Pubblicazioni

0:ID	Type	Title	Authors	Abstract	Source	Year	CNR list	Keywords	9:DOI
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
369930	Articolo in rivista	Genetic Drivers of Kidney Defects in the DiGeorge Syndrome	Lopez-Rivera, E., Liu, Y. P., Verbitsky, M., Anderson, B. R., Capone, V. P., Otto, E. A., Yan, Z., Mitrotti, A., Martino, J., Steers, N. J., Fasel, D. A., Vukojevic, K., Deng, R., Racedo, S. E., Liu, Q., Werth, M., Westland, R., Vivante, A., Makar, G. S., Bodria, M., Sampson, M. G., Gillies, C. E., Vega-Warner, V., Maiorana, M., Petrey, D. S., Honig, B., Lozanovski, V. J., Salomon, R., Heidet, L., Carpentier, W., Gaillard, D., Carrea, A., Gesualdo, L., Cusi, D., Izzi, C., Scolari, F., van Wijk, J. A. E., Arapovic, A., Saraga-Babic, M., Saraga, M., Kunac, N., Samii, A., McDonald-McGinn, D. M., Crowley, T. B., Zackai, E. H., Drozdz, D., Miklaszewska, M., Tkaczyk, M., Sikora, P., Szczepanska, M., Mizerska-Wasiak, M., Krzemien, G., Szmigielska, A., Zaniew, M., Darlow, J. M., Puri, P., Barton, D., Casolari, E., Furth, S. L., Warady, B. A., Gucev, Z., Hakonarson, H., Flogelova, H., Tasic, V., Latos-Bielenska, A., Materna-Kiryluk, A., Allegri, L., Wong, C. S., Drummond, I. A., D'Agati, V., Imamoto, A., Barasch, J. M., Hildebrandt, F., Kiryluk, K., Lifton, R. P., Morrow, B. E., Jeanpierre, C., Papaioannou, V. E., Ghiggeri, G. M., Gharavi, A. G., Katsanis, N., Sanna-Cherchi, S.	BACKGROUND The DiGeorge syndrome, the most common of the microdeletion syndromes, affects multiple organs, including the heart, the nervous system, and the kidney. It is caused by deletions on chromosome 22q11.2; the genetic driver of the kidney defects is unknown. METHODS We conducted a genomewide search for structural variants in two cohorts: 2080 patients with congenital kidney and urinary tract anomalies and 22,094 controls. We performed exome and targeted resequencing in samples obtained from 586 additional patients with congenital kidney anomalies. We also carried out functional studies using zebrafish and mice. RESULTS We identified heterozygous deletions of 22q11.2 in 1.1% of the patients with congenital kidney anomalies and in 0.01% of population controls (odds ratio, 81.5; P = 4.5x10-14). We localized the main drivers of renal disease in the DiGeorge syndrome to a 370-kb region containing nine genes. In zebrafish embryos, an induced loss of function in snap29, aifm3, and crkl resulted in renal defects; the loss of crkl alone was sufficient to induce defects. Five of 586 patients with congenital urinary anomalies had newly identified, heterozygous protein-altering variants, including a premature termination codon, in CRKL. The inactivation of Crkl in the mouse model induced developmental defects similar to those observed in patients with congenital urinary anomalies. CONCLUSIONS We identified a recurrent 370-kb deletion at the 22q11.2 locus as a driver of kidney defects in the DiGeorge syndrome and in sporadic congenital kidney and urinary tract anomalies. Of the nine genes at this locus, SNAP29, AIFM3, and CRKL appear to be critical to the phenotype, with haploinsufficiency of CRKL emerging as the main genetic driver. (Funded by the National Institutes of Health and others.)	The New England journal of medicine (Print) 376 (2017): 742-754.	2017	CUSI DANIELE	*	10.1056/NEJMoa1609009
369932	Articolo in rivista	Genome-Wide and Gene-Based Meta-Analyses Identify Novel Loci Influencing Blood Pressure Response to Hydrochlorothiazide	Salvi, Erika, Wang, Zhiying, Rizzi, Federica, Gong, Yan, McDonough, Caitrin W., Padmanabhan, Sandosh, Hiltunen, Timo P., Lanzani, Chiara, Zaninello, Roberta, Chittani, Martina, Bailey, Kent R., Sarin, Antti-Pekka, Barcella, Matteo, Melander, Olle, Chapman, Arlene B., Manunta, Paolo, Kontula, Kimmo K., Glorioso, Nicola, Cusi, Daniele, Dominiczak, Anna F., Johnson, Julie A., Barlassina, Cristina, Boerwinkle, Eric, Cooper-DeHoff, Rhonda M., Turner, Stephen T.	This study aimed to identify novel loci influencing the antihypertensive response to hydrochlorothiazide monotherapy. A genome-wide meta-analysis of blood pressure (BP) response to hydrochlorothiazide was performed in 1739 white hypertensives from 6 clinical trials within the International Consortium for Antihypertensive Pharmacogenomics Studies, making it the largest study to date of its kind. No signals reached genome-wide significance (P<5x10(-8)), and the suggestive regions (P<10(-5)) were cross-validated in 2 black cohorts treated with hydrochlorothiazide. In addition, a gene-based analysis was performed on candidate genes with previous evidence of involvement in diuretic response, in BP regulation, or in hypertension susceptibility. Using the genome-wide meta-analysis approach, with validation in blacks, we identified 2 suggestive regulatory regions linked to gap junction protein 1 gene (GJA1) and forkhead box A1 gene (FOXA1), relevant for cardiovascular and kidney function. With the gene-based approach, we identified hydroxy-delta-5-steroid dehydrogenase, 3 - and steroid -isomerase 1 gene (HSD3B1) as significantly associated with BP response (P<2.28x10(-4)). HSD3B1 encodes the 3-hydroxysteroid dehydrogenase enzyme and plays a crucial role in the biosynthesis of aldosterone and endogenous ouabain. By amassing all of the available pharmacogenomic studies of BP response to hydrochlorothiazide, and using 2 different analytic approaches, we identified 3 novel loci influencing BP response to hydrochlorothiazide. The gene-based analysis, never before applied to pharmacogenomics of antihypertensive drugs to our knowledge, provided a powerful strategy to identify a locus of interest, which was not identified in the genome-wide meta-analysis because of high allelic heterogeneity. These data pave the way for future investigations on new pathways and drug targets to enhance the current understanding of personalized antihypertensive treatment.	Hypertension (Dallas Tex., 1979) 69 (2017): 51-59.	2017	CUSI DANIELE	blood pressure response, diuretics, genome-wide association study, hydrochlorothiazide, hypertension, meta-analysis, pharmacogenomics	10.1161/HYPERTENSIONAHA.116.08267
369952	Articolo in rivista	Rett Syndrome: A Focus on Gut Microbiota	Borghi, Elisa, Borgo, Francesca, Severgnini, Marco, Savini, Miriam Nella, Casiraghi, Maria Cristina, Vignoli, Aglaia	Rett syndrome (RTT) is an X-linked neurodevelopmental disorder affecting 1 in 10,000 live female births. Changes in microbiota composition, as observed in other neurological disorders such as autism spectrum disorders, may account for several symptoms typically associated with RTT. We studied the relationship between disease phenotypes and microbiome by analyzing diet, gut microbiota, and short-chain fatty acid (SCFA) production. We enrolled eight RTT patients and 10 age- and sex-matched healthy women, all without dietary restrictions. The microbiota was characterized by 16S rRNA gene sequencing, and SCFAs concentration was determined by gas chromatographic analysis. The RTT microbiota showed a lower diversity, an enrichment in Bacteroidaceae, Clostridium spp., and Sutterella spp., and a slight depletion in Ruminococcaceae. Fecal SCFA concentrations were similar, but RTT samples showed slightly higher concentrations of butyrate and propionate, and significant higher levels in branched-chain fatty acids. Daily caloric intake was similar in the two groups, but macronutrient analysis showed a higher protein content in RTT diets. Microbial function prediction suggested in RTT subjects an increased number of microbial genes encoding for propionate and butyrate, and amino acid metabolism. A full understanding of these critical features could offer new, specific strategies for managing RTT-associated symptoms, such as dietary intervention or pre/probiotic supplementation.	International journal of molecular sciences (Online) 18 (2017).	2017	SEVERGNINI MARCO	Rett syndrome, microbiota, short-chain fatty acids, diet	10.3390/ijms18020344
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
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
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
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
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
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
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
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	*
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
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
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
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	***
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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.
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
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, CUCCA FRANCESCO, SANNA SERENA	*	10.1038/ncomms14977
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
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
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
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	*
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 (2018): 969-974.	2018	CHIAPPORI FEDERICA, MERELLI IVAN	Antiretroviral therapy; Calcium-sensing receptor; Hyperparathyroidism; Parathyroid hormone; Tenofovir disoproxil fumarate	10.1016/j.biopha.2017.11.037
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
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
382190	Articolo in rivista	Pensare il dolore	Elena Mancini	***	Giornale di metafisica (Online) 2/2017 (2017): 552-567.	2017	MANCINI ELENA	***
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	***
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
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
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
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
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
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
400632	Articolo in rivista	Early gut microbiota signature of aGvHD in children given allogeneic hematopoietic cell transplantation for hematological disorders	Elena Biagi 1, Daniele Zama 2, Simone Rampelli 1, Silvia Turroni 1, Patrizia Brigidi 1, Clarissa Consolandi 3, Marco Severgnini 3, Eleonora Picotti 2, Pietro Gasperini 2, Pietro Merli 4, Nunzia Decembrino 5, Marco Zecca 5, Simone Cesaro 6, Maura Faraci 7, Arcangelo Prete 2, Franco Locatelli 4, Andrea Pession 2, Marco Candela 1, Riccardo Masetti 2	Background The onset of acute Graft-versus-Host Disease (aGvHD) has been correlated with the gut microbiota (GM) composition, but experimental observations are still few, mainly involving cohorts of adult patients. In the current scenario where fecal microbiota transplantation has been used as a pioneer therapeutic approach to treat steroid-refractory aGvHD, there is an urgent need to expand existing observational studies of the GM dynamics in Hematopoietic Stem Cell Transplantation (HSCT). Aim of the present study is to explore the GM trajectory in 36 pediatric HSCT recipients in relation to aGvHD onset. Methods Thirty-six pediatric patients, from four transplantation centers, undergoing HSCT were enrolled in the study. Stools were collected at three time points: before HSCT, at time of engraftment and > 30 days following HSCT. Changes in the GM phylogenetic structure were studied by 16S rRNA gene Illumina sequencing and phylogenetic assignation. Results Children developing gut aGvHD had a dysbiotic GM layout before HSCT occurred. This putative aGvHD-predisposing ecosystem state was characterized by (i) reduced diversity, (ii) lower Blautia content, (iii) increase in Fusobacterium abundance. At time of engraftment, the GM structure underwent a deep rearrangement in all patients but, regardless of the occurrence of aGvHD and its treatment, it reacquired a eubiotic configuration from day 30. Conclusions We found a specific GM signature before HSCT predictive of subsequent gut aGvHD occurrence. Our data may open the way to a GM-based stratification of the risk of developing aGvHD in children undergoing HSCT, potentially useful also to identify patients benefiting from prophylactic fecal transplantation.	BMC medical genomics (2019).	2019	CONSOLANDI CLARISSA, SEVERGNINI MARCO	Gut microbiota Hematopoietic stem cell transplantation Acute graft-versus-host disease Alloreactivity 16S rRNA gene sequencing Pediatric patients
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
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
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
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
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, PRINELLI FEDERICA	adolescents; co-design; focus groups; health behavior; mHealth; mobile app; mobile phone; obesity; youth	10.2196/14118
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
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
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
443665	Articolo in rivista	Metadata compilation for the MIDI-CHIP dataset	Yannick Lara, Annick Wilmotte, Karina Sivonen, Gianluca De Bellis, Pirjo Kuuppo, Stefano Ventura, Beatrice Montarani, Peter Henderson, Lucien Hoffmann, Maciej Zalewski, Jiri Komarek	In order to be protected, biodiversity must be evaluated. For cyanobacteria, the traditional morphological measures of biodiversity are unsatisfactory. We utilize molecular markers (like SSU rRNA) to define taxa on the basis of phylogeny. In freshwater ecosystems huge populations of cyanobacteria can occur. These blooms may release toxins that make the water poisonous. A second part of the study is to compare the temporal dynamics of biodiversity in both natural and disturbed lakes. This comparative analysis requires the use of ecological indexes to summarise the diversity of the samples and allow inferences about the ecosystem to be made.	Freshwater Metadata Journal 37 (2018): 1-8.	2018	DE BELLIS GIANLUCA, VENTURA STEFANO	cyanobacteria, lakes, microcystins, diversity, taxonomy	10.15504/fmj.2018.37
444594	Articolo in rivista	Explaining Ovarian Cancer Gene Expression Profiles with Fuzzy Rules and Genetic Algorithms	Consiglio A, Casalino G, Castellano G, Grillo G, Perlino E, Vessio G, Licciulli F	The analysis of gene expression data is a complex task, and many tools and pipelines are available to handle big sequencing datasets for case-control (bivariate) studies. In some cases, such as pilot or exploratory studies, the researcher needs to compare more than two groups of samples consisting of a few replicates. Both standard statistical bioinformatic pipelines and innovative deep learning models are unsuitable for extracting interpretable patterns and information from such datasets. In this work, we apply a combination of fuzzy rule systems and genetic algorithms to analyze a dataset composed of 21 samples and 6 classes, useful for approaching the study of expression profiles in ovarian cancer, compared to other ovarian diseases. The proposed method is capable of performing a feature selection among genes that is guided by the genetic algorithm, and of building a set of if-then rules that explain how classes can be distinguished by observing changes in the expression of selected genes. After testing several parameters, the final model consists of 10 genes involved in the molecular pathways of cancer and 10 rules that correctly classify all samples.	Electronics (Basel) 10 (2021).	2021	LICCIULLI VITO FLAVIO, GRILLO GIORGIO, PERLINO ELDA, CONSIGLIO ARIANNA	computational intelligence, classification, fuzzy inference systems, genetic algorithms, next-generation sequencing, ovarian cancer, interpretable models	10.3390/electronics10040375
446774	Articolo in rivista	Lung expression of genes putatively involved in SARS-CoV-2 infection is modulated in cis by germline variants	Chiara E Cotroneo, Nunzia Mangano, Tommaso A Dragani, Francesca Colombo	Germline variants in genes involved in SARS-CoV-2 cell entry and in host innate immune responses to viruses may influence the susceptibility to infection. This study used whole-genome analyses of lung tissue to identify polymorphisms acting as expression quantitative trait loci (eQTLs) for 60 genes of relevance to SARS-CoV-2 infection susceptibility. The expression of genes with confirmed or possible roles in viral entry-replication and in host antiviral responses was studied in the non-diseased lung tissue of 408 lung adenocarcinoma patients. No gene was differently expressed by sex, but APOBEC3H levels were higher and PARP12 levels lower in older individuals. A total of 125 cis-eQTLs (false discovery rate < 0.05) was found to modulate mRNA expression of 15 genes (ABO, ANPEP, AP2A2, APOBEC3D, APOBEC3G, BSG, CLEC4G, DDX58, DPP4, FURIN, FYCO1, RAB14, SERINC3, TRIM5, ZCRB1). eQTLs regulating ABO and FYCO1 were found in COVID-19 susceptibility loci. No trans-eQTLs were identified. Genetic control of the expression of these 15 genes, which encode putative virus receptors, proteins required for vesicle trafficking, enzymes that interfere with viral replication, and other restriction factors, may underlie interindividual differences in risk or severity of infection with SARS-CoV-2 or other viruses.	European journal of human genetics (Online) (2021).	2021	COLOMBO FRANCESCA	eQTL, restriction factors, lung transcriptome, SNPs
446995	Articolo in rivista	Characterization of multi-locus imprinting disturbances and underlying genetic defects in patients with chromosome 11p15.5 related imprinting disorders	Fontana, L., Bedeschi, M. F., Maitz, S., Cereda, A., Fare, C., Motta, S., Seresini, A., D'Ursi, P., Orro, A., Pecile, V., Calvello, M., Selicorni, A., Lalatta, F., Milani, D., Sirchia, S. M., Miozzo, M., Tabano, S.	The identification of multilocus 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.D	Epigenetics 13 (2018): 897-909.	2018	ORRO ALESSANDRO, D'URSI PASQUALINA	Beckwith-Wiedemann syndrome, Silver-Russell syndrome, multilocus imprinting disturbances, targeted next-generation sequencing, epigenotype-phenotype correlations	10.1080/15592294.2018.1514230
446996	Articolo in rivista	In silico drug repositioning on F508del-CFTR: A proof-of-concept study on the AIFA library	Orro A., Uggeri M., Rusnati M., Urbinati C., Pedemonte N., Pesce E., Moscatelli M., Padoan R., Cichero E., Fossa P., D'Ursi P.	Computational drug repositioning is of growing interest to academia and industry, for its ability to rapidly screen a huge number of candidates in silico (exploiting comprehensive drug datasets) together with reduced development cost and time. The potential of drug repositioning has not been fully evaluated yet for cystic fibrosis (CF), a disease mainly caused by deletion of Phe 508 (F508del) of the cystic fibrosis transmembrane conductance regulator (CFTR) protein. F508del-CFTR is thus withheld in the endoplasmic reticulum and rapidly degraded by the ubiquitin/proteasome system. CF is still a fatal disease. Nowadays, it is treatable by some CFTR-rescuing drugs, but new-generation drugs with stronger therapeutic benefits and fewer side effects are still awaited. In this manuscript we report about the results of a pilot computational drug repositioning screening in search of F508del-CFTR-targeted drugs performed on AIFA library by means of a dedicated computational pipeline and surface plasmon resonance binding assay to experimentally validate the computational findings.	European journal of medicinal chemistry 213 (2021).	2021	ORRO ALESSANDRO, D'URSI PASQUALINA	drug repositioning	10.1016/j.ejmech.2021.113186
446997	Articolo in rivista	Evolution toward beta common chain receptor usage links the matrix proteins of HIV-1 and its ancestors to human erythropoietin	Caccuri F., D'Ursi P., Uggeri M., Bugatti A., Mazzuca P., Zani A., Filippini F., Salmona M., Ribatti D., Slevin M., Orro A., Lu W., Lio P., Gallo R.C., Caruso A.	The HIV-1 matrix protein p17 (p17) is a pleiotropic molecule impacting on different cell types. Its interaction with many cellular proteins underlines the importance of the viral protein as a major determinant of human specific adaptation. We previously showed the proangiogenic capability of p17. Here, by integrating functional analysis and receptor binding, we identify a functional epitope that displays molecular mimicry with human erythropoietin (EPO) and promotes angiogenesis through common beta chain receptor (?CR) activation. The functional EPO-like epitope was found to be present in the matrix protein of HIV-1 ancestors SIV originated in chimpanzees (SIVcpz) and gorillas (SIVgor) but not in that of HIV-2 and its ancestor SIVsmm from sooty mangabeys. According to biological data, evolution of the EPO-like epitope showed a clear differentiation between HIV-1/SIVcpz-gor and HIV-2/SIVsmm branches, thus highlighting this epitope on p17 as a divergent signature discriminating HIV-1 and HIV-2 ancestors. P17 is known to enhance HIV-1 replication. Similarly to other ?CR ligands, p17 is capable of attracting and activating HIV-1 target cells and promoting a proinflammatory microenvironment. Thus, it is tempting to speculate that acquisition of an epitope on the matrix proteins of HIV-1 ancestors capable of triggering ?CR may have represented a critical step to enhance viral aggressiveness and early human-to-human SIVcpz/gor dissemination. The hypothesis that the p17/?CR interaction and ?CR abnormal stimulation may also play a role in sustaining chronic activation and inflammation, thus marking the difference between HIV-1 and HIV-2 in term of pathogenicity, needs further investigation.	Proceedings of the National Academy of Sciences of the United States of America 118 (2021).	2021	ORRO ALESSANDRO, D'URSI PASQUALINA	HIV	10.1073/pnas.2021366118
447342	Contributo in atti di convegno	A conserved approach to non-integrated reprogramming of mammalian cells	Carlos Driscoll, Ileana Zucchi, Rolland Reinbold, Christina Barr -	The derivation of induced pluripotent stem cell (iPSC) lines from a wide range of mammalian species provides a valuable resource for comparative developmental studies. Routine reprogramming of human patient cells is being used to capture the genetic diversity of individuals to generate new cell models that can recapitulate developmental and disease processes in a dish. This strategy can be extended across genera to generate putative iPSCs from a wide range of mammalian species, using a common set of core reagents to select for pluripotent cells derived under conditions similar to those used for human iPSCs. The conservation of identity of key transcription factors is sufficient such that transduction with vectors expressing the human Oct4, Sox2, Klf4 and c-Myc cDNAs can reprogram somatic cells from a wide range of mammals without the need to clone species specific genes. A non-integrating Sendai RNA viral vector system was used to effectively reprogram fibroblasts from a range of felid species (Domestic and Asian Leopard Cat, Cheetah) and Non-Human Primate species (Rhesus Macaque and Gorilla) into stable, putative iPSC lines. While species-specific differences may exist in growth factor dependence during embryonic development in vivo, by using existing media systems that support conserved signalling pathways, putative iPSC lines were selected for that survived in vitro in human iPSC culture conditions. Of practical utility, these putative iPSC lines grow rapidly and can be cultured well beyond the point at which the parental fibroblast lines undergo senescence. The majority of putative iPSC lines derived by this non-integrating method maintain a normal diploid karyotype determined by Giemsa banding analysis. Standard in vitro and in vivo assays are underway to test the differentiation capabilities of these cell lines. Non-integrating, Sendai viral vector-based reprogramming provides a standardized and reproducible approach to generating viable animal cell models free of DNA-artefacts that complement human genome resource and cell banking efforts.	International Society for Stem Cell Research Annual Meeting, Washington DC, 21-22/05/2017	2017	ZUCCHI ILEANA, REINBOLD ROLLAND ALVONS	induced pluripotent stem cell (iPSC)
447548	Articolo in rivista	Statistical and Machine Learning Techniques in Human Microbiome Studies: Contemporary Challenges and Solutions	Isabel Moreno-Indias1, 2*, Leo Lahti3, Miroslava Nedyalkova4, Ilze Elbere5, Gennady Roshchupkin6, Muhamed Adilovic7, Onder Aydemir8, Burcu Bakir-Gungor9, Enrique Carrillo-de Santa Pau10, Domenica D'Elia11, Mahesh S. Desai12, 13, Laurent Falquet14, 15, Aycan Gundogdu16, 17, Karel Hron18, Thomas Klammsteiner19, Marta B. Lopes20, 21, Laura Judith Marcos-Zambrano10, Claudia Marques22, Michael Mason23, Patrick May24, Lejla Pa?i?25, Gianvito Pio26, Sandor Pongor27, Vasilis J. Promponas28, Piotr Przymus29, Julio Saez-Rodriguez30, Alexia Sampri31, Rajesh Shigdel32, Blaz Stres33, 34, 35, Ramona Suharoschi36, Jaak Truu37, Ciprian-Octavian Truic?38, Baiba Vilne39, Dimitrios Vlachakis40, Ercument Yilmaz41, Georg Zeller42, Aldert L. Zomer43, David Gomez-Cabrero44, Marcus J. Claesson45 on behalf of ML4Microbiome	The human microbiome has emerged as a central research topic in human biology and biomedicine. Current microbiome studies generate high-throughput omics data across different body sites, populations, and life stages. Many of the challenges in microbiome research are similar to other high-throughput studies, the quantitative analyses need to address the heterogeneity of data, specific statistical properties, and the remarkable variation in microbiome composition across individuals and body sites. This has led to a broad spectrum of statistical and machine learning challenges that range from study design, data processing, and standardization to analysis, modeling, cross-study comparison, prediction, data science ecosystems, and reproducible reporting. Nevertheless, although many statistics and machine learning approaches and tools have been developed, new techniques are needed to deal with emerging applications and the vast heterogeneity of microbiome data. We review and discuss emerging applications of statistical and machine learning techniques in human microbiome studies and introduce the COST Action CA18131 "ML4Microbiome" that brings together microbiome researchers and machine learning experts to address current challenges such as standardization of analysis pipelines for reproducibility of data analysis results, benchmarking, improvement, or development of existing and new tools and ontologies.	Frontiers in microbiology 12 (2021): 9-1.	2021	D'ELIA DOMENICA	Machine Learning, microbiome, bioinformatics, medical applications, health	10.3389/fmicb.2021.635781
448120	Articolo in rivista	Rapha Myr(R), a Blend of Sulforaphane and Myrosinase, Exerts Antitumor and Anoikis-Sensitizing Effects on Human Astrocytoma Cells Modulating Sirtuins and DNA Methylation	Tomasello, Barbara, Di Mauro, Maria Domenica, Malfa, Giuseppe Antonio, Acquaviva, Rosaria, Sinatra, Fulvia, Spampinato, Giorgia, Laudani, Samuele, Villaggio, Giusy, Bielak-Zmijewska, Anna, Grabowska, Wioleta, Barbagallo, Ignazio Alberto, Liuzzo, Maria Teresa, Sbisa', Elisabetta, Forte, Maria Grazia, Di Giacomo, Claudia, Bonucci, Massimo, Renis, Marcella	Brain and other nervous system cancers are the 10th leading cause of death worldwide. Genome instability, cell cycle deregulation, epigenetic mechanisms, cytoarchitecture disassembly, redox homeostasis as well as apoptosis are involved in carcinogenesis. A diet rich in fruits and vegetables is inversely related with the risk of developing cancer. Several studies report that cruciferous vegetables exhibited antiproliferative effects due to the multi-pharmacological functions of their secondary metabolites such as isothiocyanate sulforaphane deriving from the enzymatic hydrolysis of glucosinolates. We treated human astrocytoma 1321N1 cells for 24 h with different concentrations (0.5, 1.25 and 2.5%v/v) of sulforaphane plus active myrosinase (Rapha Myr(R)) aqueous extract (10 mg/mL). Cell viability, DNA fragmentation, PARP-1 and gamma H2AX expression were examined to evaluate genotoxic effects of the treatment. Cell cycle progression, p53 and p21 expression, apoptosis, cytoskeleton morphology and cell migration were also investigated. In addition, global DNA methylation, DNMT1 mRNA levels and nuclear/mitochondrial sirtuins were studied as epigenetic biomarkers. Rapha Myr(R)exhibited low antioxidant capability and exerted antiproliferative and genotoxic effects on 1321N1 cells by blocking the cell cycle, disarranging cytoskeleton structure and focal adhesions, decreasing the integrin alpha 5 expression, renewing anoikis and modulating some important epigenetic pathways independently of the cellular p53 status. In addition, Rapha Myr(R)suppresses the expression of the oncogenic p53 mutant protein. These findings promote Rapha Myr(R)as a promising chemotherapeutic agent for integrated cancer therapy of human astrocytoma.	International journal of molecular sciences (Online) 21 (2020).	2020	SBISA' ELISABETTA	brain cancer, sulforaphane, myrosinase, cytoskeleton morphology, cell migration, anoikis, apoptosis, oxidative stress, global DNA methylation, sirtuins, mutated p53 R213Q	10.3390/ijms21155328
448346	Articolo in rivista	The joint NETTAB/Integrative Bioinformatics 2015 Meeting: aims, topics and outcomes	Paolo Romano1*, Ralf Hofestadt2, Matthias Lange3, Domenica D'Elia4	The 15th International NETTAB workshop and the 11th Integrative Bioinformatics Symposium were held together in Bari, on October 14-16, 2016, as Joint NETTAB/IB 2015 Meeting. A special topic for the meeting was "Bioinformatics for ncRNA", but the traditional topics of both meetings series were also included in the event. About 60 scientific contributions were presented, including six keynote lectures, one special guest lecture, and many oral communications and posters. A "Two-Day Hands-on Tutorial" event was organised before the workshop. Selected full papers from some of the best works presented in Bari were submitted either to the Journal of Integrative Bioinformatics or to a purpose Call for a Supplement of BMC Bioinformatics. Here, we provide an overview of meeting aims and scope. We also shortly introduce selected papers that have been either accepted for publication in this Supplement or published in the Journal of Integrative Bioinformatics, for a more complete presentation of the outcomes of the meeting.	BMC bioinformatics 18 (2017): 1-5.	2017	D'ELIA DOMENICA	Bioinformatics, Integrative Bioinformatics	10.1186/s12859-017-1532-0
448393	Contributo in atti di convegno	Big Data analysis and reproducibility: new challenges and needs of the post-genomics era	1Efthimiadou A, 2Papakonstantinou E, 2, 3, 4 Vlachakis D, 5D'Elia D, 6Bongcam-Rudloff E	Reproducibility constitutes an important criterion for the evaluation of the quality of research and robustness of results. However, while big data are accumulating at a fast pace, data management, integration, sharing and interpretation become rather challenging. The massive amount of different kinds of data produced need standardised approaches for their production and processing. To enable researchers to assure and ensure the quality of data and research results, uniform and widely adopted procedures, pipelines, data repositories, bioinformatics tools and data-sharing platforms are mandatory. Many efforts in this direction have been made in the last decade by scientists and by the governing bodies, funding agency and publishers. The application of FAIR (Findable, Accessible, Interoperable, Reusable) and Open Science principles to life sciences research are the most important results produced by the combination of all these efforts. Nevertheless, a lot of work is still necessary for these principles and their application to be integrated and fully implemented by the whole scientific community. Obstacles are represented by many different factors, the most important being the still unequal pre- and post-degree education of researchers from different countries of the EU, difficulties of scientists to adopt standards and standard operating procedures (SOP) because of their lack or because of missing guidelines, to mention only the most relevant ones. In this scenario, the EMBnet workshop will discuss main factors affecting reproducibility of life sciences research and explore the need for standards with a particular focus on the reproducibility of computer-aided drug design and metagenomic assemblies.	11th International Conference, ICT Innovations 2019 - Big Data Processing and Mining, pp. 253-257, Ohrid, North Macedonia, October 17-19, 2019	2019	D'ELIA DOMENICA	Standards, Computer-aided drug design, Reproducibility, Life Sciences, Metagenomics assemblies, Workshop
449181	Articolo in rivista	Access & Benefit Sharing in the Nagoya Protocol : Implementation Gaps	Ilja Richard Pavone	Il Protocollo di Nagoya e la sua attuazione.	Anuario brasileiro de direito internacional 2 (2018): 129-154.	2018	PAVONE ILJA RICHARD	Nagoya Protocol, Benefit Sharing, Implementation Gap
449314	Articolo in rivista	Dare voce ai pazienti nella ricerca scientifica sulle malattie rare e sui farmaci 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 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
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
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
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
369829	Articolo in rivista	Cabozantinib Eradicates Advanced Murine Prostate Cancer by Activating Anti-Tumor Innate Immunity.	Patnaik A., Swanson K.D., Csizmadia E., Solanki A., Landon-Brace N., Gehring M.P., Helenius K., Olson B.M., Pyzer A.R., Wang L.C., Elemento O., Novak J, Thornley T.B., Asara J.M., Montaser L., Timmons J.J., Morgan T.M., Wang Y., Levantini E., Clohessy J.G., Kelly K., Pandolfi P.P., Rosenblatt J.M., Avigan D.E., Ye H., Karp J.M., Signoretti S., Balk S.P., Cantley L.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
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
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
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
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 B., Raggi M. E., Moretti G., Facchiano F., Mezzelani A., Villa L., Bonfanti A., Campioni A., Rossi S., Camposeo S., Soricelli S., Moracci G., Debegnach F., Gregori E., Ciceri F., Milanesi L., Marabotti A., Brera C.	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(7) (2017): 1-20.	2017	MEZZELANI ALESSANDRA MARIA, MILANESI LUCIANO	aurism syndrome, mycotoxins, environment, exposure, IgG, cytokine/chemokine	10.3390/toxins9070203
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	MLV, retroviral vectors, integration sites, LM-PCR, NGS	10.3791/55919
402273	Articolo in rivista	Tackling critical parameters in metazoan meta-barcoding experiments: a preliminary study based on coxI DNA barcode	Balech, Bachir, Sandionigi, Anna, Manzari, Caterina, Trucchi, Emiliano, Tullo, Apollonia, Licciulli, Flavio, Grillo, Giorgio, Sbisa, Elisabetta, De Felici, Stefano, Saccone, Cecilia, D'Erchia, Anna Maria, Cesaroni, Donatella, Casiraghi, Maurizio, Vicario, Saverio	Nowadays DNA meta-barcoding is a powerful instrument capable of quickly discovering the biodiversity of an environmental sample by integrating the DNA barcoding approach with High Throughput Sequencing technologies. It mainly consists of the parallel reading of informative genomic fragment/s able to discriminate living entities. Although this approach has been widely studied, it still needs optimization in some necessary steps requested in its advanced accomplishment. A fundamental element concerns the standardization of bioinformatic analyses pipelines. The aim of the present study was to underline a number of critical parameters of laboratory material preparation and taxonomic assignment pipelines in DNA meta-barcoding experiments using the cytochrome oxidase subunit-I (coxI) barcode region, known as a suitable molecular marker for animal species identification. We compared nine taxonomic assignment pipelines, including a custom in-house method, based on Hidden Markov Models. Moreover, we evaluated the potential influence of universal primers amplification bias in qPCR, as well as the correlation between GC content with taxonomic assignment results. The pipelines were tested on a community of known terrestrial invertebrates collected by pitfall traps from a chestnut forest in Italy. Although the present analysis was not exhaustive and needs additional investigation, our results suggest some potential improvements in laboratory material preparation and the introduction of additional parameters in taxonomic assignment pipelines. These include the correct setup of OTU clustering threshold, the calibration of GC content affecting sequencing quality and taxonomic classification, as well as the evaluation of PCR primers amplification bias on the final biodiversity pattern. Thus, careful attention and further validation/optimization of the above-mentioned variables would be required in a DNA meta-barcoding experimental routine.	PeerJ 6 (2018).	2018	BALECH BACHIR, TULLO APOLLONIA, LICCIULLI VITO FLAVIO, GRILLO GIORGIO, VICARIO SAVERIO, MANZARI CATERINA, SBISA' ELISABETTA	GC content, DNA metabarcoding, Amplification bias, Taxonomic assignment, coxI, Biodiversity, Carabids, High Throughput Sequencing	10.7717/peerj.4845
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
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
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
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
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, COSSU FEDERICA, MAURI PIETRO LUIGI	*	10.1111/1462-2920.13918
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
380053	Articolo in rivista	ITSoneDB: a comprehensive collection of eukaryotic ribosomal RNA Internal Transcribed Spacer 1 (ITS1) sequences.	Santamaria M., Fosso B., Licciulli F., Balech B., Larini I., Grillo G., De Caro G., Liuni S., Pesole G.	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): D127-D132.	2017	LICCIULLI VITO FLAVIO, GRILLO GIORGIO, LIUNI SABINO, SANTAMARIA MONICA, BALECH BACHIR	DNA metabarcoding, Database, Eukaryotic communities	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	When studying the relationship between nutrition and disease, researchers are interested in evaluating the role of the quantitative aspect of the diet (total energy intake) separately from its qualitative aspect (nutrient composition). The use and interpretation of energy-adjustment regression models in nutritional epidemiology was much debated, particularly in the 1990s,1-5 but the critical point is the fact that it is not possible to disentangle the generic effect of total energy from that of the separate components of energy (proteins, fats and carbohydrates) that make up the total by means of multivariate analysis. The mathematics underlying regression analysis will fail if there is perfect collinearity amongst the independent variables, and this occurs when they are exact linear functions of each other. In energy-adjusted models, perfect collinearity exists since each macronutrient component of energy can be expressed as a combination of the total energy and the other sources, such as energy from proteins = total energy - energy from fats - energy from carbohydrates. Despite having four variables in this case, we only have three degrees of freedom and unless one of the four terms is removed from the regression model, mathematical calculation cannot be made because the information as a whole is overlapped. Essentially, the heart of the matter lies in the compositional nature of the dietary data.	European journal of clinical nutrition (2017).	2017	PRINELLI FEDERICA, CORREA LEITE MARIA LEA	nutritional epidemiology	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	Alzheimer's Disease, Parkinson's Disease, cancer, risk factors, health information systems	10.1097/WAD.0000000000000204
374938	Articolo in rivista	Role of mycotoxins in the pathobiology of autism: A first evidence	De Santis B., Brera C., Mezzelani A., Soricelli S., Ciceri F., Moretti G., Debegnach F., Bonaglia M. C., Villa L., Molteni M., Raggi M. E.	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 22 (2017): 132-144.	2017	MEZZELANI ALESSANDRA MARIA	Autism, Gene-environment interaction, Mycotoxins, Ochratoxin A, gastro-intestinal disorders, intestinal permeability, dysbiosis, fungi	10.1080/1028415X.2017.1357793
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	acute myeloid leukemia, MYC, dmin, ring chromosomes, chromothripsis, neocentromeres, fusion transcripts, circular RNA, PVT1
380142	Articolo in rivista	Zebrafish Tmem230a cooperates with the Delta/Notch signaling pathway to modulate endothelial cell number in angiogenic vessels	Carra S., Sangiorgio L., Pelucchi P., Cermenati S., Mezzelani A., Martino V., Palizban M., Albertini A., Gotte M., Kehler J., Deflorian G., Beltrame M., Giordano A., Reinbold R., Cotelli F., Bellipanni G., Zucchi I.	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): 1455-1467.	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	10.1002/jcp.26032
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.
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 M., Nuzziello N., Licciulli F., Consiglio A., Simone M., Viterbo R.G., Creanza T.M., Ancona N., Tortorella C., Margari L., Grillo G., Giordano P., Liuni S., Trojano M.	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) 27 (2018): 66-79.	2018	CONSIGLIO ARIANNA, NUZZIELLO NICOLETTA, ANCONA NICOLA, LICCIULLI VITO FLAVIO, GRILLO GIORGIO, LIGUORI MARIA, LIUNI SABINO, CREANZA TERESA MARIA	genes, multiple sclerosis, pediatrics, rna, messenger, micrornas, candidate disease gene, massively-parallel genome sequencing	10.1093/hmg/ddx385
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	plasma cell dyscrasias, multiple myeloma, APOBEC, mutational patterns	10.1038/leu.2017.345
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
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
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
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
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
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
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
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 (2019): 1867-1878.	2019	CAUDAI CLAUDIA, ZOPPE' MONICA MARIA, MERELLI IVAN, SALERNO EMANUELE, TONAZZINI ANNA	Chromosome conformation capture, Chromatin configuration, Bayesian estimation	10.1109/TCBB.2018.2838669
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	HIV, capsid, nucleoporin, nuclear import, integration	10.1128/JVI.00648-18
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.
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
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
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
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 F., Faienza M.F., Caratozzolo M.F., Brunetti G., Chiara M., Horner D.S., Annese A., D'Erchia A.M., Consiglio A., Pesole G., Sbisa E., Inzaghi E., Cianfarani S., Tullo A.	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 (Online) 13 (2018): 1-9.	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
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
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 M, Severgnini M, Cilia R, Cassani E, Bolliri C, Caronni S, Ferri V, Cancello R, Ceccarani C, Faierman S, Pinelli G, De Bellis G, Zecca L, Cereda E, Consolandi C, Pezzoli G.	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
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
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
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
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
400152	Articolo in rivista	Inhibition of histone methyltransferase DOT1L silences ER? gene and blocks proliferation of antiestrogen-resistant breast cancer cells	Nassa G, Salvati A, Tarallo R, Gigantino V, Alexandrova E, Memoli D, Sellitto A, Rizzo F, Malanga D, Mirante T, Morelli E, Nees M, Akerfelt M, Kangaspeska S, Nyman TA, Milanesi L, Giurato G, Weisz A.	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	Breast cancer, endocrine therapy, bioinformatics	10.1126/sciadv.aav5590
401534	Articolo in rivista	Precise Gene Editing Preserves Hematopoietic Stem Cell Function following Transient p53-Mediated DNA Damage Response	Schiroli G, Conti A, Ferrari S, Della Volpe L, Jacob A, Albano L, Beretta S, Calabria A, Vavassori V, Gasparini P, Salataj E, Ndiaye-Lobry D, Brombin C, Chaumeil J, Montini E, Merelli I, Genovese P, Naldini L, Di Micco R.	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
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	***, Amyloid, Proteomics, Cryo-EM	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) 51 (2019): 885-895.	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, genome sequencing, cadmium accumulation, domestication	10.1038/s41588-019-0381
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) 20 (2019): 1-22.	2019	MARZANO FLAVIANA, TULLO APOLLONIA, PESOLE GRAZIANO, SBISA' ELISABETTA	chemoresistance; TRIM proteins; p53	10.3390/ijms20071776
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
404015	Articolo in rivista	Microstructural characterization of corticospinal tract in subacute and chronic stroke patients with distal lesions by means of advanced diffusion MRI.	Mastropietro A., Rizzo G., Fontana L., Figini M., Bernardini B., Straffi L., Marcheselli S., Ghirmai S., Nuzzi N.P., Malosio M.L., Grimaldi M.	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
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
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
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
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
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
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
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 P., Uggeri M., Urbinati C., Millo E., Paiardi G., Milanesi L., Ford R. C., Clews J., Meng X., Bergese P., Ridolfi A., Pedemonte N., Fossa P., Orro A., Rusnati M.	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. Here we describe the development of a biosensor based on F508del-CFTR in a lipid environment that proved to be endowed with a wider analytical potential in respect to the previous CFTR-based biosensors. Integrated with an appropriate computational model of the whole human F508del-CFTR in lipid environment and CFTR stability and functional assays, the new biosensor allowed the identification and characterization at the molecular level of the binding modes of some known F508del-CFTR-rescuing drugs and of a new aminoarylthiazole-Lumacaftor/Tezacaftor hybrid derivative endowed with promising F508del-CFTR-binding and rescuing activity.	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
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
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	Mitochondrial myopathy, McArdle disease, skeletal muscle oxidative metabolism, functional evaluation, near-infrared spectroscopy	10.1249/MSS.0000000000002056
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
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
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 (2019): 865-871.	2019	DI NANNI NOEMI, MILANESI LUCIANO, GNOCCHI MATTEO, MOSCA ETTORE, MOSCATELLI MARCO	multi-omics, biological networks	10.1093/bioinformatics/btz652
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
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
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
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
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
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
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
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
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
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
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
425426	Articolo in rivista	Fatty acid synthase mediates EGFR palmitoylation in EGFR mutated non-small cell lung cancer	Ali A., Levantini E., Teo J.T., Goggi J., Clohessy J.G., Wu C.S., Chen L., Yang H., Krishnan I., Kocher O., Zhang J., Soo R.A., Bhakoo K., Chin T.M., Tenen D.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
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
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
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
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
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
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
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
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
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, BIANCHI FABRIZIO	COVID-19, Elderly, Influenza, Italy, SARS-CoV-2, Vaccine	10.3390/vaccines8040669
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
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
448155	Articolo in rivista	Classification and Personalized Prognostic Assessment on the Basis of Clinical and Genomic Features in Myelodysplastic Syndromes	Matteo Bersanelli, PhD1,2, Erica Travaglino, BSc3, Manja Meggendorfer, PhD4, Tommaso Matteuzzi, PhD1,2, Claudia Sala, PhD1,2, Ettore Mosca, PhD5, Chiara Chiereghin, PhD3, Noemi Di Nanni, PhD5, Matteo Gnocchi, MSc5, Matteo Zampini, PhD3, Marianna Rossi, MD3, Giulia Maggioni, MD3,6, Alberto Termanini, PhD3, Emanuele Angelucci, MD7, Massimo Bernardi, MD8, Lorenza Borin, MD9, Benedetto Bruno, MD10,11, Francesca Bonifazi, MD12, Valeria Santini, MD13, Andrea Bacigalupo, MD14, Maria Teresa Voso, MD15, Esther Oliva, MD16, Marta Riva, MD17, Marta Ubezio, MD3, Lucio Morabito, MD3, Alessia Campagna, MD3, Claudia Saitta, MSc18, Victor Savevski, MEng3, Enrico Giampieri, PhD2,19, Daniel Remondini, PhD1,2, Francesco Passamonti, MD20, Fabio Ciceri, MD8, Niccolo Bolli, MD21,22, Alessandro Rambaldi, MD23, Wolfgang Kern, MD4, Shahram Kordasti, MD24,25, Francesc Sole, PhD26, Laura Palomo, PhD26, Guillermo Sanz, MD27,28, Armando Santoro, MD3,6, Uwe Platzbecker, MD29, Pierre Fenaux, MD30, Luciano Milanesi, PhD5, Torsten Haferlach, MD4, Gastone Castellani, PhD2,19, Matteo G. Della Porta, MD3,6	Purpose: Recurrently mutated genes and chromosomal abnormalities have been identified in myelodysplastic syndromes (MDS). We aim to integrate these genomic features into disease classification and prognostication. Methods: We retrospectively enrolled 2,043 patients. Using Bayesian networks and Dirichlet processes, we combined mutations in 47 genes with cytogenetic abnormalities to identify genetic associations and subgroups. Random-effects Cox proportional hazards multistate modeling was used for developing prognostic models. An independent validation on 318 cases was performed. Results: We identify eight MDS groups (clusters) according to specific genomic features. In five groups, dominant genomic features include splicing gene mutations (SF3B1, SRSF2, and U2AF1) that occur early in disease history, determine specific phenotypes, and drive disease evolution. These groups display different prognosis (groups with SF3B1 mutations being associated with better survival). Specific co-mutation patterns account for clinical heterogeneity within SF3B1- and SRSF2-related MDS. MDS with complex karyotype and/or TP53 gene abnormalities and MDS with acute leukemia-like mutations show poorest prognosis. MDS with 5q deletion are clustered into two distinct groups according to the number of mutated genes and/or presence of TP53 mutations. By integrating 63 clinical and genomic variables, we define a novel prognostic model that generates personally tailored predictions of survival. The predicted and observed outcomes correlate well in internal cross-validation and in an independent external cohort. This model substantially improves predictive accuracy of currently available prognostic tools. We have created a Web portal that allows outcome predictions to be generated for user-defined constellations of genomic and clinical features. Conclusion: Genomic landscape in MDS reveals distinct subgroups associated with specific clinical features and discrete patterns of evolution, providing a proof of concept for next-generation disease classification and prognosis.	Journal of clinical oncology (2021): 1223-1233.	2021	GNOCCHI MATTEO, MOSCA ETTORE	myelodysplastic syndromes, MDS, disease classification, prognostication	10.1200/JCO.20.01659
433524	Articolo in rivista	Disruption of redox homeostasis for combinatorial drug efficacy in K-Ras tumors as revealed by metabolic connectivity profiling	Daniela Gaglio 1, 2, Marcella Bonanomi 2, 3, Silvia Valtorta 1, 2, 4, Rohit Bharat 23, Marilena Ripamonti 1, 2, Federica Conte 2, 5, Giulia Fiscon 2, 5, Nicole Righi 2, 3, Elisabetta Napodano 1, 2, Federico Papa 2, 5, Isabella Raccagni 1, 2, 6, Seth J Parker 7, 8, Ingrid Cifola 9, Tania Camboni 9, Paola Paci 2, 5, 10, Anna Maria Colangelo 2, 3, Marco Vanoni 2, 3, Christian M Metallo 7, 8, Rosa Maria Moresco 1, 2, 4, Lilia Alberghina 2, 3	Background: Rewiring of metabolism induced by oncogenic K-Ras in cancer cells involves both glucose and glutamine utilization sustaining enhanced, unrestricted growth. The development of effective anti-cancer treatments targeting metabolism may be facilitated by the identification and rational combinatorial targeting of metabolic pathways. Methods: We performed mass spectrometric metabolomics analysis in vitro and in vivo experiments to evaluate the efficacy of drugs and identify metabolic connectivity. Results: We show that K-Ras-mutant lung and colon cancer cells exhibit a distinct metabolic rewiring, the latter being more dependent on respiration. Combined treatment with the glutaminase inhibitor CB-839 and the PI3K/aldolase inhibitor NVP-BKM120 more consistently reduces cell growth of tumor xenografts. Maximal growth inhibition correlates with the disruption of redox homeostasis, involving loss of reduced glutathione regeneration, redox cofactors, and a decreased connectivity among metabolites primarily involved in nucleic acid metabolism. Conclusions: Our findings open the way to develop metabolic connectivity profiling as a tool for a selective strategy of combined drug repositioning in precision oncology.	Cancer & metabolism 8 (2020): 22.	2020	MORESCO ROSA MARIA, VALTORTA SILVIA, RACCAGNI ISABELLA, FISCON GIULIA, CONTE FEDERICA, PACI PAOLA, NAPODANO ELISABETTA, CIFOLA INGRID, GAGLIO DANIELA, RIPAMONTI MARILENA	Combinatorial drug treatment; Glutamine; Glycolysis; Metabolic cancer therapy; Metabolic connectivity; Metabolic rewiring; Metabolic signature; Precision oncology.	10.1186/s40170-020-00227-4
448974	Articolo in rivista	Network Diffusion Promotes the Integrative Analysis of Multiple Omics	Di Nanni N., Bersanelli M., Milanesi L., Mosca E.	The development of integrative methods is one of the main challenges in bioinformatics. Network-based methods for the analysis of multiple gene-centered datasets take into account known and/or inferred relations between genes. In the last decades, the mathematical machinery of network diffusion--also referred to as network propagation--has been exploited in several network-based pipelines, thanks to its ability of amplifying association between genes that lie in network proximity. Indeed, network diffusion provides a quantitative estimation of network proximity between genes associated with one or more different data types, from simple binary vectors to real vectors. Therefore, this powerful data transformation method has also been increasingly used in integrative analyses of multiple collections of biological scores and/or one or more interaction networks. We present an overview of the state of the art of bioinformatics pipelines that use network diffusion processes for the integrative analysis of omics data. We discuss the fundamental ways in which network diffusion is exploited, open issues and potential developments in the field. Current trends suggest that network diffusion is a tool of broad utility in omics data analysis. It is reasonable to think that it will continue to be used and further refined as new data types arise (e.g. single cell datasets) and the identification of system-level patterns will be considered more and more important in omics data analysis.	Frontiers in genetics 11 (2020).	2020	DI NANNI NOEMI, MILANESI LUCIANO, MOSCA ETTORE	integrative analysis, omics data, biological networks, precision medicine, network-diffusion	10.3389/fgene.2020.00106
448995	Contributo in atti di convegno	Network diffusion on multiple-layers: current approaches and integrative analysis of Rheumatoid Arthritis data	Di Nanni N, Gnocchi M, Moscatelli M, Milanesi L, Mosca E	Network Diffusion has been proposed in several applications, thanks to its ability of amplifying biological signals and prioritizing genes that may be associated with a disease. Not surprising, the success of Network Diffusion on a "single layer" led to the first approaches for the joint analysis of multi-omics data. Here, we review integrative methods based on Network Diffusion that have been proposed with several aims (e.g. patient stratification, module detection, function prediction). We used Network Diffusion to analyse, in the context of physical and functional protein-protein interactions, genetic variation, DNA methylation and gene expression data from a study on Rheumatoid Arthritis. We identified functionally related genes with multiple alterations.	Methods, tools & platforms for Personalized Medicine in the Big Data Era - NETTAB 2017 Workshop Collection, 16-18/10/2017	2017	DI NANNI NOEMI, MILANESI LUCIANO, GNOCCHI MATTEO, MOSCA ETTORE, MOSCATELLI MARCO	Rheumatoid Arthritis, Network diffusion, multiple omics data	10.7287/peerj.preprints.3310v1
449227	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 (2019).	2019	MILANESI LUCIANO, D'URSI PASQUALINA, MAURI PIETRO LUIGI	DMD, IGF2, IGF2R, muscle regeneration, muscular dystrophy	10.15252/emmm.201911019
401952	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	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 (integrative Small RNA Tool-kit), an automated pipeline to analyze smallRNA-Seq data.	Bioinformatics (Oxf., Print) 33 (2017): 938-940.	2017	MILANESI LUCIANO	sncRNAs, Bioinformatics	10.1093/bioinformatics/btw734
449311	Articolo in rivista	Deliberative models for the allocation of resources in healthcare: The case of dengue in Tanzania|Modelli deliberativi per l'allocazione delle risorse in sanita: Il caso della dengue in Tanzania	Mancini E., Zagarella R.M.	In decision-making processes in support of health systems in developing countries, the predominant use of technical approaches (based on economic instruments) has been the main roadmap for identifying health priorities. However, these approaches reveal the limitations, from an ethical point of view, of failing to include an analysis of values and the cultural context and of being scarcely responsive to the real health demands of the population. They also conceal a significant conflict between the underlying values, such as efficiency and equity. Our analysis addresses the participated and deliberative models of resource allocation, and especially the approach developed by Norman Daniels - known as Accountability for Reasonableness (A4R) - with the aim of offering a method for identifying "correct" priorities, which are not defined on the basis of pre-established choices of values, but deriving from a legitimate decision- making process (transparent and negotiated between all the stakeholders involved). To test the enforceability in real circumstances (especially for low-income countries) of the A4R model, the article proposes the analysis of a case study. Specifically, a practical application of the A4R on the prioritisation of Dengue law enforcement interventions in Tanzania is being examined, in order to illustrate what was successful in this particular case, what difficulties were encountered and what reactions were generated by the population.	Medicina e morale 68 (2019): 313-335.	2019	MANCINI ELENA	Deliberation, resource allocation, Accountability for Reasonableness, dengue, Tanzania	10.4081/mem.2019.589
449315	Articolo in rivista	L'autosperimentazione nelle malattie rare: analisi dei profili etici e indicazioni per una possibile governance	Elena Mancini	Le malattie rare raggruppano un numero elevato di patologie molto diverse tra loro, accumunate, dalla bassissima frequenza statistica nella popolazione (penetranza). Ne consegue una scarsissima numerosita di pazienti per ogni singola patologia e una loro distribuzione in diverse aree geografiche, fattori che comportano oggettive difficolta nel reclutamento dei pazienti in studi sperimentali e nel coordinamento e organizzazione della ricerca con conseguente ridotta possibilita di effettuare studi clinici e ricerche di carattere genetico. In tale quadro, al fine di fare fronte alle drammatiche necessita di assistenza socio-sanitaria, cura e riabilitazione dei malati rari, sono sorte, in gran parte per merito degli stessi familiari, le associazioni di malati rari. Attualmente tali associazioni svolgono un'attivita significativa nella proposizione, organizzazione, partecipazione diretta e pubblicazione dei risultati di ricerche scientifiche. Tale ruolo, rende le associazioni dei pazienti protagoniste anche nel sostegno all'organizzazione e realizzazione di studi clinici e sperimentazioni di farmaci in modo del tutto autonomo e indipendente da controlli da parte delle autorita sanitarie e dei comitati etici. Tale fenomeno noto come "Research Led by Participants" e stato reso possibile dalle enormi potenzialita di contatto e organizzazione offerte dalla rete che ha consentito la creazione di comunita virtuali di pazienti, di siti e blog dedicati all'informazione e comunicazione, e piu recentemente, alla raccolta di dati, alla pubblicazione di risultati di ricerche condotte dai malati, nonche al reclutamento degli stessi per la conduzione di tali studi, secondo il modello proposto, ad esempio, dal sito PatientsLikeMe. Non possono tuttavia essere trascurati gli importanti aspetti etici implicati dalla ricerca condotta dai partecipanti. Tali aspetti concernono, come evidente, sia la validita scientifica di tali studi che la protezione dei soggetti che aderiscono alla sperimentazione. Si tratta di una forma di sperimentazione del tutto nuova che richiede la capacita di proporre una modalita di gestione condivisa tra cittadini/pazienti, "terzo settore", ricercatori, istituzioni e comitati etici in grado di valorizzarne i potenziali benefici conoscitivi creando regole etiche "misurate" su tali circostanze. Nell'articolo sara proposto un modello teorico di governance del fenomeno e saranno indicati possibili criteri etici operativi.	Medicina e morale 66 (2017): 45-61.	2017	MANCINI ELENA	malattie rare, associazioni dei pazienti, autosperimentazione, etica della ricerca, medicina partecipativa, governance.
449316	Articolo in rivista	Il programma di eliminazione della filariasi linfatica in Bangladesh: un modello esportabile?	Elena Mancini	Nel 1971, al termine della sanguinosissima guerra di separazione dal Pakistan, il Bangladesh appariva un paese senza speranza. L'elevatissima crescita demografica -una delle maggiori al mondo- le calamita naturali quali alluvioni e tifoni, la poverta grave e diffusa - con una percentuale di popolazione sotto la soglia di poverta intorno al 30% - la situazione politica interna, con instabilita sociale e latenti conflitti etnici, rendevano il pronostico piu che verosimile. A distanza di 40 anni, il BGD e riuscito a smentire in gran parte tale previsione, conseguendo successi nello sviluppo economico, nella salute pubblica e nella trasformazione sociale. Il controllo del tasso di fertilita, la lotta a "big killer" quali la TBC e la diarrea infantile, il miglioramento delle condizioni igieniche e la realizzazione di presidi sanitari territoriali di prima assistenza (community-clinic), efficaci campagne sanitarie, il contrasto di malattie endemiche, sono stati ottenuti grazie all'impiego coordinato delle misure sanitarie dei programmi internazionali. Risultati, questi, conseguiti attraverso una politica sanitaria basata su una proficua collaborazione tra il Ministero della salute nazionale (Ministry of Health and Family Welfare), ONG, organismi sanitari internazionali, istituzioni e fondazioni internazionali. Il BGD ha cosi conseguito il traguardo della pressoche totale eliminazione delle malattie neglette endemiche nel paese (leishmaniosi viscerale, filariasi linfatica, dengue, lebbra, parassitosi intestinali - infezioni da elminti). L'articolo valuta i fattori che hanno caratterizzato il successo nel programma di eliminazione della filariasi linfatica. Dall'analisi di tali fattori e derivato un possibile modello di governance per la lotta alle malattie neglette in regioni endemiche comparabili sotto il profilo geo-politico.	Medicina e morale 66 (2017): 495-511.	2017	MANCINI ELENA	filariasi linfatica, Bangladesh, community-based approach, capability approach, equita, Dichiarazione di Alma Ata.
449973	Articolo in rivista	Mass spectrometry-based tear proteomics for noninvasive biomarker discovery	Ponzini E. 1, Santambrogio C. 2, De Palma A. 3, Mauri P. 3, Tavazzi S. 1-4, Grandori R. 2.	The lacrimal film has attracted increasing interest in the last decades as a potential source of biomarkers of physiopathological states, due to its accessibility, moderate complexity, and responsiveness to ocular and systemic diseases. High-performance liquid chromatography-mass spectrometry (LC-MS) has led to effective approaches to tear proteomics, despite the intrinsic limitations in sample amounts. This review focuses on the recent progress in strategy and technology, with an emphasis on the potential for personalized medicine. After an introduction on lacrimal-film composition, examples of applications to biomarker discovery are discussed, comparing approaches based on pooled-sample and single-tear analysis. Then, the most critical steps of the experimental pipeline, that is, tear collection, sample fractionation, and LC-MS implementation, are discussed with reference to proteome-coverage optimization. Advantages and challenges of the alternative procedures are highlighted. Despite the still limited number of studies, tear quantitative proteomics, including single-tear investigation, could offer unique contributions to the identification of low-invasiveness, sustained-accessibility biomarkers, and to the development of personalized approaches to therapy and diagnosis.	Mass spectrometry reviews (Online) (2021): 1-19.	2021	DE PALMA ANTONELLA, MAURI PIETRO LUIGI	lacrimal film, liquid biopsies, peripheral body fluids, personalized medicine, single-tear analysis, personalized medicine, single-tear analysis, tear collection and fractionation methods, lacrimal film, lacrimal film, proteomics, tear film	10.1002/mas.21691
412657	Articolo in rivista	Potato Virus Y Infection Alters Small RNA Metabolism and Immune Response in Tomato	Prigigallo M.I., Kriznik M., De Paola D., Catalano D., Gruden K., Finetti-Sialer M.M., Cillo F.	Potato virus Y (PVY) isolate PVYC-to induces growth reduction and foliar symptoms in tomato, but new vegetation displays symptom recovery at a later stage. In order to investigate the role of micro(mi)RNA and secondary small(s)RNA-regulated mechanisms in tomato defenses against PVY, we performed sRNA sequencing from healthy and PVYC-to infected tomato plants at 21 and 30 days post-inoculation (dpi). A total of 792 miRNA sequences were obtained, among which were 123 canonical miRNA sequences, many isomiR variants, and 30 novel miRNAs. MiRNAs were mostly overexpressed in infected vs. healthy plants, whereas only a few miRNAs were underexpressed. Increased accumulation of isomiRs was correlated with viral infection. Among miRNA targets, enriched functional categories included resistance (R) gene families, transcription and hormone factors, and RNA silencing genes. Several 22-nt miRNAs were shown to target R genes and trigger the production of 21-nt phased sRNAs (phasiRNAs). Next, 500 phasiRNA-generating loci were identified, and were shown to be mostly active in PVY-infected tissues and at 21 dpi. These data demonstrate that sRNA-regulated host responses, encompassing miRNA alteration, diversification within miRNA families, and phasiRNA accumulation, regulate R and disease-responsive genes. The dynamic regulation of miRNAs and secondary sRNAs over time suggests a functional role of sRNA-mediated defenses in the recovery phenotype.	Viruses 11 (2019).	2019	PRIGIGALLO MARIA ISABELLA, CILLO FABRIZIO, FINETTI SIALER MARIELLA MATILDE, CATALANO DOMENICO, DE PAOLA DOMENICO	RNA silencing; plant defense response; Solanum lycopersicum; Potato virus Y; molecular plantvirus interactions; microRNA; secondary small interfering RNA; phasiRNA; small RNA sequencing	10.3390/v11121100
396362	Articolo in rivista	A cytosolic Ezh1 isoform modulates a PRC2-Ezh1 epigenetic adaptive response in postmitotic cells	Bodega B., Marasca F., Ranzani V., Cherubini A., Della Valle F., Neguembor M.V., Wassef M., Zippo A., Lanzuolo C., Pagani M., Orlando V.	The evolution of chromatin-based epigenetic cell memory may be driven not only by the necessity for cells to stably maintain transcription programs, but also by the need to recognize signals and allow plastic responses to environmental stimuli. The mechanistic role of the epigenome in adult postmitotic tissues, however, remains largely unknown. In vertebrates, two variants of the Polycomb repressive complex (PRC2-Ezh2 and PRC2-Ezh1) control gene silencing via methylation of histone H3 on Lys27 (H3K27me). Here we describe a reversible mechanism that involves a novel isoform of Ezh1 (Ezh1?). Ezh1? lacks the catalytic SET domain and acts in the cytoplasm of skeletal muscle cells to control nuclear PRC2-Ezh1 activity in response to atrophic oxidative stress, by regulating Eed assembly with Suz12 and Ezh1? (the canonical isoform) at their target genes. We report a novel PRC2-Ezh1 function that utilizes Ezh1? as an adaptive stress sensor in the cytoplasm, thus allowing postmitotic cells to maintain tissue integrity in response to environmental changes.	Nature structural & molecular biology 24 (2017): 444-452.	2017	LANZUOLO CHIARA	Polycomb, EZH1	10.1038/nsmb.3392
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
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
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
417820	Articolo in rivista	Moderate Intensity Resistive Training Reduces Oxidative Stress and Improves Muscle Mass and Function in Older Individuals	Vezzoli A, Mrakic-Sposta S, Montorsi M, Porcelli S, Vago P, Cereda F, Longo S, Maggio M, Narici M.	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
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) 20 (2020): 1-11.	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
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'Elia https://orcid.org/0000-0003-3787-383616	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 (2021).	2021	D'ELIA DOMENICA	Open Data, Open Access, Open Science, FAIR Principles, Standardisation, Education, Quality Management	10.12688/f1000research.27500.2
449867	Articolo in rivista	99mTc-Radiolabeled Silica Nanocarriers for Targeted Detection and Treatment of HER2-Positive Breast Cancer	Rainone P., De Palma A., Sudati F., Roffia V., Rigamonti V., Salvioni L., Colombo M., Ripamonti M., Spinelli A.E., Mazza D., Mauri P., Moresco R.M., Prosperi D., Belloli S.	Introduction. The overexpression of Human Epidermal Growth Factor Receptor 2 (HER2) is usually associated with aggressive and infiltrating breast cancer (BC) phenotype, and metastases. Functionalized silica-based nanocarriers (SiNPs) can be labeled for in vivo imaging applications and loaded with chemotherapy drugs, making possible the simultaneous noninvasive diagnosis and treatment (theranostic) for HER2-positive BC. Methods. Firstly, FITC-filled SiNPs, were engineered with two different amounts of Hc-TZ (trastuzumab half-chain) per single nanoparticle (1:2 and 1:8, SiNPs to Hc-TZ ratio), which was 99mTc-radiolabeled at histidine residues for ex vivo and in vivo biodistribution evaluations. Secondly, nanoparticles were loaded with DOX and their in vitro and ex vivo/in vivo delivery was assessed, in comparison with liposomal Doxorubicin (Caelyx). Finally, the treatment efficacy of DOX-SiNPs-TZ (1:8 Hc-TZ) was evaluated in vivo by PET and supported by MS-based proteomics profiling of tumors. Results. SiNPs-TZ (1:8 Hc-TZ) tumor uptake was significantly greater than that of SiNPs-TZ (1:2 Hc-TZ) at 6 hours post-injection (p.i.) in ex vivo biodistribution experiment. At 24 h p.i., radioactivity values remained steady. Fluorescence microscopy, confirmed the presence of radiolabeled SiNPs-TZ (1:8 Hc-TZ) within tumor even at later times. SiNPs-TZ (1:8 Hc-TZ) nanoparticles loaded with Doxorubicin (DOX-SiNPs-TZ) showed a similar DOX delivery capability than Caelyx (at 6 h p.i.), in in vitro and ex vivo assays. Nevertheless, at the end of treatment, tumor volume was significantly reduced by DOX-SiNPs-TZ (1:8 Hc-TZ), compared to Caelyx and DOX-SiNPs treatment. Proteomics study identified 88 high stringent differentially expressed proteins comparing the three treatment groups with controls. Conclusion. These findings demonstrated a promising detection specificity and treatment efficacy for our system (SiNPs-TZ, 1:8 Hc-TZ), encouraging its potential use as a new theranostic agent for HER2-positive BC lesions. In addition, proteomic profile confirmed that a set of proteins, related to tumor aggressiveness, were positively affected by targeted nanoparticles.	International journal of nanomedicine (Online) 16 (2021): 1943-1960.	2021	MORESCO ROSA MARIA, BELLOLI SARA, ROFFIA VALENTINA, RAINONE PAOLO, DE PALMA ANTONELLA, RIPAMONTI MARILENA	HER2-positive BC, targeted silica nanoparticles, TZ-half chain conjugation, 99mTc-radiolabeling, SPECT imaging, doxorubicin-loaded nanoparticles	10.2147/IJN.S276033
453349	Contributo in volume	EPICOVID19 INDAGINE EPIDEMIOLOGICA NAZIONALE COVID-19	Fulvio Adorni, Federica Prinelli	Epicovid19 e un'indagine online promossa nel mese di aprile 2020 con l'obiet-tivo di stimare su territorio nazionale il numero di casi sospetti di infezione da sars-cov-2 e identificarne fattori potenzialmente associati nella popolazione generale durante il periodo pandemico.L'indagine e stata diffusa attraverso siti web istituzionali, mailing list, social me-dia e comunicati stampa, con l'invito alla popolazione adulta a compilare un questionario online.Nel questionario sono state raccolte informazioni socio-demografiche, legate a eventuale sintomatologia, contatti con casi covid-19, stato di salute, morbilita e consumo di farmaci, accesso al tampone naso-faringeo, caratteristiche abi-tative e abitudini di vita. Il questionario e stato implementato sulla piattaforma eusurvey dell'Unione Europea, dopo l'approvazione da parte del Comitato Eti-co dell'inmi Lazzaro Spallanzani irccs.In poco piu di un mese il questionario e stato compilato da circa 200.000 resi-denti in Italia, distribuiti sul territorio nazionale proporzionalmente alla diffu-sione geografica del virus in quel periodo, con tassi di partecipazione regionale (x100.000 abitanti) che variavano tra 628 per la Lombardia e 73 per la Calabria.La tipologia di dati pianificata per la raccolta e la grande quantita di questio-nari compilati ha consentito di articolare studi su diverse ipotesi di ricerca, con pubblicazioni sul quadro di sintomatologia di casi covid-19 e sull'associazione tra vaccinazione anti-pneumococcica o anti-influenzale e infezione da sars-cov-2 anche in relazione a specifiche categorie di popolazione.Il questionario del progetto epicovid19 costituisce uno strumento validato agile e accessibile, a costo zero, che puo essere utilizzato per il monitoraggio in fasi epidemiche future e per la definizione di programmi di sorveglianza e inter-vento nonche per decisioni di politica sanitaria.https://epicovid19.itb.cnr.it/risultati	, pp. 92-92. Roma: CNR, 2021	2021	ADORNI FULVIO DANIELE, PRINELLI FEDERICA	COVID-19, indagine on-line, epidemiologia, studio nazionale	10.36173/PLURIMI-2020-2
453220	Articolo in rivista	Advantages of using graph databases to explore chromatin conformation capture experiments.	D. D'Agostino, P. Lio, M. Aldinucci, I. Merelli	Background High-throughput sequencing Chromosome Conformation Capture (Hi-C) allows the study of DNA interactions and 3D chromosome folding at the genome-wide scale. Usually, these data are represented as matrices describing the binary contacts among the different chromosome regions. On the other hand, a graph-based representation can be advantageous to describe the complex topology achieved by the DNA in the nucleus of eukaryotic cells. Methods Here we discuss the use of a graph database for storing and analysing data achieved by performing Hi-C experiments. The main issue is the size of the produced data and, working with a graph-based representation, the consequent necessity of adequately managing a large number of edges (contacts) connecting nodes (genes), which represents the sources of information. For this, currently available graph visualisation tools and libraries fall short with Hi-C data. The use of graph databases, instead, supports both the analysis and the visualisation of the spatial pattern present in Hi-C data, in particular for comparing different experiments or for re-mapping omics data in a space-aware context efficiently. In particular, the possibility of describing graphs through statistical indicators and, even more, the capability of correlating them through statistical distributions allows highlighting similarities and differences among different Hi-C experiments, in different cell conditions or different cell types. Results These concepts have been implemented in NeoHiC, an open-source and user-friendly web application for the progressive visualisation and analysis of Hi-C networks based on the use of the Neo4j graph database (version 3.5).	BMC bioinformatics 22 (2021): 43.	2021	D'AGOSTINO DANIELE, MERELLI IVAN	Hi-c, Chromatin capture, Graph databases, Graph visualisation	10.1186/s12859-020-03937-0
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
455280	Articolo in rivista	SARS-CoV-2 Infection Remodels the Phenotype and Promotes Angiogenesis of Primary Human Lung Endothelial Cells	Francesca Caccuri, Antonella Bugatti, Alberto Zani, Antonella De Palma, Dario Di Silvestre, Ekta Manocha, Federica Filippini, Serena Messali, Paola Chiodelli, Giovanni Campisi, Simona Fiorentini, Fabio Facchetti, Pierluigi Mauri, Arnaldo Caruso	SARS-CoV-2-associated acute respiratory distress syndrome (ARDS) and acute lung injury are life-threatening manifestations of severe viral infection. The pathogenic mechanisms that lead to respiratory complications, such as endothelialitis, intussusceptive angiogenesis, and vascular leakage remain unclear. In this study, by using an immunofluorescence assay and in situ RNA-hybridization, we demonstrate the capability of SARS-CoV-2 to infect human primary lung microvascular endothelial cells (HL-mECs) in the absence of cytopathic effects and release of infectious particles. Preliminary data point to the role of integrins in SARS-CoV-2 entry into HL-mECs in the absence of detectable ACE2 expression. Following infection, HL-mECs were found to release a plethora of proinflammatory and pro-angiogenic molecules, as assessed by microarray analyses. This conditioned microenvironment stimulated HL-mECs to acquire an angiogenic phenotype. Proteome analysis confirmed a remodeling of SARS-CoV-2-infected HL-mECs to inflammatory and angiogenic responses and highlighted the expression of antiviral molecules as annexin A6 and MX1. These results support the hypothesis of a direct role of SARS-CoV-2-infected HL-mECs in sustaining vascular dysfunction during the early phases of infection. The construction of virus-host interactomes will be instrumental to identify potential therapeutic targets for COVID-19 aimed to inhibit HL-mEC-sustained inflammation and angiogenesis upon SARS-CoV-2 infection.	Microorganisms 9 (2021).	2021	DE PALMA ANTONELLA, DI SILVESTRE DARIO, MAURI PIETRO LUIGI	COVID-19, endothelial cell dysfunction, infection, angiogenesis, proteome	10.3390/ microorganisms9071438
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	cellular neuroscience, Parkinson's disease	10.1038/s41531-018-0050-8
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 with age in dopamine neurons of the substantia nigra (SN). Interindividual variability in dopamine function may result in varying levels of NM accumulation in the SN; however, the ability of NM-MRI to measure dopamine function in nonneurodegenerative conditions has not been established. Here, we validated that NM-MRI signal intensity in postmortem midbrain specimens correlated with regional NM concentration even in the absence of neurodegeneration, a prerequisite for its use as a proxy for dopamine function. We then validated a voxelwise NM-MRI approach with sufficient anatomical sensitivity to resolve SN subregions. Using this approach and a multimodal dataset of molecular PET and fMRI data, we further showed the NM-MRI signal was related to both dopamine release in the dorsal striatum and resting blood flow within the SN. These results suggest that NM-MRI signal in the SN is a proxy for function of dopamine neurons in the nigrostriatal pathway. As a proof of concept for its clinical utility, we show that the NM-MRI signal correlated to severity of psychosis in schizophrenia and individuals at risk for schizophrenia, consistent with the well-established dysfunction of the nigrostriatal pathway in psychosis. Our results indicate that 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
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
369335	Articolo in rivista	T cell neoepitope discovery in colorectal cancer by high throughput profiling of somatic mutations in expressed genes	Mennonna D., Maccalli C., Romano M.C., Garavaglia C., Capocefalo F., Bordoni R., Severgnini M., De Bellis G., Sidney J., Sette A., Gori A., Longhi R., Braga M., Ghirardelli L., Baldari L., Orsenigo E., Albarello L., Zino E., Fleischhauer K., Mazzola G., Ferrero N., Amoroso A., Casorati G., Parmiani G., Dellabona P.	Objective Patient-specific (unique) tumour antigens, encoded by somatically mutated cancer genes, generate neoepitopes that are implicated in the induction of tumour-controlling T cell responses. Recent advancements in massive DNA sequencing combined with robust T cell epitope predictions have allowed their systematic identification in several malignancies. Design We undertook the identification of unique neoepitopes in colorectal cancers (CRCs) by using high-throughput sequencing of cDNAs expressed by standard cancer cell cultures, and by related cancer stem/initiating cells (CSCs) cultures, coupled with a reverse immunology approach not requiring human leukocyte antigen (HLA) allele-specific epitope predictions. Results Several unique mutated antigens of CRC, shared by standard cancer and related CSC cultures, were identified by this strategy. CD8(+) and CD4(+) T cells, either autologous to the patient or derived from HLA-matched healthy donors, were readily expanded in vitro by peptides spanning different cancer mutations and specifically recognised differentiated cancer cells and CSC cultures, expressing the mutations. Neoepitope-specific CD8(+) T cell frequency was also increased in a patient, compared with healthy donors, supporting the occurrence of clonal expansion in vivo. Conclusions These results provide a proof-of-concept approach for the identification of unique neoepitopes that are immunogenic in patients with CRC and can also target T cells against the most aggressive CSC component.	Gut 66 (2017): 454-463.	2017	LONGHI RENATO, DE BELLIS GIANLUCA, BORDONI ROBERTA, SEVERGNINI MARCO, GORI ALESSANDRO	antigens, Cancer immunobiology, colorectal cancer, gene mutation, immune response	10.1136/gutjnl-2015-309453
455754	Articolo in rivista	Interaction of Neuromelanin with Xenobiotics and Consequences for Neurodegeneration; Promising Experimental Models	Capucciati A., Zucca F.A., Monzani E., Zecca L., Casella L., Hofer T.	Neuromelanin (NM) accumulates in catecholamine long-lived brain neurons that are lost in neurodegenerative diseases. NM is a complex substance made of melanic, peptide and lipid components. NM formation is a natural protective process since toxic endogenous metabolites are removed during its formation and as it binds excess metals and xenobiotics. However, disturbances of NM synthesis and function could be toxic. Here, we review recent knowledge on NM formation, toxic mechanisms involving NM, go over NM binding substances and suggest experimental models that can help identifying xenobiotic modulators of NM formation or function. Given the high likelihood of a central NM role in age-related human neurodegenerative diseases such as Parkinson's and Alzheimer's, resembling such diseases using animal models that do not form NM to a high degree, e.g., mice or rats, may not be optimal. Rather, use of animal models (i.e., sheep and goats) that better resemble human brain aging in terms of NM formation, as well as using human NM forming stem cellbased in vitro (e.g., mid-brain organoids) models can be more suitable. Toxicants could also be identified during chemical synthesis of NM in the test tube.	Antioxidants 10 (2021): 824.	2021	ZECCA LUIGI, ZUCCA FABIO ANDREA	adverse outcome pathway (AOP), iron, locus coeruleus, MPTP, quinone, substantia nigra	10.3390/antiox10060824
456350	Contributo in atti di convegno	Inclusion design and functionalities of a personalized virtual coach for wellbeing to facilitate a universal access for older adults	El Kamali M., Angelini L., Caon M., Carrino F., Standoli C.E., Perego P., Andreoni G., Palumbo F., Mastropietro A., Khaled O.A., Mugellini E.	The current research proposes a technological system "NESTORE" designed for and with older adults in four different countries in order to improve and sustain their wellbeing. The system personalized activities and architecture, co-designed interfaces, and its multilingual aspect aim to establish an 'inclusion' criterion based on the user's sociocultural profile and health condition.	IEA 2021 - 21st Congress of the International Ergonomics Association, pp. 239-246, Online conference, 13-18/06/2021	2021	PALUMBO FILIPPO, MASTROPIETRO ALFONSO	Virtual coach, Conversational agent, Inclusive design, Wellbeing, Older adults	10.1007/978-3-030-74605-6_30
456359	Articolo in rivista	Microglia-Derived Small Extracellular Vesicles Reduce Glioma Growth by Modifying Tumor Cell Metabolism and Enhancing Glutamate Clearance through miR-124	Carmela Serpe 1, Lucia Monaco 1, Michela Relucenti 2, Ludovica Iovino 3, Pietro Familiari 4, Ferdinando Scavizzi 5, Marcello Raspa 5, Giuseppe Familiari 2, Laura Civiero 3, 6, Igea D'Agnano 7, Cristina Limatola 8, 9, Myriam Catalano 1	Brain homeostasis needs continuous exchange of intercellular information among neurons, glial cells, and immune cells, namely microglial cells. Extracellular vesicles (EVs) are active players of this process. All the cells of the body, including the brain, release at least two subtypes of EVs, the medium/large EVs (m/lEVs) and small EVs (sEVs). sEVs released by microglia play an important role in brain patrolling in physio-pathological processes. One of the most common and malignant forms of brain cancer is glioblastoma. Altered intercellular communications constitute a base for the onset and the development of the disease. In this work, we used microglia-derived sEVs to assay their effects in vitro on murine glioma cells and in vivo in a glioma model on C57BL6/N mice. Our findings indicated that sEVs carry messages to cancer cells that modify glioma cell metabolism, reducing lactate, nitric oxide (NO), and glutamate (Glu) release. sEVs affect Glu homeostasis, increasing the expression of Glu transporter Glt-1 on astrocytes. We demonstrated that these effects are mediated by miR-124 contained in microglia-released sEVs. The in vivo benefit of microglia-derived sEVs results in a significantly reduced tumor mass and an increased survival of glioma-bearing mice, depending on miR-124.	Cells (2021).	2021	RASPA MARCELLO, D'AGNANO IGEA, SCAVIZZI FERDINANDO	microglia; extracellular vesicles; brain tumors; glioma; neurotoxicity; glutamate; Glt-1; miR-124
456568	Articolo in rivista	Mobility and muscle strength trajectories in old age: the beneficial effect of Mediterranean diet in combination with physical activity and social support	Marguerita Saadeh 1 2, Federica Prinelli 3 4, Davide L Vetrano 3 5, Weili Xu 3, Anna-Karin Welmer 3 6, Serhiy Dekhtyar 3, Laura Fratiglioni 3 7, Amaia Calderon-Larranaga 3	Introduction: Decline in physical function varies substantially across older individuals due to several extrinsic modifiable factors such as dietary patterns, physical activity and social support. We aimed to determine the association of these factors and their interaction with mobility and muscle strength decline. Methods: We analyzed data from 1686 functionally healthy individuals aged 60 + from the population-based Swedish National study on Aging and Care in Kungsholmen (SNAC-K). The Mediterranean Diet Score (MDS) was calculated based on a validated food frequency questionnaire. Self-reported physical activity was categorized based on current recommendations, and social support was measured according to participants' perceived material and psychological support from relatives and friends. Participants' physical function was assessed over 12 years through changes in walking speed (m/s) and chair stand time (s). Linear mixed models adjusted for socio-demographic and clinical factors were used. In order to explore the combined effect of the different exposures, two indicator variables were created by cross-classifying individuals' levels of Mediterranean diet adherence and social support or physical activity. Results: Participants with a high adherence to Mediterranean diet were primarily < 78 years (82.3%), women (56.1%), married (61.1%), with university education (52.8%), high levels of social support (39.3%) and health-enhancing levels of physical activity (51.5%). A one-point increase in MDS (score range 0-9) was associated with less annual deterioration in walking speed (?*time[year] = 0.001; p = 0.024) and chair-stand time (?*time[year] = -0.014; p = 0.008). The potential protective effect of Mediterranean diet was highest among participants reporting high social support (?*time[year] = -0.065, p = 0.026 for chair stands) and high physical activity (?*time[year] = 0.010, p = 0.001 for walking speed), beyond the effect of each exposure individually. Conclusion: A higher adherence to Mediterranean diet, especially in combination with recommended levels of physical activity and high social support, may contribute to delay the decline in physical function observed with aging.	The international journal of behavioural nutrition and physical activity (Online) 18 (2021): 1-11.	2021	PRINELLI FEDERICA	Mediterranean diet, Mobility, Muscle strength, Older adults, Physical activity, Social support	10.1186/s12966-021-01192-x.
446600	Articolo in rivista	Shotgun proteomics of isolated urinary extracellular vesicles for investigating respiratory impedance in healthy preschoolers	Ferrante G, Rossi R, Cilluffo G, Di Silvestre D, Brambilla A, De Palma A, Villa C, Malizia V, Gagliardo R, Torrente Y, Corsello G, Viegi G, Mauri P, La Grutta S	Urine proteomic applications in children suggested their potential in discriminating between healthy subjects from those with respiratory diseases. The aim of the current study was to combine protein fractionation, by urinary extracellular vesicle isolation, and proteomics analysis in order to establish whether different patterns of respiratory impedance in healthy preschoolers can be characterized from a protein fingerprint. Twenty-one 3-5-yr-old healthy children, representative of 66 recruited subjects, were selected: 12 late preterm (LP) and 9 full-term (T) born. Children underwent measurement of respiratory impedance through Forced Oscillation Technique (FOT) and no significant differences between LP and T were found. Unbiased clustering, based on proteomic signatures, stratified three groups of children (A, B, C) with significantly different patterns of respiratory impedance, which was slightly worse in group A than in groups B and C. Six proteins (Tripeptidyl peptidase I (TPP1), Cubilin (CUBN), SerpinA4, SerpinF1, Thy-1 membrane glycoprotein (THY1) and Angiopoietin-related protein 2 (ANGPTL2)) were identified in order to type the membership of subjects to the three groups. The differential levels of the six proteins in groups A, B and C suggest that proteomic-based profiles of urinary fractionated exosomes could represent a link between respiratory impedance and underlying biological profiles in healthy preschool children.	Molecules (Basel, Online) 26 (2021): 1-14.	2021	DE PALMA ANTONELLA, ROSSI ROSSANA, FERRANTE GIULIANA, VIEGI GIOVANNI, GAGLIARDO ROSALIA PAOLA, DI SILVESTRE DARIO, LA GRUTTA STEFANIA, CILLUFFO GIOVANNA, MALIZIA VELIA	extracellular vesicle, urine fractionation, proteomics, forced oscillation technique, preschooler healthy children	10.3390/molecules26051258
452856	Articolo in rivista	Integration of multiple resolution data in 3D chromatin reconstruction using ChromStruct	Caudai C., Zoppe M., Tonazzini A., Merelli I., Salerno E.	The three-dimensional structure of chromatin in the cellular nucleus carries important information that is connected to physiological and pathological correlates and dysfunctional cell behaviour. As direct observation is not feasible at present, on one side, several experimental techniques have been developed to provide information on the spatial organization of the DNA in the cell; on the other side, several computational methods have been developed to elaborate experimental data and infer 3D chromatin conformations. The most relevant experimental methods are Chromosome Conformation Capture and its derivatives, chromatin immunoprecipitation and sequencing techniques (CHIP-seq), RNA-seq, fluorescence in situ hybridization (FISH) and other genetic and biochemical techniques. All of them provide important and complementary information that relate to the three-dimensional organization of chromatin. However, these techniques employ very different experimental protocols and provide information that is not easily integrated, due to different contexts and different resolutions. Here, we present an open-source tool, which is an expansion of the previously reported code ChromStruct, for inferring the 3D structure of chromatin that, by exploiting a multilevel approach, allows an easy integration of information derived from different experimental protocols and referred to different resolution levels of the structure, from a few kilobases up to Megabases. Our results show that the introduction of chromatin modelling features related to CTCF CHIA-PET data, histone modification CHIP-seq, and RNA-seq data produce appreciable improvements in ChromStruct's 3D reconstructions, compared to the use of HI-C data alone, at a local level and at a very high resolution.	Biology (Basel) 10 (2021): 338.	2021	MERELLI IVAN, ZOPPE' MONICA MARIA, CAUDAI CLAUDIA, SALERNO EMANUELE, TONAZZINI ANNA	Chromatin conformation, bayesian statistics, HI-C data, Chromatin conformation capture, CTCF CHIA-PET data, CHIP-seq, RNA-seq	10.3390/biology10040338
454585	Articolo in rivista	Hardware and Software Solutions for Energy-Efficient Computing in Scientific Programming	D. D'Agostino, I. Merelli, M. Aldinucci, D. Cesini	Energy consumption is one of the major issues in today's computer science, and an increasing number of scientific communities are interested in evaluating the tradeoff between time-to-solution and energy-to-solution. Despite, in the last two decades, computing which revolved around centralized computing infrastructures, such as supercomputing and data centers, the wide adoption of the Internet of Things (IoT) paradigm is currently inverting this trend due to the huge amount of data it generates, pushing computing power back to places where the data are generated--the so-called fog/edge computing. This shift towards a decentralized model requires an equivalent change in the software engineering paradigms, development environments, hardware tools, languages, and computation models for scientific programming because the local computational capabilities are typically limited and require a careful evaluation of power consumption. This paper aims to present how these concepts can be actually implemented in scientific software by presenting the state of the art of powerful, less power-hungry processors from one side and energy-aware tools and techniques from the other one.	Scientific programming 2021 (2021): ID 5514284.	2021	D'AGOSTINO DANIELE, MERELLI IVAN	energy efficiency, energy consumption, SoC, low power	10.1155/2021/5514284
457088	Articolo in rivista	Role of Lamin A/C as Candidate Biomarker of Aggressiveness and Tumorigenicity in Glioblastoma Multiforme	Giuliana Gatti 1, +, Laura Vilardo 2, +, Carla Musa 2, +, Chiara Di Pietro 3, Fabrizio Bonaventura 3, Ferdinando Scavizzi 3, Alessio Torcinaro 3, Barbara Bucci 4, Raffaele Saporito 4, Ivan Arisi 5, Francesca De Santa 3, Marcello Raspa 3, Loredana Guglielmi 2, *, Igea D'Agnano 2, *	Nuclear lamina components have long been regarded as scaffolding proteins, forming a dense fibrillar structure necessary for the maintenance of the nucleus shape in all the animal kingdom. More recently, mutations, aberrant localisation and deregulation of these proteins have been linked to several diseases, including cancer. Using publicly available data we found that the increased expression levels of the nuclear protein Lamin A/C correlate with a reduced overall survival in The Cancer Genome Atlas Research Network (TCGA) patients affected by glioblastoma multiforme (GBM). We show that the expression of the LMNA gene is linked to the enrichment of cancerrelated pathways, particularly pathways related to cell adhesion and cell migration. Mimicking the modulation of LMNA in a GBM preclinical cancer model, we confirmed both in vitro and in vivo that the increased expression of LMNA is associated with an increased aggressiveness and tumorigenicity. In addition, delving into the possible mechanism behind LMNA-induced GBM aggressiveness and tumorigenicity, we found that the mTORC2 component, Rictor, plays a central role in mediating these effects.	Biomedicines 9 (2021).	2021	RASPA MARCELLO, DI PIETRO CHIARA, DE SANTA FRANCESCA, VILARDO LAURA, D'AGNANO IGEA, SCAVIZZI FERDINANDO	Lamin A/C; glioblastoma; Rictor	10.3390/ biomedicines9101343
457516	Articolo in rivista	An Investigation of the Role of Common and Rare Variants in a Large Italian Multiplex Family of Multiple Sclerosis Patients	Nadia Barizzone, Rachele Cagliani, Chiara Basagni, Ferdinando Clarelli, Laura Mendozzi, Cristina Agliardi, Diego Forni, Martina Tosi, Elisabetta Mascia, Francesco Favero, Davide Cora, Lucia Corrado, Melissa Sorosina, Federica Esposito, Miriam Zuccala, Domizia Vecchio, Maria Liguori, Cristoforo Comi, Giancarlo Comi, Vittorio Martinelli, Massimo Filippi, Maurizio Leone, Filippo Martinelli-Boneschi, Domenico Caputo, Manuela Sironi, Franca Rosa Guerini, Sandra D'Alfonso	Known multiple sclerosis (MS) susceptibility variants can only explain half of the disease's estimated heritability, whereas low-frequency and rare variants may partly account for the missing heritability. Thus, here we sought to determine the occurrence of rare functional variants in a large Italian MS multiplex family with five affected members. For this purpose, we combined linkage analysis and next-generation sequencing (NGS)-based whole exome and whole genome sequencing (WES and WGS, respectively). The genetic burden attributable to known common MS variants was also assessed by weighted genetic risk score (wGRS). We found a significantly higher burden of common variants in the affected family members compared to that observed among sporadic MS patients and healthy controls (HCs). We also identified 34 genes containing at least one low-frequency functional variant shared among all affected family members, showing a significant enrichment in genes involved in specific biological processes--particularly mRNA transport--or neurodegenerative diseases. Altogether, our findings point to a possible pathogenic role of different low-frequency functional MS variants belonging to shared pathways. We propose that these rare variants, together with other known common MS variants, may account for the high number of affected family members within this MS multiplex family.	Genes (Basel) (2021).	2021	LIGUORI MARIA	multiple sclerosis; multiplex families; linkage study; NGS; rare variants	10.3390/genes12101607
457749	Contributo in volume	Pharmacoepigenomics in neurodegenerative diseases	Nicoletta Nuzziello and Maria Liguori	In this chapter, the recent advancements in the mentioned areas of research in pharmacoepigenomics will be highlighted, including the most recently discovered and promising epigenetic therapies that aim to improve NDD treatment. We will focus on a subset of NDDs, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), in which evidence supporting the contribution of pharmacoepigenomics has been best established.	Medical Epigenetics, edited by Dr. Trygve Tollefsbol, pp. 559-581. New York: Elsevier, 2021	2021	NUZZIELLO NICOLETTA, LIGUORI MARIA	Epigenomics, Pharmacoepigenomics, Neurodegenerative diseases
453930	Articolo in rivista	High biodiversity in a limited mountain area revealed in the traditional production of Historic Rebel cheese by an integrated microbiota-lipidomic approach	Federica Turri, Paola Cremonesi, Giovanna Battelli, Marco Severgnini, Milena Brasca, Gustavo Gandini, Flavia Pizzi	Historic Rebel (HR) cheese is an Italian heritage cheese, produced from raw milk during the summer grazing period in the Alps. The aim of this work was (i) to characterize the cheese microbiota, by 16S rRNA gene amplicons sequencing, and the volatile and non-volatile lipophilic fraction, by Gas Chromatography and Dynamic Headspace Extraction-Gas Chromatography-Mass Spectrometry, and (ii) to evaluate their respective associations. HR cheese was dominated by Firmicutes phylum (99% of the entire abundance). The core microbiota was formed by Streptococcus, Lactobacillus, Lactococcus, Leuconostoc and Pediococcus genera together representing 87.2-99.6% of the total abundance. The polyunsaturated fatty acids composition showed a high PUFA n-3, PUFA n-6 and CLA content, two fold higher than typical plain cheeses, positively correlated with pasture altitude. A complex volatilome was detected, dominated in terms of abundance by ketones, fatty acids and alcohols. Total terpene levels increased at higher altitudes, being the main terpenes compounds ?-pinene, camphene and ?-pinene. The HR cheese showed a great diversity of bacterial taxa and lipophilic fractions among producers, despite belonging to a small alpine area, revealing a scarce cheese standardization and a chemical fingerprint of a typical mountain cheese produced during the grazing period. A deeper knowledge of the variability of HR cheese due to its composition in microbial community and volatile compounds will be appreciated, in particular, by elite consumers looking for niche products, adding economic value to farming in these alpine areas.	Scientific reports (Nature Publishing Group) 11 (2021).	2021	GANDINI GUSTAVO, BATTELLI GIOVANNA, BRASCA MILENA, SEVERGNINI MARCO, CREMONESI PAOLA, TURRI FEDERICA, PIZZI FLAVIA	mountain cheese; high-throughput sequencing; microbiota; volatile; terpenoids composition; fatty acids	10.1038/s41598-021-89959-x
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.
395429	Articolo in rivista	A multi-cellular 3D bioprinting approach for vascularized heart tissue engineering based on HUVECs and iPSC-derived cardiomyocytes	Maiullari, Fabio, Maiullari, Fabio, Costantini, Marco, Costantini, Marco, Milan, Marika, Pace, Valentina, Chirivi, Maila, Maiullari, Silvia, Rainer, Alberto, Baci, Denisa, Marei, Hany El Sayed, Seliktar, Dror, Gargioli, Cesare, Bearzi, Claudia, Bearzi, Claudia, Rizzi, Roberto, Rizzi, Roberto	The myocardium behaves like a sophisticated orchestra that expresses its true potential only if each member performs the correct task harmonically. Recapitulating its complexity within engineered 3D functional constructs with tailored biological and mechanical properties, is one of the current scientific priorities in the field of regenerative medicine and tissue engineering. In this study, driven by the necessity of fabricating advanced model of cardiac tissue, we present an innovative approach consisting of heterogeneous, multi-cellular constructs composed of Human Umbilical Vein Endothelial Cells (HUVECs) and induced pluripotent cell-derived cardiomyocytes (iPSC-CMs). Cells were encapsulated within hydrogel strands containing alginate and PEG-Fibrinogen (PF) and extruded through a custom microfluidic printing head (MPH) that allows to precisely tailor their 3D spatial deposition, guaranteeing a high printing fidelity and resolution. We obtained a 3D cardiac tissue compose of iPSC-derived CMs with a high orientation index imposed by the different defined geometries and blood vessel-like shapes generated by HUVECs which, as demonstrated by in vivo grafting, better support the integration of the engineered cardiac tissue with host's vasculature.	Scientific report (London Research Institute) 8 (2018).	2018	RIZZI ROBERTO, BEARZI CLAUDIA	3d bioprinting	10.1038/s41598-018-31848-x
395427	Articolo in rivista	Givinostat reduces adverse cardiac remodeling through regulating fibroblasts activation article	Milan, M.a, Pace, V.a, Maiullari, F.a, b, Chirivi, M.a, Baci, D.a, Maiullari, S.a, Madaro, L.c, Maccari, S.d, Stati, T.d, Marano, G.d, Frati, G.e, f, Puri, P.L.g, De Falco, E.e, Bearzi, C.aEmail Author, Rizzi, R.a, b	Cardiovascular diseases (CVDs) are a major burden on the healthcare system: indeed, over two million new cases are diagnosed every year worldwide. Unfortunately, important drawbacks for the treatment of these patients derive from our current inability to stop the structural alterations that lead to heart failure, the common endpoint of many CVDs. In this scenario, a better understanding of the role of epigenetics-hereditable changes of chromatin that do not alter the DNA sequence itself-is warranted. To date, hyperacetylation of histones has been reported in hypertension and myocardial infarction, but the use of inhibitors for treating CVDs remains limited. Here, we studied the effect of the histone deacetylase inhibitor Givinostat on a mouse model of acute myocardial infarction. We found that it contributes to decrease endothelial-To-mesenchymal transition and inflammation, reducing cardiac fibrosis and improving heart performance and protecting the blood vessels from apoptosis through the modulatory effect of cardiac fibroblasts on endothelial cells. Therefore, Givinostat may have potential for the treatment of CVDs.	Cell death and disease 9 (2018).	2018	RIZZI ROBERTO, BEARZI CLAUDIA	cardiac	10.1038/s41419-017-0174-5
457984	Articolo in rivista	Bovine Milk Microbiota: Comparison among Three Different DNA Extraction Protocols To Identify a Better Approach for Bacterial Analysis	Cremonesi P.1, Severgnini M.2, Romano A3, 4., Sala L.3, Luini M.1, 3, Castiglioni B1	The bovine udder is colonized by a huge quantity of microorganisms that constitute the intramammary ecosystem, with a specific role in modulating not only udder homeostasis and mastitis susceptibility, but also the quality of the dairy products. However, generating high-quality bacterial DNA can be critical, especially starting from a complex biological matrix like milk, characterized by high fat, protein, and calcium contents. Here, bacterial DNA was recovered from a commercial ultra-high-temperature (UHT) milk sample artificially spiked with a predetermined mock community composition and from three bulk tank milk (raw milk) samples. The DNA was isolated using three different protocols to evaluate the effect of the extraction procedures on the milk microbiota composition. In the mock community experiment, the bacterial profiles generated by the three DNA extraction protocols were profoundly different, with the genera Staphylococcus, Lactobacillus, Listeria, and Salmonella underestimated by all the protocols. Only one protocol revealed values close to the expected abundances for Escherichia/Shigella spp., Bacillus spp., Enterococcus spp., and Pseudomonas spp. On the other hand, the nonspiked UHT milk sample exhibited a similar microbiota composition, revealing the prevalence of Acinetobacter spp., for all the DNA extraction protocols. For the raw milk samples, the three DNA extraction kits performed differently, revealing significant separations in both the microbial richness (alpha diversity) and composition (beta diversity). Our study highlights the presence of significant differences among these procedures, probably due to the different DNA extracting capacities and to the different properties of the milk samples, revealing that the selection of DNA extraction protocol is a critical point. IMPORTANCE The advance of high-throughput technologies has increased our knowledge of the world of microorganisms, especially of microbial populations inhabiting living animals. This study provides evidence that milk, as other complex sources, could be critical for generating high-quality DNA for microbiota analysis. In addition, it demonstrates that the microbial population highlighted by metagenomic studies changes in relation to different DNA extraction procedures, revealing that attention should be paid especially when comparing different studies.	ASM perspectives (2021).	2021	CASTIGLIONI BIANCA MARIA ELISABETTA, SEVERGNINI MARCO, CREMONESI PAOLA	bacterial DNA extraction, bulk tank milk, milk microbiome, mock community	10.1128/Spectrum.00374-21
459211	Articolo in rivista	Autism spectrum disorders: Analysis of mobile elements at 7q11.23 williams-beuren region by comparative genomics	Cupaioli F.A., Fallerini C., Mencarelli M.A., Perticaroli V., Filippini V., Mari F., Renieri A., Mezzelani A.	Autism spectrum disorders (ASD) are a group of complex neurodevelopmental disorders, characterized by a deficit in social interaction and communication. Many genetic variants are associated with ASD, including duplication of 7q11.23 encompassing 26-28 genes. Symmetrically, the hemizygous deletion of 7q11.23 causes Williams-Beuren syndrome (WBS), a multisystem disorder characterized by "hyper-sociability" and communication skills. Interestingly, deletion of four non-exonic mobile elements (MEs) in the "canine WBS locus" were associated with the behavioral divergence between the wolf and the dog and dog sociability and domestication. We hypothesized that indel of these MEs could be involved in ASD, associated with its different phenotypes and useful as biomarkers for patient stratification and therapeutic design. Since these MEs are non-exonic they have never been discovered before. We searched the corresponding MEs and loci in humans by comparative genomics. Interestingly, they mapped on different but ASD related genes. The loci in individuals with phenotypically different autism and neurotypical controls were amplified by PCR. A sub-set of each amplicon was sequenced by Sanger. No variant resulted associated with ASD and neither specific phenotypes were found but novel small-scale insertions and SNPs were discovered. Since MEs are hyper-methylated and epigenetically modulate gene expression, further investigation in ASD is necessary.	Genes (Basel) 12 (2021).	2021	MEZZELANI ALESSANDRA MARIA, CUPAIOLI FRANCESCA ANNA	transposable elements, Williams-Beuren syndrome, dog sociability, comparative genomics, 7q11.23, indel, hyper-methylated, sociability, dosage sensitive genes, genetic variants	10.3390/genes12101605
459431	Articolo in rivista	Log-ratio transformations for dietary compositions: numerical and conceptual questions	Maria Lea Correa Leite	When evaluating the impact of macronutrient intakes on health outcomes, researchers in nutritional epidemiology are mostly interested in two types of information: the relative importance of the individual macronutrients and the absolute effect of total energy intake. However, the usual substitution models do not allow these separate effects to be disentangled. Dietary data are typical examples of compositional data, which convey relative information and are, therefore, meaningfully expressed in the form of ratios. Various formulations of log-ratios have been proposed as a means of analysing compositional data, and their interrelationships when they are used as predictors in regression models have been previously reported. This note describes the application of distinct log-ratio transformations to the composition of dietary macronutrients and discusses the interpretative implications of using them as explanatory variables in regression models together with a term for the total composition (total energy intake). It also provides examples that consider serum glucose levels as the health outcome and are based on data coming from an Italian population-based study. The log-ratio transformation of dietary data has both numerical and conceptual advantages, and overcomes the drawbacks of traditional substitution models.	Journal of nutritional science (2021).	2021	CORREA LEITE MARIA LEA	Compositional data, Dietary data, Energy intake, Log-ratio transformation, Macronutrients, Nutrient balances	10.1017/jns.2021.93
459985	Articolo in rivista	Clinical relevance of clonal hematopoiesis in persons aged >=80 years	Rossi M., Meggendorfer M., Zampini M., Tettamanti M., Riva E., Travaglino E., Bersanelli M., Mandelli S., Antonella Galbussera A., Mosca E., Saba E., Chiereghin C., Manes N., Milanesi C., Ubezio M., Morabito L., Peano C., Solda G., Asselta R., Duga S., Selmi C., De Santis M., Malik K., Maggioni G., Bicchieri M., Campagna A., Tentori C.A., Russo A., Civilini E., Allavena P., Piazza R., Corrao G., Sala C., Termanini A., Giordano L., Detoma P., Malabaila A., Sala L., Rosso S., Zanetti R., Saitta C., Riva E., Condorelli G., Passamonti F., Santoro A., Sole F., Platzbecker U., Fenaux P., Bolli N., Castellani G., Kern W., Vassiliou G.S., Haferlach T., Lucca U., Della Porta M.G.	Clonal hematopoiesis of indeterminate potential (CHIP) is associated with increased risk of cancers and inflammation-related diseases. This phenomenon becomes common in persons aged >=80 years, in whom the implications of CHIP are not well defined. We performed a mutational screening in 1794 persons aged >=80 years and investigated the relationships between CHIP and associated pathologies. Mutations were observed in one-third of persons aged >=80 years and were associated with reduced survival. Mutations in JAK2 and splicing genes, multiple mutations (DNMT3A, TET2, and ASXL1 with additional genetic lesions), and variant allele frequency >=0.096 had positive predictive value for myeloid neoplasms. Combining mutation profiles with abnormalities in red blood cell indices improved the ability of myeloid neoplasm prediction. On this basis, we defined a predictive model that identifies 3 risk groups with different probabilities of developing myeloid neoplasms. Mutations in DNMT3A, TET2, ASXL1, or JAK2 were associated with coronary heart disease and rheumatoid arthritis. Cytopenia was common in persons aged >=80 years, with the underlying cause remaining unexplained in 30% of cases. Among individuals with unexplained cytopenia, the presence of highly specific mutation patterns was associated with myelodysplastic-like phenotype and a probability of survival comparable to that of myeloid neoplasms. Accordingly, 7.5% of subjects aged >=80 years with cytopenia had presumptive evidence of myeloid neoplasm. In summary, specific mutational patterns define different risk of developing myeloid neoplasms vs inflammatory-associated diseases in persons aged >=80 years. In individuals with unexplained cytopenia, mutational status may identify those subjects with presumptive evidence of myeloid neoplasms.	Blood 138 (2021): 2093-2105.	2021	MOSCA ETTORE	clonal hematopoiesis, myeloid neoplasms, mutational screening	10.1182/blood.2021011320
459988	Articolo in rivista	Multi-omic analyses in Abyssinian cats with primary renal amyloid deposits	Genova, Francesca, Nonnis, Simona, Maffioli, Elisa, Tedeschi, Gabriella, Strillacci, Maria Giuseppina, Carisetti, Michela, Sironi, Giuseppe, Cupaioli, Francesca Anna, Di Nanni, Noemi, Mezzelani, Alessandra, Mosca, Ettore, Helps, Christopher R., Leegwater, Peter A.J., Dorso, Laetitia, Buckley, Reuben M., Aberdein, Danielle, Alves, Paulo C., Andersson, Asa Ohlsson, Barsh, Gregory S., Bellone, Rebecca R., Bergstrom, Tomas F., Boyko, Adam R., Brockman, Jeffrey A., Casal, Margret L., Castelhano, Marta G., Distl, Ottmar, Dodman, Nicholas H., Ellinwood, N. Matthew, Fogle, Jonathan E., Forman, Oliver P., Garrick, Dorian J., Ginns, Edward I., Haase, Bianca, Haggstrom, Jens, Harvey, Robert J., Hasegawa, Daisuke, Hernandez, Isabel, Hytonen, Marjo K., Kaukonen, Maria, Kaelin, Christopher B., Kosho, Tomoki, Leclerc, Emilie, Lear, Teri L., Leeb, Tosso, Li, Ronald H.L., Lohi, Hannes, Magnuson, Mark A., Malik, Richard, Mane, Shrinivasrao P., Munday, John S., Murphy, William J., Pedersen, Niels C., Peterson-Jones, Simon M., Rothschild, Max F., Rusbridge, Clare, Shapiro, Beth, Stern, Joshua A., Swanson, William F., Terio, Karen A., Todhunter, Rory J., Warren, Wesley C., Wilcox, Elizabeth A., Wildschutte, Julia H., Yu, Yoshihiko, Lyons, Leslie A., Longeri, Maria	The amyloidoses constitute a group of diseases occurring in humans and animals that are characterized by abnormal deposits of aggregated proteins in organs, affecting their structure and function. In the Abyssinian cat breed, a familial form of renal amyloidosis has been described. In this study, multi-omics analyses were applied and integrated to explore some aspects of the unknown pathogenetic processes in cats. Whole-genome sequences of two affected Abyssinians and 195 controls of other breeds (part of the 99 Lives initiative) were screened to prioritize potential disease-associated variants. Proteome and miRNAome from formalin-fixed paraffin-embedded kidney specimens of fully necropsied Abyssinian cats, three affected and three non-amyloidosis-affected were characterized. While the trigger of the disorder remains unclear, overall, (i) 35,960 genomic variants were detected; (ii) 215 and 56 proteins were identified as exclusive or overexpressed in the affected and control kidneys, respectively; (iii) 60 miRNAs were differentially expressed, 20 of which are newly described. With omics data integration, the general conclusions are: (i) the familial amyloid renal form in Abyssinians is not a simple monogenic trait; (ii) amyloid deposition is not triggered by mutated amyloidogenic proteins but is a mix of proteins codified by wild-type genes; (iii) the form is biochemically classifiable as AA amyloidosis.	Scientific reports (Nature Publishing Group) 11 (2021).	2021	MEZZELANI ALESSANDRA MARIA, MOSCA ETTORE, CUPAIOLI FRANCESCA ANNA	amyloidoses, multi-omics, amyloidoses, amyloidoses, amyloidosis, abyssinian cat, Abyssinian cat	10.1038/s41598-021-87168-0
460133	Contributo in volume	Role of Syndecan-1 in Cancer Stem Cells	Sherif Abel-Aziz Ibrahim1, Hebatallah Hassan1, Rolland Reinbold2, Nancy Adriana Espinoza-Sanchez3, Burkhard Greve4*, Martin Gotte3*	Syndecan-1 (CD138) is a cell surface heparan sulfate proteoglycan that is frequently misexpressed in cancer. Under physiological conditions, it is involved in the regulation of processes as diverse as leukocyte recruitment, wound repair, angiogenesis, exosome formation and epithelial-to-mesenchymal transition. Apart from a role as adhesion molecule and modulator of proteolysis, Syndecan-1 has a pivotal function as a co-receptor for multiple signal transduction pathways, including Wnt, hedgehog, FGF, and NF-kB/IL-6/JAK-STAT signaling. Notably, the activity of these pathways plays an important role in determining the functional state of cancer stem cells. This cell population shares several properties with stem cells, and has been linked to cancer recurrence due to its property of increased resistance to chemo- and radiation therapy. In this review, we will summarize the current knowledge on the role of Syndecan-1 in cancer stem cell function. Due to its simultaneous involvement as an enhancer of multiple stemness-associated signaling pathways, Syndecan-1 emerges as an attractive target for novel therapeutic approaches, which could be utilized to overcome recurrence after an otherwise successful therapy.	Proteoglycans in Stem Cells From Development to Cancer, pp. 279-308, 2021	2021	REINBOLD ROLLAND ALVONS	Syndecan-1, heparan sulfate, cancer stem cells, morphogen, Wnt, hedgehog, FGF, notch, IL-6, NF-kB, JAK/STAT, therapeutic resistance
455917	Articolo in rivista	Identification of a targetable KRAS-mutant epithelial population in non-small cell lung cancer	Maroni G., Bassal M.A., Krishnan I., Fhu C.W., Savova V., Zilionis R., Maymi V.A., Pandell N., Csizmadia E., Zhang J., Storti B., Castano J., Panella R., Li J., Gustafson C.E., Fox S., Levy R.D., Meyerovitz C.V., Tramontozzi P.J., Vermilya K., De Rienzo A., Crucitta S., Basseres D.S., Weetall M., Branstrom A., Giorgetti A., Ciampi R., Del Re M., Danesi R., Bizzarri R., Yang H., Kocher O., Klein A.M., Welner R.S., Bueno R., Magli M.C., Clohessy J.G., Ali A., Tenen D.G., Levantini E.	Lung cancer is the leading cause of cancer deaths. Tumor heterogeneity, which hampers development of targeted therapies, was herein deconvoluted via single cell RNA sequencing in aggressive human adenocarcinomas (carrying Kras-mutations) and comparable murine model. We identified a tumor-specific, mutant-KRAS-associated subpopulation which is conserved in both human and murine lung cancer. We previously reported a key role for the oncogene BMI-1 in adenocarcinomas. We therefore investigated the effects of in vivo PTC596 treatment, which affects BMI-1 activity, in our murine model. Post-treatment, MRI analysis showed decreased tumor size, while single cell transcriptomics concomitantly detected near complete ablation of the mutant-KRAS-associated subpopulation, signifying the presence of a pharmacologically targetable, tumor-associated subpopulation. Our findings therefore hold promise for the development of a targeted therapy for KRAS-mutant adenocarcinomas.	Communications biology 4 (2021): 370-1-370-15.	2021	BIZZARRI RANIERI, LEVANTINI ELENA, STORTI BARBARA, MARONI GIORGIA	scRNAseq, high-resolution transcriptomics, NSCLC, BMI1, therapeutic targeting, transformed epithelial cells, single cell analysis, murine models, PTC596, MRI, targeted therapy	10.1038/s42003-021-01897-6
460763	Articolo in rivista	A shotgun proteomic platform for a global mapping of lymphoblastoid cells to gain insight into nasu-hakola disease	De Palma A., Agresta A.M., Viglio S., Rossi R., D'amato M., Di Silvestre D., Mauri P., Iadarola P.	Nasu-Hakola Disease (NHD) is a recessively inherited systemic leukodystrophy disorder characterized by a combination of frontotemporal presenile dementia and lytic bone lesions. NHD is known to be genetically related to a structural defect of TREM2 and DAP12, two genes that encode for different subunits of the membrane receptor signaling complex expressed by microglia and osteoclast cells. Because of its rarity, molecular or proteomic studies on this disorder are absent or scarce, only case reports based on neuropsychological and genetic tests being reported. In light of this, the aim of this paper is to provide evidence on the potential of a label-free proteomic platform based on the Multidimensional Protein Identification Technology (MudPIT), combined with in-house software and on-line bioinformatics tools, to characterize the protein expression trends and the most involved pathways in NHD. The application of this approach on the Lymphoblastoid cells from a family composed of individuals affected by NHD, healthy carriers and control subjects allowed for the identification of about 3000 distinct proteins within the three analyzed groups, among which proteins anomalous to each category were identified. Of note, several differentially expressed proteins were associated with neurodegenerative processes. Moreover, the protein networks highlighted some molecular pathways that may be involved in the onset or progression of this rare frontotemporal disorder. Therefore, this fully automated MudPIT platform which allowed, for the first time, the generation of the whole protein profile of Lymphoblastoid cells from Nasu-Hakola subjects, could be a valid approach for the investigation of similar neurodegenerative diseases.	International journal of molecular sciences (Print) 22 (2021).	2021	ROSSI ROSSANA, DE PALMA ANTONELLA, DI SILVESTRE DARIO, MAURI PIETRO LUIGI	Nasu-Hakola Disease, frontotemporal dementia, TREM2, proteomics, MudPIT, Lymphoblastoid cells	10.3390/ijms22189959
460764	Articolo in rivista	Single-tear proteomics: A feasible approach to precision medicine	Ponzini E., Ami D., Duse A., Santambrogio C., De Palma A., Di Silvestre D., Mauri P., Pezzoli F., Natalello A., Tavazzi S., Grandori R.	Lacrimal fluid is an attractive source of noninvasive biomarkers, the main limitation being the small sample amounts typically collected. Advanced analytical methods to allow for proteomics profiling from a few microliters are needed to develop innovative biomarkers, with attractive perspectives of applications to precision medicine. This work describes an effective, analytical pipeline for single-tear analysis by ultrahigh-resolution, shotgun proteomics from 23 healthy human volunteers, leading to high-confidence identification of a total of 890 proteins. Highly reproducible quantification was achieved by either peak intensity, peak area, or spectral counting. Hierarchical clustering revealed a stratification of females vs. males that did not emerge from previous studies on pooled samples. Two subjects were monitored weekly over 3 weeks. The samples clustered by withdrawal time of day (morning vs. afternoon) but not by follow-up week, with elevated levels of components of the immune system in the morning samples. This study demonstrates feasibility of single-tear quantitative proteomics, envisaging contributions of this unconventional body fluid to individualized approaches in biomedicine.	International journal of molecular sciences (Print) 22 (2021).	2021	DE PALMA ANTONELLA, DI SILVESTRE DARIO, MAURI PIETRO LUIGI	lacrimal film, liquid biopsies, peripheral body fluids, personalized medicine, single-tear analysis, mass-spectrometry-based proteomics	10.3390/ijms221910750
461356	Articolo in rivista	Distribution of ermb, ermf, tet(W), and tet(m) resistance genes in the vaginal ecosystem of women during pregnancy and puerperium	Severgnini, Marco, Camboni, Tania, Ceccarani, Camilla, Morselli, Sara, Cantiani, Alessia, Zagonari, Sara, Patuelli, Giulia, Pedna, Maria Federica, Sambri, Vittorio, Foschi, Claudio, Consolandi, Clarissa, Marangoni, Antonella	The inhabitants of the vaginal ecosystem can harbor genetic determinants conferring antimicrobial resistance. However, detailed data about the distribution of resistance genes in the vaginal microbiome of pregnant women are still lacking. Therefore, we assessed the presence of macrolide (i.e., erm genes) and tetracycline (i.e., tet genes) resistance markers in the vaginal environment of Caucasian women at different gestational ages. Furthermore, the detection of resistance genes was related to the composition of the vaginal microbiota. A total of 228 vaginal samples, collected at different trimesters of pregnancy or during the puerperium, were tested for the presence of ermB, ermF, tet(W), and tet(M) by in-house end-point PCR assays. The composition of the vaginal microbiota was assessed through a microscopic evaluation (i.e., Nugent score) and by means of sequencing V3-V4 hypervariable regions of the bacterial 16 rRNA gene. Overall, the most detected resistance gene was tet(M) (76.7%), followed by ermB (55.2%). In 17% of women, mainly with a 'normal' vaginal microbiota, no resistance genes were found. Except for tet(W), a significant correlation between the positivity of resistance genes and a dysbiotic vaginal status (i.e., bacterial vaginosis (BV)) was noticed. Indeed, samples positive for at least one resistance determinant were characterized by a decrease in Lactobacillus spp. and an increase of BV-related genera (Prevotella, Gardnerella, Atopobium, Sneathia). A high predominance of vaginal Lactobacillus spp. (>85%) was associated with a lower risk of tet(W) gene detection, whereas the presence of Megasphaera (>1%) increased the risk of positivity for all analyzed genes. Different types of vaginal microbiota are associated with peculiar resistance profiles, being a lactobacilli-dominated ecosystem poor in or free of resistance genes. These data could open new perspectives for promoting maternal and neonatal health.	Pathogens 10 (2021).	2021	CECCARANI CAMILLA, CAMBONI TANIA, CONSOLANDI CLARISSA, SEVERGNINI MARCO	Macrolide, Pregnancy, Resistance genes, Tetracyclines, Vaginal microbiome, Women's health	10.3390/pathogens10121546
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
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
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
453346	Articolo in rivista	Association Between Smoking and SARS-CoV-2 Infection: Cross-sectional Study of the EPICOVID19 Internet-Based Survey.	Prinelli F, Bianchi F, Drago G, Ruggieri S, Sojic A, Jesuthasan N, Molinaro S, Bastiani L, Maggi S, Noale M, Galli M, Giacomelli A, Antonelli Incalzi R, Adorni F, Cibella F	BACKGROUND: Several studies have reported a low prevalence of current smoking among hospitalized COVID-19 cases; however, no definitive conclusions can be drawn. OBJECTIVE: We investigated the association of tobacco smoke exposure with nasopharyngeal swab (NPS) test results for SARS-CoV-2 infection and disease severity accounting for possible confounders. METHODS: The nationwide, self-administered, cross-sectional web-based Italian National Epidemiological Survey on COVID-19 (EPICOVID19) was administered to an Italian population of 198,822 adult volunteers who filled in an online questionnaire between April 13 and June 2, 2020. For this study, we analyzed 6857 individuals with known NPS test results. The associations of smoking status and the dose-response relationship with a positive NPS test result and infection severity were calculated as odds ratios (ORs) with 95% CIs by means of logistic and multinomial regression models adjusting for sociodemographic, clinical, and behavioral characteristics. RESULTS: Out of the 6857 individuals (mean age 47.9 years, SD 14.1; 4516/6857, 65.9% female), 63.2% (4334/6857) had never smoked, 21.3% (1463/6857) were former smokers, and 15.5% (1060/6857) were current smokers. Compared to nonsmokers, current smokers were younger, were more educated, were less affected by chronic diseases, reported COVID-19-like symptoms less frequently, were less frequently hospitalized, and less frequently tested positive for COVID-19. In multivariate analysis, current smokers had almost half the odds of a positive NPS test result (OR 0.54, 95% CI 0.45-0.65) compared to nonsmokers. We also found a dose-dependent relationship with tobacco smoke: mild smokers (adjusted OR [aOR] 0.76, 95% CI 0.55-1.05), moderate smokers (aOR 0.56, 95% CI 0.42-0.73), and heavy smokers (aOR 0.38, 95% CI 0.27-0.53). This inverse association also persisted when considering the severity of the infection. Current smokers had a statistically significantly lower probability of having asymptomatic (aOR 0.50, 95% CI 0.27-0.92), mild (aOR 0.65, 95% CI 0.53-0.81), and severe infections (aOR 0.27, 95% CI 0.17-0.42) compared to those who never smoked. CONCLUSIONS: Current smoking was negatively associated with SARS-CoV-2 infection with a dose-dependent relationship. Ad hoc experimental studies are needed to elucidate the mechanisms underlying this association.	JMIR public health and surveillance Online 7 (2021): 1-17.	2021	JESUTHASAN NITHIYA, SOJIC ALEKSANDRA, DRAGO GASPARE, RUGGIERI SILVIA, BIANCHI FABRIZIO, MAGGI STEFANIA, NOALE MARIANNA, MOLINARO SABRINA, ADORNI FULVIO DANIELE, BASTIANI LUCA, PRINELLI FEDERICA, CIBELLA FABIO	SARS-CoV-2, COVID-19, smoking habit, dose-response relationship, nasopharyngeal swab testing, infection severity, web-based survey, self-reported, cross-sectional design	10.2196/27091
449432	Articolo in rivista	Age-Related Changes in Clinical Presentation of Covid-19: the EPICOVID19 Web-Based Survey	Trevisan, Caterina, Noale, Marianna, Prinelli, Federica, Maggi, Stefania, Sojic, Aleksandra, Di Bari, Mauro, Molinaro, Sabrina, Bastiani, Luca, Andrea Giacomelli, Andrea, Galli, Massimo, Adorni, Fulvio, Antonelli Incalzi, Raffaele, Pedone, Claudio	Background: The influence of aging and multimorbidity on Covid-19 clinical presentation is still unclear. Objectives: We investigated whether the association between symptoms (or cluster of symptoms) and positive SARS-CoV-2 nasopharyngeal swab (NPS) was different according to patients' age and presence of multimorbidity. Methods: The study included 6680 participants in the EPICOVID19 web-based survey, who reported information about symptoms from February to June 2020 and who underwent at least one NPS. Symptom clusters were identified through hierarchical cluster analysis. The associations between symptoms (and clusters of symptoms) and positive NPS were investigated through multivariable binary logistic regression in the sample stratified by age (<65 vs >=65 years) and number of chronic diseases (0 vs 1 vs >=2). Results: The direct association between taste/smell disorders and positive NPS was weaker in older and multimorbid patients than in their younger and healthier counterparts. Having reported no symptoms reduced the chance of positive NPS by 86% in younger (95%CI: 0.11-0.18), and by 46% in older participants (95%CI: 0.37-0.79). Of the four symptom clusters identified (asymptomatic, generic, flu-like, and combined generic and flu-like symptoms), those associated with a higher probability of SARS-CoV-2 infection were the flu-like for older people, and the combined generic and flu-like for the younger ones. Conclusions: Older age and pre-existing chronic diseases may influence the clinical presentation of Covid-19. Symptoms at disease onset tend to aggregate differently by age. New diagnostic algorithms considering age and chronic conditions may ease Covid-19 diagnosis and optimize health resources allocation.	European journal of internal medicine (Leic.) 86 (2021): 41-47.	2021	SOJIC ALEKSANDRA, MAGGI STEFANIA, NOALE MARIANNA, MOLINARO SABRINA, ADORNI FULVIO DANIELE, BASTIANI LUCA, PRINELLI FEDERICA	Aged, COVID-19, Differential Diagnosis, Multimorbidity, SARS-CoV-2	10.1016/j.ejim.2021.01.028
457994	Articolo in rivista	Highly differentiated soil bacterial communities in Victoria Land macro-areas (Antarctica)	Severgnini, Marco, Canini, Fabiana, Consolandi, Clarissa, Camboni, Tania, Paolo D'Acqui, Luigi, Mascalchi, Cristina, Ventura, Stefano, Zucconi, Laura	Ice-free areas of Victoria Land, in Antarctica, are characterized by different terrestrial ecosystems, that are dominated by microorganisms supporting highly adapted communities. Despite the unique conditions of these ecosystems, reports on their bacterial diversity are still fragmentary. From this perspective, 60 samples from 14 localities were analyzed. These localities were distributed in coastal sites with differently developed biological soil crusts, inner sites in the McMurdo Dry Valleys with soils lacking of plant coverage, and a site called Icarus Camp, with a crust developed on a thin locally weathered substrate of the underlying parent granitic-rock. Bacterial diversity was studied through 16S rRNA metabarcoding sequencing. Communities diversity, composition and the abundance and composition of different taxonomic groups were correlated to soil physicochemical characteristics. Firmicutes, Bacteroidetes, Cyanobacteria and Proteobacteria dominated these communities. Most phyla were mainly driven by soil granulometry, an often disregarded parameter and other abiotic parameters. Bacterial composition differed greatly among the three macrohabitats, each having a distinct bacterial profile. Communities within the two main habitats (coastal and inner ones) were well differentiated from each other as well, therefore depending on site-specific physicochemical characteristics. A core community of the whole samples was observed, mainly represented by Firmicutes and Bacteroidetes.	FEMS microbiology, ecology (print) 97 (2021).	2021	CAMBONI TANIA, D'ACQUI LUIGI PAOLO, MASCALCHI CRISTINA, CONSOLANDI CLARISSA, SEVERGNINI MARCO, VENTURA STEFANO	16S, edaphic parameters, environmental filtering, metabarcoding, soil communities, Victoria Land	10.1093/femsec/fiab087
458731	Articolo in rivista	Burden of rare coding variants in an Italian cohort of familial multiple sclerosis	Mascia E*1, Clarelli F*1, Zauli A1, Guaschino C1, 2, Sorosina M1, Barizzone N3, Basagni C3, Santoro S1, Ferre L1, 4, Bonfiglio S5, Biancolini D5, Pozzato M6, Guerini FR7, Protti A8, Liguori M9, Moiola L4, Vecchio D10, Bresolin N11, Comi G 12, Filippi M4, 13-15, Esposito F1, 4, D'Alfonso S3, Martinelli-Boneschi F**1, 6, 11	Background: Multiple Sclerosis (MS) is a chronic inflammatory and neurodegenerative demyelinating disease of the central nervous system. It is a complex and heterogeneous disease caused by a combination of genetic and environmental factors, and it can cluster in families. Objective: to evaluate at gene-level the aggregate contribution of predicted damaging low-frequency and rare variants to MS risk in multiplex families Methods: we performed whole exome sequencing (WES) in 28 multiplex MS families with at least 3 MS cases (81 affected and 42 unaffected relatives) and 38 unrelated healthy controls. A gene-based burden test was then performed, focusing on two sets of candidate genes: i) literature-driven selection and ii) data-driven selection. Results: We identified 11 genes enriched with predicted damaging low-frequency and rare variants in MS compared to healthy individuals. Among them, UBR2 and DST were the two genes with the strongest enrichment (p=5x10-4 and 3x10-4, respectively); interestingly enough the association signal in UBR2 is driven by rs62414610, which was present in 25% of analysed families. Conclusion: Despite limitations, this is one of the first studies evaluating the aggregate contribution of predicted damaging low-frequency and rare variants in MS families using WES data. A replication effort in independent cohorts is warranted to validate our findings and to evaluate the role of identified genes in MS pathogenesis.	Journal of neuroimmunology (Online) (2022).	2022	LIGUORI MARIA	Multiple Sclerosis; family-based study; candidate gene; rare variants; burden test.	10.1016/j.jneuroim.2021.577760
461825	Articolo in rivista	Development and preliminary testing of a system for the multimodal analysis of gait training n a virtual reality environment	Piazza, Caterina, Pirovano, Ileana, Mastropietro, Alfonso, Genova, Chiara, Gagliardi, Chiara, Turconi, Anna Carla, Malerba, Giorgia, Panzeri, Daniele, Maghini, Cristina, Reni, Gianluigi, Rizzo, Giovanna, Biffi, Emilia	Gait training in a virtual reality (VR) environment is promising for children affected by different disorders. However, the efficacy of VR therapy is still under debate, and more research is needed to clarify its effects on clinical conditions. The combination of VR with neuroimaging methods, such as the electroencephalography (EEG), might help in answering this need. The aim of the present work was to set up and test a system for the multimodal analysis of the gait pattern during VR gait training of pediatric populations by analyzing the EEG correlates as well as the kinematic and kinetic parameters of the gait. An EEG system was integrated with the Gait Real-time Analysis Interactive Lab (GRAIL). We developed and validated, with healthy adults (n = 5) and children (n = 4, healthy or affected by cerebral palsy (CP)), the hardware and software integration of the two systems, which allowed the synchronization of the acquired signals and a reliable identification of the initial contact (IC) of each gait cycle, showing good sensitivity and critical success index values. Moreover, we tested the multimodal acquisition by successfully analyzing EEG data and kinematic and kinetic parameters of one healthy child and one child with CP. This system gives the possibility of monitoring the effect of the VR therapy and studying the neural correlates of gait.	Electronics (Basel) 10 (2021).	2021	PIROVANO ILEANA, RIZZO GIOVANNA, MASTROPIETRO ALFONSO	EEG, Gait analysis, Gait rehabilitation, Multimodal acquisition, Virtual reality	10.3390/electronics10222838
461826	Articolo in rivista	A multi-domain ontology on healthy ageing for the characterization of older adults status and behaviour	Mastropietro A., Palumbo F., Orte S., Girolami M., Furfari F., Baronti P., Candea C., Roecke C., Tarro L., Sykora M., Porcelli S., Rizzo G.	Ageing is a multi-factorial physiological process and the development of novel IoT systems, tools and devices, specifically targeted to older people, must be based on a holistic framework built on robust scientific knowledge in different health domains. Furthermore, interoperability must be guaranteed using standardized frameworks or approaches. These aspects still largely lack in the specific literature. The main aim of the paper is to develop a new ontology (the NESTORE ontology) to extend the available ontologies provided by universAAL-IoT (uAAL-IoT). The ontology is based on a multidomain healthy ageing holistic model, structuring well-assessed scientific knowledge, specifically targeted to healthy older adults aged between 65 and 75. The tool is intended to support, and standardize heterogeneous data about ageing in compliance with the uAAL-IoT framework. The NESTORE ontology covers all the relevant concepts to represent 3 significant domains of ageing: (1) Physiological Status and Physical Activity Behaviour; (2) Nutrition; and (3) Cognitive and Mental Status and Social Behaviour. In total, 12 sub-ontologies were modelled with more than 60 classes and sub-classes referenced among them by using more than 100 relations and around 20 enumerations. The proposed ontology increases the uAAL collection by 40%. NESTORE ontology provides innovation both in terms of semantic content and technological approach. The thorough use of this ontology can support the development of a decision support system, to promote healthy ageing, with the capacity to do dynamic multi-scale modelling of user-specific data based on the semantic annotations of users' profile.	Journal of ambient intelligence & humanized computing (Print) (2021).	2021	RIZZO GIOVANNA, FURFARI FRANCESCO, BARONTI PAOLO, GIROLAMI MICHELE, PORCELLI SIMONE, PALUMBO FILIPPO, MASTROPIETRO ALFONSO	Cognition, Healthy ageing model, Knowledge representation and reasoning, Nutrition, Ontology, OWL, Physical activity, Social behaviour	10.1007/s12652-021-03627-6
461827	Contributo in atti di convegno	Assessment of muscular sustained fatigue: A TD-NIRS and sEMG study	Re, R., Scano, A., Pirovano, I., Manunza, M. E., Spinelli, L., Contini, D., Torricelli, A.	We assess the muscular fatigue during sustained exercises with both sEMG and TD-NIRS. We found that during the "slow" phase of TD-NIRS signal, the best fatigue biomarkers are: MF, O2Hb, HHb and SO2.	European Conference on Biomedical Optics, 20/06/2021	2021	PIROVANO ILEANA, SPINELLI LORENZO CLEMENTE, SCANO ALESSANDRO	NIRS, fatigue, EMG, muscle, sustained, TD-NIRS
461828	Contributo in atti di convegno	Rehabilitation monitoring after bed rest in elderly: TD-NIRS and sEMG preliminary study	Pirovano, I., Laurini, A., Tomba, A., Scano, A., Re, R., Caserta, A., Spinelli, L., Contini, D., Cubeddu, R., Panella, L., Torricelli, A.	We report on a preliminary longitudinal study on 21 elderly patients to non-invasively quantify rehabilitation outcomes in skeletal muscle after bed-rest by a combined approach based on TD-NIRS (for hemodynamics) and sEMG (for myoelectric recordings).	European Conferences on Biomedical Optics, 20/06/2021	2021	PIROVANO ILEANA, SPINELLI LORENZO CLEMENTE, SCANO ALESSANDRO	NIRS, TD-NIRS, EMG, muscle, rehabilitation, patients, sarcopenia
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
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
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
455673	Articolo in rivista	A Multi-Variate framework to assess reliability and discrimination power of Bayesian estimation of Intravoxel Incoherent Motion parameters	E. Scalco, A. Mastropietro, A. Bodini, S. Marzi, G. Rizzo	Purpose: To propose a multivariate multi-step framework for a systematic assessment of the estimation reliability and discriminability of Intravoxel Incoherent Motion (IVIM) model parameters. Methods: Monte-Carlo simulations were generated on a range of SNRs and in different IVIM combinations considering: i) a dense discretization with 24 b-values; ii) a discretization with 9 b-values. A state-of-the-art Bayesian fitting method was adopted. The framework assessed: i) the best model between mono- and bi-exponential, through the BIC index; ii) the fitting accuracy; iii) the power in discriminating two different IVIM parameters distributions of estimated coefficients, using a multivariate test. Exemplificative oncologic cases were also presented. Results: The bi-exponential fitting was reliable for perfusion fraction higher than 5%, with high accuracy in D estimation, acceptable error for f, but high uncertainty in D*. The discrimination of two distributions is generally feasible if differences in D values (at least 0.3 x10^(-3) mm^2 /s) are present; in the case of similar D values, a minimal difference of 5% in f can be discriminated just in case of balanced sample size and dense b-values discretization, whereas the impact of D* is quite negligible. These results were also supported by clinical examples. Conclusions: IVIM model is generally accurate in estimating diffusion, but uncertainties related to perfusion estimation are not negligible and compromise the discrimination power when different populations should be differentiated. The proposed framework should be adopted as interpretative guidelines to better understand when IVIM model applied on real data can provide reliable findings.	Physica medica (Online) 89 (2021): 11-19.	2021	RIZZO GIOVANNA, BODINI ANTONELLA, SCALCO ELISA, MASTROPIETRO ALFONSO	Bayesian fitting, IVIM-MRI, multivariate distribution, model selection, Monte Carlo simulations	10.1016/j.ejmp.2021.07.025
457879	Articolo in rivista	Accessibility to SARS-CoV-2 swab test during the Covid-19 pandemic: Did age make the difference?	Trevisan, Caterina, Pedone, Claudio, Maggi, Stefania, Noale, Marianna, Di Bari, Mauro, Sojic, Aleksandra, Molinaro, Sabrina, Giacomelli, Andrea, Bianchi, Fabrizio, Tavio, Marcello, Rusconi, Stefano, Pagani, Gabriele, Galli, Massimo, Prinelli, Federica, Adorni, Fulvio, Antonelli Incalzi, Raffaele	Although COVID-19 affects older people more severely, health policies during the first wave of the pandemic often prioritized younger individuals. We investigated whether age had influenced the access to a diagnostic test for SARS-CoV-2 infection and whether clinical complexity and healthcare resources availability could have impacted such differences. This work included 126,741 Italian participants in the EPICOVID19 web-based survey, who reported having had contacts with known/suspected COVID-19 cases (epidemiological criterion) and/or COVID-19-like signs/symptoms (clinical criterion) from February to June 2020. Data on sociodemographic, medical history and access to SARS-CoV-2 nasopharyngeal swab (NPS) were collected. Logistic regressions estimated the probability of accessing NPS as a function of age and the possible modifying effect of chronic diseases' number and residential areas in such association. A total of 6136 (4.8%) participants had undergone an NPS. Older participants had lower NPS frequencies than the younger ones when reporting epidemiological (14.9% vs. 8.8%) or both epidemiological and clinical criteria (17.5% vs. 13.7%). After adjustment for potential confounders, including epidemiological and clinical criteria, the chance of NPS access decreased by 29% (OR=0.71, 95%CI:0.63-0.79) in older vs. younger individuals. Such disparity was accentuated in areas with greater healthcare resources. In conclusion, in the first wave of the pandemic, age may have affected the access to COVID-19 diagnostic testing, disadvantaging older people.	Health policy (Amst. Print) (2021).	2021	SOJIC ALEKSANDRA, BIANCHI FABRIZIO, MAGGI STEFANIA, NOALE MARIANNA, MOLINARO SABRINA, ADORNI FULVIO DANIELE, PRINELLI FEDERICA	Ageism, COVID-19 diagnostic testing, Health Resources, Multimorbidity	10.1016/j.healthpol.2021.10.002
459975	Articolo in rivista	Transmembrane Protein TMEM230, a Target of Glioblastoma Therapy	Cinzia Cocola1, 2+, Valerio Magnaghi3+, Edoardo Abeni1+, Paride Pelucchi1?, Valentina Martino1?, Laura Vilardo1, Eleonora Piscitelli1, Arianna Consiglio1, Giorgio Grillo1, Ettore Mosca1, Roberta Gualtierotti4, Daniela Mazzaccaro5, Gina La Sala6, Chiara Di Pietro6, Mira Palizban7, Sabino Liuni1, Giuseppina DePedro8, Stefano Morara9, Giovanni Nano5, 10, James Kehler11, Burkhard Greve12, Alessio Noghero13, 14, Daniela Marazziti6, Federico Bussolino14, 15, Gianfranco Bellipanni16, Igea D'Agnano1, Martin Gotte7, Ileana Zucchi1*, Rolland Reinbold1*	Glioblastomas (GBM) are the most aggressive tumors originating in the brain. Histopathologic features include circuitous, disorganized, and highly permeable blood vessels with intermittent blood flow. These features contribute to the inability to direct therapeutic agents to tumor cells. Known targets for anti-angiogenic therapies provide minimal or no effect in overall survival of 12-15 months following diagnosis. Identification of novel targets therefore remains an important goal for effective treatment of highly vascularized tumors such as GBM. We previously demonstrated in zebrafish that a balanced level of expression of the transmembrane protein TMEM230/C20ORF30 was required to maintain normal blood vessel structural integrity and promote proper vessel network formation. To investigate whether TMEM230 has a role in the pathogenesis of GBM, we analyzed its prognostic value in patient tumor gene expression datasets and performed cell functional analysis. TMEM230 was found necessary for growth of U87-MG cells, a model of human GBM. Downregulation of TMEM230 resulted in loss of U87 migration, substratum adhesion, and re-passaging capacity. Conditioned media from U87 expressing endogenous TMEM230 induced sprouting and tubule-like structure formation of HUVECs. Moreover, TMEM230 promoted vascular mimicry-like behavior of U87 cells. Gene expression analysis of 702 patients identified that TMEM230 expression levels distinguished high from low grade gliomas. Transcriptomic analysis of patients with gliomas revealed molecular pathways consistent with properties observed in U87 cell assays. Within low grade gliomas, elevated TMEM230 expression levels correlated with reduced overall survival independent from tumor subtype. Highest level of TMEM230 correlated with glioblastoma and ATP-dependent microtubule kinesin motor activity, providing a direction for future therapeutic intervention. Our studies support that TMEM230 has both glial tumor and endothelial cell intracellular and extracellular functions. Elevated levels of TMEM230 promote glial tumor cell migration, extracellular scaffold remodeling, and hypervascularization and abnormal formation of blood vessels. Downregulation of TMEM230 expression may inhibit both low grade glioma and glioblastoma tumor progression and promote normalization of abnormally formed blood vessels. TMEM230 therefore is both a promising anticancer and antiangiogenic therapeutic target for inhibiting GBM tumor cells and tumor-driven angiogenesis.	Frontiers in cellular neuroscience (2021).	2021	PISCITELLI ELEONORA, COCOLA CINZIA, MARTINO VALENTINA, ABENI EDOARDO, LIUNI SABINO, ZUCCHI ILEANA, GRILLO GIORGIO, DI PIETRO CHIARA, PELUCCHI PARIDE, MOSCA ETTORE, LA SALA GINA, CONSIGLIO ARIANNA, REINBOLD ROLLAND ALVONS, VILARDO LAURA, D'AGNANO IGEA, MORARA STEFANO, MARAZZITI DANIELA	cargo vesicle transport, angiogenesis and normalization of vascular network, tumor cell migration and adhesion, anticancer and antiangiogenic theraglioma, kinesin motor proteinspy	10.3389/fncel.2021.703431
463481	Articolo in rivista	Dancing With Parkinson's Disease: The SI-ROBOTICS Study Protocol	Bevilacqua, Roberta, Benadduci, Marco, Bonfigli, Anna Rita, Riccardi, Giovanni Renato, Melone, Giovanni, La Forgia, Angela, Macchiarulo, Nicola, Rossetti, Luca, Marzorati, Mauro, Rizzo, Giovanna, Di Bitonto, Pierpaolo, Potenza, Ada, Fiorini, Laura, Cortellessa Loizzo, Federica Gabriella, La Viola, Carlo, Cavallo, Filippo, Leone, Alessandro, Rescio, Gabriele, Caroppo, Andrea, Manni, Andrea, Cesta, Amedeo, Cortellessa, Gabriella, Fracasso, Francesca, Orlandini, Andrea, Umbrico, Alessandro, Rossi, Lorena, Maranesi, Elvira	Introduction: Parkinson's disease (PD) is one of the most frequent causes of disability among older people, characterized by motor disorders, rigidity, and balance problems. Recently, dance has started to be considered an effective exercise for people with PD. In particular, Irish dancing, along with tango and different forms of modern dance, may be a valid strategy to motivate people with PD to perform physical activity. The present protocol aims to implement and evaluate a rehabilitation program based on a new system called "SI-ROBOTICS," composed of multiple technological components, such as a social robotic platform embedded with an artificial vision setting, a dance-based game, environmental and wearable sensors, and an advanced AI reasoner module. Methods and Analysis: For this study, 20 patients with PD will be recruited. Sixteen therapy sessions of 50 min will be conducted (two training sessions per week, for 8 weeks), involving two patients at a time. Evaluation will be primarily focused on the acceptability of the SI-ROBOTICS system. Moreover, the analysis of the impact on the patients' functional status, gait, balance, fear of falling, cardio-respiratory performance, motor symptoms related to PD, and quality of life, will be considered as secondary outcomes. The trial will start in November 2021 and is expected to end by April 2022. Discussions: The study aims to propose and evaluate a new approach in PD rehabilitation, focused on the use of Irish dancing, together with a new technological system focused on helping the patient perform the dance steps and on collecting kinematic and performance parameters used both by the physiotherapist (for the evaluation and planning of the subsequent sessions) and by the system (to outline the levels of difficulty of the exercise). Ethics and Dissemination: The study was approved by the Ethics Committee of the IRCCS INRCA. It was recorded in ClinicalTrials.gov on the number NCT05005208. The study findings will be used for publication in peer-reviewed scientific journals and presentations in scientific meetings.	Frontiers in public health 9 (2021).	2021	UMBRICO ALESSANDRO, MANNI ANDREA, RIZZO GIOVANNA, MARZORATI MAURO, CORTELLESSA GABRIELLA, LEONE ALESSANDRO, ORLANDINI ANDREA, FRACASSO FRANCESCA, RESCIO GABRIELE, CAROPPO ANDREA, CESTA AMEDEO	balance, gait, Irish dance, older people, Parkinson's disease, rehabilitation, social assistive robotics, technology acceptance	10.3389/fpubh.2021.780098