriptome: Influence of sex and age | Dugo, Matteo, Cotroneo, Chiara E., Lavoie-Charland, Emilie, Incarbone, Matteo, Santambrogio, Luigi, Rosso, Lorenzo, Van Den Berge, Maarten, Nickle, David, Pare, Peter D., Bosse, Yohan, Dragani, Tommaso A., Colombo, Francesca | Background: Sex and age strongly influence the pathophysiology of human lungs, but scarce information is available about their effects on pulmonary gene expression. Methods: We followed a discovery-validation strategy to identify sex- and age-related transcriptional differences in lung. Results: We identified transcriptional profiles significantly associated with sex (215 genes; FDR < 0.05) and age at surgery (217 genes) in non-involved lung tissue resected from 284 lung adenocarcinoma patients. When these profiles were tested in three independent series of non-tumor lung tissue from an additional 1,111 patients, we validated the association with sex and age for 25 and 22 genes, respectively. Among the 17 sex-biased genes mapping on chromosome X, 16 have been reported to escape X-chromosome inactivation in other tissues or cells, suggesting that this mechanism influences lung transcription too. Our 22 agerelated genes partially overlap with genes modulated by age in other tissues, suggesting that the aging process has similar consequences on gene expression in different organs. Finally, seven genes whose expression was modulated by sex in non-tumor lung tissue, but no age-related gene, were also validated using publicly available data from 990 lung adenocarcinoma samples, suggesting that the physiological regulatory mechanisms are only partially active in neoplastic tissue. Conclusions: Gene expression in non-tumor lung tissue is modulated by both sex and age. These findings represent a validated starting point for research on the molecular mechanisms underlying the observed differences in the course of lung diseases among men and women of different ages. | PloS one 11 (2016). | 2016 | COLOMBO FRANCESCA | gene expression, lung parenchyma, sex, age, inflammation | 10.1371/journal.pone.0167460 |
| 426898 | Articolo in rivista | Expression quantitative trait analysis reveals fine germline transcript regulation in mouse lung tumors | Cotroneo, Chiara E., Dassano, Alice, Colombo, Francesca, Pettinicchio, Angela, Lecis, Daniele, Dugo, Matteo, De Cecco, Loris, Dragani, Tommaso A., Manenti, Giacomo | Gene expression modulates cellular functions in both physiologic and pathologic conditions. Herein, we carried out a genetic linkage study on the transcriptome of lung tumors induced by urethane in an (A/J x C57BL/6)F4 intercross population, whose individual lung tumor multiplicity (Nlung) is linked to the genotype at the Pulmonary adenoma susceptibility 1 (Pas1) locus. We found that expression levels of 1179 and 1579 genes are modulated by an expression quantitative trait locus (eQTL) in cis and in trans, respectively (LOD score > 5). Of note, the genomic area surrounding and including the Pas1 locus regulated 14 genes in cis and 857 genes in trans. In lung tumors of the same (A/J x C57BL/6)F4 mice, we found 1124 genes whose transcript levels associated with Nlung (FDR < 0.001). The expression levels of about a third of these genes (n = 401) were regulated by the genotype at the Pas1 locus. Pathway analysis of the sets of genes associated with Nlung and regulated by Pas1 revealed a set of 14 recurrently represented genes that are components or targets of the Ras-Erk and Pi3k-Akt signaling pathways. Altogether our results illustrate the architecture of germline control of gene expression in mouse lung cancer: they highlight the importance of Pas1 as a tumor-modifier locus, attribute to it a novel role as a major regulator of transcription in lung tumor nodules and strengthen the candidacy of the Kras gene as the effector of this locus. | Cancer letters (Print) 375 (2016): 221-230. | 2016 | COLOMBO FRANCESCA | Animal models, Expression quantitative trait loci, Gene expression, Lung cancer, Pas1, Transcriptome | 10.1016/j.canlet.2016.02.054 |
| 426899 | Articolo in rivista | Read-through transcripts in normal human lung parenchyma are down-regulated in lung adenocarcinoma | Pintarelli, Giulia, Dassano, Alice, Cotroneo, Chiara E., Galvan, Antonella, Noci, S. Sara, Piazza, Rocco, Pirola, Alessandra, Spinelli, Roberta, Incarbone, Matteo, Palleschi, A. Alessandro, Rosso, Lorenzo, Santambrogio, Luigi, Dragani, Tommaso A., Colombo, Francesca | Read-through transcripts result from the continuous transcription of adjacent, similarly oriented genes, with the splicing out of the intergenic region. They have been found in several neoplastic and normal tissues, but their pathophysiological significance is unclear. We used high-throughput sequencing of cDNA fragments (RNA-Seq) to identify read-through transcripts in the non-involved lung tissue of 64 surgically treated lung adenocarcinoma patients. A total of 52 distinct read-through species was identified, with 24 patients having at least one read-through event, up to a maximum of 17 such transcripts in one patient. Sanger sequencing validated 28 of these transcripts and identified an additional 15, for a total of 43 distinct read-through events involving 35 gene pairs. Expression levels of 10 validated read-through transcripts were measured by quantitative PCR in pairs of matched non-involved lung tissue and lung adenocarcinoma tissue from 45 patients. Higher expression levels were observed in normal lung tissue than in the tumor counterpart, with median relative quantification ratios between normal and tumor varying from 1.90 to 7.78; the difference was statistically significant (P < 0.001, Wilcoxon's signed-rank test for paired samples) for eight transcripts: ELAVL1-TIMM44, FAM162B-ZUFSP, IFNAR2-IL10RB, INMT-FAM188B, KIAA1841-C2orf74, NFATC3-PLA2G15, SIRPB1-SIRPD, and SHANK3-ACR. This report documents the presence of read-through transcripts in apparently normal lung tissue, with inter-individual differences in patterns and abundance. It also shows their down-regulation in tumors, suggesting that these chimeric transcripts may function as tumor suppressors in lung tissue. | Oncotarget 7 (2016): 27889-27898. | 2016 | COLOMBO FRANCESCA | Conjoined genes, Gene fusion, Lung adenocarcinoma, Read-through transcripts, RNA-Seq | 10.18632/oncotarget.8556 |
| 427315 | Articolo in rivista | Gcn5p and Ubp8p Affect Protein Ubiquitylation and Cell Proliferation by Altering the Fermentative/Respiratory Flux Balance in Saccharomyces cerevisiae | Antonella De Palma, Giulia Fanelli, Elisabetta Cretella, Veronica De Luca, Raffaele Antonio Palladino, Valentina Panzeri, Valentina Roffia, Michele Saliola, Pierluigi Mauri, Patrizia Filetici | Protein ubiquitylation regulates not only endocellular trafficking and proteasomal degradation but also the catalytic activity of enzymes. In Saccharomyces cerevisiae, we analyzed the composition of the ubiquitylated proteomes in strains lacking acetyltransferase Gcn5p, Ub-protease Ubp8p, or both to understand their involvement in the regulation of protein ubiquitylation. We analyzed His6Ub proteins with a proteomic approach coupling micro-liquid chromatography and tandem mass spectrometry (LC-MS/MS) in gcn5?, ubp8? and ubp8? gcn5? strains. The Ub-proteome altered in the absence of Gcn5p, Ubp8p, or both was characterized, showing that 43% of the proteins was shared in all strains, suggesting their functional relationship. Remarkably, all major glycolytic enzymes showed increased ubiquitylation. Phosphofructokinase 1, the key enzyme of glycolytic flux, showed a higher and altered pattern of ubiquitylation in gcn5? and ubp8? strains. Severe defects of growth in poor sugar and altered glucose consumption confirmed a direct role of Gcn5p and Ubp8p in affecting the REDOX balance of the cell. IMPORTANCE We propose a study showing a novel role of Gcn5p and Ubp8p in the process of ubiquitylation of the yeast proteome which includes main glycolytic enzymes. Interestingly, in the absence of Gcn5p and Ubp8p glucose consumption and redox balance were altered in yeast. We believe that these results and the role of Gcn5p and Ubp8p in sugar metabolism might open new perspectives of research leading to novel protocols for counteracting the enhanced glycolysis in tumors. | MBio 11 (2020): 1-16. | 2020 | FILETICI PATRIZIA, DE PALMA ANTONELLA, MAURI PIETRO LUIGI | ubiquitylation, Gcn5p, Ubp8p, glycolytic flux, sugar utilization | 10.1128/mBio.01504-20 |
| 427615 | Articolo in rivista | Syndecan-1-Dependent Regulation of Heparanase Affects Invasiveness, Stem Cell Properties, and Therapeutic Resistance of Caco2 Colon Cancer Cells | Sampath Kumar Katakam, Paride Pelucchi, Cinzia Cocola, Rolland Reinbold, Israel Vlodavsky, Burkhard Greve, Martin Gotte . | The heparan sulfate proteoglycan Syndecan-1 binds cytokines, morphogens and extracellular matrix components, regulating cancer stem cell properties and invasiveness. Syndecan-1 is modulated by the heparan sulfate-degrading enzyme heparanase, but the underlying regulatory mechanisms are only poorly understood. In colon cancer pathogenesis, complex changes occur in the expression pattern of Syndecan-1 and heparanase during progression from well-differentiated to undifferentiated tumors. Loss of Syndecan-1 and increased expression of heparanase are associated with a change in phenotypic plasticity and an increase in invasiveness, metastasis and dedifferentiation. Here we investigated the regulatory and functional interplay of Syndecan-1 and heparanase employing siRNA-mediated silencing and plasmid-based overexpression approaches in the human colon cancer cell line Caco2. Heparanase expression and activity were upregulated in Syndecan-1 depleted cells. This increase was linked to an upregulation of the transcription factor Egr1, which regulates heparanase at the promoter level. Inhibitor experiments demonstrated an impact of focal adhesion kinase, Wnt and ROCK-dependent signaling on this process. siRNA-depletion of Syndecan-1, and upregulation of heparanase increased the colon cancer stem cell phenotype based on sphere formation assays and phenotypic marker analysis (Side-population, NANOG, KLF4, NOTCH, Wnt, and TCF4 expression). Syndecan-1 depletion increased invasiveness of Caco2 cells in vitro in a heparanase-dependent manner. Finally, upregulated expression of heparanase resulted in increased resistance to radiotherapy, whereas high expression of enzymatically inactive heparanase promoted chemoresistance to paclitaxel and cisplatin. Our findings provide a new avenue to target a stemness-associated signaling axis as a therapeutic strategy to reduce metastatic spread and cancer recurrence. | Frontiers in oncology (2020). | 2020 | COCOLA CINZIA, PELUCCHI PARIDE, REINBOLD ROLLAND ALVONS | cancer stem cells; colon cancer; heparan sulfate; heparanase; proteoglycan; syndecan. | 10.3389/fonc.2020.00774. eCollection 2020. |
| 408178 | Articolo in rivista | Methionine oxidation in ?-synuclein inhibits its propensity for ordered secondary structure | Ponzini E, De Palma A, Cerboni L, Natalello A, Rossi R, Moons R, Konijnenberg A, Narkiewicz J, Legname G, Sobott F, Mauri P, Santambrogio C, Grandori R. | ?-Synuclein (AS) is an intrinsically disordered protein highly expressed in dopaminergic neurons. Its amyloid aggregates are the major component of Lewy bodies, a hallmark of Parkinson's disease (PD). AS is particularly exposed to oxidation of its methionine residues, both in vivo and in vitro Oxidative stress has been implicated in PD and oxidized ?-synuclein has been shown to assemble into soluble, toxic oligomers, rather than amyloid fibrils. However, the structural effects of methionine oxidation are still poorly understood. In this work, oxidized AS was obtained by prolonged incubations with dopamine (DA) or epigallocatechin-3-gallate (EGCG), two inhibitors of AS aggregation, indicating that EGCG promotes the same final oxidation product as DA. The conformational transitions of the oxidized and non-oxidized protein were monitored by complementary biophysical techniques, including MS, ion mobility (IM), CD, and FTIR spectroscopy assays. Although the two variants displayed very similar structures under conditions that stabilize highly disordered or highly ordered states, differences emerged in the intermediate points of transitions induced by organic solvents, such as trifluoroethanol (TFE) and methanol (MeOH), indicating a lower propensity of the oxidized protein for forming either ?- or ?-type secondary structures. Furthermore, oxidized AS displayed restricted secondary-structure transitions in response to dehydration and slightly amplified tertiary-structure transitions induced by ligand binding. This difference in susceptibility to induced folding could explain the loss of fibrillation potential observed for oxidized AS. Finally, site-specific oxidation kinetics point out a minor delay in Met-127 modification, likely due to the effects of AS intrinsic structure. | Journal of biological chemistry (Online) 294 (2019): 5657-5665. | 2019 | ROSSI ROSSANA, DE PALMA ANTONELLA, MAURI PIETRO LUIGI | Fourier transform IR (FTIR); amyloid; circular dichroism (CD); dopamine; epigallocatechin-3-gallate; ion mobility (IM); mass spectrometry (MS); methionine oxidation; neurodegenerative disease; ?-synuclein (?-synuclein) | 10.1074/jbc.RA118.001907 |
| 431650 | Articolo in rivista | BL1391: an established cell line from a human malignant peripheral nerve sheath tumor with unique genomic features | Tolomeo, Doron, Agostini, Antonio, Macchia, Gemma, L'Abbate, Alberto, Severgnini, Marco, Cifola, Ingrid, Frassanito, Maria Antonia, Racanelli, Vito, Solimando, Antonio Giovanni, Haglund, Felix, Mertens, Fredrik, Storlazzi, Clelia Tiziana | Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive tumors, accounting for around 5% of all soft tissue sarcomas. A better understanding of the pathogenesis of these tumors and the development of effective treatments are needed. In this context, established tumor cell lines can be very informative, as they may be used for in-depth molecular analyses and improvement of treatment strategies. Here, we present the genomic and transcriptomic profiling analysis of a MPNST cell line (BL1391) that was spontaneously established in our laboratory from a primary tumor that had not been exposed to genotoxic treatment. This cell line shows peculiar genetic features, such as a large marker chromosome composed of high-copy number amplifications of regions from chromosomes 1 and 11 with an embedded neocentromere. Moreover, the transcriptome profiling revealed the presence of several fusion transcripts involving the CACHD1, TNMA4, MDM4, and YAP1 genes, all of which map to the amplified regions of the marker. BL1391 could be a useful tool to study genomic amplifications and neocentromere seeding in MPNSTs and to develop new therapeutic strategies. | Human cell 34 (2021): 238-245. | 2021 | CIFOLA INGRID, SEVERGNINI MARCO | Amplification, BL1391, Fusion transcript, MPNST, Neocentromere | 10.1007/s13577-020-00418-7 |
| 408507 | Contributo in volume | Investigating the Role of MicroRNA and Transcription Factor Co-regulatory Networks in Multiple Sclerosis Pathogenesis | Nicoletta Nuzziello, Laura Vilardo, Paride Pelucchi, Arianna Consiglio, Sabino Liuni, Maria Trojano, Maria Liguori | MicroRNAs (miRNAs) and transcription factors (TFs) play key roles in complex multifactorial diseases like multiple sclerosis (MS). Starting from the miRNomic profile previously associated with a co- hort of pediatric MS (PedMS) patients, we applied a combined mo- lecular and computational approach in order to verify published data in patients with adult-onset MS (AOMS). Six out of the 13 selected miRNAs (miR-320a, miR-125a-5p, miR-652-3p, miR-185-5p, miR- 942-5p, miR-25-3p) were significantly upregulated in PedMS and AOMS patients, suggesting that they may be considered circulating biomarkers distinctive of the disease independently from age. A com- putational and unbiased miRNA-based screening of target genes not necessarily associated to MS was then performed in order to provide an extensive view of the genetic mechanisms underlying the disease. A comprehensive MS-specific miRNA-TF co-regulatory network was hypothesized; among others, SP1, RELA, NF-?B, TP53, AR, MYC, HDAC1, and STAT3 regulated the transcription of 61 targets. Inter- estingly, NF-?B and STAT3 cooperatively regulate the expression of immune response genes and control the cross-talk between inflam- matory and immune cells. Further functional analysis will be per- formed on the identified critical hubs. Above all, in our view, this ap- proach supports the need of multidisciplinary strategies for shedding light into the pathogenesis of MS. | Top 5 Contributions in Molecular Sciences: 2nd Edition, 2019 | 2019 | VILARDO LAURA, NUZZIELLO NICOLETTA, LIGUORI MARIA, PELUCCHI PARIDE, LIUNI SABINO, CONSIGLIO ARIANNA | Multiple Sclerosis; miRNAs; Transcription Factors; Target Genes; Bioinformatics; Circulating Biomarkers; Pathogenesis | 10.29290/TCMOLSC.2.3.2019.2-35 |
| 431702 | Contributo in atti di convegno | A Predictive Model for MicroRNA Expressions in Pediatric Multiple Sclerosis Detection | Casalino G., Castellano G., Consiglio A., Liguori M., Nuzziello N., Primiceri D. | MicroRNAs (miRNAs) are a set of short non coding RNAs that play significant regulatory roles in cells. The study of miRNA data can be of valuable support for the early diagnosis of multifactorial diseases such as pediatric Multiple Sclerosis. However the analysis of miRNA expressions poses several challenges due to high dimensionality and imbalance of data. In this paper we present a data science workflow to develop a predictive model that is intended to support the clinicians in the diagnosis of Multiple Sclerosis starting from miRNA data produced by Next-Generation Sequencing. The goal is to create an effective model able to predict the pathological condition of a patient starting from his miRNA expression profile. Based on the proposed workflow, the miRNA dataset is firstly preprocessed in order to reduce its high dimensionality (from 1287 features to 40 features) and to mitigate class imbalance. Then a classification model is learnt from data via neural network training. Results show that the model defined by using the 40 data-driven selected features achieves an overall classification accuracy of 94% on test data and overcomes the model based on 42 features selected by the experts that achieves only 83% of overall accuracy. | MDAI 2019: Modeling Decisions for Artificial Intelligence, pp. 177-188, 4-6/09/2019 | 2019 | NUZZIELLO NICOLETTA, LIGUORI MARIA, CONSIGLIO ARIANNA | microRNA expression, Next-Generation Sequencing, Pediatric Multiple Sclerosis, Feature selection, Artificial neural networks, Classification | 10.1007/978-3-030-26773-5_16 |
| 431720 | Articolo in rivista | Faecal microbiota transplantation for the treatment of diarrhoea induced by tyrosine-kinase inhibitors in patients with metastatic renal cell carcinoma | Ianiro G., Rossi E., Thomas A.M., Schinzari G., Masucci L., Quaranta G., Settanni C.R., Lopetuso L.R., Armanini F., Blanco-Miguez A., Asnicar F., Consolandi C., Iacovelli R., Sanguinetti M., Tortora G., Gasbarrini A., Segata N., Cammarota G. | Diarrhoea is one of the most burdensome and common adverse events of chemotherapeutics, and has no standardised therapy to date. Increasing evidence suggests that the gut microbiome can influence the development of chemotherapy-induced diarrhoea. Here we report findings from a randomised clinical trial of faecal microbiota transplantation (FMT) to treat diarrhoea induced by tyrosine kinase inhibitors (TKI) in patients with metastatic renal cell carcinoma (ClinicalTrials.gov number: NCT04040712). The primary outcome is the resolution of diarrhoea four weeks after the end of treatments. Twenty patients are randomised to receive FMT from healthy donors or placebo FMT (vehicle only). Donor FMT is more effective than placebo FMT in treating TKI-induced diarrhoea, and a successful engraftment is observed in subjects receiving donor faeces. No serious adverse events are observed in both treatment arms. The trial meets pre-specified endpoints. Our findings suggest that the therapeutic manipulation of gut microbiota may become a promising treatment option to manage TKI-dependent diarrhoea. | Nature communications 11 (2020). | 2020 | CONSOLANDI CLARISSA | Metagenomics | 10.1038/s41467-020-18127-y |
| 431121 | Articolo in rivista | Exercise prescription for health: Italian perspective. Italian guidelines for exercise prescription in healthy adults (18-65 years) | Porcelli, Simone, Bianchi, Giovanni A., Agnello, Luca, Manferdelli, Giorgio, Mastropietro, Alfonso, Pigozzi, Fabio, Casasco, Maurizio | Exercise prescription has been widely deepened and discussed by National and International Organizations. Lack of physical activity has been demonstrated to be associated to premature all causes mortality and chronic diseases. Although developing an active lifestyle is one of the most effective preventive treatment for chronic diseases, more than 25% of adults doesn't match the current guidelines about physical exercise around the world. The existing guidelines suggest the practice of moderate-intensity physical activity in combination with muscle-strengthening and flexibility exercises; none of them takes into consideration sedentariness and the amount of exercise performed during everyday-life activities. The aim of this article is to guide clinicians in exercise prescription by reviewing current international guidelines and introducing the new concept of "corrections factors": the amount of sedentary time is converted in more minutes of physical exercise; daily-life activities (e.g. steps) lessen the amount of time a person should perform physical exercise. These guidelines are currently under review to be utilized by Italian Health system as fundamental reference for exercise prescription. | Medicina dello sport (Testo stamp.) 73 (2020): 140-164. | 2020 | PORCELLI SIMONE, MASTROPIETRO ALFONSO | Guidelines, Exercise, Health promotion, Italy | 10.23736/S0025-7826.20.03689-3 |
| 431732 | Articolo in rivista | Orthonormal balances as a means of characterizing dietary exposure | Leite, Maria Lea Correa | Evaluating the effect of nutritional components on health outcomes is hampered by technical difficulties that are closely related to the compositional nature of dietary data. Compositional data consist of parts of a whole and, on the basis of the assumption that any relevant information they provide is contained in the ratios between them, procedures based on log-ratio transformations have been proposed for their analysis. It has been previously suggested that nutrient compositions can be analyzed using isometric log-ratio transformations which allow the compositions to be represented by a system of orthogonal coordinates corresponding to the log-contrasts between the compositional parts. One particular expression of these contrasts is called balances, and the aim of this note is to provide a step-by-step description of how to construct orthonormal balances and show how they can be applied to dietary data by means of an example based on data coming from an Italian population-based study. Nutrient balances are new variables that can be included as covariates in regression models. After fitting a linear regression model using estimates of relative fat mass as a response variable, scores indicating the obesogenic potential of foods can be defined on the basis of their nutritional contents and the estimated effect of the balances on relative fat mass. This approach to evaluating the relationship between diet and health outcomes provides insights into the roles of specific nutrient ratios and foods within a comprehensive and integrated framework that complies with the essentially compositional nature of dietary data. | Nutrition research (NY. N.Y.) 81 (2020): 90-96. | 2020 | CORREA LEITE MARIA LEA | Compositional data, Diet, Isometric log-ratios, Methods, Nutrient ratios, Obesity | 10.1016/j.nutres.2020.06.016 |
| 431749 | Articolo in rivista | The association between influenza and pneumococcal vaccinations and sars-cov-2 infection: Data from the epicovid19 web-based survey | Noale, Marianna, Trevisan, Caterina, Maggi, Stefania, Incalzi, Raffaele Antonelli, Pedone, Claudio, Di Bari, Mauro, Adorni, Fulvio, Jesuthasan, Nithiya, Sojic, Aleksandra, Galli, Massimo, Giacomelli, Andrea, Molinaro, Sabrina, Bianchi, Fabrizio, Mastroianni, Claudio, Prinelli, Federica | The present study aims to evaluate whether influenza and pneumococcal vaccinations are associated with positive nasopharyngeal swab (NPS) testing to detect SARS-CoV-2. Data from the Italian cross-sectional web-based survey (EPICOVID19), based on a self-selection sample of individuals aged >=18, were considered. The probability of a positive SARS-CoV-2 NPS test result as a function of influenza or anti-pneumococcal vaccination was evaluated using multivariable logistic regression, stratifying analysis by age (<65 years, >=65 years). From April 2020, 170,731 individuals aged <65 years and 28,097 >=65 years filled out the EPICOVID19 questionnaire. Influenza and anti-pneumococcal vaccinations were received, respectively, by 16% and 2% of those <65 years, and by 53% and 13% of those >=65 years. SARS-CoV-2 NPS testing was reported by 6680 participants. Anti-pneumococcal and influenza vaccinations were associated with a decreased probability of a SARS-CoV-2 NPS positive test in the younger participants (OR = 0.61, 95% CI 0.41-0.91; OR = 0.85, 95%CI 0.74-0.98; respectively). A significantly lower probability of a positive test result was detected in the individuals >=65 years who received anti-pneumococcal vaccination (OR = 0.56, 95%CI 0.33-0.95). These results need to be confirmed by further investigations, but they are relevant given the probable coexistence of influenza, bacterial infections, and COVID-19 over the coming autumn-winter season. | Vaccines (Basel) 8 (2020): 1-12. | 2020 | JESUTHASAN NITHIYA, SOJIC ALEKSANDRA, MAGGI STEFANIA, NOALE MARIANNA, MOLINARO SABRINA, ADORNI FULVIO DANIELE, PRINELLI FEDERICA, BIANCHI FABRIZIO | COVID-19, Influenza vaccination, Nasopharyngeal swab testing, Pneumococcal vaccination, SARS-CoV-2, Web-based survey | 10.3390/vaccines8030471 |
| 431763 | Articolo in rivista | Interactome-Seq: A Protocol for Domainome Library Construction, Validation and Selection by Phage Display and Next Generation Sequencing | Soluri, Maria Felicia, Puccio, Simone, Caredda, Giada, Grillo, Giorgio, Licciulli, Vito Flavio, Consiglio, Arianna, Edomi, Paolo, Santoro, Claudio, Sblattero, Daniele, Peano, Clelia | Folding reporters are proteins with easily identifiable phenotypes, such as antibiotic resistance, whose folding and function is compromised when fused to poorly folding proteins or random open reading frames. We have developed a strategy where, by using TEM-1 beta-lactamase (the enzyme conferring ampicillin resistance) on a genomic scale, we can select collections of correctly folded protein domains from the coding portion of the DNA of any intronless genome. The protein fragments obtained by this approach, the so called "domainome", will be well expressed and soluble, making them suitable for structural/functional studies. By cloning and displaying the "domainome" directly in a phage display system, we have showed that it is possible to select specific protein domains with the desired binding properties (e.g., to other proteins or to antibodies), thus providing essential experimental information for gene annotation or antigen identification. | Journal of visualized experiments (2018). | 2018 | LICCIULLI VITO FLAVIO, GRILLO GIORGIO, PEANO CLELIA, CONSIGLIO ARIANNA | Biology, Issue 140, Phage display, Next Generation Sequencing, Interactome, Protein domain, web tool, folding reporter, protein structure | 10.3791/56981 |
| 356380 | Articolo in rivista | Identification of a patient affected by "Juvenile-chronic" Tay Sachs disease in South Italy. | Liguori M., Tagarelli G., Romeo N., Bagala A., Spadafora P. | Tay-Sachs disease (TSD) is an autosomal recessive neurodegenerative disorder characterized by lysosomal enzyme ?-hexosaminidase A deficiency resulting in GM2 ganglioside accumulation mainly in neurons. Here we report about a 30-years old woman from an isolated village of Calabria with early-onset severe bipolar depression and cerebellar ataxia. ?-hexosaminidase A activity determination suggested a diagnosis of TSD. The molecular analysis of the HEXA gene, encoding for the ?-subunit of ?-hexosaminidase A, showed a Gly269Ser mutation in compound heterozygosity with a Leu127Arg change. To the best of our knowledge, the first mutation was never reported in Italy, whereas Leu127Arg has been identified in two Italian acute infantile TSD. We believe that the clinical phenotype of our patient is quite unusual since she presented a very early (9 years) severe bipolar depression as the first clinical onset of the disease. At present, the patient is 38-years old and she can be therefore classified as "juvenile-chronic TSD". Moreover, this case suggests a probable high frequency of HEXA mutations in Calabria. In fact, the proband's parents although consanguineous and originating from the same and isolated village of south Italy, carried two different mutations. This occurrence might be due to a founder effect in an area of Jewish origin. We believe that the identification of TSD carriers might have important implications in the genetic counseling of this population. | Neurological sciences (Testo stamp.) 28 (2016): 1-3. | 2016 | ROMEO NELIDE, SPADAFORA PATRIZIA, LIGUORI MARIA, TAGARELLI GIUSEPPE, BAGALA' ANGELO | Ataxia; Hexa gene; Juvenile-chronic onset; Psychosis; TSD; Tay Sachs | 10.1007/s10072-016-2646-2 |
| 431966 | Articolo in rivista | Are In silico approaches applicable as a first step for the prediction of e-liquid toxicity in e-cigarettes? | Daniele Zarini, Alessandro Sangion, Emanuele Ferri, Enrico Caruso, Sara Zucchi, Alessandro Orro, Ester Papa | Recent studies have raised concerns about e-cigarette liquid inhalation toxicity by reporting the presence of chemicals with European Union CLP toxicity classification. In this scenario, the regulatory context is still developing and is not yet up to date with vaping current reality. Due to the paucity of toxicological studies, robust data regarding which components in e-liquids exhibit potential toxicities, are still inconsistent. In this study we applied computational methods for estimating the toxicity of poorly studied chemicals as a useful tool for predicting the acute toxicity of chemicals contained in e-liquids. The purpose of this study was 3-fold: (a) to provide a lower tier assessment of the potential health concerns associated with e-liquid ingredients, (b) to prioritize e-liquid ingredients by calculating the e-tox index, and (c) to estimate acute toxicity of e-liquid mixtures. QSAR models were generated using QSARINS software to fill the acute toxicity data gap of 264 e-liquid ingredients. As a second step, the potential acute toxicity of e-liquids mixtures was evaluated. Our preliminary data suggest that a computational approach may serve as a roadmap to enable regulatory bodies to better regulate e-liquid composition and to contribute to consumer health protection. | Chemical research in toxicology 33 (2020). | 2020 | ORRO ALESSANDRO | QSAR, Bioinformatics, e-cigarettes | 10.1021/acs.chemrestox.0c00136 |
| 431969 | Articolo in rivista | Recent Strategic Advances in CFTR Drug Discovery: An Overview | Rusnati, Marco, D'Ursi, Pasqualina, Pedemonte, Nicoletta, Urbinati, Chiara, Ford, Robert C., Cichero, Elena, Uggeri, Matteo, Orro, Alessandro, Fossa, Paola | Cystic fibrosis transmembrane conductance regulator (CFTR)-rescuing drugs have already transformed cystic fibrosis (CF) from a fatal disease to a treatable chronic condition. However, new-generation drugs able to bind CFTR with higher specificity/affinity and to exert stronger therapeutic benefits and fewer side effects are still awaited. Computational methods and biosensors have become indispensable tools in the process of drug discovery for many important human pathologies. Instead, they have been used only piecemeal in CF so far, calling for their appropriate integration with well-tried CF biochemical and cell-based models to speed up the discovery of new CFTR-rescuing drugs. This review will give an overview of the available structures and computational models of CFTR and of the biosensors, biochemical and cell-based assays already used in CF-oriented studies. It will also give the reader some insights about how to integrate these tools as to improve the efficiency of the drug discovery process targeted to CFTR. | International journal of molecular sciences (Online) 21 (2020). | 2020 | ORRO ALESSANDRO, D'URSI PASQUALINA | CFTR, drug discovery, bioinformatics, biosensors | 10.3390/ijms21072407 |
| 431971 | Articolo in rivista | Use of (Q)SAR models to investigate potential CMR properties of e-liquid ingredients | Zarini, D., Zucchi, S., Trampolin, I., Orro, A., Ferri, E. | Electronic cigarettes (e-cigs) are designed to heat and aerosolized mixtures of propylene glycol, glycerol, flavorings, humectants and, optionally, nicotine. Unlike cigarettes, the process involves no tobacco and no combustion; however, the inhalation and exhalation of vapour is reminiscent of smoking. In this context, the use of these devices, might play an important role in smoking cessation and reduction; however, there is still a lack of international consensus over the public health role of the e-cig. Despite the large use of e-cigs, still few toxicological studies are available on the potential long term effects of inhaled of many characterizing flavors used in e-cig products. For instance, the FDA GRAS (Generally Recognized As Safe) designation for some flavorings compounds and for propylene glycol, does not apply to inhalation, and currently, there are no controlled long-term studies of the effects of inhaling heated aerosolized mixture in humans. Thus, there is legitimate concern over the health effects of chronically inhaling these substances and the lack of toxicological studies. In this respect, the aim of this study was to determine potential Cancerogenic, Mutagenic and Reprotoxic (CMR) properties of several e-liquid ingredients by means of in silico methods. With reference to our e-liquid ingredients and CMR effects, we first conducted an in depth screening, through the literature reviews; and we found experimental data gap for all the three categories. Specifically, for the investigated e-liquid ingredients, we observed 35%, 85% and 70% of experimental data gap for Cancerogenicity, Mutagenicity and Reprotoxicity effects, respectively. By following a battery approach, almost all data gaps were successfully filled using Quantitative Structure-Activity Relationship (Q) SAR methods. The predictions were performed using several open source software (VEGA, Toxtree, ToxRead and T.E.S.T.) and the results were combined to obtain the highest possible prediction accuracy (consensus approach). This in silico study is a part of a broader integrated approach (literature research, in chemico, in vitro and computational analysis) specifically designed to assess the potential risk associated with characterizing lavors and e-liquid ingredients. | Toxicology letters 314 (2019): S134-S134. | 2019 | ORRO ALESSANDRO | QSAR, Bioinformatics, e-cigarettes | |
| 431721 | Articolo in rivista | Transcriptomic Analysis ofRhodococcus opacusR7 Grown ono-Xylene by RNA-Seq | Zampolli, Jessica, Di Canito, Alessandra, Manconi, Andrea, Milanesi, Luciano, Di Gennaro, Patrizia, Orro, Alessandro | Xylenes are considered one of the most common hazardous sources of environmental contamination. The biodegradation of these compounds has been often reported, rarer the ability to oxidize theortho-isomer. Among fewo-xylene-degrading bacteria,Rhodococcus opacusR7 is well known for its capability to degrade diverse aromatic hydrocarbons and toxic compounds, includingo-xylene as only carbon and energy source. This work shows for the first time the RNA-seq approach to elucidate the genetic determinants involved in theo-xylene degradation pathway inR. opacusR7. Transcriptomic data showed 542 differentially expressed genes that are associated with the oxidation of aromatic hydrocarbons and stress response, osmotic regulation and central metabolism. Gene ontology (GO) enrichment and KEGG pathway analysis confirmed significant changes in aromatic compound catabolic processes, fatty acid metabolism,beta-oxidation, TCA cycle enzymes, and biosynthesis of metabolites when cells are cultured in the presence ofo-xylene. Interestingly, the most up-regulated genes belong to theakbgene cluster encoding for the ethylbenzene (Akb) dioxygenase system. Moreover, the transcriptomic approach allowed identifying candidate enzymes involved in R7o-xylene degradation for their likely participation in the formation of the metabolites that have been previously identified. Overall, this approach supports the identification of several oxidative systems likely involved ino-xylene metabolism confirming thatR. opacusR7 possesses a redundancy of sequences that converge ino-xylene degradation through R7 peculiar degradation pathway. This work advances our understanding ofo-xylene metabolism in bacteria belonging toRhodococcusgenus and provides a framework of useful enzymes (molecular tools) that can be fruitfully targeted for optimizedo-xylene consumption. | Frontiers in microbiology 11 (2020). | 2020 | ORRO ALESSANDRO, MILANESI LUCIANO, MANCONI ANDREA | Rhodococcus opacus, o-xylene, RNA-seq, oxygenases, stress response, environmental contamination | 10.3389/fmicb.2020.01808 |
| 396706 | Articolo in rivista | Pseudomonas aeruginosa mutants defective in glucose uptake have pleiotropic phenotype and altered virulence in non-mammal infection models | Raneri, Matteo, Pinatel, Eva, Peano, Clelia, Rampioni, Giordano, Leonia, Livia, Bianconi, Irene, Jousson, Olivier, Dalmasio, Chiara, Ferrante, Palma, Briani, Federica | Pseudomonas spp. are endowed with a complex pathway for glucose uptake that relies on multiple transporters. In this work we report the construction and characterization of Pseudomonas aeruginosa single and multiple mutants with unmarked deletions of genes encoding outer membrane (OM) and inner membrane (IM) proteins involved in glucose uptake. We found that a triple Delta gltKGF Delta gntP Delta kguT mutant lacking all known IM transporters (named GUN for Glucose Uptake Null) is unable to grow on glucose as unique carbon source. More than 500 genes controlling both metabolic functions and virulence traits show differential expression in GUN relative to the parental strain. Consistent with transcriptomic data, the GUN mutant displays a pleiotropic phenotype. Notably, the genome-wide transcriptional profile and most phenotypic traits differ between the GUN mutant and the wild type strain irrespective of the presence of glucose, suggesting that the investigated genes may have additional roles besides glucose transport. Finally, mutants carrying single or multiple deletions in the glucose uptake genes showed attenuated virulence relative to the wild type strain in Galleria mellonella, but not in Caenorhabditis elegans infection model, supporting the notion that metabolic functions may deeply impact P. aeruginosa adaptation to specific environments found inside the host. | Scientific reports (Nature Publishing Group) 8 (2018). | 2018 | PEANO CLELIA, PINATEL EVA MARIA | RNA-sequencing, Bacteria | 10.1038/s41598-018-35087-y |
| 396707 | Articolo in rivista | The Helicobacter pylori Heat-Shock Repressor HspR: Definition of Its Direct Regulon and Characterization of the Cooperative DNA-Binding Mechanism on Its Own Promoter | Pepe, Simona, Pinatel, Eva, Fiore, Elisabetta, Puccio, Simone, Peano, Clelia, Brignoli, Tarcisio, Vannini, Andrea, Danielli, Alberto, Scarlato, Vincenzo, Roncarati, Davide | The ability of pathogens to perceive environmental conditions and modulate gene expression accordingly is a crucial feature for bacterial survival. In this respect, the heat-shock response, a universal cellular response, allows cells to adapt to hostile environmental conditions and to survive during stress. In the major human pathogen Helicobacter pylori the expression of chaperone-encoding operons is under control of two auto-regulated transcriptional repressors, HrcA and HspR, with the latter acting as the master regulator of the regulatory circuit. To further characterize the HspR regulon in H. pylori, we used global transcriptome analysis (RNA-sequencing) in combination with Chromatin Immunoprecipitation coupled with deep sequencing (ChIP-sequencing) of HspR genomic binding sites. Intriguingly, these analyses showed that HspR is involved in the regulation of different crucial cellular functions through a limited number of genomic binding sites. Moreover, we further characterized HspR-DNA interactions through hydroxyl-radical footprinting assays. This analysis in combination with a nucleotide sequence alignment of HspR binding sites, revealed a peculiar pattern of DNA protection and highlighted sequence conservation with the HAIR motif (an HspR-associated inverted repeat of Streptomyces spp.). Site-directed mutagenesis demonstrated that the HAIR motif is fundamental for HspR binding and that additional nucleotide determinants flanking the HAIR motif are required for complete binding of HspR to its operator sequence spanning over 70 bp of DNA. This finding is compatible with a model in which possibly a dimer of HspR recognizes the HAIR motif overlapping its promoter for binding and in turn cooperatively recruits two additional dimers on both sides of the HAIR motif. | Frontiers in microbiology 9 (2018). | 2018 | PEANO CLELIA, PUCCIO SIMONE, PEANO CLELIA, PINATEL EVA MARIA | heat-shock response, HspR repressor, ChIP-seq, RNA-sequencing, transcriptome | 10.3389/fmicb.2018.01887 |
| 432349 | Articolo in rivista | Blockade of IGF2R improves muscle regeneration and ameliorates Duchenne muscular dystrophy | Bella, Pamela, Farini, Andrea, Banfi, Stefania, Parolini, Daniele, Tonna, Noemi, Meregalli, Mirella, Belicchi, Marzia, Erratico, Silvia, D'Ursi, Pasqualina, Bianco, Fabio, Legato, Mariella, Ruocco, Chiara, Sitzia, Clementina, Sangiorgi, Simone, Villa, Chiara, D'Antona, Giuseppe, Milanesi, Luciano, Nisoli, Enzo, Mauri, PierLuigi, Torrente, Yvan | Duchenne muscular dystrophy (DMD) is a debilitating fatal X-linked muscle disorder. Recent findings indicate that IGFs play a central role in skeletal muscle regeneration and development. Among IGFs, insulinlike growth factor 2 (IGF2) is a key regulator of cell growth, survival, migration and differentiation. The type 2 IGF receptor (IGF2R) modulates circulating and tissue levels of IGF2 by targeting it to lysosomes for degradation. We found that IGF2R and the store-operated Ca2+ channel CD20 share a common hydrophobic binding motif that stabilizes their association. Silencing CD20 decreased myoblast differentiation, whereas blockade of IGF2R increased proliferation and differentiation in myoblasts via the calmodulin/calcineurin/NFAT pathway. Remarkably, anti-IGF2R induced CD20 phosphorylation, leading to the activation of sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) and removal of intracellular Ca2+. Interestingly, we found that IGF2R expression was increased in dystrophic skeletal muscle of human DMD patients and mdx mice. Blockade of IGF2R by neutralizing antibodies stimulated muscle regeneration, induced force recovery and normalized capillary architecture in dystrophic mdx mice representing an encouraging starting point for the development of new biological therapies for DMD. | EMBO molecular medicine (Print) 12 (2020). | 2020 | MILANESI LUCIANO, D'URSI PASQUALINA, MAURI PIETRO LUIGI | DMD, IGF2, IGF2R, muscle regeneration, muscular dystrophy | |
| 432878 | Articolo in rivista | The Heparan Sulfate Sulfotransferases HS2ST1 and HS3ST2 Are Novel Regulators of Breast Cancer Stem-Cell Properties | Felipe C. O. B. Teixeira1, 2, Archana Vijaya Kumar2, Sampath Kumar Katakam2, Cinzia Cocola3, Paride Pelucchi3, Monika Graf2?, Ludwig Kiesel2, Rolland Reinbold3, Mauro S. G. Pavao1, Burkhard Greve4*, Martin Gotte2* | Heparan sulfate (HS) is a glycosaminoglycan found mainly in its protein-conjugated form at the cell surface and the extracellular matrix. Its high sulfation degree mediates functional interactions with positively charged amino acids in proteins. 2-O sulfation of iduronic acid and 3-O sulfation of glucosamine in HS are mediated by the sulfotransferases HS2ST and HS3ST, respectively, which are dysregulated in several cancers. Both sulfotransferases regulate breast cancer cell viability and invasion, but their role in cancer stem cells (CSCs) is unknown. Breast CSCs express characteristic markers such as CD44C/CD24?=low, CD133 and ALDH1 and are involved in tumor initiation, formation, and recurrence. We studied the influence of HS2ST1 and HS3ST2 overexpression on the CSC phenotype in breast cancer cell lines representative of the triple-negative (MDA-MB-231) and hormone-receptor positive subtype (MCF-7). The CD44C/CD24?=low phenotype was significantly reduced in MDA-MB-231 cells after overexpression of both enzymes, remaining unaltered in MCF-7 cells. ALDH1 activity was increased after HS2ST1 and HS3ST2 overexpression in MDA-MB-231 cells and reduced after HS2ST1 overexpression in MCF-7 cells. Colony and spheroid formation were increased after HS2ST1 and HS3ST2 overexpression in MCF-7 cells. Moreover, MDA-MB-231 cells overexpressing HS2ST1 formed more colonies and could not generate spheres. The phenotypic changes were associated with complex changes in the expression of the stemness-associated notch and Wnt-signaling pathways constituents, syndecans, heparanase and Sulf1. The results improve our understanding of breast CSC function and mark a subtype-specific impact of HS modifications on the CSC phenotype of triple-negative and hormone receptor positive breast cancer model cell lines. | Frontiers in Cell and Developmental Biology 8 (2020). | 2020 | PELUCCHI PARIDE, COCOLA CINZIA, REINBOLD ROLLAND ALVONS | breast cancer, sulfotransferase, heparan sulfate, epithelial-to-mesenchymal transition, cancer stem cell (CSC), syndecan, notch, Sulf1 | |
| 426241 | Articolo in rivista | Digenic inheritance of subclinical variants in Noonan Syndrome patients: an alternative pathogenic model? | Ferrari, Luca, Mangano, Eleonora, Bonati, Maria Teresa, Monterosso, Ilaria, Capitanio, Daniele, Chiappori, Federica, Brambilla, Ilaria, Gelfi, Cecilia, Battaglia, Cristina, Bordoni, Roberta, Riva, Paola | Noonan syndrome (NS) is an autosomal-dominant disorder with variable expressivity and locus heterogeneity. Despite several RAS pathway genes were implicated in NS, 20-30% of patients remain without molecular diagnosis, suggesting the involvement of further genes or multiple mechanisms. Eight patients out of 60, negative for conventional NS mutation analysis, with heterogeneous NS phenotype were investigated by means of target resequencing of 26 RAS/MAPK pathway genes. A trio was further characterized by means of whole-exome sequencing. Protein modeling and in silico prediction of protein stability allowed to identify possible pathogenic RAS pathway variants in four NS patients. A new c.355T>C variant in LZTR1 was found in patient 43. Two patients co-inherited variants in LRP1 and LZTR1 (patient 53), or LRP1 and SOS1 genes (patient 67). The forth patient (56) carried a compound heterozygote of RASAL3 gene variants and also an A2ML1 variant. While these subclinical variants are singularly present in healthy parents, they co-segregate in patients, suggesting their addictive effect and supporting a digenic inheritance, as alternative model to a more common monogenic transmission. The ERK1/2 and SAPK/JNK activation state, assessed on immortalized lymphocytes from patients 53 and 67 showed highest phosphorylation levels compared to their asymptomatic parents. These findings together with the lack of their co-occurrence in the 1000Genomes database strengthen the hypothesis of digenic inheritance in a subset of NS patients. This study suggests caution in the exclusion of subclinical variants that might play a pathogenic role providing new insights for alternative hereditary mechanisms. | European journal of human genetics (2020). | 2020 | BATTAGLIA CRISTINA, BORDONI ROBERTA, MANGANO ELEONORA, CHIAPPORI FEDERICA CATERINA | Noonan syndrome | 10.1038/s41431-020-0658-0 |
| 417296 | Contributo in atti di convegno | Analysis of DNA tandem repeats in ALS from Whole Genome Sequencing: Role of FRA10Ac1 gene repeat expansion in ALS | Corrado L., Genovese L., Mangano E., Croce R., Di Pierro A., Geraci F., Bordoni R., D'Aurizio R., Barizzone N., De Marchi F., Mazzini L., De Bellis G., Manzini G., Severgnini M., Pellegrini M., D'Alfonso S. | The C9ORF72 gene repeat expansion is the most frequent cause of ALS. Long repeats alleles in ATXN-1, ATXN-2, and NIPA1 genes are associated to ALS susceptibility. Tandem Repeat Polymorphisms (TRPs) are good candidates for missing hereditability in ALS (40%), although they were never systematically analyzed as they represent a remarkable challenge to NGS. The aim of this study is to perform a systematic analysis of TRPs in ALS by combining NGS and novel bioinformatics tools. We performed our analysis from whole genome sequencing data (WGS) of 70 ALS cases. TRPs were evaluated by means of a software developed within our consortium to detect tandem repeat expansion. Validation of expanded loci was conducted by Repeat primer PCR We identified an ALS patient with a CGG expansion in 5'UTR of FRA10AC1 gene. To explore the possible role of this CGG expansion in ALS we screened a cohort of 337 ALS and 285 controls and we found 3 expanded patients (0.9%) and no control. We failed to replicated this result in a second cohort of 426 ALS patients and 733 controls (1 ALS (0.2%) and 5 controls (0.7%)) Overall, we observed the CGG expansion in 4/763 (0.5%) ALS patients and 5/1018 controls (0.5%). FRA10AC1 gene expression was not silenced by the expansion. The software we developed can detect epeat expansions from WGS data, although FRA10AC1 CGG expansion seems not to be involved in ALS pathogenesis. Conversely to what previously reported, large CGG expansion at this locus do not decrease gene expression | 52nd European Society of Human Genetics (ESHG) Conference, pp. 1489-1489, Gothenburg, 2019 | 2019 | GENOVESE LOREDANA MARIALUISA, PELLEGRINI MARCO, BORDONI ROBERTA, SEVERGNINI MARCO, GERACI FILIPPO, D'AURIZIO ROMINA, MANGANO ELEONORA | Computational Biology | |
| 433243 | Articolo in rivista | Ten simple rules on how to write a standard operating procedure | Hollmann, Susanne(1), Frohme, Marcus(2), Endrullat, Christoph(3), Kremer, Andreas(4), D'Elia, Domenica(5), Regierer, Babette(6), Nechyporenko, Alina(6) | Research publications and data nowadays should be publicly available on the internet and, theoretically, usable for everyone to develop further research, products, or services. The long-term accessibility of research data is, therefore, fundamental in the economy of the research production process. However, the availability of data is not sufficient by itself, but also their quality must be verifiable. Measures to ensure reuse and reproducibility need to include the entire research life cycle, from the experimental design to the generation of data, quality control, statistical analysis, interpretation, and validation of the results. Hence, high-quality records, particularly for providing a string of documents for the verifiable origin of data, are essential elements that can act as a certificate for potential users (customers). These records also improve the traceability and transparency of data and processes, therefore, improving the reliability of results. Standards for data acquisition, analysis, and documentation have been fostered in the last decade driven by grassroot initiatives of researchers and organizations such as the Research Data Alliance (RDA). Nevertheless, what is still largely missing in the life science academic research are agreed procedures for complex routine research workflows. Here, well-crafted documentation like standard operating procedures (SOPs) offer clear direction and instructions specifically designed to avoid deviations as an absolute necessity for reproducibility. | PLoS computational biology 16 (2020). | 2020 | D'ELIA DOMENICA | standards, standard operating procedure | 10.1371/journal.pcbi.1008095 |
| 433246 | Articolo in rivista | Plant miRNAs reduce cancer cell proliferation by targeting MALAT1 and NEAT1: a beneficial cross-kingdom interaction | Flaviana Marzano, Mariano Francesco Caratozzolo, Arianna Consiglio, Flavio Licciulli, Sabino Liuni, Elisabetta Sbisa', Domenica D'Elia*, Apollonia Tullo*, Domenico Catalano | MicroRNAs (miRNAs) are ubiquitous regulators of gene expression, evolutionarily conserved in plants and mammals. In recent years, although a growing number of papers debate the role of plant miRNAs on human gene expression, the molecular mechanisms through which this effect is achieved are still not completely elucidated. Some evidence suggest that this interaction might be sequence specific, and in this work, we investigated this possibility by transcriptomic and bioinformatics approaches. Plant and human miRNA sequences from primary databases were collected and compared for their similarities (global or local alignments). Out of 2,588 human miRNAs, 1,606 showed a perfect match of their seed sequence with the 5? end of 3,172 plant miRNAs. Further selections were applied based on the role of the human target genes or of the miRNA in cell cycle regulation (as an oncogene, tumor suppressor, or a biomarker for prognosis, or diagnosis in cancer). Based on these criteria, 20 human miRNAs were selected as potential functional analogous of 7 plant miRNAs, which were in turn transfected in different cell lines to evaluate their effect on cell proliferation. A significant decrease was observed in colorectal carcinoma HCT116 cell line. RNA-Seq demonstrated that 446 genes were differentially expressed 72 h after transfection. Noteworthy, we demonstrated that the plant mtr-miR-5754 and gma-miR4995 directly target the tumor-associated long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) and nuclear paraspeckle assembly transcript 1 (NEAT1) in a sequence-specific manner. In conclusion, according to other recent discoveries, our study strengthens and expands the hypothesis that plant miRNAs can have a regulatory effect in mammals by targeting both protein-coding and non-coding RNA, thus suggesting new biotechnological applications. | Frontiers in genetics 11 (2020). | 2020 | MARZANO FLAVIANA, TULLO APOLLONIA, D'ELIA DOMENICA, LICCIULLI VITO FLAVIO, CATALANO DOMENICO, LIUNI SABINO, CARATOZZOLO MARIANO FRANCESCO, CONSIGLIO ARIANNA, SBISA' ELISABETTA | cancer, MALAT1, NEAT1, nutrition, plant miRNA, long non-coding | 10.3389/fgene.2020.552490/full |
| 433263 | Contributo in atti di convegno | Prediction of New Associations between ncRNAs and Diseases Exploiting Multi-Type Hierarchical Clustering | Barracchia E.P., Pio G., D'Elia D., Ceci M. | The study of functional associations between ncRNAs and human diseases is a pivotal task of modern research to develop new and more effective therapeutic approaches. Nevertheless, it is not a trivial task since it involves entities of different types, such as microRNAs, lncRNAs or target genes. Such complexity can be faced by representing the involved biological entities and their relationships as a network and by exploiting network-based computational approaches able to identify new associations. However, existing methods are limited to homogeneous networks or can exploit only a limited set of the features of biological entities. To overcome the limitations of existing approaches, we proposed the system LP-HCLUS, which analyzes heterogeneous networks consisting of several types of objects and relationships, each possibly described by a set of features, and extracts hierarchically organized, possibly overlapping, multi-type clusters that are subsequently exploited to predict new ncRNA-disease associations. Our experimental evaluation shows that, according to both quantitative (i.e., TPR@k, ROC and PR curves) and qualitative criteria, LP-HCLUS produces better results. | SEBD 2020 -28th SYMPOSIUM ON ADVANCED DATABASE SYSTEMS, pp. 160-167, Villasimius, Sardinia, Italy, 21/06/2020, 21-24/06/2020 | 2020 | D'ELIA DOMENICA | machine learning, Hierarchical Clustering, big data | |
| 434533 | Articolo in rivista | "Hi This Is NESTORE, Your Personal Assistant": Design of an Integrated IoT System for a Personalized Coach for Healthy Aging | Palumbo F., Crivello A., Furfari F., Girolami M., Mastropietro A., Manferdelli G., Rocke C., Guye S., Salva Casanovas A., Caon M., Carrino F., Khaled O.A., Mugellini E., Denna E., Mauri M., Ward D., Subias-Beltran P., Orte S., Candea C., Candea G., Rizzo G. | In the context of the fourth revolution in healthcare technologies, leveraging monitoring and personalization across different domains becomes a key factor for providing useful services to maintain and promote well-being. This is even more crucial for older people, with aging being a complex multi-dimensional and multi-factorial process which can lead to frailty. The NESTORE project was recently funded by the EU Commission with the aim of supporting healthy older people to sustain their well-being and capacity to live independently. It is based on a multi-dimensional model of the healthy aging process that covers physical activity, nutrition, cognition, and social activity. NESTORE is based on the paradigm of the human-in-the-loop cyber-physical system that, exploiting the availability of Internet of Things technologies combined with analytics in the cloud, provides a virtual coaching system to support healthy aging. This work describes the design of the NESTORE methodology and its IoT architecture. We first model the end-user under several domains, then we present the NESTORE system that, analyzing relevant key-markers, provides coaching activities and personalized feedback to the user. Finally, we describe the validation strategy to assess the effectiveness of NESTORE as a coaching platform for healthy aging. | Frontiers in digital health (2020). | 2020 | MANFERDELLI GIORGIO, RIZZO GIOVANNA, FURFARI FRANCESCO, GIROLAMI MICHELE, PALUMBO FILIPPO, MASTROPIETRO ALFONSO, CRIVELLO ANTONINO | e-health, virtual coach, IoT, sensor network, digital health | 10.3389/fdgth.2020.545949 |
| 434776 | Articolo in rivista | A reliable strategy for single-cell RNA sequencing analysis using cryoconserved primary cortical cells. | Verrillo, Lucia, Mangano, Eleonora, Drongitis, Denise, Merelli, Ivan, Pischedda, Francesca, Piccoli, Giovanni, Consolandi, Clarissa, Bordoni, Roberta, Miano, Maria Giuseppina | BACKGROUND: The application of single-cell RNA sequencing (scRNASeq) represents a unique approach to identify hundreds to millions of cells in mammalian cortical multilayers at different stages of embryogenesis. ScRNASeq technology applied to neurological studies requires the use of fresh starting materials because standard cryopreservation methods do not guarantee high viability of cortical primary cells derived from dissected brain areas. NEW METHOD: Here we set up and validate an innovative strategy to perform scRNASeq studies in cryopreserved primary cortical cells isolated from E15.5 mouse embryo. In order to freeze cortical primary cells, we have employed Neurostore, a medium able to guarantee high viability and cell composition of embryonic cortex after thawing. COMPARISON WITH EXISTING METHODS: We showed for the first time the possibility to run scRNASeq experiments on primary cortical cells in an off-line set-up, ensuring cellular integrity and diversity. RESULTS: By trypan blue assay and flow cytometry analysis, we found that Neurostore-cryopreserved cortical cells showed approximately 95 % of viability. Satisfactory RNA recovery and cDNA libraries were achieved. Transcriptome sequencing of 35,763 cryoconserved single cells yielded a robust data-set, identifying 25 cell clusters in three biological samples. Prevalence of peculiar neural populations before and after the cryopreservation-resuscitation procedure was verified by marker gene expression and immunofluorescence analysis. CONCLUSIONS: Our findings support the evidence that frozen primary cortical cells can be successfully employed in scRNASeq experiments allowing an unprecedented flexibility in experimental procedures, such as sample preparation and subsequent processing steps performed in different locations. | Journal of neuroscience methods 347 (2020): 108960. | 2020 | DRONGITIS DENISE, VERRILLO LUCIA, BORDONI ROBERTA, MIANO MARIA GIUSEPPINA, CONSOLANDI CLARISSA, MERELLI IVAN, MANGANO ELEONORA | Single-cell RNA sequencing, Embryonic mouse brain, E15.5, Primary cortical cells, Cryopreservation | 10.1016/j.jneumeth.2020.108960 |
| 419118 | Articolo in rivista | Dysfunctional polycomb transcriptional repression contributes to Lamin A/C dependent muscular dystrophy | Bianchi A1, 2, Mozzetta C2, Pegoli G3, Lucini F1, Valsoni S1, 3, Rosti V4, Petrini C5, Cortesi A1, Gregoretti F6, Antonelli L6, Oliva G6, De Bardi M3, Rizzi R1, 4, Bodega B1, Pasini D7, 8, Ferrari F5, 9, Bearzi C1, 10, Lanzuolo C3, 4. | Lamin A is a component of the inner nuclear membrane that, together with epigenetic factors, organizes the genome in higher order structures required for transcriptional control. Mutations in the Lamin A/C gene cause several diseases, belonging to the class of laminopathies, including muscular dystrophies. Nevertheless, molecular mechanisms involved in the pathogenesis of Lamin A-dependent dystrophies are still largely unknown. Polycomb group of proteins (PcG) are epigenetic repressors and Lamin A interactors, primarily involved in the maintenance of cell identity. Using a murine model of Emery-Dreifuss Muscular Dystrophy (EDMD), we showed here that Lamin A loss deregulated PcG positioning in muscle satellite stem cells leading to de-repression of non-muscle specific genes and p16INK4a, a senescence driver encoded in the Cdkn2a locus. This aberrant transcriptional programme caused impairment in self-renewal, loss of cell identity and premature exhaustion of quiescent satellite cell pool. Genetic ablation of Cdkn2a locus restored muscle stem cell properties in Lamin A/C null dystrophic mice. Our findings established a direct link between Lamin A and PcG epigenetic silencing and indicated that Lamin A-dependent muscular dystrophy can be ascribed to intrinsic epigenetic dysfunctions of muscle stem cells. | The journal of clinical investigation (Online) 130 (2020): 2408-2421. | 2020 | GREGORETTI FRANCESCO, OLIVA GENNARO, ANTONELLI LAURA, LANZUOLO CHIARA, BEARZI CLAUDIA, MOZZETTA CHIARA, FERRARI FRANCESCO | medline | 10.1172/JCI128161 |
| 435758 | Articolo in rivista | Raw Milk Microbiota Modifications as Affected by Chlorine Usage for Cleaning Procedures: The Trentingrana PDO Case | Cremonesi, Paola, Morandi, Stefano, Ceccarani, Camilla, Battelli, Giovanna, Castiglioni, Bianca, Cologna, Nicola, Goss, Andrea, Severgnini, Marco, Mazzucchi, Massimiliano, Partel, Erika, Tamburini, Alberto, Zanini, Lucio, Brasca, Milena | Milk microbiota represents a key point in raw milk cheese production and contributes to the development of typical flavor and texture for each type of cheese. The aim of the present study was to evaluate the influence of chlorine products usage for cleaning and sanitizing the milking equipment on (i) raw milk microbiota; (ii) the deriving whey-starter microbiota; and (iii) Trentingrana Protected Designation of Origin (PDO) cheese microbiota and volatilome. Milk samples from three farms affiliated to a Trentingrana PDO cheese factory were collected three times per week during a 6-weeks period in which a sodium hypochlorite detergent (period C) was used and during a subsequent 6-weeks period of non-chlorine detergent usage (period NC). Samples were subjected to microbiological [Standard Plate Count; coliforms; coagulase-positive staphylococci; and lactic acid bacteria (LAB)] and metagenomic analysis (amplification of V3-V4 regions of 16S rRNA gene performed on Illumina MiSeq platform). In addition, cheese volatilome was determined by SPME-GC-MS. In the transition from period C to period NC, higher SPC and LAB counts in milk were recorded. Milk metagenomic analysis showed a peculiar distinctive microbiota composition for the three farms during the whole experimental period. Moreover, differences were highlighted comparing C and NC periods in each farm. A difference in microbial population related to chlorine usage in bulk milk and vat samples was evidenced. Moreover, chlorine utilization at farm level was found to affect the whey-starter population: the usually predominant Lactobacillus helveticus was significantly reduced during NC period, whereas Lactobacillus delbrueckii had the exact opposite trend. Alpha- and beta-diversity revealed a separation between the two treatment periods with a higher presence of L. helveticus, L. delbrueckii, and Streptococcus thermophilus in cheese samples after NC detergent period. Cheese volatilome analysis showed a slight decrease in lipolysis during C period in the inner part of the cheese wheel. Although preliminary, these results suggest a profound influence on milk and cheese microbiota, as well as on raw milk cheese production and quality, due to the use of chlorine. However, further studies will be needed to better understand the complex relationship between chlorine and microbiota along all the cheese production steps. | Frontiers in microbiology 11 (2020). | 2020 | CECCARANI CAMILLA, BATTELLI GIOVANNA, CASTIGLIONI BIANCA MARIA ELISABETTA, BRASCA MILENA, SEVERGNINI MARCO, MORANDI STEFANO, CREMONESI PAOLA | chlorine, whey-starter, cheese, milking equipment, biodiversity | 10.3389/fmicb.2020.564749 |
| 435896 | Articolo in rivista | Self-Reported Symptoms of SARS-CoV-2 Infection in a Nonhospitalized Population in Italy: Cross-Sectional Study of the EPICOVID19 Web-Based Survey | Adorni, Fulvio, Prinelli, Federica, Bianchi, Fabrizio, Giacomelli, Andrea, Pagani, Gabriele, Bernacchia, Dario, Rusconi, Stefano, Maggi, Stefania, Trevisan, Caterina, Noale, Marianna, Molinaro, Sabrina, Bastiani, Luca, Fortunato, Loredana, Jesuthasan, Nithiya, Sojic, Aleksandra, Pettenati, Carla, Tavio, Marcello, Andreoni, Massimo, Mastroianni, Claudio, Incalzi, Raffaele Antonelli, Galli, Massimo | Background: Understanding the occurrence of symptoms resembling those of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in a large nonhospitalized population at the peak of the epidemic in Italy is of paramount importance; however, data are currently scarce. Objective: The aims of this study were to evaluate the association of self-reported symptoms with SARS-CoV-2 nasopharyngeal swab (NPS) test results in nonhospitalized individuals and to estimate the occurrence of symptoms associated with coronavirus disease (COVID-19) in a larger nontested population. Methods: EPICOVID19 is a self-administered cross-sectional voluntary web-based survey of adults throughout Italy who completed an anonymous questionnaire in the period of April 13 to 21, 2020. The associations between symptoms potentially related to SARS-CoV-2 infection and NPS results were calculated as adjusted odds ratios (aORs) with 95% CIs by multiple logistic regression analysis controlling for age, sex, education, smoking habits, and number of comorbidities. Thereafter, for each symptom and for combinations of the symptoms, we calculated the sensitivity, specificity, accuracy, and areas under the curve (AUCs) in a receiver operating characteristic (ROC) analysis to estimate the occurrence of COVID-19-like infection in the nontested population. Results: A total of 171,310 people responded to the survey, of whom 102,543 (59.9%) were women; mean age 47.4 years. Out of the 4785 respondents with known NPS test results, 4392 were not hospitalized. Among the 4392 nonhospitalized respondents, those with positive NPS tests (856, 19.5%) most frequently reported myalgia (527, 61.6%), olfactory and taste disorders (507, 59.2%), cough (466, 54.4%), and fever (444, 51.9%), whereas 7.7% were asymptomatic. Multiple regression analysis showed that olfactory and taste disorders (aOR 10.3, 95% CI 8.4-12.7), fever (aOR 2.5, 95% CI 2.0-3.1), myalgia (aOR 1.5, 95% CI 1.2-1.8), and cough (aOR 1.3, 95% CI 1.0-1.6) were associated with NPS positivity. Having two to four of these symptoms increased the aOR from 7.4 (95% CI 5.6-9.7) to 35.5 (95% CI 24.6-52.2). The combination of the four symptoms showed an AUC of 0.810 (95% CI 0.795-0.825) in classifying positive NPS test results and then was applied to the nonhospitalized and nontested sample (n=165,782). We found that 7739 to 20,103 of these 165,782 respondents (4.4% to 12.1%) had experienced symptoms suggestive of COVID-19 infection. Conclusions: Our results suggest that self-reported symptoms are reliable indicators of SARS-CoV-2 infection in a pandemic context. A nonnegligible number of symptomatic respondents (up to 12.1%) were undiagnosed and potentially contributed to the spread of the infection. | JMIR public health and surveillance Online 6 (2020): 461-474. | 2020 | JESUTHASAN NITHIYA, SOJIC ALEKSANDRA, MAGGI STEFANIA, NOALE MARIANNA, MOLINARO SABRINA, ADORNI FULVIO DANIELE, FORTUNATO LOREDANA, BASTIANI LUCA, PRINELLI FEDERICA, BIANCHI FABRIZIO | SARS-CoV-2, COVID-19, voluntary respondents, web-based survey, self-reported symptom, nasopharyngeal swab testing, cross-sectional | 10.2196/21866 |
| 436946 | Articolo in rivista | A Pilot Longitudinal Evaluation of MicroRNAs for Monitoring the Cognitive Impairment in Pediatric Multiple Sclerosis | Nicoletta Nuzziello, Arianna Consiglio, Rosa Gemma Viterbo, Flavio Licciulli, Sabino Liuni, Maria Trojano, Maria Liguori. | MicroRNAs (miRNAs), a class of non-coding RNAs, seem to play a key role in complex diseases like multiple sclerosis (MS), as well as in many cognitive functions associated with the disease. In a previous cross-sectional evaluation on pediatric MS (PedMS) patients, the expression of some miRNAs and their target genes were found to be associated with the scores of some neuropsychiatric tests, thus suggesting that they may be involved in early processes of cognitive impairment. To verify these data, we asked the same patients to be re-evaluated after a 1-year interval; unfortunately, only nine of them agreed to this further clinical and molecular analysis. The main results showed that 13 dierentially expressed miRNAs discriminated the two time-points. Among them, the expression of miR-182-5p, miR-320a-3p, miR-744-5p and miR-192-5p significantly correlated with the attention and information processing speed performances, whereas the expression of miR-182-5p, miR-451a, miR-4742-3p and miR-320a-3p correlated with the expressive language performances. The analysis of mRNA expression uncovered 58 predicted and/or validated miRNA-target pairs, including 23 target genes, some of them already associated with cognitive impairment, such as the transducing beta like 1 X-linked receptor-1 gene (TBL1XR1), correlated to disorders of neurodevelopment; the Snf2 related CREBBP activator protein gene (SRCAP) that was found implicated in a rare form of dementia; and the glia maturation factor beta gene (GMFB), which has been reported to be implicated in neurodegeneration and neuroinflammation. No molecular pathways involving the most targeted genes survived the adjustment for multiple data. Although preliminary, these findings showed the feasibility of the methods also applied to longitudinal investigations, as well as the reliability of the obtained results. These findings should be confirmed in larger PedMS cohorts in order to identify early markers of cognitive impairment, towards which more ecient therapeutic eorts can be addressed. | Applied sciences (2020). | 2020 | NUZZIELLO NICOLETTA, LICCIULLI VITO FLAVIO, LIGUORI MARIA, LIUNI SABINO, CONSIGLIO ARIANNA | pediatric multiple sclerosis; microRNA; gene target; high-throughput next-generation sequencing | 10.3390/app10228274 |
| 437128 | Articolo in rivista | Multi-steps registration protocol for multimodal MR images of hip skeletal muscles in a longitudinal study | Fontana L., Mastropietro A., Scalco E., Peruzzo D., Beretta E., Strazzer S., Arrigoni F., Rizzo G. | Image registration is crucial in multimodal longitudinal skeletal muscle Magnetic Resonance Imaging (MRI) studies to extract reliable parameters that can be used as indicators for physio/pathological characterization of muscle tissue and for assessing the effectiveness of treatments. This paper aims at proposing a reliable registration protocol and evaluating its accuracy in a longitudinal study. The hips of 6 subjects were scanned, in a multimodal protocol, at 2 different time points by a 3 Tesla scanner; the proposed multi-step registration pipeline is based on rigid and elastic transformations implemented in SimpleITK using a multi-resolution technique. The effects of different image pre-processing (muscle masks, isotropic voxels) and different parameters' values (learning rates and mesh sizes) were quantitatively assessed using standard accuracy indexes. Rigid registration alone does not provide satisfactory accuracy for inter-sessions alignment and a further elastic step is needed. The use of isotropic voxels, combined with the muscle masking, provides the best result in terms of accuracy. Learning rates can be increased to speed up the process without affecting the final results. The protocol described in this paper, complemented by open-source software, can be a useful guide for researchers that approach for the first time the issues related to the muscle MR image registration. | Applied sciences 10 (2020): 1-16. | 2020 | FONTANA LUCIA, RIZZO GIOVANNA, SCALCO ELISA, MASTROPIETRO ALFONSO | image registration, accuracy evaluation, skeletal muscle, multimodal MRI | 10.3390/app10217823 |
| 437246 | Articolo in rivista | Change of Communication Strategy to Increase Engagement during the SARS-Cov-2Pandemic: The Experience of the European GEMMA Project in Italy | Cupaioli Francesca Anna1, Corrivetti Giulio2, Tamburro Ilaria3, Fasano Alessio4, Mezzelani Alessandra1* | Scientific projects need solid communication plan. GEMMA is a multicenter EU-Horizon2020 project for biomedical research in autism requiring the enrollment of 600 infants at risk of developing autism in different countries. The Communication& Dissemination work-package had the early goal to create engagement among autism related stakeholders to maximize children recruitment also through social media and website. Because ofCOVID-19 lockdown, the recruitment has been temporarily suspended, as well as schools suspended face-to-face lessons opting for remote teaching. Since children with autism suffer discomfort with routine changes and need special distance education, GEMMA communication has turned toward a COVID-19ad-hoc strategy developing or selecting "technology and inclusion" webinars and "inclusive apps". These sustained children with autism, their parents and teachers in special distance education and entertainment. The results showed the success of specific inclusive tools and languages in scientific outreach activities and the possibility to maintain stakeholder engagement also in emergency situation. | International Journal of Humanities Social Sciences and Education 7 (2020). | 2020 | MEZZELANI ALESSANDRA MARIA, CUPAIOLI FRANCESCA ANNA | COVID-19, Lockdown, Change of strategy, Public engagement, Science and technology, Social inclusion, Accessibility, Distance education | 10.20431/2349-0381.0709013 |
| 438653 | Articolo in rivista | The need for standardisation in life science research - an approach to excellence and trust | Susanne Hollmann https://orcid.org/0000-0001-9032-20351, 2, Andreas Kremer3, ?pela Baebler https://orcid.org/0000-0003-4776-71644, Christophe Trefois https://orcid.org/0000-0002-8991-68105, Kristina Gruden4, Witold R. Rudnicki6, Weida Tong7, Aleksandra Gruca8, Erik Bongcam-Rudloff9, Chris T. Evelo https://orcid.org/0000-0002-5301-314210, 11, Alina Nechyporenko12, Marcus Frohme13, David ?afranek14, Babette Regierer https://orcid.org/0000-0002-5263-45532, 15, Domenica D'Elia16 | Today, academic researchers benefit from the changes driven by digital technologies and the enormous growth of knowledge and data, on globalisation, enlargement of the scientific community, and the linkage between different scientific communities and the society. To fully benefit from this development, however, information needs to be shared openly and transparently. Digitalisation plays a major role here because it permeates all areas of business, science and society and is one of the key drivers for innovation and international cooperation. To address the resulting opportunities, the EU promotes the development and use of collaborative ways to produce and share knowledge and data as early as possible in the research process, but also to appropriately secure results with the European strategy for Open Science (OS). It is now widely recognised that making research results more accessible to all societal actors contributes to more effective and efficient science; it also serves as a boost for innovation in the public and private sectors. However for research data to be findable, accessible, interoperable and reusable the use of standards is essential. At the metadata level, considerable efforts in standardisation have already been made (e.g. Data Management Plan and FAIR Principle etc.), whereas in context with the raw data these fundamental efforts are still fragmented and in some cases completely missing. The CHARME consortium, funded by the European Cooperation in Science and Technology (COST) Agency, has identified needs and gaps in the field of standardisation in the life sciences and also discussed potential hurdles for implementation of standards in current practice. Here, the authors suggest four measures in response to current challenges to ensure a high quality of life science research data and their re-usability for research and innovation. | F1000Research 9 (2020). | 2020 | D'ELIA DOMENICA | Open Data, Open Access, Open Science, FAIR Principles, Standardisation, Education, Quality Management | 10.12688/f1000research.27500.1 |
| 438872 | Articolo in rivista | SAMMY-seq reveals early alteration of heterochromatin and deregulation of bivalent genes in Hutchinson-Gilford Progeria Syndrome | Sebestyen E, Marullo F, Lucini F, Petrini C, Bianchi A, Valsoni S, Olivieri I, Antonelli L, Gregoretti F, Oliva G, Ferrari F, Lanzuolo C. | Hutchinson-Gilford progeria syndrome is a genetic disease caused by an aberrant form of Lamin A resulting in chromatin structure disruption, in particular by interfering with lamina associated domains. Early molecular alterations involved in chromatin remodeling have not been identified thus far. Here, we present SAMMY-seq, a high-throughput sequencing-based method for genome-wide characterization of heterochromatin dynamics. Using SAMMY-seq, we detect early stage alterations of heterochromatin structure in progeria primary fibroblasts. These structural changes do not disrupt the distribution of H3K9me3 in early passage cells, thus suggesting that chromatin rearrangements precede H3K9me3 alterations described at later passages. On the other hand, we observe an interplay between changes in chromatin accessibility and Polycomb regulation, with site-specific H3K27me3 variations and transcriptional dysregulation of bivalent genes. We conclude that the correct assembly of lamina associated domains is functionally connected to the Polycomb repression and rapidly lost in early molecular events of progeria pathogenesis. | Nature communications 11 (2020): 6274. | 2020 | MARULLO FABRIZIA, VALSONI SARA, GREGORETTI FRANCESCO, OLIVA GENNARO, ANTONELLI LAURA, LANZUOLO CHIARA, FERRARI FRANCESCO | SAMMY-seq, Hutchinson-Gilford Progeria Syndrome | 10.1038/s41467-020-20048-9 |
| 439001 | Articolo in rivista | Missed opportunities of flu vaccination in Italian target categories: Insights from the online epicovid 19 survey | Giacomelli, Andrea, Galli, Massimo, Maggi, Stefania, Pagani, Gabriele, Incalzi, Raffaele Antonelli, Pedone, Claudio, Di Bari, Mauro, Noale, Marianna, Trevisan, Caterina, Bianchi, Fabrizio, Tavio, Marcello, Andreoni, Massimo, Mastroianni, Claudio, Sojic, Aleksandra, Prinelli, Federica, Adorni, Fulvio | We aimed to assess the reported rate of flu vaccination in the 2019/2020 season for respondents to the Italian nationwide online EPICOVID 19 survey. A national convenience sample of volunteers aged 18 or older was assessed between 13 April and 2 June 2020. Flu vaccine rates were calculated for all classes of age. The association between the independent variables and the flu vaccine was assessed by applying a multivariable binary logistic regression model. Of the 198,822 respondents, 41,818 (21.0%) reported having received a flu vaccination shot during the last influenza season. In particular, 15,009 (53.4%) subjects aged 65 years or older received a flu vaccination shot. Being 65 years aged or older (Adjusted Odds Ratios (aOR) 3.06, 95% Confidence Interval (CI) 2.92-3.20) and having a high education level (aOR 1.34. 95%CI 1.28-1.41) were independently associated to flu vaccination. Heart and lung diseases were the morbidities associated with the higher odds of being vaccinated (aOR 1.97 (95%CI 1.86-2.09) and aOR 1.92 (95%CI 1.84-2.01), respectively). Nursing home residents aged >= 65 years showed lower odds of being vaccinated (aOR 0.39 (95%CI 0.28-0.54)). Our data indicate the need for an urgent public heath effort to fill the gap of missed vaccination opportunities reported in the past flu seasons. | Vaccines (Basel) 8 (2020): 1-12. | 2020 | SOJIC ALEKSANDRA, MAGGI STEFANIA, NOALE MARIANNA, ADORNI FULVIO DANIELE, PRINELLI FEDERICA | COVID-19, Elderly, Influenza, Italy, SARS-CoV-2, Vaccine | 10.3390/vaccines8040669 |
| 440074 | Articolo in rivista | Endogenous activated small interfering RNAs in virus-infected Brassicaceae crops show a common host gene-silencing pattern affecting photosynthesis and stress response | Leonetti P., Ghasemzadeh A., Consiglio A., Gursinsky T., Behrens S.E., Pantaleo V. | Viral infections are accompanied by a massive production of small interfering RNAs (siRNAs) of plant origin, such as virus-activated (va)siRNAs, which drive the widespread silencing of host gene expression, and whose effects in plant pathogen interactions remain unknown. By combining phenotyping and molecular analyses, we characterized vasiRNAs that are associated with typical mosaic symptoms of cauliflower mosaic virus infection in two crops, turnip (Brassica rapa) and oilseed rape (Brassica napus), and the reference plantArabidopsis thaliana. We identified 15 loci in the three infected plant species, whose transcripts originate vasiRNAs. These loci appear to be generally affected by virus infections in Brassicaceae and encode factors that are centrally involved in photosynthesis and stress response, such as Rubisco activase (RCA), senescence-associated protein, heat shock protein HSP70, light harvesting complex, and membrane-related protein CP5. During infection, the expression of these factors is significantly downregulated, suggesting that their silencing is a central component of the plant's response to virus infections. Further findings indicate an important role for 22 nt long vasiRNAs in the plant's endogenous RNA silencing response. Our study considerably enhances knowledge about the new class of vasiRNAs that are triggered in virus-infected plants and will help to advance strategies for the engineering of gene clusters involved in the development of crop diseases. | New phytologist (Print) (2020). | 2020 | PANTALEO VITANTONIO, LEONETTI PAOLA, CONSIGLIO ARIANNA | 22-nt sRNAs, CaMV, disease phenotype, oilseed rape, photosynthetic-related genes, plant defense, turnip | 10.1111/nph.16932 |
| 440085 | Contributo in atti di convegno | Evaluation of Cognitive Impairment in Pediatric Multiple Sclerosis with Machine Learning: An Exploratory Study of miRNA Expressions | Casalino Gabriella (1), Vessio Gennaro (1), Consiglio Arianna (2) | Multiple Sclerosis (MS) is a demyelinating autoimmune disease that usually affects young adults; however, recently some symptoms of cognitive impairment have been recognized as early signs of MS onset in pediatric patients (PedMS). The underlying relationships between these two conditions, as well as their molecular markers, have not been fully understood yet. In this work, we analyze microRNAs (miRNAs) expression profiles of PedMS patients with machine learning algorithms in order to create effective models able to detect the presence of cognitive impairment. In particular, we compare three different classification algorithms, fed with features automatically selected by a feature selection strategy. Experimental results show that linear support vector machines achieved the best performance. Moreover, we discuss the importance of ten of the most discriminant automatically selected miRNAs. A graphical analysis of these features highlights the relationships among miRNAs and the two classes the patients belongs to. | 2020 IEEE Conference on Evolving and Adaptive Intelligent Systems (EAIS), 27-29/05/2020 | 2020 | CONSIGLIO ARIANNA | pediatric multiple sclerosis, cognitive impairment, microRNA, bioinformatics, machine learning, artificial intelligence | 10.1109/EAIS48028.2020.9122758 |
| 441881 | Articolo in rivista | Oleh Hornykiewicz, a giant in the understanding and treatment of Parkinson disease. | Zecca L, Pifl C, Fahn S, Sulzer D, Fariello RG | Oleh Hornykiewicz (November 17, 1926-May 26, 2020), by demonstrating the loss of dopamine neurons in Parkinson's disease, introducing the effort to treat the disorder with L-DOPA, and other innovative research, improved the lives of countless individuals and transformed neurology and medical science. Here we celebrate the life and great achievements of an outstanding scientist. | NPJ Parkinson's disease 7 (2021). | 2021 | ZECCA LUIGI | Parkinson's Disease | 10.1038/s41531-020-00149-4. |
| 441226 | Articolo in rivista | Rapid COVID-19 Screening Based on Self-Reported Symptoms: Psychometric Assessment and Validation of the EPICOVID19 Short Diagnostic Scale | Bastiani L, Fortunato L, Pieroni S, Bianchi F, Adorni F, Prinelli F, Giacomelli A, Pagani G, Maggi S, Trevisan C, Noale M, Jesuthasan N, Sojic A, Pettenati C, Andreoni M, Antonelli Incalzi R, Galli M, Molinaro S. | Background: Confirmed COVID-19 cases have been registered in more than 200 countries, and as of July 28, 2020, over 16 million cases have been reported to the World Health Organization. This study was conducted during the epidemic peak of COVID-19 in Italy. The early identification of individuals with suspected COVID-19 is critical in immediately quarantining such individuals. Although surveys are widely used for identifying COVID-19 cases, outcomes, and associated risks, no validated epidemiological tool exists for surveying SARS-CoV-2 infection in the general population. Objective: We evaluated the capability of self-reported symptoms in discriminating COVID-19 to identify individuals who need to undergo instrumental measurements. We defined and validated a method for identifying a cutoff score. Methods: Our study is phase II of the EPICOVID19 Italian national survey, which launched in April 2020 and included a convenience sample of 201,121 adults who completed the EPICOVID19 questionnaire. The Phase II questionnaire, which focused on the results of nasopharyngeal swab (NPS) and serological tests, was mailed to all subjects who previously underwent NPS tests. Results: Of 2703 subjects who completed the Phase II questionnaire, 694 (25.7%) were NPS positive. Of the 472 subjects who underwent the immunoglobulin G (IgG) test and 421 who underwent the immunoglobulin M test, 22.9% (108/472) and 11.6% (49/421) tested positive, respectively. Compared to NPS-negative subjects, NPS-positive subjects had a higher incidence of fever (421/694, 60.7% vs 391/2009, 19.5%; P<.001), loss of taste and smell (365/694, 52.6% vs 239/2009, 11.9%; P<.001), and cough (352/694, 50.7% vs 580/2009, 28.9%; P<.001). With regard to subjects who underwent serological tests, IgG-positive subjects had a higher incidence of fever (65/108, 60.2% vs 43/364, 11.8%; P<.001) and pain in muscles/bones/joints (73/108, 67.6% vs 71/364, 19.5%; P<.001) than IgG-negative subjects. An analysis of self-reported COVID-19 symptom items revealed a 1-factor solution, the EPICOVID19 diagnostic scale. The following optimal scores were identified: 1.03 for respiratory problems, 1.07 for chest pain, 0.97 for loss of taste and smell 0.97, and 1.05 for tachycardia (ie, heart palpitations). These were the most important symptoms. For adults aged 18-84 years, the cutoff score was 2.56 (sensitivity: 76.56%; specificity: 68.24%) for NPS-positive subjects and 2.59 (sensitivity: 80.37%; specificity: 80.17%) for IgG-positive subjects. For subjects aged >=60 years, the cutoff score was 1.28, and accuracy based on the presence of IgG antibodies improved (sensitivity: 88.00%; specificity: 89.58%). Conclusions: We developed a short diagnostic scale to detect subjects with symptoms that were potentially associated with COVID-19 from a wide population. Our results support the potential of self-reported symptoms in identifying individuals who require immediate clinical evaluations. Although these results come from the Italian pandemic period, this short diagnostic scale could be optimized and tested as a screening tool for future similar pandemics. | JMIR. Journal of medical internet research 23 (2021): 1-12. | 2021 | JESUTHASAN NITHIYA, SOJIC ALEKSANDRA, MAGGI STEFANIA, NOALE MARIANNA, MOLINARO SABRINA, ADORNI FULVIO DANIELE, FORTUNATO LOREDANA, PIERONI STEFANIA, BASTIANI LUCA, PRINELLI FEDERICA, BIANCHI FABRIZIO | COVID-19;, screening, diagnostic scale, validation, assessment, diagnostic, symptom, survey, algorithm | 10.2196/23897 |
| 442085 | Articolo in rivista | 36-kDa Annexin A3 Isoform Negatively Modulates Lipid Storage in Clear Cell Renal Cell Carcinoma Cells | Bombelli, Silvia, Torsello, Barbara, De Marco, Sofia, Lucarelli, Giuseppe, Cifola, Ingrid, Grasselli, Chiara, Strada, Guido, Bovo, Giorgio, Perego, Roberto A., Bianchi, Cristina | The adipocyte-like morphology of clear cell renal cell carcinoma (ccRCC) cells results from a gradedependent neutral lipid accumulation; however, the molecular mechanism and role in renal cancer progression have yet to be clarified. ccRCC shows a gene expression signature consistent with adipogenesis, and the phospholipid-binding protein annexin A3 (AnxA3), a negative regulator of adipocyte differentiation, is down-regulated in RCC and shows a differential expression pattern for two isoforms of 36 and 33 kDa. Using primary cell cultures and cell lines, we investigated the involvement of AnxA3 isoforms in lipid storage modulation of ccRCC cells. We found that the increased accumulation of lipids into ccRCC cells correlated with a decrease of the 36/33 isoform ratio. Treatment with adipogenic medium induced a significant increment of lipid storage in ccRCC cells that had a low 36-kDa AnxA3 expression and 36/33 ratio. The 36-kDa AnxA3 silencing in ccRCC cells increased lipid storage induced by adipogenic medium. These data suggest that 36-kDa AnxA3 negatively modulates the response to adipogenic treatment and may act as negative regulator of lipid storage in ccRCC cells. The subcellular distribution of AnxA3 in the cellular endocytic compartment suggests its involvement in modulation of vesicular trafficking, and it might serve as a putative mechanism of lipid storage regulation in ccRCC cells, opening novel translational outcomes. | The American journal of pathology (Print) 190 (2020): 2317-2326. | 2020 | CIFOLA INGRID | ccRCC, lipid storage, Annexin A3, isoforms | 10.1016/j.ajpath.2020.08.008 |
| 442465 | Articolo in rivista | Overexpression of Vesicular Monoamine Transporter-2 may Block Neurotoxic Metabolites from Cytosolic Dopamine: a Potential Neuroprotective Therapy for Parkinson's Disease | Segura-Aguilar J., Sulzer D., Zucca F.A., Zecca L. | The loss of nigrostriatal dopaminergic neurons containing neuromelanin underlies the motor symptoms of Parkinson's disease. Neuromelanin accumulation into autophagic lysosomes is evidence of ongoing cytosolic dopamine stress in these neurons during normal aging. The formation of neuromelanin is likely neuroprotective, as oxidation of cytosolic dopamine to quinones and aldehydes, as reviewed here, can produce a host of neurotoxic sequela. In addition to sequestration of dopamine and its metabolites in autophagic lysosomes, the uptake of dopamine into monoaminergic neurons mediated by vesicular monoamine transporter-2 (VMAT- 2), prevents dopamine oxidation. Dopamine is stable in monoaminergic vesicles due to their low pH, and thus overexpression of VMAT-2 may provide a target for potential neuroprotective therapy in Parkinson's disease. | Clinical pharmacology and translational medicine Online 3 (2019): 143-148. | 2019 | ZECCA LUIGI, ZUCCA FABIO ANDREA | vesicular monoamine transporter-2, cytosolic dopamine, neurotoxicity, Parkinson's disease, neuroprotection | |
| 442490 | Articolo in rivista | The Genome-wide impact of Nipblb loss-of-function on Zebrafish gene expression | Spreafico M., Mangano E., Mazzola M., Consolandi C., Bordoni R., Battaglia C., Bicciato S., Marozzi A., Pistocchi A. | Transcriptional changes normally occur during development but also underlie differences between healthy and pathological conditions. Transcription factors or chromatin modifiers are involved in orchestrating gene activity, such as the cohesin genes and their regulator NIPBL. In our previous studies, using a zebrafish model for nipblb knockdown, we described the effect of nipblb loss-of-function in specific contexts, such as central nervous system development and hematopoiesis. However, the genome-wide transcriptional impact of nipblb loss-of-function in zebrafish embryos at diverse developmental stages remains under investigation. By RNA-seq analyses in zebrafish embryos at 24 h post-fertilization, we examined genome-wide effects of nipblb knockdown on transcriptional programs. Differential gene expression analysis revealed that nipblb loss-of-function has an impact on gene expression at 24 h post fertilization, mainly resulting in gene inactivation. A similar transcriptional effect has also been reported in other organisms, supporting the use of zebrafish as a model to understand the role of Nipbl in gene regulation during early vertebrate development. Moreover, we unraveled a connection between nipblb-dependent differential expression and gene expression patterns of hematological cell populations and AML subtypes, enforcing our previous evidence on the involvement of NIPBL-related transcriptional dysregulation in hematological malignancies. | International journal of molecular sciences (Print) 21 (2020): 1-12. | 2020 | MANGANO ELEONORA, BORDONI ROBERTA, CONSOLANDI CLARISSA | RNASeq, transcriptomics | 10.3390/ijms21249719 |
| 442541 | Articolo in rivista | Genome, environment, microbiome and metabolome in autism (GEMMA) study design: Biomarkers identification for precision treatment and primary prevention of autism spectrum disorders by an integrated multi-omics systems biology approach | Troisi, Jacopo, Autio, Reija, Beopoulos, Thanos, Bravaccio, Carmela, Carraturo, Federica, Corrivetti, Giulio, Cunningham, Stephen, Devane, Samantha, Fallin, Daniele, Fetissov, Serguei, Gea, Manuel, Giorgi, Antonio, Iris, Francois, Joshi, Lokesh, Kadzielski, Sarah, Kraneveld, Aletta, Kumar, Himanshu, Ladd-Acosta, Christine, Leader, Geraldine, Mannion, Arlene, Maximin, Elise, Mezzelani, Alessandra, Milanesi, Luciano, Naudon, Laurent, Peralta Marzal, Lucia N., Pardo, Paula Perez, Prince, Naika Z., Rabot, Sylvie, Roeselers, Guus, Roos, Christophe, Roussin, Lea, Scala, Giovanni, Tuccinardi, Francesco Paolo, Fasano, Alessio | Autism Spectrum Disorder (ASD) affects approximately 1 child in 54, with a 35-fold increase since 1960. Selected studies suggest that part of the recent increase in prevalence is likely attributable to an improved awareness and recognition, and changes in clinical practice or service availability. However, this is not sufficient to explain this epidemiological phenomenon. Research points to a possible link between ASD and intestinal microbiota because many children with ASD display gastro-intestinal problems. Current large-scale datasets of ASD are limited in their ability to provide mechanistic insight into ASD because they are predominantly cross-sectional studies that do not allow evaluation of perspective associations between early life microbiota composition/function and later ASD diagnoses. Here we describe GEMMA (Genome, Environment, Microbiome and Metabolome in Autism), a prospective study supported by the European Commission, that follows at-risk infants from birth to identify potential biomarker predictors of ASD development followed by validation on large multi-omics datasets. The project includes clinical (observational and interventional trials) and pre-clinical studies in humanized murine models (fecal transfer from ASD probands) and in vitro colon models. This will support the progress of a microbiome-wide association study (of human participants) to identify prognostic microbiome signatures and metabolic pathways underlying mechanisms for ASD progression and severity and potential treatment response. | Brain sciences 10 (2020): 1-16. | 2020 | MEZZELANI ALESSANDRA MARIA, MILANESI LUCIANO | Autism, Biomarker discovery, Metabolomics, Microbiome, Precise medicine, Study design | 10.3390/brainsci10100743 |
| 442592 | Articolo in rivista | Gut Microbiota Functional Dysbiosis Relates to Individual Diet in Subclinical Carotid Atherosclerosis | Andrea Baragetti, Marco Severgnini, Elena Olmastroni, Carola Conca Dioguardi, Elisa Mattavelli, Andrea Angius, Luca Rotta, Javier Cibella, Giada Caredda, Clarissa Consolandi, Liliana Grigore, Fabio Pellegatta, Flavio Giavarini, Donatella Caruso, Giuseppe Danilo Norata, Alberico Luigi Catapano and Clelia Peano | Gut Microbiota (GM) dysbiosis associates with Atherosclerotic Cardiovascular Diseases (ACVD), but whether this also holds true in subjects without clinically manifest ACVD represents a challenge of personalized prevention. We connected exposure to diet (self-reported by food diaries) and markers of Subclinical Carotid Atherosclerosis (SCA) with individual taxonomic and functional GM profiles (from fecal metagenomic DNA) of 345 subjects without previous clinically manifest ACVD. Subjects without SCA reported consuming higher amounts of cereals, starchy vegetables, milky products, yoghurts and bakery products versus those with SCA (who reported to consume more mechanically separated meats). The variety of dietary sources significantly overlapped with the separations in GM composition between subjects without SCA and those with SCA (RV coefficient between nutrients quantities and microbial relative abundances at genus level = 0.65, pvalue = 0.047). Additionally, specific bacterial species (Faecalibacterium prausnitzii in the absence of SCA and Escherichia coli in the presence of SCA) are directly related to over-representation of metagenomic pathways linked to different dietary sources (sulfur oxidation and starch degradation in absence of SCA, and metabolism of amino acids, syntheses of palmitate, choline, carnitines and Trimethylamine n-oxide in presence of SCA). These findings might contribute to hypothesize future strategies of personalized dietary intervention for primary CVD prevention setting. | Nutrients (2021). | 2021 | SEVERGNINI MARCO, CONSOLANDI CLARISSA, PEANO CLELIA | Atherosclerotic Cardiovascular Diseases; Gut Microbiota; next generation sequencing | |
| 368306 | Articolo in rivista | Major Action of Endogenous Lysyl Oxidase in Clear Cell Renal Cell Carcinoma Progression and Collagen Stiffness Revealed by Primary Cell Cultures | Di Stefano, Vitalba, Torsello, Barbara, Bianchi, Cristina, Cifola, Ingrid, Mangano, Eleonora, Bovo, Giorgio, Cassina, Valeria, De Marco, Sofia, Corti, Roberta, Meregalli, Chiara, Bombelli, Silvia, Vigano, Paolo, Battaglia, Cristina, Strada, Guido, Perego, Roberto A. | Human clear cell renal cell carcinoma (ccRCC) is therapy resistant; therefore, it is worthwhile studying in depth the molecular aspects of its progression. In ccRCC the biallelic inactivation of the VHL gene Leads to stabilization of hypoxia-inducible factors (HIFs). Among the targets of HIF-1 alpha transcriptional activity is the LOX gene, which codes for the inactive proenzyme (Pro-Lox) from which, after extra cellular secretion and proteolysis, derives the active enzyme (Lox) and the propeptide (Lox-PP). By increasing stiffness of extracellular matrix by collagen crosslinking, Lox promotes tumor progression and metastasis. Lox and Lox-PP can reenter the cells where Lox promotes cell proliferation and invasion, whereas Lox-PP acts as tumor suppressor because of its Ras recision and apoptotic activity. Few data are available concerning LOX in ccRCC. Using an in vitro model of ccRCC primary cell cultures, we performed, for the first time in ccRCC, a detailed study of endogenous LOX and also investigated their transcriptomic profile. We found that endogenous LOX is overexpressed in ccRCC, is involved in a positive-regulative loop with HIF-1 alpha and has a major action on ccRCC progression through cellular adhesion, migration, and collagen matrix stiffness increment; however, the oncosuppressive action of Lox-PP was not found to prevail. These findings may suggest translational approaches for new therapeutic strategies in ccRCC. | The American journal of pathology (Print) 186 (2016): 2473-2485. | 2016 | MANGANO ELEONORA, BATTAGLIA CRISTINA, CIFOLA INGRID | * | 10.1016/j.ajpath.2016.05.019 |
| 368307 | Articolo in rivista | MicroRNAs are associated with blood-pressure effects of exposure to particulate matter: Results from a mediated moderation analysis | Motta, Valeria, Favero, Chiara, Dioni, Laura, Iodice, Simona, Battaglia, Cristina, Angelici, Laura, Vigna, Luisella, Pesatori, Angela Cecilia, Bollati, Valentina | Aims Exposure to particulate air pollution is associated with increased blood pressure (BP), a well-established risk factor for cardiovascular disease. To elucidate the mechanisms underlying this relationship, we investigated whether the effects of particulate matter of less than 10 ?m in aerodynamic diameter (PM10) on BP are mediated by microRNAs. Methods and results We recruited 90 obese individuals and we assessed their PM10 exposure 24 and 48 h before the recruitment day. We performed multivariate linear regression models to investigate the effects of PM10 on BP. Using the TaqMan(R) Low-Density Array, we experimentally evaluated and technically validated the expression levels of 377 human miRNAs in peripheral blood. We developed a mediated moderation analysis to estimate the proportion of PM10 effects on BP that was mediated by miRNA expression. PM10 exposure 24 and 48 h before the recruitment day was associated with increased systolic BP (?=1.22 mmHg, P=0.019; ?=1.24 mmHg, P=0.019, respectively) and diastolic BP (?=0.67 mmHg, P=0.044; ?=0.91 mmHg, P=0.007, respectively). We identified nine miRNAs associated with PM10 levels 48 h after exposure. A conditional indirect effect (CIE=-0.1431) of PM10 on diastolic BP, which was mediated by microRNA-101, was found in individuals with lower values of mean body mass index. Conclusions Our data provide evidence that miRNAs are a molecular mechanism underlying the BP-related effects of air pollution exposure, and indicate miR-101 as epigenetic mechanism to be further investigated. | Environmental research (N. Y. N. Y., Print) 146 (2016): 274-281. | 2016 | BATTAGLIA CRISTINA | Air pollution, Microrna, Blood pressure, Cardiovascular disease, Obesity | 10.1016/j.envres.2016.01.010 |
| 368311 | Articolo in rivista | The Italian Consensus Conference on Pain in Neurorehabilitation: rationale and methodology | Tamburin, Stefano, Paolucci, Stefano, Magrinelli, Francesca, Musicco, Massimo, Sandrini, Giorgio | Pain is very common in the neurorehabilitation setting, where it may not only represent a target for treatment but can also negatively influence rehabilitation procedures directly or through the side effects of painkillers. To date, there are neither guidelines nor consensus on how to assess and treat pain in neurorehabilitation. Because of the very scanty pieces of evidence on this topic, the Italian Consensus Conference on Pain in Neurorehabilitation (ICCPN) was promoted under the auspices of different scientific societies. This article illustrates the rationale, methodology, and topics of the ICCPN. The recommendations of the ICCPN will offer some information on how to deal with pain in neurorehabilitation and may represent the starting point for further studies. | Journal of pain research 9 (2016): 311-318. | 2016 | MUSICCO MASSIMO | assessment, consensus conference, neurology, pain, rehabilitation, treatment | 10.2147/JPR.S84646 |
| 368312 | Articolo in rivista | "Delirium Day": a nationwide point prevalence study of delirium in older hospitalized patients using an easy standardized diagnostic tool | Bellelli, Giuseppe, Morandi, Alessandro, Di Santo, Simona G., Mazzone, Andrea, Cherubini, Antonio, Mossello, Enrico, Bo, Mario, Bianchetti, Angelo, Rozzini, Renzo, Zanetti, Ermellina, Musicco, Massimo, Ferrari, Alberto, Ferrara, Nicola, Trabucchi, Marco | Background To date, delirium prevalence in adult acute hospital populations has been estimated generally from pooled findings of single-center studies and/or among specific patient populations. Furthermore, the number of participants in these studies has not exceeded a few hundred. To overcome these limitations, we have determined, in a multicenter study, the prevalence of delirium over a single day among a large population of patients admitted to acute and rehabilitation hospital wards in Italy. Methods This is a point prevalence study (called "Delirium Day") including 1867 older patients (aged 65 years or more) across 108 acute and 12 rehabilitation wards in Italian hospitals. Delirium was assessed on the same day in all patients using the 4AT, a validated and briefly administered tool which does not require training. We also collected data regarding motoric subtypes of delirium, functional and nutritional status, dementia, comorbidity, medications, feeding tubes, peripheral venous and urinary catheters, and physical restraints. Results The mean sample age was 82.0 +- 7.5 years (58 % female). Overall, 429 patients (22.9 %) had delirium. Hypoactive was the commonest subtype (132/344 patients, 38.5 %), followed by mixed, hyperactive, and nonmotoric delirium. The prevalence was highest in Neurology (28.5 %) and Geriatrics (24.7 %), lowest in Rehabilitation (14.0 %), and intermediate in Orthopedic (20.6 %) and Internal Medicine wards (21.4 %). In a multivariable logistic regression, age (odds ratio [OR] 1.03, 95 % confidence interval [CI] 1.01-1.05), Activities of Daily Living dependence (OR 1.19, 95 % CI 1.12-1.27), dementia (OR 3.25, 95 % CI 2.41-4.38), malnutrition (OR 2.01, 95 % CI 1.29-3.14), and use of antipsychotics (OR 2.03, 95 % CI 1.45-2.82), feeding tubes (OR 2.51, 95 % CI 1.11-5.66), peripheral venous catheters (OR 1.41, 95 % CI 1.06-1.87), urinary catheters (OR 1.73, 95 % CI 1.30-2.29), and physical restraints (OR 1.84, 95 % CI 1.40-2.40) were associated with delirium. Admission to Neurology wards was also associated with delirium (OR 2.00, 95 % CI 1.29-3.14), while admission to other settings was not. Conclusions Delirium occurred in more than one out of five patients in acute and rehabilitation hospital wards. Prevalence was highest in Neurology and lowest in Rehabilitation divisions. The "Delirium Day" project might become a useful method to assess delirium across hospital settings and a benchmarking platform for future surveys. | BMC medicine 14 (2016). | 2016 | DI SANTO SIMONA GABRIELLA, MUSICCO MASSIMO | Delirium, Prevalence, Hospital, Multicenter, 4AT | 10.1186/s12916-016-0649-8 |
| 368313 | Articolo in rivista | EMpowerment of PArents in THe Intensive Care Questionnaire: Translation and Validation in Italian PICUs | Wolfler, Andrea MD, Giannini, Alberto MD, Finistrella, Martina RN, Salvo, Ida MD, Calderini, Edoardo MD, Frasson, Giulia MD, Dall'Oglio, Immacolata RN, Di Furia, Michela RN, Iuzzolino, Rossella RN, Musicco, Massimo RN, Latour, Jos M. PhD, RN, FEfCCNa | Objectives: To translate and validate the EMpowerment of PArents in THe Intensive Care questionnaire to measure parent satisfaction and experiences in Italian PICUs. Design: Prospective, multicenter study. Setting: Four medical/surgical Italian PICUs in three tertiary hospitals. Patients: Families of children, 0-16 years old, admitted to the PICUs were invited to participate. Inclusion criteria were PICU length of stay greater than 24 hours and good comprehension of Italian language by parents/guardians. Exclusion criteria were readmission within 6 months and parents of a child who died in the PICU. Interventions: Distribution, at PICU discharge, of the EMpowerment of PArents in THe Intensive Care questionnaire with 65 items divided into five domains and a six-point rating scale: 1 " certainly no" to 6 "certainly yes." Measurements and Main Results: Back and forward translations of the EMpowerment of PArents in THe Intensive Care questionnaire between Dutch (original version) and Italian languages were deployed. Cultural adaptation of the instrument was confirmed by a consultation with a representative parent group (n = 10). Totally, 150 of 190 parents (79%) participated in the study. On item level, 12 statements scored a mean below 5.0. The Cronbach's ?, measured for internal consistency, on domain level was between 0.67 and 0.96. Congruent validity was measured by correlating the five domains with four gold standard satisfaction measures and showed adequate correlations (rs, 0.41-0.71; p < 0.05). No significant differences occurred in the nondifferential validity testing between three children's characteristics and the domains; excepting parents with a child for a surgical and planned admission were more satisfied on information and organization issues. Conclusions: The Italian version of the EMpowerment of PArents in THe Intensive Care questionnaire has satisfactory reliability and validity estimates and seems to be appropriate for Italian PICU setting. It is an important instrument providing benchmark data to be used in the process of quality improvement toward the development of a family-centered care philosophy within Italian PICUs. | Pediatric critical care medicine (Online) 18 (2016): e77-e85. | 2016 | MUSICCO MASSIMO | * | 10.1097/PCC.0000000000001031 |
| 346554 | Articolo in rivista | Integrative transcriptomic and protein analysis of human bronchial BEAS-2B exposed to seasonal urban particulate matter. | Longhin, Eleonora, Capasso, Laura, Battaglia, Cristina, Proverbio, Maria Carla, Cosentino, Cristina, Cifola, Ingrid, Mangano, Eleonora, Camatini, Marina, Gualtieri, Maurizio | BACKGROUND: Exposure to particulate matter (PM) is associated with various health effects. Physico-chemical properties influence the toxicological impact of PM, nonetheless the mechanisms underlying PM-induced effects are not completely understood. OBJECTIVES: Human bronchial epithelial cells were used to analyse the pathways activated after exposure to summer and winter urban PM and to identify possible markers of exposure. METHODS: BEAS-2B cells were exposed for 24 h to 10 ?g/cm(2) of winter PM2.5 (wPM) and summer PM10 (sPM) sampled in Milan. A microarray technology was used to profile the cells gene expression. Genes and microRNAs were analyzed by bioinformatics technique to identify pathways involved in cellular responses. Selected genes and pathways were validated at protein level (western blot, membrane protein arrays and ELISA). RESULTS: The molecular networks activated by the two PM evidenced a correlation among oxidative stress, inflammation and DNA damage responses. sPM induced the release of pro-inflammatory mediators, although miR-146a and genes related to inflammation resulted up-regulated by both PM. Moreover both PM affected a set of genes, proteins and miRNAs related to antioxidant responses, cancer development, extracellular matrix remodeling and cytoskeleton organization, while miR-29c, implicated in epigenetic modification, resulted up-regulated only by wPM. sPM effects may be related to biological and inorganic components, while wPM apparently related to the high content of organic compounds. CONCLUSIONS: These results may be helpful for the individuation of biomarkers for PM exposure, linked to the specific PM physico-chemical properties. | Environmental pollution (1987) 209 (2016): 87-98. | 2016 | MANGANO ELEONORA, BATTAGLIA CRISTINA, CIFOLA INGRID | Biomarker of exposure; Global gene expression; Global micro RNA expression; Integrated molecular signature; Particulate matter | 10.1016/j.envpol.2015.11.013 |
| 368331 | Articolo in rivista | For whom should the coin flip? Therapeutic Interests and the Ethics of Clinical Research | Annoni M. | Should clinical research and clinical practice be oriented according to the same moral principles? In this short article I explain why adopting a more person-centered view in research ethics provides an interesting answer to this question, and what implica-tions such a view has for rethinking how randomized trials are currently designed. | The Future of Science and Ethics (Online) 1 (2016): 27-28. | 2016 | ANNONI MARCO ANGELO MARIA | * | |
| 368333 | Articolo in rivista | "Paolo Legrenzi, Armando Massarenti, La buona logica. Imparare a pensare, Milano, Raffaello Cortina Editore, 2015" | Zagarella R.M. | * | The Future of Science and Ethics (Online) 1 (2016): 186-188. | 2016 | ZAGARELLA ROBERTA MARTINA | * | |
| 368334 | Articolo in rivista | Grandi diritti per piccoli pazienti | Mancini E. | * | The Future of Science and Ethics (Online) (2016): 98-100. | 2016 | MANCINI ELENA | * | |
| 368342 | Articolo in rivista | Virus ingegnerizzati e dual-use research: profili etici | Pievani T., Redi C.A., Annoni M. | * | The Future of Science and Ethics (Online) 1 (2016): 124-133. | 2016 | ANNONI MARCO ANGELO MARIA | * | |
| 367081 | Articolo in rivista | microRNA miR-200b affects proliferation, invasiveness and stemness of endometriotic cells by targeting ZEB1, ZEB2 and KLF4 | Eggers, Julia C., Martino, Valentina, Reinbold, Rolland, Schaefer, Sebastian D., Kiesel, Ludwig, Starzinski-Powitz, Anna, Schuering, Andreas N., Kemper, Bjoern, Greve, Burkhard, Goette, Martin | Endometriosis is characterized by growth of endometrial tissue at ectopic locations. Down-regulation of microRNA miR-200b is observed in endometriosis and malignant disease, driving tumour cells towards an invasive state by enhancing epithelial-to-mesenchymal transition (EMT). miR-200b up-regulation may inhibit EMT and invasive growth in endometriosis. To study its functional impact on the immortalized endometriotic cell line 12Z, the stromal cell line ST-T1b, and primary endometriotic stroma cells, a transient transfection approach with microRNA precursors was employed. Expression of bioinformatically predicted targets of miR-200b was analysed by qPCR. The cellular phenotype was monitored by Matrigel invasion assays, digital-holographic video microscopy and flow cytometry. qPCR revealed significant down-regulation of ZEB1 (P < 0.05) and ZEB2 (P < 0.01) and an increase in E-cadherin (P < 0.01). miR-200b overexpression decreased invasiveness (P < 0.0001) and cell motility (P < 0.05). In contrast, cell proliferation (P < 0.0001) and the stemness-associated side population phenotype (P < 0.01) were enhanced following miR-200b transfection. These properties were possibly due to up-regulation of the pluripotency-associated transcription factor KLF4 (P < 0.05) and require attention when considering therapeutic strategies. In conclusion, up-regulation of miR-200b reverts EMT, emerging as a potential therapeutic approach to inhibit endometriotic cell motility and invasiveness. (C) 2016 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved. | Reproductive biomedicine online (Print) 32 (2016): 434-445. | 2016 | REINBOLD ROLLAND ALVONS, MARTINO VALENTINA | EMT, endometriosis, microRNA, miR-200b, stem cells, subfertility | 10.1016/j.rbmo.2015.12.013 |
| 367082 | Articolo in rivista | A Myc-driven self-reinforcing regulatory network maintains mouse embryonic stem cell identity | Fagnocchi, Luca, Cherubini, Alessandro, Hatsuda, Hiroshi, Fasciani, Alessandra, Mazzoleni, Stefania, Poli, Vittoria, Berno, Valeria, Rossi, Riccardo L., Reinbold, Rolland, Endele, Max, Schroeder, Timm, Rocchigiani, Marina, Szkarlat, Zaneta, Oliviero, Salvatore, Dalton, Stephen, Zippo, Alessio | Stem cell identity depends on the integration of extrinsic and intrinsic signals, which directly influence the maintenance of their epigenetic state. Although Myc transcription factors play a major role in stem cell self-renewal and pluripotency, their integration with signalling pathways and epigenetic regulators remains poorly defined. We addressed this point by profiling the gene expression and epigenetic pattern in ESCs whose growth depends on conditional Myc activity. Here we show that Myc potentiates the Wnt/beta-catenin signalling pathway, which cooperates with the transcriptional regulatory network in sustaining ESC self-renewal. Myc activation results in the transcriptional repression of Wnt antagonists through the direct recruitment of PRC2 on these targets. The consequent potentiation of the autocrine Wnt/beta-catenin signalling induces the transcriptional activation of the endogenous Myc family members, which in turn activates a Myc-driven self-reinforcing circuit. Thus, our data unravel a Myc-dependent self-propagating epigenetic memory in the maintenance of ESC self-renewal capacity. | Nature communications 7 (2016). | 2016 | REINBOLD ROLLAND ALVONS | Stem cell | 10.1038/ncomms11903 |
| 367083 | Articolo in rivista | Genomic and expression analyses of Tursiops truncatus T cell receptor gamma (TRG) and alpha/delta (TRA/TRD) loci reveal a similar basic public ?? repertoire in dolphin and human | Linguiti G., Antonacci R., Tasco G., Grande F., Casadio R., Massari S., Castelli V., Consiglio A., Lefranc M.-P., Ciccarese S. | Background: The bottlenose dolphin (Tursiops truncatus) is a mammal that belongs to the Cetartiodactyla and have lived in marine ecosystems for nearly 60 millions years. Despite its popularity, our knowledge about its adaptive immunity and evolution is very limited. Furthermore, nothing is known about the genomics and evolution of dolphin antigen receptor immunity. Results: Here we report a evolutionary and expression study of Tursiops truncatus T cell receptor gamma (TRG) and alpha/delta (TRA/TRD) genes. We have identified in silico the TRG and TRA/TRD genes and analyzed the relevant mature transcripts in blood and in skin from four subjects. The dolphin TRG locus is the smallest and simplest of all mammalian loci as yet studied. It shows a genomic organization comprising two variable (V1 and V2), three joining (J1, J2 and J3) and a single constant (C), genes. Despite the fragmented nature of the genome assemblies, we deduced the TRA/TRD locus organization, with the recent TRDV1 subgroup genes duplications, as it is expected in artiodactyls. Expression analysis from blood of a subject allowed us to assign unambiguously eight TRAV genes to those annotated in the genomic sequence and to twelve new genes, belonging to five different subgroups. All transcripts were productive and no relevant biases towards TRAV-J rearrangements are observed. Blood and skin from four unrelated subjects expression data provide evidence for an unusual ratio of productive/unproductive transcripts which arise from the TRG V-J gene rearrangement and for a "public" gamma delta TR repertoire. The productive cDNA sequences, shared both in the same and in different individuals, include biases of the TRGV1 and TRGJ2 genes. The high frequency of TRGV1-J2/TRDV1- D1-J4 productive rearrangements in dolphins may represent an interesting oligo-clonal population comparable to that found in human with the TRGV9- JP/TRDV2-D-J T cells and in primates. Conclusions: Although the features of the TRG and TRA/TRD loci organization reflect those of the so far examined artiodactyls, genomic results highlight in dolphin an unusually simple TRG locus. The cDNA analysis reveal productive TRA/TRD transcripts and unusual ratios of productive/unproductive TRG transcripts. Comparing multiple different individuals, evidence is found for a "public" gamma delta TCR repertoire thus suggesting that in dolphins as in human the gamma delta TCR repertoire is accompanied by selection for public gamma chain. | BMC genomics 17 (2016). | 2016 | CONSIGLIO ARIANNA | Dolphin genome, Expression analysis, IMGT, T cell receptor, TRA/TRD locus, TRAV and TRDV genes, TRG locus, TRGJ and TRGC genes, TRGV | 10.1186/s12864-016-2841-9 |
| 367086 | Articolo in rivista | Placebo effects and the ethics of therapeutic communication: A pragmatic perspective | Annoni M., Miller F.G. | In this article we explore the ethics of manipulating verbal information for the sake of influencing health outcomes through placebo and nocebo responses. Recent scientific research on placebo and nocebo effects has drawn attention to the ways in which communication by health professionals may modulate the symptoms of patients across an array of highly prevalent conditions such as pain, depression, anxiety, insomnia, irritable bowel syndrome, migraine, and Parkinson's disease. The positive and negative effects of clinicians' communication on patient outcomes pose important ethical issues, which we describe in this article under the label of "the ethics of therapeutic communication" (TC). We begin by reviewing available evidence supporting the claim that doctor-patient communication has therapeutic effects. We then identify in truthfulness, helpfulness, and pragmatism three morally relevant considerations that can guide clinicians in therapeutic communication with their patients. Finally, we examine the ethics of using TC to enhance the effectiveness of proven medical interventions and open-label placebos. | Kennedy Institute of Ethics journal (Online) 26 (2016): 79-103. | 2016 | ANNONI MARCO ANGELO MARIA | * | 10.1353/ken.2016.0004 |
| 367087 | Contributo in volume | Reason and Emotions in Ethical Counselling | Annoni, MA | * | Ethical Counselling and Medical Decision-Making in the Era of Personalised Medicine A Practice-Oriented Guide, edited by Boniolo, Giovanni, Sanchini, Virginia, 2016 | 2016 | ANNONI MARCO ANGELO MARIA | * | |
| 367088 | Articolo in rivista | Perche argomentiamo? Consenso e dissenso tra retorica e democrazia | Roberta Martina Zagarella | Is agreement the purpose of argumentation? This article compares two different approaches to argumentation, analysing its political effects. The comparison is undertaken in the first section of the paper considering two main groups of argumentation theories; one group in which argumentation aims to resolve a disagreement or a difference of opinion in order to reach an agreement (e.g. VAN EEMEREN e GROOTENDORST 2004; VAN EEMEREN et. al. 1993) and one group which is concerned with deep disagreements. The second section questions some political implications of the agreement-oriented perspective, which is often connected with a normative discussion model and with a negative evaluation of pathos and ethos. The last part of the paper outlines the socio-political advantages of a rhetorical approach to agreement and disagreement, which includes logos as well as pathos and ethos. In particular, the so-called rhetoric of dissensus, which takes into account the personal dimension of argumentation, shows the constructive dimension of conflict and the democratic value of polemic discourses and ad hominem arguments. | Rivista italiana di filosofia del linguaggio (2016): 310-318. | 2016 | ZAGARELLA ROBERTA MARTINA | rhetoric, argumentation, agreement, disagreement, ad hominem | 10.4396/2016BC26 |
| 367089 | Articolo in rivista | La forza persuasiva delle teorie del complotto | Roberta Martina Zagarella | * | Quaderni della ginestra 17 (2016): 39-44. | 2016 | ZAGARELLA ROBERTA MARTINA | * | |
| 367090 | Articolo in rivista | Diritto alla salute, equita e governance delle malattie neglette e della poverta | Elena Mancini | L'articolo esamina la salute quale diritto umano fondamentale nelle principali Carte internazionali. Sara in particolare ricostruito il percorso storico-concettuale che ha portato al riconoscimento della natura complessa e inclusiva del diritto alla salute. Il fallimento delle politiche sanitarie mirate a sconfiggere singole malattie - come avvenuto nel caso della malaria - ha imposto una maggiore attenzione verso i determinanti sociali della salute, dando origine ad un processo che ha portato a concepire la salute quale problema di equita internazionale la cui soluzione richiede la realizzazione di condizioni sociali, economiche e ambientali e la promozione di liberta umane fondamentali. Il diritto a godere del piu alto livello di salute ricomprende oltre al diritto all'accesso a cure mediche e a farmaci di qualita, anche la disponibilita di misure igieniche, di corrette informazioni sanitarie e la protezione di liberta fondamentali quali la liberta dall'esclusione sociale e il possesso di titoli per l'accesso concreto alle cure essenziali primarie. Viene proposta una interpretazione dei diversi modelli di giustizia sanitaria elaborati per l'individuazione delle priorita nella utilizzazione delle risorse sanitarie, nella pianificazione degli interventi anche a livello internazionale e per la valutazione dei risultati da questi conseguiti in termini di equita e di protezione dei diritti umani. Sono esaminati gli indicatori e i parametri utilizzati per monitorare la progressiva realizzazione del diritto alla salute e l'efficacia degli interventi internazionali nel promuovere l'accesso universale alle cure con particolare attenzione alle strategie di contrasto delle malattie neglette e della poverta. In particolare viene illustrato il modello delle liberta sostanziali quali "capacitazioni" teorizzato da Amartya Sen e sviluppato da Martha Nussbaum nelle sue possibili applicazioni nell'ambito dell'accesso universale alle cure e delle possibili linee di azione della solidarieta internazionale. | Medicina e morale (2016). | 2016 | MANCINI ELENA | malattie neglette, determinanti sociali delle malattie, diritto alla salute, solidarieta, capacitazioni / neglected tropical diseases, social determinants of health, right to health, solidarity, capabilities | 10.4081/mem.2016.444 |
| 355132 | Articolo in rivista | An atomistic view of Hsp70 allosteric crosstalk: From the nucleotide to the substrate binding domain and back | Chiappori F., Merelli I., Milanesi L., Colombo G., Morra G. | The Hsp70 is an allosterically regulated family of molecular chaperones. They consist of two structural domains, NBD and SBD, connected by a flexible linker. ATP hydrolysis at the NBD modulates substrate recognition at the SBD, while peptide binding at the SBD enhances ATP hydrolysis. In this study we apply Molecular Dynamics (MD) to elucidate the molecular determinants underlying the allosteric communication from the NBD to the SBD and back. We observe that local structural and dynamical modulation can be coupled to large-scale rearrangements, and that different combinations of ligands at NBD and SBD differently affect the SBD domain mobility. Substituting ADP with ATP in the NBD induces specific structural changes involving the linker and the two NBD lobes. Also, a SBD-bound peptide drives the linker docking by increasing the local dynamical coordination of its C-terminal end: a partially docked DnaK structure is achieved by combining ATP in the NBD and peptide in the SBD. We propose that the MD-based analysis of the inter domain dynamics and structure modulation could be used as a tool to computationally predict the allosteric behaviour and functional response of Hsp70 upon introducing mutations or binding small molecules, with potential applications for drug discovery. | Scientific reports (Nature Publishing Group) 6 (2016): 126-130. | 2016 | CHIAPPORI FEDERICA, COLOMBO GIORGIO, MORRA GIULIA | FREE-ENERGY CALCULATIONS; BOUND-CONSTRAINED OPTIMIZATION; STREPTOCOCCAL PROTEIN-G; REPLICA-EXCHANGE METHOD; ABSOLUTE FREE-ENERGIES; MOLECULAR SIMULATION; BIOMOLECULAR SYSTEMS; ORTHOGONAL SPACE; DYNAMICS; EFFICIENT | 10.1038/srep23474 |
| 367446 | Articolo in rivista | Differential Proteomics Based on Multidimensional Protein Identification Technology to Understand the Biogenesis of Outer Membrane of Escherichia coli | Martorana, Alessandra M., Motta, Sara, Sperandeo, Paola, Mauri, Pierluigi, Polissi, Alessandra | Cell envelope proteins in bacteria are typically difficult to characterize due to their low abundance, poor solubility, and the problematic isolation of pure surface fraction with only minimal contamination. Here we describe a method for cell membrane fractionation followed by mass spectrometry-based proteomics to analyze and determine protein abundance in bacterial membranes. | Methods in molecular biology (Clifton N.J.) 1440 (2016): 57-70. | 2016 | MOTTA SARA, MAURI PIETRO LUIGI | MudPIT, Membrane proteins, Gel-free, Gram-negative cell envelope, Outer membrane, Cell fractionation | 10.1007/978-1-4939-3676-2_5 |
| 369868 | Articolo in rivista | Evidence for three genetic loci involved in both anorexia nervosa risk and variation of body mass index (vol 22, pg 192, 2017) | Hinney, A., Kesselmeier, M., Jall, S., Volckmar, A-L, Focker, M., Antel, J., Heid, I. M., Winkler, T. W., Grant, S. F. A., Guo, Y., Bergen, A. W., Kaye, W., Berrettini, W., Hakonarson, H., Herpertz-Dahlmann, B., de Zwaan, M., Herzog, W., Ehrlich, S., Zipfel, S., Egberts, K. M., Adan, R., Brandys, M., van Elburg, A., Perica, V. Boraska, Franklin, C. S., Tschop, M. H., Zeggini, E., Bulik, C. M., Collier, D., Scherag, A., Mueller, T. D., Hebebrand, J. | The maintenance of normal body weight is disrupted in patients with anorexia nervosa (AN) for prolonged periods of time. Prior to the onset of AN, premorbid body mass index (BMI) spans the entire range from underweight to obese. After recovery, patients have reduced rates of overweight and obesity. As such, loci involved in body weight regulation may also be relevant for AN and vice versa. Our primary analysis comprised a cross-trait analysis of the 1000 single-nucleotide polymorphisms (SNPs) with the lowest Pvalues in a genome-wide association meta-analysis (GWAMA) of AN (GCAN) for evidence of association in the largest published GWAMA for BMI (GIANT). Subsequently we performed sex-stratified analyses for these 1000 SNPs. Functional ex vivo studies on four genes ensued. Lastly, a look-up of GWAMA-derived BMI-related loci was performed in the AN GWAMA. We detected significant associations (P-values o5 x 10- 5, Bonferroni-corrected Po0.05) for nine SNP alleles at three independent loci. Interestingly, all AN susceptibility alleles were consistently associated with increased BMI. None of the genes (chr. 10: CTBP2, chr. 19: CCNE1, chr. 2: CARF and NBEAL1; the latter is a region with high linkage disequilibrium) nearest to these SNPs has previously been associated with AN or obesity. Sex-stratified analyses revealed that the strongest BMI signal originated predominantly from females (chr. 10 rs1561589; Poverall: 2.47 x 10- 06/Pfemales: 3.45 x 10- 07/Pmales: 0.043). Functional ex vivo studies in mice revealed reduced hypothalamic expression of Ctbp2 and Nbeal1 after fasting. Hypothalamic expression of Ctbp2 was increased in diet-induced obese (DIO) mice as compared with age-matched lean controls. We observed no evidence for associations for the look-up of BMI-related loci in the AN GWAMA. A cross-trait analysis of AN and BMI loci revealed variants at three chromosomal loci with potential joint impact. The chromosome 10 locus is particularly promising given that the association with obesity was primarily driven by females. In addition, the detected altered hypothalamic expression patterns of Ctbp2 and Nbeal1 as a result of fasting and DIO implicate these genes in weight regulation. | Molecular psychiatry 22 (2017): 321-322. | 2017 | CUSI DANIELE | * | 10.1038/mp.2016.126 |
| 368316 | Contributo in volume | Managing NGS differential expression uncertainty with fuzzy sets | Consiglio A., Mencar C., Grillo G., Liuni S. | High-performance Next-Generation Sequencing (NGS) has become a widely used technology to characterize case-control comparison studies for RNA transcripts, such as mRNAs and small non-coding RNAs. The first step in the analysis strategies is mapping NGS reads against a reference database and a critical issue emerges in this phase: the problem of multireads. In this paper we present a novel approach to represent and quantify read mapping ambiguities through the use of fuzzy sets and possibility theory. The aim of this work is to obtain a list of candidate differential expression events, providing a description of the uncertainty of the results due to multiread presence. In a preliminary experiment on HeLa cells, the method correctly detected the possibility of false positiveness, while on a case-control study of human endobronchial biopsies, the method identified 11 genes with possible different expression, four of them with an uncertain fold change. This last result was confirmed by FDR adjusted Fisher's test, while DESeq2 did not provide significant differences between case and control. | , pp. 42-53, 2016 | 2016 | CONSIGLIO ARIANNA, GRILLO GIORGIO, LIUNI SABINO | Differential expression, Fuzzy sets, Multireads, Possibility measure, RNA-Seq | 10.1007/978-3-319-44332-4_4 |
| 368130 | Contributo in atti di convegno | Implementing a space-aware stochastic simulator on low-power architectures: a systems biology case study | L. Morganti, E. Corni, A. Ferraro, D. Cesini, D. D'Agostino, I. Merelli | In the last decade, different computing paradigms and modelling frameworks for the description and simulation of biochemical systems based on stochastic modelling have been proposed. From a computational point of view, many simulations of the model are necessary to identify the behaviour of the system. The execution of thousands of simulations can require huge amount of time, therefore the parallelization of these algorithms is highly desirable. In particular, models that consider the size of volumes and objects involved in the reaction are very timeconsuming, since many rules should be considered to take into account the position of the different molecules. In this work we present an implementation of a stochastic space-aware simulator which exploits the benefit and features of hybrid low-power computing architectures. This work shows that the simulator dynamic probabilistic approach to select possible chemical reactions can be applied and implemented in hybrid low-power low-cost architectures as well as current industry highend servers. | 25th Euromicro International Conference on Parallel, Distributed and Network-Based Processing, pp. 303-308, Saint Petersburg, 06-08/03/2017 | 2017 | D'AGOSTINO DANIELE, MERELLI IVAN | stochastic simulator, low-power devices, bioinformatics | 10.1109/PDP.2017.55 |
| 369949 | Articolo in rivista | Insight into the essential role of the Helicobacter pylori HP1043 orphan response regulator: genome-wide identification and characterization of the DNA-binding sites | Pelliciari, Simone, Pinatel, Eva, Vannini, Andrea, Peano, Clelia, Puccio, Simone, De Bellis, Gianluca, Danielli, Alberto, Scarlato, Vincenzo, Roncarati, Davide | Many bacterial regulatory genes appear to be dispensable, as they can be deleted from the genome without loss of bacterial functionalities. In Helicobacter pylori, the hp1043 gene, also known as hsrA, is one of the transcriptional regulator that is essential for cell viability. This gene could not be deleted, nor the amount of protein modulated, supporting the hypothesis that HP1043 could be involved in the regulation of crucial cellular processes. Even though detailed structural data are available for the HP1043 protein, its targets are still ill-defined. Using Chromatin Immunoprecipitation-sequencing (ChIP-seq), one of the most powerful approaches to characterize protein-DNA interactions in vivo, we were able to identify genome-wide several new HP1043 binding sites. Moreover, in vitro DNA binding assays enabled precise mapping of the HP1043 binding sites on the new targets, revealing the presence of a conserved nucleotide sequence motif. Intriguingly, a significant fraction of the newly identified binding sites overlaps promoter regions controlling the expression of genes involved in translation. Accordingly, when protein translation was blocked, a significant induction of almost all HP1043 target genes was detected. These observations prompted us to propose HP1043 as a key regulator in H. pylori, likely involved in sensing and in coordinating the response to environmental conditions that provoke an arrest of protein synthesis. The essential role of HP1043 in coordinating central cellular processes is discussed. | Scientific reports (Nature Publishing Group) 7 (2017). | 2017 | PINATEL EVA MARIA, PUCCIO SIMONE, DE BELLIS GIANLUCA, PEANO CLELIA | * | 10.1038/srep41063 |
| 369950 | Articolo in rivista | Comprehensive mapping of the Helicobacter pylori NikR regulon provides new insights in bacterial nickel responses | Vannini, Andrea, Pinatel, Eva, Costantini, Paolo Emidio, Pelliciari, Simone, Roncarati, Davide, Puccio, Simone, De Bellis, Gianluca, Peano, Clelia, Danielli, Alberto | Nickel homeostasis is important for pathogenic and ureolytic bacteria, which use this metal ion as enzymatic cofactor. For example, in the human pathogen Helicobacter pylori an optimal balance between nickel uptake and incorporation in metallo-enzymes is fundamental for colonization of the host. Nickel is also used as cofactor to modulate DNA binding of the NikR regulator, which controls transcription of genes involved in nickel trafficking or infection in many bacteria. Accordingly, there is much interest in a systematic characterization of NikR regulation. Herein we use H. pylori as a model to integrate RNA-seq and ChIP-seq data demonstrating that NikR not only regulates metal-ion transporters but also virulence factors, non-coding RNAs, as well as toxin-antitoxin systems in response to nickel stimulation. Altogether, results provide new insights into the pathobiology of H. pylori and contribute to understand the responses to nickel in other bacteria. | Scientific reports (Nature Publishing Group) 7 (2017). | 2017 | PINATEL EVA MARIA, PUCCIO SIMONE, DE BELLIS GIANLUCA, PEANO CLELIA | * | 10.1038/srep45458 |
| 369966 | Articolo in rivista | Complete mitochondrial sequences from Mesolithic Sardinia | Modi, Alessandra, Tassi, Francesca, Susca, Roberta Rosa, Vai, Stefania, Rizzi, Ermanno, De Bellis, Gianluca, Luglie, Carlo, Fortes, Gloria Gonzalez, Lari, Martina, Barbujani, Guido, Caramelli, David, Ghirotto, Silvia | Little is known about the genetic prehistory of Sardinia because of the scarcity of pre-Neolithic human remains. From a genetic perspective, modern Sardinians are known as genetic outliers in Europe, showing unusually high levels of internal diversity and a close relationship to early European Neolithic farmers. However, how far this peculiar genetic structure extends and how it originated was to date impossible to test. Here we present the first and oldest complete mitochondrial sequences from Sardinia, dated back to 10,000 yBP. These two individuals, while confirming a Mesolithic occupation of the island, belong to rare mtDNA lineages, which have never been found before in Mesolithic samples and that are currently present at low frequencies not only in Sardinia, but in the whole Europe. Preliminary Approximate Bayesian Computations, restricted by biased reference samples for Mesolithic Sardinia (the two typed samples) and Neolithic Europe (limited to central and north European sequences), suggest that the first inhabitants of the island have had a small or negligible contribution to the present-day Sardinian population, which mainly derives its genetic diversity from continental migration into the island by Neolithic times. | Scientific reports (Nature Publishing Group) 7 (2017). | 2017 | DE BELLIS GIANLUCA, RIZZI ERMANNO | NGS | 10.1038/srep42869 |
| 373533 | Articolo in rivista | Pseudoexfoliation syndrome-associated genetic variants affect transcription factor binding and alternative splicing of LOXL1 | Pasutto F., Zenkel M., Hoja U., Berner D., Uebe S., Ferrazzi F., Schodel J., Liravi P., Ozaki M., Paoli D., Frezzotti P., Mizoguchi T., Nakano S., Kubota T., Manabe S., Salvi E., Manunta P., Cusi D., Gieger C., Wichmann H.-E., Aung T., Khor C.C., Kruse F.E., Reis A., Schlotzer-Schrehardt U. | Although lysyl oxidase-like 1 (LOXL1) is known as the principal genetic risk factor for pseudoexfoliation (PEX) syndrome, a major cause of glaucoma and cardiovascular complications, no functional variants have been identified to date. Here, we conduct a genome-wide association scan on 771 German PEX patients and 1,350 controls, followed by independent testing of associated variants in Italian and Japanese data sets. We focus on a 3.5-kb four-component polymorphic locus positioned spanning introns 1 and 2 of LOXL1 with enhancer-like chromatin features. We find that the rs11638944:C>G transversion exerts a cis-acting effect on the expression levels of LOXL1, mediated by differential binding of the transcription factor RXR? (retinoid X receptor alpha) and by modulating alternative splicing of LOXL1, eventually leading to reduced levels of LOXL1 mRNA in cells and tissues of risk allele carriers. These findings uncover a functional mechanism by which common noncoding variants influence LOXL1 expression. | Nature communications 8 (2017). | 2017 | CUSI DANIELE | * | 10.1038/ncomms15466 |
| 374010 | Contributo in atti di convegno | Identification of Bacterial Biodiversity and Volatile Fraction of Bitto Storico Cheese in Different Alpine Pasture Areas | F. Turri, P. Cremonesi, G. Gandini, G. Battelli, M. Severgnini, F. Pizzi | Bitto Storico cheese is a raw milk seasonal cheese produced in the Orobic Alps, whose production is closely associated to local traditional activities and alpine pastures. The aim of this work was to characterize the microbiota diversity and the volatile fractions of cheese produced in different alpine pasture areas. Fifty-four Bitto Storico cheeses samples, produced in six different Alpine pastures, were collected and processed. Bacterial DNA was extracted using an optimized protocol and 16S rRNA gene amplicons on V3-V4 region analyzed by Miseq (Illumina). The volatile fraction was characterized by means of Solid Phase Extraction-Gas Chromatography-Mass Spectrometry (SPME-GC-MS). The microbial community of ripened cheese was mainly dominated by Firmicutes phylum with a high abundance of Streptococcaceae and Lactobacillaceae. Each Alpine area was characterized by peculiar bacterial communities, due, probably, to the pasture composition and the cheesemaking process. A total of 24 volatile compounds resulting from microbial activity and diet were found, the formers being mostly alcohols and esters, the latter being terpenes derived directly from the pasture. | 12th International Meeting on Mountain Cheese, pp. 157-160, 20/06/2017, 22/06/2017 | 2017 | GANDINI GUSTAVO, BATTELLI GIOVANNA, SEVERGNINI MARCO, CREMONESI PAOLA, TURRI FEDERICA, PIZZI FLAVIA | alpine area, cheese, bacteria, next generation sequencing, lipophilic fraction | |
| 374622 | Articolo in rivista | Nitric oxide regulates homeoprotein OTX1 and OTX2 expression in the rat myenteric plexus after intestinal ischemia-reperfusion injury | Filpa, Viviana, Carpanese, Elisa, Marchet, Silvia, Pirrone, Cristina, Conti, Andrea, Rainero, Alessia, Moro, Elisabetta, Chiaravalli, Anna Maria, Zucchi, Ileana, Moriondo, Andrea, Negrini, Daniela, Crema, Francesca, Frigo, Gianmario, Giaroni, Cristina, Porta, Giovanni | Neuronal and inducible nitric oxide synthase (nNOS and iNOS) play a protective and damaging role, respectively, on the intestinal neuromuscular function after ischemia-reperfusion (I/R) injury. To uncover the molecular pathways underlying this dichotomy we investigated their possible correlation with the orthodenticle homeobox proteins OTX1 and OTX2 in the rat small intestine myenteric plexus after in vivo I/R. Homeobox genes are fundamental for the regulation of the gut wall homeostasis both during development and in pathological conditions (inflammation, cancer). I/R injury was induced by temporary clamping the superior mesenteric artery under anesthesia, followed by 24 and 48 h of reperfusion. At 48 h after I/R intestinal transit decreased and was further reduced by N-omega-propyl-L-arginine hydrochloride (NPLA), a nNOS-selective inhibitor. By contrast this parameter was restored to control values by 1400W, an iNOS-selective inhibitor. In longitudinal muscle myenteric plexus (LMMP) preparations, iNOS, OTX1, and OTX2 mRNA and protein levels increased at 24 and 48 h after I/R. At both time periods, the number of iNOS-and OTX-immunopositive myenteric neurons increased. nNOS mRNA, protein levels, and neurons were unchanged. In LMMPs, OTX1 and OTX2 mRNA and protein upregulation was reduced by 1400W and NPLA, respectively. In myenteric ganglia, OTX1 and OTX2 staining was superimposed with that of iNOS and nNOS, respectively. Thus in myenteric ganglia iNOS-and nNOS-derived NO may promote OTX1 and OTX2 upregulation, respectively. We hypothesize that the neurodamaging and neuroprotective roles of iNOS and nNOS during I/R injury in the gut may involve corresponding activation of molecular pathways downstream of OTX1 and OTX2. | American journal of physiology: Gastrointestinal and liver physiology 312 (2017): G374-G389. | 2017 | ZUCCHI ILEANA | rat small intestine, ischemia-reperfusion, myenteric plexus, nitric oxide, OTX | 10.1152/ajpgi.00386.2016 |
| 374623 | Articolo in rivista | Clinical Features Associated with Delirium Motor Subtypes in Older Inpatients: Results of a Multicenter Study. | Morandi, Alessandro, Di Santo, Simona G, Cherubini, Antonio, Mossello, Enrico, Meagher, David, Mazzone, Andrea, Bianchetti, Angelo, Ferrara, Nicola, Ferrari, Alberto, Musicco, Massimo, Trabucchi, Marco, Bellelli, Giuseppe | OBJECTIVE: To date motor subtypes of delirium have been evaluated in single-center studies with a limited examination of the relationship between predisposing factors and motor profile of delirium. We sought to report the prevalence and clinical profile of subtypes of delirium in a multicenter study. METHODS: This is a point prevalence study nested in the "Delirium Day 2015", which included 108 acute and 12 rehabilitation wards in Italy. Delirium was detected using the 4-AT and motor subtypes were measured with the Delirium Motor Subtype Scale (DMSS). A multinomial logistic regression was used to determine the factors associated with delirium subtypes. RESULTS: Of 429 patients with delirium, the DMSS was completed in 275 (64%), classifying 21.5% of the patients with hyperactive delirium, 38.5% with hypoactive, 27.3% with mixed and 12.7% with the non-motor subtype. The 4-AT score was higher in the hyperactive subtype, similar in the hypoactive, mixed subtypes, while it was lowest in the non-motor subtype. Dementia was associated with all three delirium motor subtypes (hyperactive, OR 3.3, 95% CI: 1.2-8.7; hypoactive, OR 2.8, 95% CI: 1.2-6.5; mixed OR 2.6, 95% CI: 1.1-6.2). Atypical antipsychotics were associated with hypoactive delirium (OR 0.23, 95% CI: 0.1-0.7), while intravenous lines were associated with mixed delirium (OR 2.9, 95% CI: 1.2-6.9). CONCLUSIONS: The study shows that hypoactivedelirium is the most common subtype among hospitalized older patients. Specific clinical features were associated with different delirium subtypes. The use of standardized instruments can help to characterize the phenomenology of different motor subtypes of delirium. | American journal of geriatric psychiatry (Online) (2017). | 2017 | MUSICCO MASSIMO | 4AT; DMSS; Motor subtypes of delirium; delirium | 10.1016/j.jagp.2017.05.003 |
| 376248 | Contributo in atti di convegno | Performance and economic evaluations in adopting low power architectures: A real case analysis | D. D'Agostino, D. Cesini, E. Corni, A. Ferraro, L. Morganti, A. Quarati, I. Merelli | The continuous technological advances made the energy efficiency a major topic for greener Information Technology systems. Low power Systems-on-Chip (SoC), originally developed in the context of mobile and embedded technologies, are becoming attractive also for scientific and industrial applications given their increasing computing performances, coupled with relatively low cost and power demands. In this work, we investigate the potential of the most representative SoCs for a real life application taken from the field of molecular biology. In particular, we investigate the opportunity of using SoCs for Next-Generation Sequencing (NGS) analysis, considering different applicative scenarios, with different timing and costs requirements. We evaluate the achievable performance together with economical aspects related to the total cost of ownership for a small medium enterprise offering services of NGS sequence alignment, supporting analysis performed in hospitals, research institutes, farms and industries. | 14th International Conference on Economics of Grids, Clouds, Systems, and Services (GECON 2017), pp. 1-13, Biarritz, France, 19-21/09/2017 | 2017 | QUARATI ALFONSO, D'AGOSTINO DANIELE, MERELLI IVAN | Low power Systems-on-Chip, Next-generation sequencing, Performance and economic evaluations | |
| 378510 | Articolo in rivista | Extracellular vesicle-packaged miRNA release after short-term exposure to particulate matter is associated with increased coagulation | Pergoli, Laura, Cantone, Laura, Favero, Chiara, Angelici, Laura, Iodice, Simona, Pinatel, Eva, Hoxha, Mirjam, Dioni, Laura, Letizia, Marilena, Albetti, Benedetta, Tarantini, Letizia, Rota, Federica, Bertazzi, Pier Alberto, Tirelli, Amedea Silvia, Dolo, Vincenza, Cattaneo, Andrea, Vigna, Luisella, Battaglia, Cristina, Carugno, Michele, Bonzini, Matteo, Pesatori, Angela Cecilia, Bollati, Valentina | Background Exposure to particulate matter (PM) is associated with increased incidence of cardiovascular disease and increased coagulation, but the molecular mechanisms underlying these associations remain unknown. Obesity may increase susceptibility to the adverse effects of PM exposure, exacerbating the effects on cardiovascular diseases. Extracellular vesicles (EVs), which travel in body fluids and transfer microRNAs (miRNAs) between tissues, might play an important role in PM-induced cardiovascular risk. We sought to determine whether the levels of PM with an aerodynamic diameter <= 10 ?m (PM10) are associated with changes in fibrinogen levels, EV release, and the miRNA content of EVs (EV-miRNAs), investigating 1630 overweight/obese subjects from the SPHERE Study. Results Short-term exposure to PM10 (Day before blood drawing) was associated with an increased release of EVs quantified by nanoparticle tracking analysis, especially EVs derived from monocyte/macrophage components (CD14+) and platelets (CD61+) which were characterized by flow cytometry. We first profiled miRNAs of 883 subjects by the QuantStudio(TM) 12 K Flex Real Time PCR System and the top 40 EV-miRNAs were validated through custom miRNA plates. Nine EV-miRNAs (let-7c-5p; miR-106a-5p; miR-143-3p; miR-185-5p; miR-218-5p; miR-331-3p; miR-642-5p; miR-652-3p; miR-99b-5p) were downregulated in response to PM10 exposure and exhibited putative roles in cardiovascular disease, as highlighted by integrated network analysis. PM10 exposure was significantly associated with elevated fibrinogen levels, and five of the nine downregulated EV-miRNAs were mediators between PM10 exposure and fibrinogen levels. Conclusions Research on EVs opens a new path to the investigation of the adverse health effects of air pollution exposure. EVs have the potential to act both as markers of PM susceptibility and as potential molecular mechanism in the chain of events connecting PM exposure to increased coagulation, which is frequently linked to exposure and CVD development. | Particle and fibre toxicology 14 (2017). | 2017 | PINATEL EVA MARIA, BATTAGLIA CRISTINA | Air pollution, Extracellular vesicles, microRNAs, Fibrinogen, Cardiovascular disease | 10.1186/s12989-017-0214-4 |
| 378514 | Articolo in rivista | Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci | Aung, Tin, Ozaki, Mineo, Lee, Mei Chin, Schlotzer-Schrehardt, Ursula, Thorleifsson, Gudmar, Mizoguchi, Takanori, Igo, Robert P., Jr., Haripriya, Aravind, Williams, Susan E., Astakhov, Yury S., Orr, Andrew C., Burdon, Kathryn P., Nakano, Satoko, Mori, Kazuhiko, Abu-Amero, Khaled, Hauser, Michael, Li, Zheng, Prakadeeswari, Gopalakrishnan, Bailey, Jessica N. Cooke, Cherecheanu, Alina Popa, Kang, Jae H., Nelson, Sarah, Hayashi, Ken, Manabe, Shin-ichi, Kazama, Shigeyasu, Zarnowski, Tomasz, Inoue, Kenji, Irkec, Murat, Coca-Prados, Miguel, Sugiyama, Kazuhisa, Jarvela, Irma, Schlottmann, Patricio, Lerner, S. Fabian, Lamari, Hasnaa, Nilgun, Yildirim, Bikbov, Mukharram, Park, Ki Ho, Cha, Soon Cheol, Yamashiro, Kenji, Zenteno, Juan C., Jonas, Jost B., Kumar, Rajesh S., Perera, Shamira A., Chan, Anita S. Y., Kobakhidze, Nino, George, Ronnie, Vijaya, Lingam, Do, Tan, Edward, Deepak P., de Juan Marcos, Lourdes, Pakravan, Mohammad, Moghimi, Sasan, Ideta, Ryuichi, Bach-Holm, Daniella, Kappelgaard, Per, Wirostko, Barbara, Thomas, Samuel, Gaston, Daniel, Bedard, Karen, Greer, Wenda L., Yang, Zhenglin, Chen, Xueyi, Huang, Lulin, Sang, Jinghong, Jia, Hongyan, Jia, Liyun, Qiao, Chunyan, Zhang, Hui, Liu, Xuyang, Zhao, Bowen, Wang, Ya-Xing, Xu, Liang, Leruez, Stephanie, Reynier, Pascal, Chichua, George, Tabagari, Sergo, Uebe, Steffen, Zenkel, Matthias, Berner, Daniel, Mossboeck, Georg, Weisschuh, Nicole, Hoja, Ursula, Welge-Luessen, Ulrich-Christoph, Mardin, Christian, Founti, Panayiota, Chatzikyriakidou, Anthi, Pappas, Theofanis, Anastasopoulos, Eleftherios, Lambropoulos, Alexandros, Ghosh, Arkasubhra, Shetty, Rohit, Porporato, Natalia, Saravanan, Vijayan, Venkatesh, Rengaraj, Shivkumar, Chandrashekaran, Kalpana, Narendran, Sarangapani, Sripriya, Kanavi, Mozhgan R., Beni, Afsaneh Naderi, Yazdani, Shahin, Lashay, Alireza, Naderifar, Homa, Khatibi, Nassim, Fea, Antonio, Lavia, Carlo, Dallorto, Laura, Rolle, Teresa, Frezzotti, Paolo, Paoli, Daniela, Salvi, Erika, Manunta, Paolo, Mori, Yosai, Miyata, Kazunori, Higashide, Tomomi, Chihara, Etsuo, Ishiko, Satoshi, Yoshida, Akitoshi, Yanagi, Masahide, Kiuchi, Yoshiaki, Ohashi, Tsutomu, Sakurai, Toshiya, Sugimoto, Takako, Chuman, Hideki, Aihara, Makoto, Inatani, Masaru, Miyake, Masahiro, Gotoh, Norimoto, Matsuda, Fumihiko, Yoshimura, Nagahisa, Ikeda, Yoko, Ueno, Morio, Sotozono, Chie, Jeoung, Jin Wook, Sagong, Min, Park, Kyu Hyung, Ahn, Jeeyun, Cruz-Aguilar, Marisa, Ezzouhairi, Sidi M., Rafei, Abderrahman, Chong, Yaan Fun, Ng, Xiao Yu, Goh, Shuang Ru, Chen, Yueming, Yong, Victor H. K., Khan, Muhammad Imran, Olawoye, Olusola O., Ashaye, Adeyinka O., Ugbede, Idakwo, Onakoya, Adeola, Kizor-Akaraiwe, Nkiru, Teekhasaenee, Chaiwat, Suwan, Yanin, Supakontanasan, Wasu, Okeke, Suhanya, Uche, Nkechi J., Asimadu, Ifeoma, Ayub, Humaira, Akhtar, Farah, Kosior-Jarecka, Ewa, Lukasik, Urszula, Lischinsky, Ignacio, Castro, Vania, Perez Grossmann, Rodolfo, Megevand, Gordana Sunaric, Roy, Sylvain, Dervan, Edward, Silke, Eoin, Rao, Aparna, Sahay, Priti, Fornero, Pablo, Cuello, Osvaldo, Sivori, Delia, Zompa, Tamara, Mills, Richard A., Souzeau, Emmanuelle, Mitchell, Paul, Wang, Jie Jin, Hewitt, Alex W., Coote, Michael, Crowston, Jonathan G., Astakhov, Sergei Y., Akopov, Eugeny L., Emelyanov, Anton, Vysochinskaya, Vera, Kazakbaeva, Gyulli, Fayzrakhmanov, Rinat, Al-Obeidan, Saleh A., Owaidhah, Ohoud, Aljasim, Leyla Ali, Chowbay, Balram, Foo, Jia Nee, Soh, Raphael Q., Sim, Kar Seng, Xie, Zhicheng, Cheong, Augustine W. O., Mok, Shi Qi, Soo, Hui Meng, Chen, Xiao Yin, Peh, Su Qin, Heng, Khai Koon, Husain, Rahat, Ho, Su-Ling, Hillmer, Axel M., Cheng, Ching-Yu, Escudero-Dominguez, Francisco A., Gonzalez-Sarmiento, Rogelio, Martinon-Torres, Frederico, Salas, Antonio, Pathanapitoon, Kessara, Hansapinyo, Linda, Wanichwecharugruang, Boonsong, Kitnarong, Naris, Sakuntabhai, Anavaj, Nguyn, Hip X., Nguyn, Giang T. T., Nguyn, TrNh V., Zenz, Werner, Binder, Alexander, Klobassa, Daniela S., Hibberd, Martin L., Davila, Sonia, Herms, Stefan, Nothen, Markus M., Moebus, Susanne, Rautenbach, Robyn M., Ziskind, Ari, Carmichael, Trevor R., Ramsay, Michele, Alvarez, Lydia, Garcia, Montserrat, Gonzalez-Iglesias, Hector, Rodriguez-Calvo, Pedro P., Fernandez-Vega Cueto, Luis, Oguz, Cilingir, Tamcelik, Nevbahar, Atalay, Eray, Batu, Bilge, Aktas, Dilek, Kasim, Burcu, Wilson, M. Roy, Coleman, Anne L., Liu, Yutao, Challa, Pratap, Herndon, Leon, Kuchtey, Rachel W., Kuchtey, John, Curtin, Karen, Chaya, Craig J., Crandall, Alan, Zangwill, Linda M., Wong, Tien Yin, Nakano, Masakazu, Kinoshita, Shigeru, den Hollander, Anneke I., Vesti, Eija, Fingert, John H., Lee, Richard K., Sit, Arthur J., Shingleton, Bradford J., Wang, Ningli, Cusi, Daniele, Qamar, Raheel, Kraft, Peter, Pericak-Vance, Margaret A., Raychaudhuri, Soumya, Heegaard, Steffen, Kivela, Tero, Reis, Andre, Kruse, Friedrich E., Weinreb, Robert N., Pasquale, Louis R., Haines, Jonathan L., Thorsteinsdottir, Unnur, Jonasson, Fridbert, Allingham, R. Rand, Milea, Dan, Ritch, Robert, Kubota, Toshiaki, Tashiro, Kei, Vithana, Eranga N., Micheal, Shazia, Topouzis, Fotis, Craig, Jamie E., Dubina, Michael, Sundaresan, Periasamy, Stefansson, Kari, Wiggs, Janey L., Pasutto, Francesca, Khor, Chiea Chuen | Exfoliation syndrome (XFS) is the most common known risk factor for secondary glaucoma and a major cause of blindness worldwide. Variants in two genes, LOXL1 and CACNA1A, have previously been associated with XFS. To further elucidate the genetic basis of XFS, we collected a global sample of XFS cases to refine the association at LOXL1, which previously showed inconsistent results across populations, and to identify new variants associated with XFS. We identified a rare protective allele at LOXL1 (p.Phe407, odds ratio (OR) = 25, P = 2.9 x 10(-14)) through deep resequencing of XFS cases and controls from nine countries. A genome-wide association study (GWAS) of XFS cases and controls from 24 countries followed by replication in 18 countries identified seven genome-wide significant loci (P < 5 x 10(-8)). We identified association signals at 13q12 (POMP), 11q23.3 (TMEM136), 6p21 (AGPAT1), 3p24 (RBMS3) and 5q23 (near SEMA6A). These findings provide biological insights into the pathology of XFS and highlight a potential role for naturally occurring rare LOXL1 variants in disease biology. | Nature genetics (Print) 49 (2017): 993-+. | 2017 | CUSI DANIELE | * | 10.1038/ng.3875 |
| 378646 | Articolo in rivista | A novel network analysis approach reveals DNA damage, oxidative stress and calcium/cAMP homeostasis-associated biomarkers in frontotemporal dementia | Palluzzi, Fernando, Ferrari, Raffaele, Graziano, Francesca, Novelli, Valeria, Rossi, Giacomina, Galimberti, Daniela, Rainero, Innocenzo, Benussi, Luisa, Nacmias, Benedetta, Bruni, Amalia C., Cusi, Daniele, Salvi, Erika, Borroni, Barbara, Grassi, Mario | Frontotemporal Dementia (FTD) is the form of neurodegenerative dementia with the highest prevalence after Alzheimer's disease, equally distributed in men and women. It includes several variants, generally characterized by behavioural instability and language impairments. Although few mendelian genes (MAPT, GRN, and C9orf72) have been associated to the FTD phenotype, in most cases there is only evidence of multiple risk loci with relatively small effect size. To date, there are no comprehensive studies describing FTD at molecular level, highlighting possible genetic interactions and signalling pathways at the origin FTD-associated neurodegeneration. In this study, we designed a broad FTD genetic interaction map of the Italian population, through a novel network-based approach modelled on the concepts of disease-relevance and interaction perturbation, combining Steiner tree search and Structural Equation Model (SEM) analysis. Our results show a strong connection between Calcium/cAMP metabolism, oxidative stress-induced Serine/Threonine kinases activation, and postsynaptic membrane potentiation, suggesting a possible combination of neuronal damage and loss of neuroprotection, leading to cell death. In our model, Calcium/cAMP homeostasis and energetic metabolism impairments are primary causes of loss of neuroprotection and neural cell damage, respectively. Secondly, the altered postsynaptic membrane potentiation, due to the activation of stress-induced Serine/Threonine kinases, leads to neurodegeneration. Our study investigates the molecular underpinnings of these processes, evidencing key genes and gene interactions that may account for a significant fraction of unexplained FTD aetiology. We emphasized the key molecular actors in these processes, proposing them as novel FTD biomarkers that could be crucial for further epidemiological and molecular studies. | PloS one 12 (2017). | 2017 | CUSI DANIELE | * | 10.1371/journal.pone.0185797 |
| 378647 | Articolo in rivista | CNV-association meta-analysis in 191,161 European adults reveals new loci associated with anthropometric traits | Mace, Aurelien, Tuke, Marcus A., Deelen, Patrick, Kristiansson, Kati, Mattsson, Hannele, Noukas, Margit, Sapkota, Yadav, Schick, Ursula, Porcu, Eleonora, Rueger, Sina, McDaid, Aaron F., Porteous, David, Winkler, Thomas W., Salvi, Erika, Shrine, Nick, Liu, Xueping, Ang, Wei Q., Zhang, Weihua, Feitosa, Mary F., Venturini, Cristina, van der Most, Peter J., Rosengren, Anders, Wood, Andrew R., Beaumont, Robin N., Jones, Samuel E., Ruth, Katherine S., Yaghootkar, Hanieh, Tyrrell, Jessica, Havulinna, Aki S., Boers, Harmen, Magi, Reedik, Kriebel, Jennifer, Mueller-Nurasyid, Martina, Perola, Markus, Nieminen, Markku, Lokki, Marja-Liisa, Kahonen, Mika, Viikari, Jorma S., Geller, Frank, Lahti, Jari, Palotie, Aarno, Koponen, Paivikki, Lundqvist, Annamari, Rissanen, Harri, Bottinger, Erwin P., Afaq, Saima, Wojczynski, Mary K., Lenzini, Petra, Nolte, Ilja M., Sparso, Thomas, Schupf, Nicole, Christensen, Kaare, Perls, Thomas T., Newman, Anne B., Werge, Thomas, Snieder, Harold, Spector, Timothy D., Chambers, John C., Koskinen, Seppo, Melbye, Mads, Raitakari, Olli T., Lehtimaki, Terho, Tobin, Martin D., Wain, Louise V., Sinisalo, Juha, Peters, Annette, Meitinger, Thomas, Martin, Nicholas G., Wray, Naomi R., Montgomery, Grant W., Medland, Sarah E., Swertz, Morris A., Vartiainen, Erkki, Borodulin, Katja, Mannisto, Satu, Murray, Anna, Bochud, Murielle, Jacquemont, Sebastien, Rivadeneira, Fernando, Hansen, Thomas F., Oldehinkel, Albertine J., Mangino, Massimo, Province, Michael A., Deloukas, Panos, Kooner, Jaspal S., Freathy, Rachel M., Pennell, Craig, Feenstra, Bjarke, Strachan, David P., Lettre, Guillaume, Hirschhorn, Joel, Cusi, Daniele, Heid, Iris M., Hayward, Caroline, Mannik, Katrin, Beckmann, Jacques S., Loos, Ruth J. F., Nyholt, Dale R., Metspalu, Andres, Eriksson, Johan G., Weedon, Michael N., Salomaa, Veikko, Franke, Lude, Reymond, Alexandre, Frayling, Timothy M., Kutalik, Zoltan | There are few examples of robust associations between rare copy number variants (CNVs) and complex continuous human traits. Here we present a large-scale CNV association meta-analysis on anthropometric traits in up to 191,161 adult samples from 26 cohorts. The study reveals five CNV associations at 1q21.1, 3q29, 7q11.23, 11p14.2, and 18q21.32 and confirms two known loci at 16p11.2 and 22q11.21, implicating at least one anthropometric trait. The discovered CNVs are recurrent and rare (0.01-0.2%), with large effects on height (> 2.4 cm), weight ( 5 kg), and body mass index (BMI) (> 3.5 kg/m(2)). Burden analysis shows a 0.41 cm decrease in height, a 0.003 increase in waist-to-hip ratio and increase in BMI by 0.14 kg/m2 for each Mb of total deletion burden (P = 2.5 x 10(-10), 6.0 x 10(-5), and 2.9 x 10(-3)). Our study provides evidence that the same genes (e.g., MC4R, FIBIN, and FMO5) harbor both common and rare variants affecting body size and that anthropometric traits share genetic loci with developmental and psychiatric disorders. | Nature communications 8 (2017). | 2017 | CUSI DANIELE | Computational biology and bioinformatics; Genome-wide association studies; Quantitative trait | 10.1038/s41467-017-00556-x |
| 378648 | Articolo in rivista | PEAR1 is not a major susceptibility gene for cardiovascular disease in a Flemish population | Yang, Wen-Yi, Petit, Thibault, Cauwenberghs, Nicholas, Zhang, Zhen-Yu, Sheng, Chang-Sheng, Thijs, Lutgarde, Salvi, Erika, Izzi, Benedetta, Vandenbriele, Christophe, Wei, Fang-Fei, Gu, Yu-Mei, Jacobs, Lotte, Citterio, Lorena, Carpini, Simona Delli, Barlassina, Cristina, Cusi, Daniele, Hoylaerts, Marc F., Verhamme, Peter, Kuznetsova, Tatiana, Staessen, Jan A. | Background Platelet Endothelial Aggregation Receptor 1 (PEAR1), a membrane protein highly expressed in platelets and endothelial cells, plays a role in platelet contact-induced activation, sustained platelet aggregation and endothelial function. Previous reports implicate PEAR1 rs12041331 as a variant influencing risk in patients with coronary heart disease. We investigated whether genetic variation in PEAR1 predicts cardiovascular outcome in a white population. Methods In 1938 participants enrolled in the Flemish Study on Environment, Genes and Health Outcomes (51.3% women; mean age 43.6 years), we genotyped 9 tagging SNPs in PEAR1, measured baseline cardiovascular risk factors, and recorded Cardiovascular disease incidence. For SNPs, we contrasted cardiovascular disease incidence of minor-allele heterozygotes and homozygotes (variant) vs. major-allele homozygotes (reference) and for haplotypes carriers vs. non-carriers. In adjusted analyses, we accounted for family clusters and baseline covariables, including sex, age, body mass index, mean arterial pressure, the total-to-HDL cholesterol ratio, smoking and drinking, antihypertensive drug treatment, and history of cardiovascular disease and diabetes mellitus. Results Over a median follow-up of 15.3 years, 238 died and 181 experienced a major cardiovascular endpoint. The multivariable-adjusted hazard ratios of eight PEAR1 SNPs, including rs12566888, ranged from 0.87 to 1.07 (P >=0.35) and from 0.78 to 1.30 (P >=0.15), respectively. The hazard ratios of three haplotypes with frequency >=10% ranged from 0.93 to 1.11 (P >=0.49) for mortality and from 0.84 to 1.03 (P >=0.29) for a cardiovascular complications. These results were not influenced by intake of antiplatelet drugs, nonsteroidal anti-inflammatory drugs, or both (P-values for interaction >= 0.056). Conclusions In a White population, we could not replicate previous reports from experimental studies or obtained in patients suggesting that PEAR1 might be a susceptibility gene for cardiovascular complications. | BMC medical genetics (Online) 18 (2017). | 2017 | CUSI DANIELE | Clinical genetics, Cardiovascular risk, PEAR1, Population science, Replication research | 10.1186/s12881-017-0411-x |
| 378651 | Articolo in rivista | The risk of nephrolithiasis is causally related to inactive matrix Gla protein, a marker of vitamin K status: a Mendelian randomization study in a Flemish population. | Wei, Fang-Fei, Thijs, Lutgarde, Zhang, Zhen-Yu, Jacobs, Lotte, Yang, Wen-Yi, Salvi, Erika, Citterio, Lorena, Cauwenberghs, Nicholas, Kuznetsova, Tatiana, E A Drummen, Nadja, Hara, Azusa, Manunta, Paolo, Li, Yan, Verhamme, Peter, Allegaert, Karel, Cusi, Daniele, Vermeer, Cees, Staessen, Jan A | Background: Vitamin K (VK)-dependent ?-glutamate carboxylation and serine phosphorylation activate matrix Gla protein (MGP) to a potent locally acting inhibitor of calcification. Nephrolithiasis represents a process of unwanted calcification associated with substantial mortality and high recurrence rates. We hypothesized that the risk of nephrolithiasis increases with VK shortage, as exemplified by higher plasma levels of desphospho-uncarboxylated MGP (dp-ucMGP). Methods: In 1748 randomly recruited Flemish individuals (51.1% women; mean age 46.8 years), we determined dp-ucMGP and the prevalence of nephrolithiasis at baseline (April 1996-February 2015) and its incidence during follow-up until March 2016. We estimated the multivariable-adjusted relative risk associated with the doubling of dp-ucMGP, using logistic or Cox regression. We did a Mendelian randomization analysis using four MGP genotypes as instrumental variables. Results: With adjustments applied for sex, age and 24-h urinary volume and calcium excretion, the odds of having prevalent nephrolithiasis [ n = 144 (8.2%)] associated with dp-ucMGP was 1.31 [95% confidence interval (CI) 1.04-1.64; P = 0.022]. dp-ucMGP levels were associated (P <= 0.001) with MGP variants rs2098435 , rs4236 and rs2430692 . In the Mendelian analysis, the causal odds ratio was 3.82 (95% CI 1.15-12.7; P = 0.029). The incidence of nephrolithiasis over 12.0 years (median) was 37 cases (0.2%). With similar adjustments as before, the hazard ratio in relation to dp-ucMGP was 2.48 (95% CI 1.71-3.61; P < 0.001). Additional adjustment for a nephrolithiasis propensity score produced consistent results. Conclusion: Higher levels of inactive dp-ucMGP may be causally associated with the risk of nephrolithiasis. Whether or not VK deficiency plays a role in these observations remains to be firmly established. | Nephrology, dialysis, transplantation (Print) (2017). | 2017 | CUSI DANIELE | calcification; matrix Gla protein; nephrolithiasis; population science; vitamin K | 10.1093/ndt/gfx014 |
| 380043 | Articolo in rivista | Recommendations for the management of pulmonary fungal infections in patients with rheumatoid arthritis | Galli M1, Antinori S2, Atzeni F3, Meroni L2, Riva A2, Scire C4, Adorni F5, Quartuccio L6, Sebastiani M7, Airo P8, Bazzichi L9, Cristini F10, Del Bono V11, Manfredi A7, Viapiana O12, De Rosa F13, Favalli E14, Petrelli E15, Salvarani C16, Govoni M4, Corcione S17, Scrivo R18, Sarmati L19, Lazzarin A20, Grassi W21, Mastroianni C22, Gaeta GB23, Ferraccioli G24, Cutolo M25, De Vita S6, Lapadula G26, Matucci-Cerinic M27, Armignacco O28, Sarzi-Puttini P2 | Often life-threatening pulmonary fungal infections (PFIs) can occur in patients with rheumatoid arthritis (RA) receiving disease-modifying anti-rheumatic drugs (DMARDs). Most of the data concerning PFIs in RA patients come from case reports and retrospective case series. Of the ve most widely described PFIs, Pneumocystis jirovecii pneumonia (PJP) has rarely been seen outside Japan, pulmonary cryptococcosis has been diagnosed in only a small number of patients worldwide, pulmonary coccidioidomycosis has almost only been observed in endemic areas, the limited number of cases of pulmonary histoplasmosis have mainly occurred in the USA, and the rare cases of invasive pulmonary aspergillosis have only been encountered in leukopenic patients. Many aspects of the prophylaxis, diagnosis and treatment of PFIs in RA patients remain to be defined, as does the role of each DMARD in increasing the risk of infection, and the possibility of resuming biological and non-biological DMARD treatment after the infection has been cured. The recommendations for the management of PFIs described in this paper are the product of a consensus procedure promoted by the Italian group for the Study and Management of Infections in Patients with Rheumatic Diseases (the ISMIR group). | Clinical and Experimental Rheumatology (Online) (2017). | 2017 | ADORNI FULVIO DANIELE | * | |
| 380050 | Articolo in rivista | Multimodal MRI quantification of the common neurostructural bases within the FTD-ALS continuum. | Crespi, Chiara, Dodich, Alessandra, Cappa, Stefano F, Canessa, Nicola, Iannaccone, Sandro, Corbo, Massimo, Lunetta, Christian, Falini, Andrea, Cerami, Chiara | The continuum hypothesis linking the behavioral variant of frontotemporal dementia (bvFTD) and amyotrophic lateral sclerosis (ALS) is supported by clinical, pathological, genetic, and neuroimaging evidence. In the present multimodal magnetic resonance study, we characterized the site and extent of shared neurostructural changes in gray and white matter in 20 bvFTD and 19 ALS patients without dementia. We found an overlap of macrostructural and microstructural damage in both patient groups compared with healthy controls, involving the right orbital and the bilateral anterior cingulate cortices, the corticospinal tract and corpus callosum. The quantification of gray and white matter damage within the areas of shared alterations highlighted a higher degree of atrophy in orbitofrontal and frontomedial regions in patients with more severe executive and/or behavioral symptoms, and a higher degree of degeneration in the motor pathway in patients with more severe motor neuron disorders. Our finding provides additional evidence confirming the FTD-ALS continuum hypothesis and supports the notion of a bimodal but convergent pattern of neurostructural changes characterizing bvFTD and ALS. | Neurobiology of aging (Online) 62 (2017): 95-104. | 2017 | CRESPI CHIARA | ALS-FTD continuum hypothesis; Amyotrophic lateral sclerosis; Behavioral variant of frontotemporal dementia; Corticospinal tract; Tract-based spatial statistics; Voxel-based morphometry | 10.1016/j.neurobiolaging.2017.09.019 |
| 374938 | Articolo in rivista | Role of mycotoxins in the pathobiology of autism: A first evidence | De Santis, Barbara, Brera, Carlo, Mezzelani, Alessandra, Soricelli, Sabina, Ciceri, Francesca, Moretti, Giorgio, Debegnach, Francesca, Bonaglia, Maria Clara, Villa, Laura, Molteni, Massimo, Raggi, Maria Elisabetta | Objectives: Gene-environment interaction is an emerging hypothesis to expound not only the autism pathogenesis but also the increased incidence of neurodevelopmental disorders (such as autistic spectrum disorder, attention-deficit, hyperactivity disorder). Among xenobiotics, mycotoxins are worldwide contaminants of food that provoke toxicological effects, crucially resembling several symptoms associated with autism such as oxidative stress, intestinal permeability, and inflammation. Here, we focused on a group of mycotoxins to test their role in the manifestation of autism, try to explain their mechanism of action, and discuss possible preventive and therapeutic interventions. Methods: Autistic children (n = 52) and healthy children [n = 58 (31 siblings and 27 unrelated subjects)] were recruited and body fluids and clinical data collected. The diagnosis of autism was made according to DSM V criteria, then with GMDS 0-2, WPPSI, and ADOS. Ochratoxin A (OTA), gliotoxin, zearalenone, and sphingosine/sphinganine ratio were determined by LC analysis in sera and urines. Statistical analysis was performed by the Wilcoxon Rank Sum (Mann-Whitney) test and Spearman test. Results: By comparing the results of autistic patients with those of unrelated controls, a significant association was found for OTA levels in urines (P = 0.0002) and sera (P = 0.0017), and also comparing patients with siblings and unrelated controls together (P = 0.0081). Discussion: Our results are the first describing a possible role of OTA in the pathobiology of autism. Recalling the male prevalence of ASD (male/female = 4-5/1), it is noted that, in animal models, OTA exerts its neurotoxicity especially in males. Moreover, in vitro, OTA increases microRNA-132 that is dysregulated in autistic patients and involved in reciprocal regulation of the autism-related genes MeCP2 and PTEN. A personalized diet coupled with probiotic administration, especially OTA adsorbing Lactobacillus, could ameliorate autistic symptoms in OTA-positive patients. | Nutritional neuroscience (2017): 1-13. | 2017 | MEZZELANI ALESSANDRA MARIA | Autism, Dysbiosis, Fungi, Gastro-intestinal disorders, Gene-environment interaction, Intestinal permeability, Mycotoxins, Ochratoxin A | 10.1080/1028415X.2017.1357793 |
| 380057 | Articolo in rivista | Genetic loci associated with heart rate variability and their effects on cardiac disease risk. | Nolte IM1, Munoz ML1, Tragante V2, Amare AT1, 3, 4, Jansen R5, Vaez A1, 6, von der Heyde B7, 8, Avery CL9, Bis JC10, Dierckx B11, 12, van Dongen J13, Gogarten SM14, Goyette P15, Hernesniemi J16, 17, 18, Huikari V19, Hwang SJ20, 21, Jaju D22, Kerr KF14, Kluttig A23, Krijthe BP24, Kumar J7, 8, van der Laan SW25, Lyytikainen LP16, 17, Maihofer AX26, 27, Minassian A26, 27, van der Most PJ1, Muller-Nurasyid M28, 29, 30, Nivard M13, 31, Salvi E32, Stewart JD9, 33, Thayer JF34, Verweij N35, Wong A36, Zabaneh D37, 38, Zafarmand MH39, 40, Abdellaoui A13, 31, Albarwani S41, Albert C42, Alonso A43, Ashar F44, Auvinen J19, 45, Axelsson T46, Baker DG27, 26, de Bakker PIW47, 48, Barcella M32, Bayoumi R49, Bieringa RJ1, Boomsma D13, 31, Boucher G15, Britton AR50, Christophersen I51, 52, 53, Dietrich A54, Ehret GB55, 56, Ellinor PT52, 57, Eskola M18, 58, Felix JF24, Floras JS59, 60, Franco OH24, Friberg P61, Gademan MGJ39, Geyer MA26, Giedraitis V62, Hartman CA63, Hemerich D2, 64, Hofman A24, Hottenga JJ13, 31, Huikuri H65, Hutri-Kahonen N66, 67, Jouven X68, Junttila J65, Juonala M69, 70, Kiviniemi AM65, Kors JA71, Kumari M50, 72, Kuznetsova T73, Laurie CC14, Lefrandt JD74, Li Y75, Li Y76, 77, 78, Liao D79, Limacher MC80, Lin HJ81, 82, Lindgren CM83, 84, Lubitz SA52, 57, Mahajan A84, McKnight B10, 14, 85, Zu Schwabedissen HM86, Milaneschi Y5, Mononen N16, 17, Morris AP84, 87, Nalls MA88, Navis G89, Neijts M13, 31, Nikus K18, 90, North KE9, 91, O'Connor DT92, Ormel J63, Perz S93, Peters A30, 93, 94, Psaty BM10, 95, 96, Raitakari OT97, 98, Risbrough VB26, 27, Sinner MF29, 30, Siscovick D99, Smit JH5, Smith NL96, 100, 101, Soliman EZ102, Sotoodehnia N103, Staessen JA73, Stein PK104, Stilp AM14, Stolarz-Skrzypek K105, Strauch K28, 106, Sundstrom J107, Swenne CA108, Syvanen AC46, Tardif JC15, 109, Taylor KD110, Teumer A111, Thornton TA14, Tinker LE85, Uitterlinden AG24, 112, 113, van Setten J2, Voss A114, Waldenberger M93, 115, Wilhelmsen KC116, 117, Willemsen G13, 31, Wong Q14, Zhang ZM102, 118, Zonderman AB119, Cusi D120, 121, Evans MK119, Greiser HK122, van der Harst P35, Hassan M41, Ingelsson E7, 8, 123, Jarvelin MR19, 45, 124, 125, Kaab S29, 30, Kahonen M126, 127, Kivimaki M50, Kooperberg C85, Kuh D36, Lehtimaki T16, 17, Lind L107, Nievergelt CM26, 27, O'Donnell CJ20, 21, 128, Oldehinkel AJ63, Penninx B5, Reiner AP85, 100, Riese H63, van Roon AM74, Rioux JD15, 109, Rotter JI110, Sofer T14, Stricker BH24, 129, Tiemeier H11, 24, Vrijkotte TGM39, Asselbergs FW2, 130, 131, Brundel BJJM132, Heckbert SR10, 100, Whitsel EA9, 133, den Hoed M7, 8, Snieder H1, de Geus EJC13, 31. | Reduced cardiac vagal control reflected in low heart rate variability (HRV) is associated with greater risks for cardiac morbidity and mortality. In two-stage meta-analyses of genome-wide association studies for three HRV traits in up to 53,174 individuals of European ancestry, we detect 17 genome-wide significant SNPs in eight loci. HRV SNPs tag non-synonymous SNPs (in NDUFA11 and KIAA1755), expression quantitative trait loci (eQTLs) (influencing GNG11, RGS6 and NEO1), or are located in genes preferentially expressed in the sinoatrial node (GNG11, RGS6 and HCN4). Genetic risk scores account for 0.9 to 2.6% of the HRV variance. Significant genetic correlation is found for HRV with heart rate (-0.74| Nature communications (2017). | 2017 | CUSI DANIELE | * | | |
| 380118 | Articolo in rivista | PWHATSHAP: efficient haplotyping for future generation sequencing | Andrea Bracciali, Marco Aldinucci, Murray Patterson, Tobias Marschall, Nadia Pisanti, Ivan Merelli, Massimo Torquati | Background Haplotype phasing is an important problem in the analysis of genomics information. Given a set of DNA fragments of an individual, it consists of determining which one of the possible alleles (alternative forms of a gene) each fragment comes from. Haplotype information is relevant to gene regulation, epigenetics, genome-wide association studies, evolutionary and population studies, and the study of mutations. Haplotyping is currently addressed as an optimisation problem aiming at solutions that minimise, for instance, error correction costs, where costs are a measure of the confidence in the accuracy of the information acquired from DNA sequencing. Solutions have typically an exponential computational complexity. WhatsHap is a recent optimal approach which moves computational complexity from DNA fragment length to fragment overlap, i.e., coverage, and is hence of particular interest when considering sequencing technology's current trends that are producing longer fragments. Results Given the potential relevance of efficient haplotyping in several analysis pipelines, we have designed and engineered pWhatsHap, a parallel, high-performance version of WhatsHap. pWhatsHap is embedded in a toolkit developed in Python and supports genomics datasets in standard file formats. Building on WhatsHap, pWhatsHap exhibits the same complexity exploring a number of possible solutions which is exponential in the coverage of the dataset. The parallel implementation on multi-core architectures allows for a relevant reduction of the execution time for haplotyping, while the provided results enjoy the same high accuracy as that provided by WhatsHap, which increases with coverage. Conclusions Due to its structure and management of the large datasets, the parallelisation of WhatsHap posed demanding technical challenges, which have been addressed exploiting a high-level parallel programming framework. The result, pWhatsHap, is a freely available toolkit that improves the efficiency of the analysis of genomics information. | BMC bioinformatics (2017). | 2017 | MERELLI IVAN | HaplotypingHigh-performance computingFuture generation sequencing | 10.1186/s12859-016-1170-y |
| 380124 | Articolo in rivista | The Clinical Use of Cerebrospinal Fluid Biomarkers for Alzheimer's Disease Diagnosis: The Italian Selfie | Sancesario GM1, Toniolo S2, Chiasserini D3, Di Santo SG1,2, Zegeer J4, Bernardi G5, for SIBioC-Study Group of Clinical Biochemistry of Biological Fluids other than Blood, Musicco M6, for SINdem-ITALPLANED, Caltagirone C1,2, Parnetti L3, Bernardini S4. | Although the use of cerebrospinal fluid (CSF) amyloid beta(1-42) (A beta 42), tau (T-tau), and phosphorylated tau (p-tau(181)) gives added diagnostic and prognostic values, the diffusion is still limited in clinical practice and only a restricted number of patients receive an integrated clinico-biological diagnosis. By a survey, we aimed to do a "selfie" of the use and diffusion of CSF biomarkers of dementia in Italy, the standardization of pre-analytical procedures, the harmonization of ranges, and the participation to Quality Control programs. An online questionnaire was sent to the members of SIBioC and SINdem-ITALPLANED and to main neurological clinics all over Italy. In Italy, 25 laboratories provide biomarkers analysis in addition to a network of 15 neighboring hospitals. In sum, 40 neurological centers require CSF analyses. 7/20 regions (35%) lack CSF laboratories. Standardization of pre-analytical procedures is present in 62.02% of the laboratories; only 56.00% of the laboratories participate in International Quality Control. There is no harmonization of cut-offs. In Italy, the use of biomarkers is still limited in clinical practice. Standardization and harmonization of normal ranges are needed. To optimize and expand the use of CSF biomarkers, a cost-benefit analysis should be promoted by scientific societies and national health services. | Journal of Alzheimer's disease 55 (2017): 1659-1666. | 2017 | MUSICCO MASSIMO | Alzheimer's disease diagnosis, cerebrospinal fluid, neurodegenerative biomarkers, survey | 10.3233/JAD-160975 |
| 380142 | Articolo in rivista | Zebrafish Tmem230a cooperates with the Delta/Notch signaling pathway to modulate endothelial cell number in angiogenic vessels | Carra S1, 2, Sangiorgio L1, 2, Pelucchi P2, Cermenati S1, Mezzelani A2, Martino V2, Palizban M2, Albertini A2, Gotte M3, Kehler J2, 4, Deflorian G5, Beltrame M1, Giordano A6, 7, Reinbold R2, Cotelli F1, Bellipanni G6, 7, Zucchi I2. | During embryonic development, new arteries, and veins form from preexisting vessels in response to specific angiogenic signals. Angiogenic signaling is complex since not all endothelial cells exposed to angiogenic signals respond equally. Some cells will be selected to become tip cells and acquire migration and proliferation capacity necessary for vessel growth while others, the stalk cells become trailer cells that stay connected with pre-existing vessels and act as a linkage to new forming vessels. Additionally, stalk and tip cells have the capacity to interchange their roles. Stalk and tip cellular responses are mediated in part by the interactions of components of the Delta/Notch and Vegf signaling pathways. We have identified in zebrafish, that the transmembrane protein Tmem230a is a novel regulator of angiogenesis by its capacity to regulate the number of the endothelial cells in intersegmental vessels by co-operating with the Delta/Notch signaling pathway. Modulation of Tmem230a expression by itself is sufficient to rescue improper number of endothelial cells induced by aberrant expression or inhibition of the activity of genes associated with the Dll4/Notch pathway in zebrafish. Therefore, Tmem230a may have a modulatory role in vessel-network formation and growth. As the Tmem230 sequence is conserved in human, Tmem230 may represent a promising novel target for drug discovery and for disease therapy and regenerative medicine in promoting or restricting angiogenesis. | Journal of cellular physiology (Print) (2017). | 2017 | REINBOLD ROLLAND ALVONS, MARTINO VALENTINA, ALBERTINI ALBERTO, MEZZELANI ALESSANDRA MARIA, PELUCCHI PARIDE, ZUCCHI ILEANA | Delta/Notch signaling; Vegf signaling; angiogenesis; blood vessel formation growth; transmembrane protein 230 | |
| 380145 | Articolo in rivista | Il cervello in un mondo che invecchia. | Musicco, Massimo | Inizio con grandissimo piacere la mia collaborazione con E&P di cui ricordo l'uscita del primo numero nel secolo scorso, sentendomene sinceramente onorato. Provo ad affrontare oggi il tema "Brain ageing - Il cervello in un mondo che invecchia" a partire dai denominatori. Mi rendo conto di avventurarmi su di un terreno che e per lo piu strettamente demografico e che, quindi, non mi e particolarmente famigliare. Confido nel fatto che perdonerete la mia temerarieta e non me ne vorrete se rileverete qualche criticita o disaccordo. | Epidemiologia e prevenzione 41 (2017): 306-307. | 2017 | MUSICCO MASSIMO | * | 10.19191/EP17.5-6.P306.093 |
| 380148 | Articolo in rivista | Genetic loci associated with heart rate variability and their effects on cardiac disease risk (vol 8, pg 15805, 2017) | Nolte, Ilja M., Munoz, M. Loretto, Tragante, Vinicius, Amare, Azmeraw T., Jansen, Rick, Vaez, Ahmad, von der Heyde, Benedikt, Avery, Christy L., Bis, Joshua C., Dierckx, Bram, van Dongen, Jenny, Gogarten, Stephanie M., Goyette, Philippe, Hernesniemi, Jussi, Huikari, Ville, Hwang, Shih-Jen, Jaju, Deepali, Kerr, Kathleen F., Kluttig, Alexander, Krijthe, Bouwe P., Kumar, Jitender, van der Laan, Sander W., Lyytikainen, Leo-Pekka, Maihofer, Adam X., Minassian, Arpi, van der Most, Peter J., Mueller-Nurasyid, Martina, Nivard, Michel, Salvi, Erika, Stewart, James D., Thayer, Julian F., Verweij, Niek, Wong, Andrew, Zabaneh, Delilah, Zafarmand, Mohammad H., Abdellaoui, Abdel, Albarwani, Sulayma, Albert, Christine, Alonso, Alvaro, Ashar, Foram, Auvinen, Juha, Axelsson, Tomas, Baker, Dewleen G., de Bakker, Paul I. W., Barcella, Matteo, Bayoumi, Riad, Bieringa, Rob J., Boomsma, Dorret, Boucher, Gabrielle, Britton, Annie R., Christophersen, Ingrid, Dietrich, Andrea, Ehret, George B., Ellinor, Patrick T., Eskola, Markku, Felix, Janine F., Floras, John S., Franco, Oscar H., Friberg, Peter, Gademan, Maaike G. J., Geyer, Mark A., Giedraitis, Vilmantas, Hartman, Catharina A., Hemerich, Daiane, Hofman, Albert, Hottenga, Jouke-Jan, Huikuri, Heikki, Hutri-Kahonen, Nina, Jouven, Xavier, Junttila, Juhani, Juonala, Markus, Kiviniemi, Antti M., Kors, Jan A., Kumari, Meena, Kuznetsova, Tatiana, Laurie, Cathy C., Lefrandt, Joop D., Li, Yong, Li, Yun, Liao, Duanping, Limacher, Marian C., Lin, Henry J., Lindgren, Cecilia M., Lubitz, Steven A., Mahajan, Anubha, McKnight, Barbara, zu Schwabedissen, Henriette Meyer, Milaneschi, Yuri, Mononen, Nina, Morris, Andrew P., Nalls, Mike A., Navis, Gerjan, Neijts, Melanie, Nikus, Kjell, North, Kari E., O'Connor, Daniel T., Ormel, Johan, Perz, Siegfried, Peters, Annette, Psaty, Bruce M., Raitakari, Olli T., Risbrough, Victoria B., Sinner, Moritz F., Siscovick, David, Smit, Johannes H., Smith, Nicholas L., Soliman, Elsayed Z., Sotoodehnia, Nona, Staessen, Jan A., Stein, Phyllis K., Stilp, Adrienne M., Stolarz-Skrzypek, Katarzyna, Strauch, Konstantin, Sundstrom, Johan, Swenne, Cees A., Syvanen, Ann-Christine, Tardif, Jean-Claude, Taylor, Kent D., Teumer, Alexander, Thornton, Timothy A., Tinker, Lesley E., Uitterlinden, Andre G., van Setten, Jessica, Voss, Andreas, Waldenberger, Melanie, Wilhelmsen, Kirk C., Willemsen, Gonneke, Wong, Quenna, Zhang, Zhu-Ming, Zonderman, Alan B., Cusi, Daniele, Evans, Michele K., Greiser, Halina K., van der Harst, Pim, Hassan, Mohammad, Ingelsson, Erik, Jarvelin, Marjo-Riitta, Kaab, Stefan, Kahonen, Mika, Kivimaki, Mika, Kooperberg, Charles, Kuh, Diana, Lehtimaki, Terho, Lind, Lars, Nievergelt, Caroline M., O'Donnell, Chris J., Oldehinkel, Albertine J., Penninx, Brenda, Reiner, Alexander P., Riese, Harriette, van Roon, Arie M., Rioux, John D., Rotter, Jerome I., Sofer, Tamar, Stricker, Bruno H., Tiemeier, Henning, Vrijkotte, Tanja G. M., Asselbergs, Folkert W., Brundel, Bianca J. J. M., Heckbert, Susan R., Whitsel, Eric A., den Hoed, Marcel, Snieder, Harold, de Geus, Eco J. C. | Reduced cardiac vagal control reflected in low heart rate variability (HRV) is associated with greater risks for cardiac morbidity and mortality. In two-stage meta-analyses of genome-wide association studies for three HRV traits in up to 53,174 individuals of European ancestry, we detect 17 genome-wide significant SNPs in eight loci. HRV SNPs tag non-synonymous SNPs (in NDUFA11 and KIAA1755), expression quantitative trait loci (eQTLs) (influencing GNG11, RGS6 and NEO1), or are located in genes preferentially expressed in the sinoatrial node (GNG11, RGS6 and HCN4). Genetic risk scores account for 0.9 to 2.6% of the HRV variance. Significant genetic correlation is found for HRV with heart rate (-0.74| Nature communications 8 (2017). | 2017 | CUSI DANIELE | Cardiovascular genetics Genome-wide association studies Risk factors | 10.1038/ncomms16140 | |
| 380164 | Articolo in rivista | Revealing the complex genetic architecture of obsessive-compulsive disorder using meta-analysis. | nternational Obsessive Compulsive Disorder Foundation Genetics Collaborative (IOCDF-GC), OCD Collaborative Genetics Association Studies (OCGAS): Arnold PD, Askland KD, Barlassina C, Bellodi L, Bienvenu OJ, Black D, Bloch M, Brentani H, Burton CL, Camarena B, Cappi C, Cath D, Cavallini M, Conti D, Cook E, Coric V, Cullen BA, Cusi D, Davis LK, Delorme R, Denys D, Derks E, Eapen V, Edlund C, Erdman L, Falkai P, Figee M, Fyer AJ, Geller DA, Goes FS, Grabe H, Grados MA, Greenberg BD, Grunblatt E, Guo W, Hanna GL, Hemmings S, Hounie AG, Jenicke M, Keenan C, Kennedy J, Khramtsova EA, Konkashbaev A, Knowles JA, Krasnow J, Lange C, Lanzagorta N, Leboyer M, Lennertz L, Li B, Liang KY, Lochner C, Macciardi F, Maher B, Maier W, Marconi M, Mathews CA, Matthesien M, McCracken JT, McLaughlin NC, Miguel EC, Moessner R, Murphy DL, Neale B, Nestadt G, Nestadt P, Nicolini H, Nurmi E, Osiecki L, Pauls DL, Piacentini J, Posthuma D, Pulver AE, Qin HD, Rasmussen SA, Rauch S, Richter MA, Riddle MA, Ripke S, Ruhrmann S, Sampaio AS, Samuels JF, Scharf JM, Shugart YY, Smit J, Stein D, Stewart SE, Turiel M, Vallada H, Veenstra-VanderWeele J, Wagner M, Walitza S, Wang Y, Wendland J, Vulink N, Yu D, Zai G. | Two obsessive-compulsive disorder (OCD) genome-wide association studies (GWASs) have been published by independent OCD consortia, the International Obsessive-Compulsive Disorder Foundation Genetics Collaborative (IOCDF-GC) and the OCD Collaborative Genetics Association Study (OCGAS), but many of the top-ranked signals were supported in only one study. We therefore conducted a meta-analysis from the two consortia, investigating a total of 2688 individuals of European ancestry with OCD and 7037 genomically matched controls. No single-nucleotide polymorphisms (SNPs) reached genome-wide significance. However, in comparison with the two individual GWASs, the distribution of P-values shifted toward significance. The top haplotypic blocks were tagged with rs4733767 (P=7.1 * 10-7; odds ratio (OR)=1.21; confidence interval (CI): 1.12-1.31, CASC8/CASC11), rs1030757 (P=1.1 * 10-6; OR=1.18; CI: 1.10-1.26, GRID2) and rs12504244 (P=1.6 * 10-6; OR=1.18; CI: 1.11-1.27, KIT). Variants located in or near the genes ASB13, RSPO4, DLGAP1, PTPRD, GRIK2, FAIM2 and CDH20, identified in linkage peaks and the original GWASs, were among the top signals. Polygenic risk scores for each individual study predicted case-control status in the other by explaining 0.9% (P=0.003) and 0.3% (P=0.0009) of the phenotypic variance in OCGAS and the European IOCDF-GC target samples, respectively. The common SNP heritability in the combined OCGAS and IOCDF-GC sample was estimated to be 0.28 (s.e.=0.04).Strikingly, 65% of the SNP-based heritability in the OCGAS sample was accounted for by SNPs with minor allele frequencies of ?40%. This joint analysis constituting the largest single OCD genome-wide study to date represents a major integrative step in elucidating the genetic causes of OCD.Molecular Psychiatry advance online publication, 1 August 2017; doi:10.1038/mp.2017.154. | Molecular psychiatry (2017). | 2017 | CUSI DANIELE | * | 10.1038/mp.2017.154 |
| 380214 | Articolo in rivista | A candidate gene study identifies a haplotype of CD2 as novel susceptibility factor for systemic sclerosis. | Koumakis E1, Bouaziz M2, Dieude P3, Cauvet A4, Ruiz B4, Airo P5, Cusi D6, Matucci-Cerinic M7, Salvi E8, Cuomo G9, Hachulla E10, Diot E11, Caramaschi P12, Riccieri V13, Avouac J1, Allanore Y14. | OBJECTIVES: Systemic sclerosis (SSc) is a rare autoimmune disease (AID) with a complex genetic etiology. Evidence for a shared pathogenesis across AIDs is given by the well-known pleiotropism of autoimmune genes. Recently, several unbiased approaches have identified an association between polymorphisms of the CD2 gene, and rheumatoid arthritis (RA) susceptibility. The objective of this study was to investigate whether CD2 polymorphisms are associated with SSc. METHODS: Two SNPs of CD2, rs624988 and rs798036, were genotyped in a total of 1,786 SSc patients and 2,360 healthy individuals from two European populations (France and Italy). Meta-analyses were performed to assess whether an association exists between CD2 polymorphisms or haplotypes and SSc or its main subtypes. RESULTS: The combined analyses revealed an association between the rs624988 A allele and SSc susceptibility: padj=0.023, OR=1.14 (95%CI 1.04-1.25). Single marker analysis did not reveal any association between rs798036 and SSc. Haplotype analysis identified that the A-T haplotype, previously described in RA, was associated with higher susceptibility for SSc (padj=0.029, OR=1.14, 95%CI 1.04-1.25) and with the positive anti-centromere antibody sub-group of SSc patients (padj=0.009, OR=1.19 95%CI 1.07-1.32). Genotype-mRNA expression correlations revealed that the CD2 risk haplotype was associated with decreased CD2 mRNA expression in SSc patients. CONCLUSIONS: Our study establishes CD2 as a new susceptibility factor for SSc, in a European Caucasian population, confirming the sharing of autoimmune risk factors by SSc and RA. | Clinical and Experimental Rheumatology (Testo stamp.) 34 Suppl 100 (2016): 43-48. | 2016 | CUSI DANIELE | * | |
| 380396 | Contributo in volume | Ochratoxin A and Epigenetics | Alessandra Mezzelani | Ochratoxin A is a thermoresistant mycotoxin produced by ubiquitous molds of Aspergillus and Penicillium genera. It contaminates foodstuffs and feedstuffs worldwide and therefore is of human and animal concern. Ochratoxin A induces oxidative stress, inflammation, and fibrosis, and is nephrotoxic, hepatotoxic, and neurotoxicin particularly in male subjects. Toxicity is mainly exerted through epigenetic mechanisms. Nephrotoxicity is probably due to ochratoxin A-induced suppression of the collagen regulator mir-29b that results in an increase of translated collagen, fibrotic alteration, and nephropathy. Alternatively, ochratoxin A induces mir-132 upregulation that occurs in neurologic and psychiatric conditions as well as in oxidative stress. Undeniably, mir-132 acts in the reciprocal regulation of autism-related genes MeCP2 and PTEN decreasing the antioxidant Nrf2 that leads to the formation of high levels of reactive oxygen species. Reactive oxygen species, in turn, enhance the expression of mir-200c that impairs antioxidative mechanisms and synaptic plasticity through the reduction of HO-1 and NLGN4X. As for apoptosis, OTA exposure increases mir-122 that suppresses the anti-apoptotic genes Bcl-w and caspase-3 leading to cell death and hepatic damage. Interestingly, bothMECP And NLGN4X are involved in neurodevelopmental disorders, including autism, and are mapped on the X chromosome. As autism is a male predominant disorder, a possible contribution of ochratoxin A in its patho-genesis and in its strong male bias can be suggested. Very few papers report about ochratoxin A-induced deacetylation:cells exposed to OTA underwent to a dramatic block of histone acetyltransferases leading to mitotic arrest and Nrf2 inhibition that, again, lead to reactive oxygen species formation. Further studies are needed to obtain a complete picture of ochratoxin A-dependent epigenetic effects and to prevent or to counteract them. | Handbook of Nutrition, Diet, and Epigenetics, edited by Vinood B. Patel and Victor R. Preedy (eds.) The Editors and Editorial Advisors for the title are senior academics or teach in leading institutions including King's College London and The University of Westminster., pp. 1-20, 2017 | 2017 | MEZZELANI ALESSANDRA MARIA | Ochratoxin A, neurotoxicity, autism, MeCP2, phe, PAH, catecholamins | 10.1007/978-3-319-31143-2_33-1 |
| 382116 | Articolo in rivista | Recognition of Delirium Features in Clinical Practice: Data from the "Delirium Day 2015" National Survey. | Mossello E1, Tesi F1, Di Santo SG2, Mazzone A3, Torrini M1, Cherubini A4, Bo M5, Musicco M6,7, Bianchetti A8, Ferrari A9,10, Ferrara N11,12,13, Trabucchi M14,15,16, Morandi A16,17, Bellelli G16,18,19, Italian Study Group on Delirium. | BACKGROUND/OBJECTIVES: Delirium is underrecognized in clinical practice. The primary aim of the present multicenter study was to compare the ability of nurses to identify delirium features with a standardized assessment. The secondary aim was to identify predictors of missed or incorrect identifications of delirium by nurses. DESIGN: Point prevalence study in 120 wards across Italy. SETTING: "Delirium Day 2015." PARTICIPANTS: Inpatients aged 65 and older (N = 1,867). MEASUREMENTS: Participants and nurses were asked specific questions to investigate their perceptions of the presence of delirium features (acute cognitive change, inattention, cognitive fluctuations, impaired arousal). Delirium was identified according to the results of the Assessment Test for Delirium and Cognitive Impairment (4AT), completed by a physician. Comorbidities including dementia, disability, drug treatments, and delirium motor subtype according to the Delirium Motor Subtype Scale were recorded. RESULTS: Delirium was present in 429 subjects (23%) according to the 4AT. Cognitive fluctuations was the delirium feature that the nurses most often recognized. Nurses' perceptions of acute cognitive change, cognitive fluctuations, or impaired arousal had 84% sensitivity and 81% specificity for delirium. The nonmotor subtype of delirium was less likely to be recognized (80%) than the hyperactive (97%), mixed (92%), and hypoactive (90%) subtypes. Incorrect perception of delirium was more frequent in subjects with dementia (specificity 64%). CONCLUSIONS: The delirium feature that nurses were best able to recognize was cognitive fluctuations. The nonmotor subtype was associated with a lower recognition rate. Routine observation and registration of delirium features by nurses in clinical practice might be helpful to increase formal diagnosis of delirium. | Journal of the American Geriatrics Society (2017). | 2017 | MUSICCO MASSIMO | arousal; delirium; dementia; health services for the aged; inpatients | 10.1111/jgs.15211 |
| 382125 | Articolo in rivista | RNA Sequencing and Analysis in Microorganisms for Metabolic Network Reconstruction. | Pinatel, Eva, Peano, Clelia | There is a strict interplay between metabolic networks and transcriptional regulation in bacteria; indeed, the transcriptome regulation, affecting the expression of large gene sets, can be used to predict the likely "on" or "off" state of metabolic genes as a function of environmental factors. Up to date, many bacterial transcriptomes have been studied by RNAseq, hundreds of experiments have been performed, and Giga bases of sequences have been produced. All this transcriptional information could potentially be integrated into metabolic networks in order to obtain a more comprehensive view of their regulation and to increase their prediction power.To get high-quality transcriptomic data, to be integrated into metabolic networks, it is paramount to clearly know how to produce highly informative RNA sequencing libraries and how to manage RNA sequencing data.In this chapter, we will get across the main steps of an RNAseq experiment: from removal of ribosomal RNAs, to strand-specific library preparation, till data analysis and integration. We will try to share our experience and know-how, to give you a precise protocol to follow, and some useful recommendations or tips and tricks to adopt in order to go straightforward toward a successful RNAseq experiment. | Methods in molecular biology (Clifton N.J.) 1716 (2018): 239-265. | 2018 | PINATEL EVA MARIA, PEANO CLELIA | Data integration; Gene expression analysis; RNAseq | 10.1007/978-1-4939-7528-0_11 |
| 382130 | Articolo in rivista | Biological and prognostic impact of APOBEC-induced mutations in the spectrum of plasma cell dyscrasias and multiple myeloma cell lines. | Maura F1, 2, Petljak M2, Lionetti M1, 3, Cifola I4, Liang W5, Pinatel E4, Alexandrov LB6, 7, 8, Fullam A2, Martincorena I2, Dawson KJ2, Angelopoulos N2, Samur MK9, Szalat R9, Zamora J2, Tarpey P2, Davies H2, Corradini P1, 10, Anderson KC9, Minvielle S11, Neri A1, 3, Avet-Loiseau H12, Keats J5, Campbell PJ2, Munshi NC9, 13, Bolli N1, 2, 10. | No abstract available | Leukemia (Basingstoke, Online) (2017). | 2017 | PINATEL EVA MARIA, CIFOLA INGRID | Cancer genomics Myeloma | 10.1038/leu.2017.345 |
| 382146 | Articolo in rivista | Il bello e la via del bene, riflessioni su etica e medicina estetica | Elena Mancini | L'articolo esamina gli aspetti etici correlati alla medicina estetica. Viene evidenziata in primo luogo la capacita del medico di riconoscere le ragioni della domanda rivolta dal paziente/cliente che e sempre una richiesta di cambiamento della propria immagine, ma anche della propria identita, spesso per poter trasformare la propria storia di vita. Comunicare chiaramente cosa la medicina estetica puo fare e cosa invece non puo fare in risposta a tale richiesta e la responsabilita principale del medico di medicina estetica. Altro elemento centrale e dato dal rispetto assoluto della riservatezza e del segreto professionale che sono la condizione per consentire al paziente/cliente di ricostruire la propria identita soprattutto ove esse e lesa o vulnerabile. | The Future of Science and Ethics (Online) (2017). | 2017 | MANCINI ELENA | Medicina estetica Cosmetic medicine Etica della comunicazione Ethics of communication Privacy | |
| 382147 | Articolo in rivista | La Dichiarazione della Fondazione Veronesi sulla Research Integrity: un documento innovativo nel dibattito internazionale | Marta Rapallini | La Dichiarazione della Fondazione Veronesi rappresenta un importante passo avanti nella promozione della Research Integrity e costituisce un approccio nuovo e interessante al problema. Essa si pone nel filone delle piu importanti carte internazionali sulla RI, a partire dalla Carta europea dei ricercatori, ma propone anche un approccio innovativo. La Dichiarazione della Fondazione Veronesi riguarda, nello specifico, le condotte lesive nel rapporto tra il ricercatore e il con testo della sua ricerca, sia nel corso dell'attivita di ricerca sia nella sua valorizzazione. La promozione di principi mirati a tutelare la qualita della ricerca, anche ai fini della sua divulgazione, e essenziale per restituire alla ricerca scientifica quell'altissima reputazione che le va riconosciuta. | The Future of Science and Ethics (Online) (2017). | 2017 | RAPALLINI MARTA | Integrita della ricerca Research integrity Etica Ethics Condotte inappropriate Misconduct | |
| 382177 | Articolo in rivista | Ricerca sociale e finalita etiche: il caso della ricerca sullo sviluppo sostenibile | Carla Collicelli | L'articolo affronta il delicato rapporto tra scienze sociali ed etica focalizzandosi sulle problematiche legate al cosiddetto "divisionismo", che vuole la ricerca sociale e i suoi esiti separati dalle finalita etiche riguardanti la societa e la politica: da un lato una scienza positiva, dall'altro una disciplina normativa. Vengono passati in rassegna alcuni impor tanti contributi, sia italiani che non, che hanno promosso la necessita di partire da alcune fondamentali questioni etiche ai fini del benessere sociale e che vanno oltre la sola considerazione del PIL. A livello metodologico, oltre ad evidenziare pregi e limiti dell'individualismo metodologico, si sottolinea l'importanza delle fasi di concettualizzazione e di elaborazione di ipotesi e indicatori di ricerca, troppo spesso poste in secondo piano rispetto alla potenza dei moderni strumenti di raccolta e analisi dei dati. Infine una riflessione sull'importanza sociale ed etica, dell'utilizzo di metodi e tecniche di ricerca sociale partecipata per il coinvolgimento di tutti gli stakeholder. | The Future of Science and Ethics (Online) (2017). | 2017 | COLLICELLI CARLA | Divisionismo, Indicatori, Stakeholder | |
| 382182 | Contributo in volume | Disagio psichico e contesto sociale, il contributo della sociologia | C. Collicelli, A. Di Leo | *** | Reti di cura e disagio psichico, edited by R. Frisanco. Roma: Palombi Editori, 2017 | 2017 | COLLICELLI CARLA | *** | |
| 382187 | Contributo in volume | La prevenzione, una questione di cultura. Il punto di vista sociologico | Carla Collicelli | *** | Extra Moenia. Milano: Mondadori Bruno, 2017 | 2017 | COLLICELLI CARLA | *** | |
| 382190 | Articolo in rivista | Pensare il dolore | Elena Mancini | *** | Giornale di metafisica (Online) 2/2017 (2017): 552-567. | 2017 | MANCINI ELENA | *** | |
| 382452 | Articolo in rivista | The glucose and lipid metabolism reprogramming is gradedependent in clear cell renal cell carcinoma primary cultures and is targetable to modulate cell viability and proliferation | Bianchi C., Meregalli C., Bombelli S., Di Stefano V., Salerno F., Torsello B., De Marco S., Bovo G., Cifola I., Mangano E., Battaglia C., Strada G., Lucarelli G., Weiss R.H., Perego R.A. | Clear cell renal cell carcinoma (ccRCC) has a poor prognosis despite novel biological targeted therapies. Tumor aggressiveness and poor survival may correlate with tumor grade at diagnosis and with complex metabolic alterations, also involving glucose and lipid metabolism. However, currently no grade-specific metabolic therapy addresses these alterations. Here we used primary cell cultures from ccRCC of low- and high-grade to investigate the effect on energy state and reduced pyridine nucleotide level, and on viability and proliferation, of specific inhibition of glycolysis with 2-deoxy-D-glucose (2DG), or fatty acid oxidation with Etomoxir. Our primary cultures retained the tissue grade-dependent modulation of lipid and glycogen storage and aerobic glycolysis (Warburg effect). 2DG affected lactate production, energy state and reduced pyridine nucleotide level in high-grade ccRCC cultures, but the energy state only in low-grade. Rather, Etomoxir affected energy state in high-grade and reduced pyridine nucleotide level in low-grade cultures. Energy state and reduced pyridine nucleotide level were evaluated by ATP and reduced 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium (MTT) dye quantification, respectively. 2DG treatment impaired cell proliferation and viability of low-grade ccRCC and normal cortex cultures, whereas Etomoxir showed a cytostatic and cytotoxic effect only in high-grade ccRCC cultures. Our data indicate that in ccRCC the Warburg effect is a grade-dependent feature, and fatty acid oxidation can be activated for different grade-dependent metabolic needs. A possible grade-dependent metabolic therapeutic approach in ccRCC is also highlighted. | Oncotarget 8 (2017): 113502-113515. | 2017 | MANGANO ELEONORA, BATTAGLIA CRISTINA, CIFOLA INGRID | Fuhrman grade, Glucose and lipid metabolism reprogramming, Primary cell cultures, Renal cell carcinoma | 10.18632/oncotarget.23056 |
| 383335 | Articolo in rivista | The glucose and lipid metabolism reprogramming is grade-dependent in clear cell renal cell carcinoma primary cultures and is targetable to modulate cell viability and proliferation | Bianchi C1, Meregalli C1, Bombelli S1, Di Stefano V1, Salerno F1, Torsello B1, De Marco S1, Bovo G2, 3, Cifola I4, Mangano E4, Battaglia C5, Strada G6, Lucarelli G7, Weiss RH8, Perego RA1. | Clear cell renal cell carcinoma (ccRCC) has a poor prognosis despite novel biological targeted therapies. Tumor aggressiveness and poor survival may correlate with tumor grade at diagnosis and with complex metabolic alterations, also involving glucose and lipid metabolism. However, currently no grade-specific metabolic therapy addresses these alterations. Here we used primary cell cultures from ccRCC of low- and high-grade to investigate the effect on energy state and reduced pyridine nucleotide level, and on viability and proliferation, of specific inhibition of glycolysis with 2-deoxy-D-glucose (2DG), or fatty acid oxidation with Etomoxir. Our primary cultures retained the tissue grade-dependent modulation of lipid and glycogen storage and aerobic glycolysis (Warburg effect). 2DG affected lactate production, energy state and reduced pyridine nucleotide level in high-grade ccRCC cultures, but the energy state only in low-grade. Rather, Etomoxir affected energy state in high-grade and reduced pyridine nucleotide level in low-grade cultures. Energy state and reduced pyridine nucleotide level were evaluated by ATP and reduced 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) dye quantification, respectively. 2DG treatment impaired cell proliferation and viability of low-grade ccRCC and normal cortex cultures, whereas Etomoxir showed a cytostatic and cytotoxic effect only in high-grade ccRCC cultures. Our data indicate that in ccRCC the Warburg effect is a grade-dependent feature, and fatty acid oxidation can be activated for different grade-dependent metabolic needs. A possible grade-dependent metabolic therapeutic approach in ccRCC is also highlighted. | Oncotarget (2017). | 2017 | MANGANO ELEONORA, BATTAGLIA CRISTINA, CIFOLA INGRID | Fuhrman grade; glucose and lipid metabolism reprogramming; primary cell cultures; renal cell carcinoma | |
