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5. Looking for central tendencies in the conformational freedom of proteins using NMR measurements

Author

Clarelli, F. and Sgheri, L.

Subjects
Quantitative Biology - Biomolecules, 92D20, 92E10
Abstract

We study the conformational freedom of a protein made by two rigid domains connected by a flexible linker. The conformational freedom is represented as an unknown probability distribution on the space of allowed states. A new algorithm for the calculation of the Maximum Allowable Probability is proposed, which can be extended to any type of measurements. In this paper we use Pseudo Contact Shifts and Residual Dipolar Coupling. We reconstruct a single central tendency in the distribution and discuss in depth the results.

Published
2016
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6. A Free-Boundary Model of Corrosion

Author

Clarelli, F., De Filippo, B., Natalini, R., Bock, Hans Georg, Series editor, de Hoog, Frank, Series editor, Friedman, Avner, Series editor, Gupta, Arvind, Series editor, Nachbin, André, Series editor, Ozawa, Tohru, Series editor, Pulleyblank, William R., Series editor, Rusten, Torgeir, Series editor, Santosa, Fadil, Series editor, Seo, Jin Keun, Series editor, Tornberg, Anna-Karin, Series editor, Russo, Giovanni, editor, Capasso, Vincenzo, editor, Nicosia, Giuseppe, editor, and Romano, Vittorio, editor

Published
2016
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9. Locus for severity implicates CNS resilience in progression of multiple sclerosis

Author

Harroud, A, Stridh, PJ, McCauley, JH, Saarela, J, van den Bosch, AMR, Engelenburg, H, Beecham, A, Alfredsson, L, Alikhani, K, Amezcua, L, Andlauer, TFM, Ban, M, Barcellos, L, Barizzone, N, Berge, T, Berthele, A, Bittner, S, Bos, S, Briggs, FBS, Caillier, S, Calabresi, P, Caputo, D, Carmona-Burgos, D, Cavalla, P, Celius, E, Cerono, G, Chinea, A, Chitnis, T, Clarelli, F, Comabella, M, Comi, G, Cotsapas, C, Cree, BCA, D'Alfonso, S, Dardiotis, E, De Jager, P, Delgado, S, Dubois, B, Engel, S, Esposito, F, Fabis-Pedrini, M, Filippi, M, Fitzgerald, K, Gasperi, C, Gomez, L, Gomez, R, Hadjigeorgiou, G, Hamann, J, Held, F, Henry, R, Hillert, J, Huang, J, Huitinga, I, Islam, T, Isobe, N, Jagodic, M, Kermode, AL, Khalil, M, Kilpatrick, T, Konidari, I, Kreft, K, Lechner-Scott, J, Leone, M, Luessi, F, Malhotra, S, Manouchehrinia, A, Manrique, C, Martinelli-Boneschi, F, Martinez, A, Martinez-Maldonado, V, Mascia, E, Metz, L, Midaglia, L, Montalban, X, Oksenberg, J, Olsson, T, Oturai, A, Paakkonen, K, Parnell, GP, Patsopoulos, N, Pericak-Vance, M, Piehl, F, Rubio, J, Santaniello, A, Santoro, S, Schaefer, C, Sellebjerg, F, Shams, H, Shchetynsky, K, Silva, C, Siokas, V, Sondergaard, H, Sorosina, M, Taylor, B, Vandebergh, M, Vasileiou, E, Vecchio, D, Voortman, M, Weiner, H, Wever, D, Yong, VW, Hafler, D, Stewart, G, Compston, A, Zipp, F, Harbo, H, Hemmer, B, Goris, A, Smolders, J, Hauser, S, Kockum, I, Sawcer, S, Baranzini, S, Jonsdottir, I, Blanco, Y, Llufriu, S, Madireddy, L, Saiz, A, Villoslada, P, Stefansson, K, Harbo, HF, Sawcer, SJ, Baranzini, SE, Harroud, A, Stridh, PJ, McCauley, JH, Saarela, J, van den Bosch, AMR, Engelenburg, H, Beecham, A, Alfredsson, L, Alikhani, K, Amezcua, L, Andlauer, TFM, Ban, M, Barcellos, L, Barizzone, N, Berge, T, Berthele, A, Bittner, S, Bos, S, Briggs, FBS, Caillier, S, Calabresi, P, Caputo, D, Carmona-Burgos, D, Cavalla, P, Celius, E, Cerono, G, Chinea, A, Chitnis, T, Clarelli, F, Comabella, M, Comi, G, Cotsapas, C, Cree, BCA, D'Alfonso, S, Dardiotis, E, De Jager, P, Delgado, S, Dubois, B, Engel, S, Esposito, F, Fabis-Pedrini, M, Filippi, M, Fitzgerald, K, Gasperi, C, Gomez, L, Gomez, R, Hadjigeorgiou, G, Hamann, J, Held, F, Henry, R, Hillert, J, Huang, J, Huitinga, I, Islam, T, Isobe, N, Jagodic, M, Kermode, AL, Khalil, M, Kilpatrick, T, Konidari, I, Kreft, K, Lechner-Scott, J, Leone, M, Luessi, F, Malhotra, S, Manouchehrinia, A, Manrique, C, Martinelli-Boneschi, F, Martinez, A, Martinez-Maldonado, V, Mascia, E, Metz, L, Midaglia, L, Montalban, X, Oksenberg, J, Olsson, T, Oturai, A, Paakkonen, K, Parnell, GP, Patsopoulos, N, Pericak-Vance, M, Piehl, F, Rubio, J, Santaniello, A, Santoro, S, Schaefer, C, Sellebjerg, F, Shams, H, Shchetynsky, K, Silva, C, Siokas, V, Sondergaard, H, Sorosina, M, Taylor, B, Vandebergh, M, Vasileiou, E, Vecchio, D, Voortman, M, Weiner, H, Wever, D, Yong, VW, Hafler, D, Stewart, G, Compston, A, Zipp, F, Harbo, H, Hemmer, B, Goris, A, Smolders, J, Hauser, S, Kockum, I, Sawcer, S, Baranzini, S, Jonsdottir, I, Blanco, Y, Llufriu, S, Madireddy, L, Saiz, A, Villoslada, P, Stefansson, K, Harbo, HF, Sawcer, SJ, and Baranzini, SE

Abstract

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) that results in significant neurodegeneration in the majority of those affected and is a common cause of chronic neurological disability in young adults1,2. Here, to provide insight into the potential mechanisms involved in progression, we conducted a genome-wide association study of the age-related MS severity score in 12,584 cases and replicated our findings in a further 9,805 cases. We identified a significant association with rs10191329 in the DYSF-ZNF638 locus, the risk allele of which is associated with a shortening in the median time to requiring a walking aid of a median of 3.7 years in homozygous carriers and with increased brainstem and cortical pathology in brain tissue. We also identified suggestive association with rs149097173 in the DNM3-PIGC locus and significant heritability enrichment in CNS tissues. Mendelian randomization analyses suggested a potential protective role for higher educational attainment. In contrast to immune-driven susceptibility3, these findings suggest a key role for CNS resilience and potentially neurocognitive reserve in determining outcome in MS.

Published
2023

13. An Investigation of the Role of Common and Rare Variants in a Large Italian Multiplex Family of Multiple Sclerosis Patients

Author

Barizzone, N, Cagliani, R, Basagni, C, Clarelli, F, Mendozzi, L, Agliardi, C, Forni, D, Tosi, M, Mascia, E, Favero, F, Cora, D, Corrado, L, Sorosina, M, Esposito, F, Zuccala, M, Vecchio, D, Liguori, M, Comi, C, Comi, G, Martinelli, V, Filippi, M, Leone, M, Martinelli-Boneschi, F, Caputo, D, Sironi, M, Guerini, F, D'Alfonso, S, Barizzone N, Cagliani R, Basagni C, Clarelli F, Mendozzi L, Agliardi C, Forni D, Tosi M, Mascia E, Favero F, Cora D, Corrado L, Sorosina M, Esposito F, Zuccala M, Vecchio D, Liguori M, Comi C, Comi G, Martinelli V, Filippi M, Leone M, Martinelli-Boneschi F, Caputo D, Sironi M, Guerini FR, D'Alfonso S, Barizzone, N, Cagliani, R, Basagni, C, Clarelli, F, Mendozzi, L, Agliardi, C, Forni, D, Tosi, M, Mascia, E, Favero, F, Cora, D, Corrado, L, Sorosina, M, Esposito, F, Zuccala, M, Vecchio, D, Liguori, M, Comi, C, Comi, G, Martinelli, V, Filippi, M, Leone, M, Martinelli-Boneschi, F, Caputo, D, Sironi, M, Guerini, F, D'Alfonso, S, Barizzone N, Cagliani R, Basagni C, Clarelli F, Mendozzi L, Agliardi C, Forni D, Tosi M, Mascia E, Favero F, Cora D, Corrado L, Sorosina M, Esposito F, Zuccala M, Vecchio D, Liguori M, Comi C, Comi G, Martinelli V, Filippi M, Leone M, Martinelli-Boneschi F, Caputo D, Sironi M, Guerini FR, and D'Alfonso S

Abstract

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.

Published
2021

15. Response to interferon-beta treatment in multiple sclerosis patients: a genome-wide association study

Author

Mahurkar, S, Moldovan, M, Suppiah, V, Sorosina, M, Clarelli, F, Liberatore, G, Malhotra, S, Montalban, X, Antigüedad, A, Krupa, M, Jokubaitis, V G, McKay, F C, Gatt, P N, Fabis-Pedrini, M J, Martinelli, V, Comi, G, Lechner-Scott, J, Kermode, A G, Slee, M, Taylor, B V, Vandenbroeck, K, Comabella, M, Boneschi, F M, Australian, The, and King, C

Published
2016
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17. Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility

Author

Patsopoulos, NA, Baranzini, SE, Santaniello, A, Shoostari, P, Cotsapas, C, Wong, G, Beecham, AH, James, T, Replogle, J, Vlachos, IS, McCabe, C, Pers, TH, Brandes, A, White, C, Keenan, B, Cimpean, M, Winn, P, Panteliadis, IP, Robbins, A, Andlauer, TFM, Zarzycki, O, Dubois, B, Goris, A, Sondergaard, HB, Sellebjerg, F, Sorensen, PS, Ullum, H, Thorner, LW, Saarela, J, Cournu-Rebeix, I, Damotte, V, Fontaine, B, Guillot-Noel, L, Lathrop, M, Vukusic, S, Berthele, A, Pongratz, V, Gasperi, C, Graetz, C, Grummel, V, Hemmer, B, Hoshi, M, Knier, B, Korn, T, Lill, CM, Luessi, F, Muhlau, M, Zipp, F, Dardiotis, E, Agliardi, C, Amoroso, A, Barizzone, N, Benedetti, MD, Bernardinelli, L, Cavalla, P, Clarelli, F, Comi, G, Cusi, D, Esposito, F, Ferre, L, Galimberti, D, Guaschino, C, Leone, MA, Martinelli, V, Moiola, L, Salvetti, M, Sorosina, M, Vecchio, D, Zauli, A, Santoro, S, Mancini, N, Zuccala, M, Mescheriakova, J, van Duijn, C, Bos, SD, Celius, EG, Spurkland, A, Comabella, M, Montalban, X, Alfredsson, L, Bomfim, IL, Gomez-Cabrero, D, Hillert, J, Jagodic, M, Linden, M, Piehl, F, Jelcic, I, Martin, R, Sospedra, M, Baker, A, Ban, M, Hawkins, C, Hysi, P, Kalra, S, Karpe, F, Khadake, J, Lachance, G, Molyneux, P, Neville, M, Thorpe, J, Bradshaw, E, Caillier, SJ, Calabresi, P, Cree, BAC, Cross, A, Davis, M, de Bakker, PWI, Delgado, S, Dembele, M, Edwards, K, Fitzgerald, K, Frohlich, IY, Gourraud, PA, Haines, JL, Hakonarson, H, Kimbrough, D, Isobe, N, Konidari, I, Lathi, E, Lee, MH, Li, T, An, D, Zimmer, A, Madireddy, L, Manrique, CP, Mitrovic, M, Olah, M, Patrick, E, Pericak-Vance, MA, Piccio, L, Schaefer, C, Weiner, H, Lage, K, Scott, RJ, Lechner-Scott, J, Leal, R, Moscato, P, Booth, DR, Stewart, GJ, Vucic, S, Pame, G, BamettO, M, Mason, D, GriffithS, L, Broadley, S, Tajouri, L, Baxter, A, Slee, M, Taylor, BV, Charlesworth, J, Kilpatrick, TJ, Rubio, J, Jokubaitis, V, Wiley, J, Butzkueven, H, Leslie, S, Motyer, A, Stankovich, J, Carroll, WM, Kermode, AG, Edrin, M, Barclay, M, Peyrin-Biroulet, L, Chamaillard, M, Colombe, JF, Cottone, M, Croft, A, D'Inca, R, Halfvarson, J, Hanigan, K, Henderson, P, Hugot, JP, Karban, A, Kennedy, NA, Khan, MA, Lemann, M, Levine, A, Massey, D, Milla, M, Motoey, GW, Ng, SME, Oikonomnou, J, Peeters, H, Proctor, DD, Rahier, JF, Roberts, R, Rutgeerts, P, Seibold, F, Stronati, L, Taylor, KM, Torkvist, L, Ublick, K, Van Limbergen, J, Van Gossum, A, Vatn, MH, Zhang, H, Zhang, W, Donnelly, P, Barroso, I, Blackwe, JM, Bramon, E, Brown, MA, Casas, JP, Corvin, A, Deloukas, P, Duncanson, A, Jankowski, J, Markus, HS, Mathew, CG, Palmer, CNA, Plomin, R, Rautanen, A, Sawcer, SJ, Trembath, RC, Viswanathan, AC, Wood, NW, Spencer, CCA, Band, G, Bellenguez, C, Freeman, C, Hellenthal, G, Giannoulatou, E, Pirinen, M, Pearson, R, Strange, A, Sul, Z, Vukcevic, DA, Langford, C, Hunt, SE, Edkins, S, Gwilliam, R, Blackburn, H, Bumpstead, SJ, Dronov, S, Gillman, M, Gray, E, Hammond, N, Jayakumar, A, McCann, OT, Liddle, J, Potter, SC, Ravindrarajah, R, Ricketts, M, Waller, M, Weston, P, Widaa, S, Whittaker, P, Compston, A, Hafler, D, Harbo, HF, Hauser, SL, Stewart, G, D'Alfonso, S, Hadjigeorgiou, G, Taylor, B, Barcellos, LF, Booth, D, Hintzen, R, Kockum, I, Martinelli-Boneschi, F, McCauley, JL, Oksenberg, JR, Oturai, A, Sawcer, S, Ivinson, AJ, Olsson, T, De Jager, PL, Patsopoulos, Na, Baranzini, Se, Santaniello, A, Shoostari, P, Cotsapas, C, Wong, G, Beecham, Ah, James, T, Replogle, J, Vlachos, I, Mccabe, C, Pers, Th, Brandes, A, White, C, Keenan, B, Cimpean, M, Winn, P, Panteliadis, Ip, Robbins, A, Andlauer, Tfm, Zarzycki, O, Dubois, B, Goris, A, Sondergaard, Hb, Sellebjerg, F, Sorensen, P, Ullum, H, Thorner, Lw, Saarela, J, Cournu-Rebeix, I, Damotte, V, Fontaine, B, Guillot-Noel, L, Lathrop, M, Vukusic, S, Berthele, A, Pongratz, V, Gasperi, C, Graetz, C, Grummel, V, Hemmer, B, Hoshi, M, Knier, B, Korn, T, Lill, Cm, Luessi, F, Muhlau, M, Zipp, F, Dardiotis, E, Agliardi, C, Amoroso, A, Barizzone, N, Benedetti, Md, Bernardinelli, L, Cavalla, P, Clarelli, F, Comi, G, Cusi, D, Esposito, F, Ferre, L, Galimberti, D, Guaschino, C, Leone, Ma, Martinelli, V, Moiola, L, Salvetti, M, Sorosina, M, Vecchio, D, Zauli, A, Santoro, S, Mancini, N, Zuccala, M, Mescheriakova, J, van Duijn, C, Bos, Sd, Celius, Eg, Spurkland, A, Comabella, M, Montalban, X, Alfredsson, L, Bomfim, Il, Gomez-Cabrero, D, Hillert, J, Jagodic, M, Linden, M, Piehl, F, Jelcic, I, Martin, R, Sospedra, M, Baker, A, Ban, M, Hawkins, C, Hysi, P, Kalra, S, Karpe, F, Khadake, J, Lachance, G, Molyneux, P, Neville, M, Thorpe, J, Bradshaw, E, Caillier, Sj, Calabresi, P, Cree, Bac, Cross, A, Davis, M, de Bakker, Pwi, Delgado, S, Dembele, M, Edwards, K, Fitzgerald, K, Frohlich, Iy, Gourraud, Pa, Haines, Jl, Hakonarson, H, Kimbrough, D, Isobe, N, Konidari, I, Lathi, E, Lee, Mh, Li, T, An, D, Zimmer, A, Madireddy, L, Manrique, Cp, Mitrovic, M, Olah, M, Patrick, E, Pericak-Vance, Ma, Piccio, L, Schaefer, C, Weiner, H, Lage, K, Scott, Rj, Lechner-Scott, J, Leal, R, Moscato, P, Booth, Dr, Stewart, Gj, Vucic, S, Pame, G, Bametto, M, Mason, D, Griffiths, L, Broadley, S, Tajouri, L, Baxter, A, Slee, M, Taylor, Bv, Charlesworth, J, Kilpatrick, Tj, Rubio, J, Jokubaitis, V, Wiley, J, Butzkueven, H, Leslie, S, Motyer, A, Stankovich, J, Carroll, Wm, Kermode, Ag, Edrin, M, Barclay, M, Peyrin-Biroulet, L, Chamaillard, M, Colombe, Jf, Cottone, M, Croft, A, D'Inca, R, Halfvarson, J, Hanigan, K, Henderson, P, Hugot, Jp, Karban, A, Kennedy, Na, Khan, Ma, Lemann, M, Levine, A, Massey, D, Milla, M, Motoey, Gw, Ng, Sme, Oikonomnou, J, Peeters, H, Proctor, Dd, Rahier, Jf, Roberts, R, Rutgeerts, P, Seibold, F, Stronati, L, Taylor, Km, Torkvist, L, Ublick, K, Van Limbergen, J, Van Gossum, A, Vatn, Mh, Zhang, H, Zhang, W, Donnelly, P, Barroso, I, Blackwe, Jm, Bramon, E, Brown, Ma, Casas, Jp, Corvin, A, Deloukas, P, Duncanson, A, Jankowski, J, Markus, H, Mathew, Cg, Palmer, Cna, Plomin, R, Rautanen, A, Sawcer, Sj, Trembath, Rc, Viswanathan, Ac, Wood, Nw, Spencer, Cca, Band, G, Bellenguez, C, Freeman, C, Hellenthal, G, Giannoulatou, E, Pirinen, M, Pearson, R, Strange, A, Sul, Z, Vukcevic, Da, Langford, C, Hunt, Se, Edkins, S, Gwilliam, R, Blackburn, H, Bumpstead, Sj, Dronov, S, Gillman, M, Gray, E, Hammond, N, Jayakumar, A, Mccann, Ot, Liddle, J, Potter, Sc, Ravindrarajah, R, Ricketts, M, Waller, M, Weston, P, Widaa, S, Whittaker, P, Compston, A, Hafler, D, Harbo, Hf, Hauser, Sl, Stewart, G, D'Alfonso, S, Hadjigeorgiou, G, Taylor, B, Barcellos, Lf, Booth, D, Hintzen, R, Kockum, I, Martinelli-Boneschi, F, Mccauley, Jl, Oksenberg, Jr, Oturai, A, Sawcer, S, Ivinson, Aj, Olsson, T, De Jager, Pl, Neurology, and Immunology

Subjects
0301 basic medicine, Multiple Sclerosis, Quantitative Trait Loci, Inheritance Patterns, Cell Cycle Proteins, Genome-wide association study, Biology, Major histocompatibility complex, Polymorphism, Single Nucleotide, Major Histocompatibility Complex, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, Immune system, Gene Frequency, Autoimmune Process, medicine, Humans, RNA-Seq, X chromosome, Genetics, Chromosomes, Human, X, Multidisciplinary, Microglia, Multiple sclerosis, GTPase-Activating Proteins, Chromosome Mapping, Genomics, medicine.disease, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, Genetic Loci, Case-Control Studies, biology.protein, Genome-Wide Association Study, 030217 neurology & neurosurgery
Abstract

Genetic roots of multiple sclerosis The genetics underlying who develops multiple sclerosis (MS) have been difficult to work out. Examining more than 47,000 cases and 68,000 controls with multiple genome-wide association studies, the International Multiple Sclerosis Genetics Consortium identified more than 200 risk loci in MS (see the Perspective by Briggs). Focusing on the best candidate genes, including a model of the major histocompatibility complex region, the authors identified statistically independent effects at the genome level. Gene expression studies detected that every major immune cell type is enriched for MS susceptibility genes and that MS risk variants are enriched in brain-resident immune cells, especially microglia. Up to 48% of the genetic contribution of MS can be explained through this analysis. Science , this issue p. eaav7188 ; see also p. 1383

Published
2019

19. Impact of MS genetic loci on familial aggregation, clinical phenotype, and disease prediction

Author

Esposito F, Guaschino C, Sorosina M, Clarelli F, Ferre' L, Mascia E, Santoro S, Pagnesi M, Radaelli M, Colombo B, Moiola L, Rodegher M, Stupka E, Martinelli V, Martinelli Boneschi F., COMI , GIANCARLO, Esposito, F, Guaschino, C, Sorosina, M, Clarelli, F, Ferre', L, Mascia, E, Santoro, S, Pagnesi, M, Radaelli, M, Colombo, B, Moiola, L, Rodegher, M, Stupka, E, Martinelli, V, Comi, Giancarlo, and Martinelli Boneschi, F.

Published
2015

20. Inverse correlation of genetic risk score with age at onset in bout-onset and progressive-onset multiple sclerosis

Author

Sorosina M, Esposito F, Guaschino C, Clarelli F, Barizzone N, Osiceanu AM, Brambilla P, Mascia E, Cavalla P, Gallo P, PROGRESSO, PROGEMUS, Martinelli V, Leone M, COMI , GIANCARLO, D'Alfonso S, Martinelli Boneschi F., Sorosina, M, Esposito, F, Guaschino, C, Clarelli, F, Barizzone, N, Osiceanu, Am, Brambilla, P, Mascia, E, Cavalla, P, Gallo, P, Progresso, Progemu, Martinelli, V, Leone, M, Comi, Giancarlo, D'Alfonso, S, and Martinelli Boneschi, F.

Published
2015

21. The burden of multiple sclerosis variants in continental Italians and Sardinians

Author

Barizzone N, Zara I, Sorosina M, Lupoli S, Porcu E, Pitzalis M, Zoledziewska M, Esposito F, Leone M, Mulas A, Cocco E, Ferrigno P, Guerini FR, Brambilla P, Farina G, Murru R, Deidda F, Sanna S, Loi A, Barlassina C, Vecchio D, Zauli A, Clarelli F, Braga D, Poddie F, Cantello R, Martinelli V, Frau J, Lorefice L, Pugliatti M, Rosati G, PROGEMUS Consortium PROGRESSO Consortium, Melis M, Marrosu MG, Cusi D, Cucca F, Martinelli Boneschi F, D'Alfonso S., COMI , GIANCARLO, Barizzone, N, Zara, I, Sorosina, M, Lupoli, S, Porcu, E, Pitzalis, M, Zoledziewska, M, Esposito, F, Leone, M, Mulas, A, Cocco, E, Ferrigno, P, Guerini, Fr, Brambilla, P, Farina, G, Murru, R, Deidda, F, Sanna, S, Loi, A, Barlassina, C, Vecchio, D, Zauli, A, Clarelli, F, Braga, D, Poddie, F, Cantello, R, Martinelli, V, Comi, Giancarlo, Frau, J, Lorefice, L, Pugliatti, M, Rosati, G, PROGEMUS Consortium PROGRESSO, Consortium, Melis, M, Marrosu, Mg, Cusi, D, Cucca, F, Martinelli Boneschi, F, and D'Alfonso, S.

Published
2015

22. A gain-of-function sodium channelβ2-subunit mutation in painful diabetic neuropathy

Author

Alsaloum, Matthew, Estacion, Mark, Almomani, Rowida, Gerrits, Monique M., Boenhof, Gidon J., Ziegler, Dan, Malik, Rayaz, Ferdousi, Maryam, Lauria, Giuseppe, Merkies, Ingemar S. J., Faber, Catharina G., Dib-Hajj, Sulayman, Waxman, Stephen G., de Greef, B., Hoeijmakers, J. G. J., Sopacua, M., Smeets, H. J. M., Vanoevelen, J. M., Eijkenboom, Lindsey, P., Almomani, R., Taiana, M., Marchi, M., Lombardi, R., Cazzato, D., Boneschi, F. M., Zauli, A., Clarelli, F., Santoro, S., Lopez, A.B., Quattrini, A., Cestele, S., Chever, O., Tavakoli, M., Malik, R., Kapetis, D., Xenakis, M. N., Mantegazza, M., Battiato, F., Strom, A., MUMC+: DA KG Lab Centraal Lab (9), RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, RS: MHeNs - R3 - Neuroscience, MUMC+: KIO Kemta (9), Promovendi MHN, Klinische Genetica, RS: FHML MaCSBio, RS: GROW - R4 - Reproductive and Perinatal Medicine, and Genetica & Celbiologie

Subjects
0301 basic medicine, Diabetic neuropathy, Action Potentials, medicine.disease_cause, Bioinformatics, ACTIVATION, DOMAIN IV, 0302 clinical medicine, Diabetic Neuropathies, Dorsal root ganglion, Ganglia, Spinal, voltage-gated sodium channels, sodium channel beta-subunits, NEURONS, Mutation, Chronic pain, PREVALENCE, SEGMENT IVS6, medicine.anatomical_structure, Gain of Function Mutation, EXCITABILITY, FAST INACTIVATION, Neuropathic pain, Voltage-Gated Sodium Channel beta Subunits, Molecular Medicine, ALPHA-SUBUNIT, Ion Channel Gating, Research Article, POTENTIALS, Tetrodotoxin, Open Reading Frames, 03 medical and health sciences, Cellular and Molecular Neuroscience, Protein Domains, Diabetes mellitus, medicine, Humans, NA(V)1.8 MUTATION, neuropathic pain, business.industry, Sodium channel, medicine.disease, HEK293 Cells, 030104 developmental biology, Anesthesiology and Pain Medicine, Peripheral neuropathy, Neuralgia, business, 030217 neurology & neurosurgery
Abstract

Diabetes mellitus is a global challenge with many diverse health sequelae, of which diabetic peripheral neuropathy is one of the most common. A substantial number of patients with diabetic peripheral neuropathy develop chronic pain, but the genetic and epigenetic factors that predispose diabetic peripheral neuropathy patients to develop neuropathic pain are poorly understood. Recent targeted genetic studies have identified mutations in alpha-subunits of voltage-gated sodium channels (Na(v)s) in patients with painful diabetic peripheral neuropathy. Mutations in proteins that regulate trafficking or functional properties of Na(v)s could expand the spectrum of patients with Na-v-related peripheral neuropathies. The auxiliary sodium channel beta-subunits (beta 1-4) have been reported to increase current density, alter inactivation kinetics, and modulate subcellular localization of Na-v. Mutations in beta-subunits have been associated with several diseases, including epilepsy, cancer, and diseases of the cardiac conducting system. However, mutations in beta-subunits have never been shown previously to contribute to neuropathic pain. We report here a patient with painful diabetic peripheral neuropathy and negative genetic screening for mutations in SCN9A, SCN10A, and SCN11A-genes encoding sodium channel alpha-subunit that have been previously linked to the development of neuropathic pain. Genetic analysis revealed an aspartic acid to asparagine mutation, D109N, in the beta 2-subunit. Functional analysis using current-clamp revealed that the beta 2-D109N rendered dorsal root ganglion neurons hyperexcitable, especially in response to repetitive stimulation. Underlying the hyperexcitability induced by the beta 2-subunit mutation, as evidenced by voltage-clamp analysis, we found a depolarizing shift in the voltage dependence of Na(v)1.7 fast inactivation and reduced use-dependent inhibition of the Na(v)1.7 channel.

Published
2019
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23. Genetic burden of common variants in progressive and bout-onset multiple sclerosis

Author

SOROSINA M, BRAMBILLA P, CLARELLI F, BARIZZONE N, LUPOLI S, GUASCHINO C, OSICEANU AM, MOIOLA L, GHEZZI A, CONIGLIO G, PATTI F, MANCARDI G, MANUNTA P, GLORIOSO N, GUERINI FR, BERGAMASCHI R, PERLA F, PROGRESSO, PROGEMUS, MARTINELLI V, CUSI D, LEONE M, COMI G, D'ALFONSO S, MARTINELLI BONESCHI F, Among the collaborators, TEDESCHI, Gioacchino, Sorosina, M, Brambilla, P, Clarelli, F, Barizzone, N, Lupoli, S, Guaschino, C, Osiceanu, Am, Moiola, L, Ghezzi, An, Coniglio, G, Patti, F, Mancardi, G, Manunta, P, Glorioso, N, Guerini, Fr, Bergamaschi, R, Perla, F, Martinelli, V, Cusi, D, Leone, M, Comi, G, D’Alfonso, S, MARTINELLI-BONESCHI, F, PROGRESSO STUDY, Group, PROGEMUS STUDY, Group, Ghezzi, A, Progresso, Progemu, D'Alfonso, S, MARTINELLI BONESCHI, F, D'Ambrosio, Alessandro, and Tedeschi, Gioacchino

Subjects
Oncology, Male, Genome-wide association study, Sex Factor, Disease, Heritability, Multiple sclerosis, Primary progressive, Relapsing-remitting, Adolescent, Adult, Aged, Aged, 80 and over, Female, Genetic Markers, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Italy, Magnetic Resonance Imaging, Middle Aged, Multiple Sclerosis, Chronic Progressive, Phenotype, Risk Factors, Sex Factors, Young Adult, Polymorphism, Single Nucleotide, Neurology, Neurology (clinical), Genetic Marker, 80 and over, Genetic risk, Genetics, Multiple Sclerosis, Chronic Progressive, Explained variation, Human, medicine.medical_specialty, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, Internal medicine, medicine, Multiple sclerosi, business.industry, Risk Factor, medicine.disease, business
Abstract

Background: The contribution of genetic variants underlying the susceptibility to different clinical courses of multiple sclerosis (MS) is still unclear. Objective: The aim of the study is to evaluate and compare the proportion of liability explained by common SNPs and the genetic burden of MS-associated SNPs in progressive onset (PrMS) and bout-onset (BOMS) cases. Methods: We estimated the proportion of variance in disease liability explained by 296,391 autosomal SNPs in cohorts of Italian PrMS and BOMS patients using the genome-wide complex trait analysis (GCTA) tool, and we calculated a weighted genetic risk score (wGRS) based on the known MS-associated loci. Results: Our results identified that common SNPs explain a greater proportion of phenotypic variance in BOMS (36.5%±10.1%) than PrMS (20.8%±6.0%) cases, and a trend of decrease was observed when testing primary progressive (PPMS) without brain MRI inflammatory activity ( p = 7.9 × 10−3). Similarly, the wGRS and the variance explained by MS-associated SNPs were higher in BOMS than PPMS in males (wGRS: 6.63 vs 6.51, p = 0.04; explained variance: 4.8%±1.5% vs 1.7%±0.6%; p = 0.05). Conclusions: Our results suggest that the liability of disease is better captured by common genetic variants in BOMS than PrMS cases. The absence of inflammatory activity and male gender further raise the difference between clinical courses.

Published
2014

24. Response to interferon-beta treatment in multiple sclerosis patients: A genome-wide association study

Author

Mahurkar, S., Moldovan, M., Suppiah, V., Sorosina, M., Clarelli, F., Liberatore, G., Malhotra, S., Montalban, X., Antigüedad, A., Krupa, M., Jokubaitis, V.G., McKay, F.C., Gatt, P.N., Fabis-Pedrini, M.J., Martinelli, V., Comi, G., Lechner-Scott, J., Kermode, A.G., Slee, M., Taylor, B.V., Vandenbroeck, K., Comabella, M., Boneschi, F.M., King, C., Mahurkar, S., Moldovan, M., Suppiah, V., Sorosina, M., Clarelli, F., Liberatore, G., Malhotra, S., Montalban, X., Antigüedad, A., Krupa, M., Jokubaitis, V.G., McKay, F.C., Gatt, P.N., Fabis-Pedrini, M.J., Martinelli, V., Comi, G., Lechner-Scott, J., Kermode, A.G., Slee, M., Taylor, B.V., Vandenbroeck, K., Comabella, M., Boneschi, F.M., and King, C.

Abstract

Up to 50% of multiple sclerosis (MS) patients do not respond to interferon-beta (IFN-β) treatment and determination of response requires lengthy clinical follow-up of up to 2 years. Response predictive genetic markers would significantly improve disease management. We aimed to identify IFN-β treatment response genetic marker(s) by performing a two-stage genome-wide association study (GWAS). The GWAS was carried out using data from 151 Australian MS patients from the ANZgene/WTCCC2 MS susceptibility GWAS (responder (R)=51, intermediate responders=24 and non-responders (NR)=76). Of the single-nucleotide polymorphisms (SNP) that were validated in an independent group of 479 IFN-β-treated MS patients from Australia, Spain and Italy (R=273 and NR=206), eight showed evidence of association with treatment response. Among the replicated associations, the strongest was observed for FHIT (Fragile Histidine Triad; combined P-value 6.74 × 10−6) and followed by variants in GAPVD1 (GTPase activating protein and VPS9 domains 1; combined P-value 5.83 × 10−5) and near ZNF697 (combined P-value 8.15 × 10−5).

Published
2017

25. Genetic burden of common variants in progressive and bout-onset multiple sclerosis

Author

Sorosina, M, Brambilla, P, Clarelli, F, Barizzone, N, Lupoli, S, Guaschino, C, Osiceanu, Am, Moiola, L, Ghezzi, A, Coniglio, G, Patti, F, Mancardi, G, Manunta, P, Glorioso, N, Guerini, Fr, Bergamaschi, R, Perla, F, Martinelli, V, Cusi, D, Leone, M, Comi, G, D'Alfonso, S, Martinelli Boneschi, F. F., Liberatore, G, Rodegher, M, Rossi, P, Radaelli, M, Colombo, B, Annovazzi, P, Capra, R, Amato, Mp, Nacmias, B, D'Ambrosio, A, Tedeschi, G, Cavalla, P, D'Amico, E, Galimberti, D, Scarpini, E, Atzori, M, Gallo, Paolo, Bucello, S, Grimaldi, L, Capello, E, Naldi, P, Di Sapio, A, Caputo, D, Rosso, G, Cordera, S, Cavallo, R, Benedetti, D, and Salvetti, M.

Published
2013

26. Genome-wide association study of progressive and bout-onset multiple sclerosis patients

Author

Martinelli Boneschi, F., Esposito, F., Clarelli, F., Barrizzone, N., Liberatore, G., Brambilla, P., Rodegher, M., Sorosina, M., Guaschino, C., Cavalla, P., Patti, E., Galimberti, D., Scarpini, E., Lupoli, S., Capra, R., Tedeschi, G., Mancardi, G., Coniglio, G., Grimaldi, L., Ghezzi, A., Cusi, D., Martinelli, V., Leone, M., D’Alfonso, S., and Comi, G.

Subjects
Settore MED/26 - Neurologia
Published
2012

30. Analysis of genes, pathways and networks involved in disease severity and age at onset in primary-progressive multiple sclerosis

Author

Giacalone, G, primary, Clarelli, F, additional, Osiceanu, AM, additional, Guaschino, C, additional, Brambilla, P, additional, Sorosina, M, additional, Liberatore, G, additional, Zauli, A, additional, Esposito, F, additional, Rodegher, M, additional, Ghezzi, A, additional, Galimberti, D, additional, Patti, F, additional, Barizzone, N, additional, Guerini, F, additional, Martinelli, V, additional, Leone, M, additional, Comi, G, additional, D’Alfonso, S, additional, and Martinelli Boneschi, F, additional

Published
2015
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33. AMDA 2.13: A major update for automated cross-platform microarray data analysis

Author

Kapetis, D, Clarelli, F, Vitulli, F, de Rosbo, N, Beretta, O, Foti, M, Castagnoli, P, Zolezzi, F, FOTI, MARIA, CASTAGNOLI, PAOLA, Zolezzi, F., Kapetis, D, Clarelli, F, Vitulli, F, de Rosbo, N, Beretta, O, Foti, M, Castagnoli, P, Zolezzi, F, FOTI, MARIA, CASTAGNOLI, PAOLA, and Zolezzi, F.

Abstract

Microarray platforms require analytical pipelines with modules for data pre-processing including data normalization, statistical analysis for identification of differentially expressed genes, cluster analysis, and functional annotation. We previously developed the Automated Microarray Data Analysis (AMDA, version 2.3.5) pipeline to process Affymetrix 3′ IVT GeneChips. The availability of newer technologies that demand open-source tools for microarray data analysis has impelled us to develop an updated multi-platform version, AMDA 2.13. It includes additional quality control metrics, annotation-driven (annotation grade of Affymetrix NetAffx) and signal-driven (Inter-Quartile Range) gene filtering, and approaches to experimental design. To enhance understanding of biological data, differentially expressed genes have been mapped into KEGG pathways. Finally, a more stable and user-friendly interface was designed to integrate the requirements for different platforms. AMDA 2.13 allows the analysis of Affymetrix (cartridges and plates) and whole transcript probe design (Gene 1.0/1.1 ST and Exon 1.0 ST GeneChips), Illumina Bead Arrays, and one-channel Agilent 4×44 arrays. Relative to early versions, it supports various experimental designs and delivers more insightful biological understanding and up-to-date annotations.

Published
2012

36. A fluid dynamics multidimensional model of biofilm growth: stability, influence of environment and sensitivity.

Author

CLARELLI, F., DI RUSSO, C., NATALINI, R., and RIBOT, M.

Subjects
*FLUID dynamics, *BIOFILMS, *CYANOBACTERIA, *BACTERIAL growth, *EFFECT of light on bacteria
Abstract

In this article, we study in detail the fluid dynamics system proposed in Clarelli et al. (2013, J. Math. Biol., 66, 1387-1408) to model the formation of cyanobacteria biofilms. After analysing the linear stability of the unique non-trivial equilibrium of the system, we introduce in the model the influence of light and temperature, which are two important factors for the development of a cyanobacteria biofilm. Since the values of the coefficients we use for our simulations are estimated through information found in the literature, some sensitivity and robustness analyses on these parameters are performed. All these elements enable us to control and to validate the model we have already derived and to present some numerical simulations in the 2D and the 3D cases. [ABSTRACT FROM AUTHOR]

Published
2016
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39. Thin plate approximation in active infrared thermography.

Author

Inglese, G. and Clarelli, F.

Subjects
*APPROXIMATION theory, *THERMOGRAPHY, *HEAT flux, *MATHEMATICAL regularization, *STATISTICAL smoothing
Abstract

In this work, we find and test a new approximated formula (based on the thin plate approximation), for recovering small, unknown damages on the inaccessible surface of a thin conducting (aluminium) plate. We solve this inverse problem from a controlled heat flux and a sequence of temperature maps on the accessible front boundary of our sample. We heat the front boundary by means of a sinusoidal flux. In the meanwhile, we take a sequence of temperature maps of the same side by means of an infrared camera. This procedure is called active infrared thermography. The solution of the heat equation on the accessible boundary of the damaged sample simulates the collection of data. We use domain derivative to linearize the boundary value problem for heat equation. Then, Fourier analysis on the periodic component of solutions leads us to an elliptic BVP. Finally, we apply perturbation theory in order to find out an approximation of the damage. Numerical tests obtained with synthetic data are encouraging. The solution of the heat equation on the accessible boundary of the damaged sample simulates the collection of data by means of the infrared camera. We use domain derivative to linearize the BVP for heat equation. Then, Fourier analysis on the periodic component of solutions leads us to an elliptic BVP. Finally, we apply the perturbation theory in(ais the thickness of our sample) in order to find out an approximation of the damage. Numerical tests obtained with synthetic data are encouraging. [ABSTRACT FROM AUTHOR]

Published
2015
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40. Predictors of effectiveness of multidisciplinary rehabilitation treatment on motor dysfunction in multiple sclerosis.

Author

Liberatore, G, Clarelli, F, Nuara, A, Ungaro, D, Gatti, R, Rovaris, M, Martinelli, V, Comola, M, Comi, G, Rossi, P, and Martinelli-Boneschi, F

Subjects
*REHABILITATION centers, *MULTIPLE sclerosis, *THERAPEUTICS, *MEDICAL care, *LOGISTIC regression analysis
Abstract

The article focuses on a study that identify the short-term effectiveness of a short-term intensive multiple sclerosis multidisciplinary rehabilitation treatment in multiple sclerosis (MS) patients and analyzed the impact of MD rehabilitation. In the study, 212 consecutive patients were analyzed and multivariate logistic regression models have been tested. Study found that rehabilitation program is able to produce a short-term relevant improvement on clinical and functional outcome measures.

Published
2014
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42. Contribution of Rare and Low-Frequency Variants to Multiple Sclerosis Susceptibility in the Italian Continental Population

Author

Ferdinando Clarelli, Nadia Barizzone, Eleonora Mangano, Miriam Zuccalà, Chiara Basagni, Santosh Anand, Melissa Sorosina, Elisabetta Mascia, Silvia Santoro, PROGEMUS, PROGRESSO, Franca Rosa Guerini, Eleonora Virgilio, Antonio Gallo, Alessandro Pizzino, Cristoforo Comi, Vittorio Martinelli, Giancarlo Comi, Gianluca De Bellis, Maurizio Leone, Massimo Filippi, Federica Esposito, Roberta Bordoni, Filippo Martinelli Boneschi, Sandra D'Alfonso, P Crociani, D Vecchio, P Ragonese, A Gajofatto, E Scarpini, A Bertolotto, D Caputo, C Gasperini, F Granella, S Cordera, P Cavallo, R Cavallo, R Bergamaschi, G Ristori, C Solaro, F Martinelli, F Passantino, M Pugliatti, A Gallo, L Brambilla, C Clerico, F Capone, F Esposito, G Liberatore, M Rodegher, p Rossi, M Radaelli, L Moiola, B Colombo, A Ghezzi, A Annovazzi, R Capra, G Coniglio, M. P Amato, B Nacmias, G Tedeschi, A D’Ambrosio, P Cavalla, F Patti, E D’Amico, D Galimberti, P Gallo, M Atzori, L Grimaldi, S Bucello, G Mancardi, E Capello, Clarelli, F, Barizzone, N, Mangano, E, Zuccalà, M, Basagni, C, Anand, S, Sorosina, M, Mascia, E, Santoro, S, Guerini, Fr, Virgilio, E, Gallo, A, Pizzino, A, Comi, C, Martinelli, V, Comi, G, De Bellis, G, Leone, M, Filippi, M, Esposito, F, Bordoni, R, Martinelli-Boneschi, F, D’Alfonso, S, Clarelli, F., Barizzone, N., Mangano, E., Zuccala, M., Basagni, C., Anand, S., Sorosina, M., Mascia, E., Santoro, S., Guerini, F. R., Virgilio, E., Gallo, A., Pizzino, A., Comi, C., Martinelli, V., Comi, G., De Bellis, G., Leone, M., Filippi, M., Esposito, F., Bordoni, R., Martinelli Boneschi, F., and D'Alfonso, S.

Subjects
multiple sclerosi, Genetics, rare variants, Molecular Medicine, QH426-470, pool sequencing, multiple sclerosis, burden test, EFCAB13, Genetics (clinical), Original Research
Abstract

Genome-wide association studies identified over 200 risk loci for multiple sclerosis (MS) focusing on common variants, which account for about 50% of disease heritability. The goal of this study was to investigate whether low-frequency and rare functional variants, located in MS-established associated loci, may contribute to disease risk in a relatively homogeneous population, testing their cumulative effect (burden) with gene-wise tests. We sequenced 98 genes in 588 Italian patients with MS and 408 matched healthy controls (HCs). Variants were selected using different filtering criteria based on allelic frequency and in silico functional impacts. Genes showing a significant burden (n = 17) were sequenced in an independent cohort of 504 MS and 504 HC. The highest signal in both cohorts was observed for the disruptive variants (stop-gain, stop-loss, or splicing variants) located in EFCAB13, a gene coding for a protein of an unknown function (p < 10–4). Among these variants, the minor allele of a stop-gain variant showed a significantly higher frequency in MS versus HC in both sequenced cohorts (p = 0.0093 and p = 0.025), confirmed by a meta-analysis on a third independent cohort of 1298 MS and 1430 HC (p = 0.001) assayed with an SNP array. Real-time PCR on 14 heterozygous individuals for this variant did not evidence the presence of the stop-gain allele, suggesting a transcript degradation by non-sense mediated decay, supported by the evidence that the carriers of the stop-gain variant had a lower expression of this gene (p = 0.0184). In conclusion, we identified a novel low-frequency functional variant associated with MS susceptibility, suggesting the possible role of rare/low-frequency variants in MS as reported for other complex diseases.

Published
2022

43. An Investigation of the Role of Common and Rare Variants in a Large Italian Multiplex Family of Multiple Sclerosis Patients

Author

Cristoforo Comi, Filippo Martinelli-Boneschi, Lucia Corrado, Rachele Cagliani, Martina Tosi, Cristina Agliardi, Francesco Favero, Giancarlo Comi, Nadia Barizzone, Melissa Sorosina, Massimo Filippi, Ferdinando Clarelli, Davide Corà, Domenico Caputo, Elisabetta Mascia, Manuela Sironi, Maria Liguori, Chiara Basagni, Vittorio Martinelli, Domizia Vecchio, Miriam Zuccalà, Federica Esposito, Maurizio Leone, Diego Forni, Sandra D'Alfonso, Franca Rosa Guerini, Laura Mendozzi, Barizzone, N., Cagliani, R., Basagni, C., Clarelli, F., Mendozzi, L., Agliardi, C., Forni, D., Tosi, M., Mascia, E., Favero, F., Cora, D., Corrado, L., Sorosina, M., Esposito, F., Zuccala, M., Vecchio, D., Liguori, M., Comi, C., Comi, G., Martinelli, V., Filippi, M., Leone, M., Martinelli-Boneschi, F., Caputo, D., Sironi, M., Guerini, F. R., and D'Alfonso, S.

Subjects
Adult, Male, DNA Copy Number Variations, Genetic Linkage, multiple sclerosis, multiplex families, linkage study, NGS, rare variants, Biology, QH426-470, Article, Multiple sclerosis, 03 medical and health sciences, 0302 clinical medicine, Missing heritability problem, Genetic linkage, Exome Sequencing, medicine, Genetics, Humans, Multiplex, Genetic Predisposition to Disease, Gene, Exome, Genetics (clinical), Genetic Association Studies, 030304 developmental biology, Aged, Linkage study, Whole genome sequencing, Aged, 80 and over, 0303 health sciences, Whole Genome Sequencing, Genome, Human, High-Throughput Nucleotide Sequencing, Rare variants, Heritability, Middle Aged, medicine.disease, Pedigree, Italy, Multiplex families, Female, 030217 neurology & neurosurgery
Abstract

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.

Published
2021
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44. Identification of differential DNA methylation associated with multiple sclerosis: A family-based study

Author

Ferdinando Clarelli, S. Bonfiglio, Massimo Filippi, Federica Esposito, A. Protti, Giulia Barbiera, Filippo Martinelli-Boneschi, Vittorio Martinelli, E. Stupka, Silvia Santoro, Elisabetta Mascia, Clara Guaschino, Francesca Giannese, Melissa Sorosina, Dejan Lazarevic, Jose Manuel Garcia-Manteiga, Davide Cittaro, Garcia-Manteiga, J. M., Clarelli, F., Bonfiglio, S., Mascia, E., Giannese, F., Barbiera, G., Guaschino, C., Sorosina, M., Santoro, S., Protti, A., Martinelli, V., Cittaro, D., Lazarevic, D., Stupka, E., Filippi, M., Esposito, F., and Martinelli-Boneschi, F.

Subjects
0301 basic medicine, Adult, Male, Multiple Sclerosis, Immunology, Genomics, Biology, Epigenesis, Genetic, 03 medical and health sciences, Young Adult, 0302 clinical medicine, medicine, Immunology and Allergy, Humans, Multiplex, Epigenetics, Gene, Aged, Genetics, Multiple sclerosis, Methylation, DNA Methylation, Middle Aged, medicine.disease, Pedigree, 030104 developmental biology, Differentially methylated regions, Neurology, Italy, DNA methylation, Female, Neurology (clinical), 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Multiple Sclerosis (MS) is caused by a still unknown interplay between genetic and environmental factors. Epigenetics, including DNA methylation, represents a model for environmental factors to influence MS risk. Twenty-six affected and 26 unaffected relatives from 8 MS multiplex families were analysed in a multicentric Italian study using MeDIP-Seq, followed by technical validation and biological replication in two additional families of differentially methylated regions (DMRs) using SeqCap Epi Choice Enrichment kit (Roche®). Associations from MeDIP-Seq across families were combined with aggregation statistics, yielding 162 DMRs at FDR ≤ 0.1. Technical validation and biological replication led to 2 hypo-methylated regions, which point to NTM and BAI3 genes, and to 2 hyper-methylated regions in PIK3R1 and CAPN13. These 4 novel regions contain genes of potential interest that need to be tested in larger cohorts of patients.

Published
2021

45. Early evidence of disease activity during fingolimod predicts medium-term inefficacy in relapsing-remitting multiple sclerosis

Author

Francesca Sangalli, Laura Ferrè, Ferdinando Clarelli, Andrea Mogavero, Vittorio Martinelli, Federica Esposito, Lucia Moiola, Bruno Colombo, Giancarlo Comi, Massimo Filippi, Ferre, L., Mogavero, A., Clarelli, F., Moiola, L., Sangalli, F., Colombo, B., Martinelli, V., Comi, G., Filippi, M., and Esposito, F.

Subjects
Drug, medicine.medical_specialty, Multiple Sclerosis, media_common.quotation_subject, Disease activity, Lesion, Multiple sclerosis, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Multiple Sclerosis, Relapsing-Remitting, Internal medicine, medicine, Humans, 030212 general & internal medicine, fingolimod, media_common, early prediction, medicine.diagnostic_test, Proportional hazards model, business.industry, Fingolimod Hydrochloride, Natalizumab, real world, Magnetic resonance imaging, medicine.disease, Fingolimod, Neurology, Female, Neurology (clinical), medicine.symptom, business, disease activity, 030217 neurology & neurosurgery, Immunosuppressive Agents, Cohort study, medicine.drug
Abstract

Background: Fingolimod (FTY) is an effective second-line drug for relapsing-remitting multiple sclerosis, with ~50% patients showing no evidence of disease activity (NEDA) after 2 years. Nonetheless, the early identification of non-responders is extremely important, to promptly address them to more aggressive drugs. Objectives: This cohort study evaluates FTY medium-term effectiveness, searching for early markers of treatment failure. Patients and methods: Three hundred eighty patients starting FTY were enrolled and classified according to NEDA and time to first relapse criteria at 4-year follow-up. Logistic and Cox regression analyses were applied to identify early predictors of non-response. Results: At 4 years, 65.6% of patients were free from relapses and 35.4% had NEDA. Female gender was associated with a higher risk of non-response. Moreover, evidence of clinical and/or magnetic resonance imaging (MRI) activity during the first year of treatment was highly predictive of disease activity in the follow-up: the positive predictive value for non-response was 0.74 for the presence of ⩾1 relapse, 0.73 for the presence of ⩾1 active MRI lesion, and 0.83 for the presence of both clinical and MRI activity. Conclusions: FTY effectiveness persists at medium-term follow-up; a close monitoring during the first year of treatment is warranted to early identify non-responders requiring treatment optimization.

Published
2020

46. Effectiveness and baseline factors associated to fingolimod response in a real-world study on multiple sclerosis patients

Author

Ferdinando Clarelli, Francesca Sangalli, Giacomo Sferruzza, Massimo Filippi, Loredana Storelli, F. Martinelli Boneschi, Marta Radaelli, Vittorio Martinelli, Lucia Moiola, Federica Esposito, Laura Ferrè, Bruno Colombo, Maria A. Rocca, Giancarlo Comi, Esposito, F., Ferrè, L., Clarelli, F., Rocca, M. A., Sferruzza, G., Storelli, L., Radaelli, M., Sangalli, F., Moiola, L., Colombo, B., Martinelli Boneschi, F., Comi, G., Filippi, M., and Martinelli, V.

Subjects
Adult, Male, Treatment response, medicine.medical_specialty, Neurology, Multiple Sclerosis, Time Factors, Gadolinium, Disease, Antibodies, Monoclonal, Humanized, Cohort Studies, 03 medical and health sciences, Disability Evaluation, 0302 clinical medicine, Natalizumab, Internal medicine, medicine, Humans, Multiple sclerosi, 030212 general & internal medicine, Neuroradiology, Prognostic factor, business.industry, Fingolimod Hydrochloride, Multiple sclerosis, Effectivene, Brain, Fingolimod, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Treatment Outcome, Italy, Real-world, Cohort, Female, Neurology (clinical), business, 030217 neurology & neurosurgery, Immunosuppressive Agents, medicine.drug, MRI
Abstract

Background: Treatment choice in multiple sclerosis (MS) is crucial for optimizing risk–benefit profile. Objective: To assess fingolimod (FTY) effectiveness and identify baseline features associated to disease activity in a large Italian cohort of Relapsing–Remitting (RR) MS patients. Methods: Three-hundred sixty-seven RRMS patients starting FTY treatment at San Raffaele Hospital (Milan-Italy) underwent clinical and MRI evaluations for 2 years. Treatment response was assessed considering the proportion of patients with no evidence of disease activity (NEDA) and recording the time to first relapse. Primary analyses were performed stratifying for Natalizumab (NTZ) treatment in the year before (NO_NTZ vs NTZ group), to account for post-NTZ reactivation. Results: Almost half of patients were NEDA after 2 years, 53.4% in the NO_NTZ group and 36.2% in the NTZ group. Despite an opposite trend during the first 6–12 months, at 2-year follow-up the two groups were comparable for relapses and number of new/enlarging T2 and Gd-enhancing lesions. Baseline parameters of higher disease activity (ARR, Gd enhancing lesions and age at onset) were associated with increased likelihood of failing NEDA criteria or with shorter time to relapse (p < 0.05). Conclusions: Our data strengthen FTY effectiveness in everyday clinical practice, even in patients switching from NTZ treatment. Baseline parameters of inflammatory activity are the most important prognostic factors for mid-term disease reactivation also during second-line treatment with FTY, providing hints on how to select therapies towards a more personalized management.

Published
2018

47. Pharmacogenetic study of long-term response to interferon-β treatment in multiple sclerosis

Author

Federica Esposito, Giuseppe Liberatore, Bruno Colombo, Ana Maria Osiceanu, Elisabetta Mascia, Melissa Sorosina, Giulia Pavan, Silvia Santoro, Ferdinando Clarelli, F. Martinelli-Boneschi, Lucia Moiola, Giancarlo Comi, Vittorio Martinelli, Clarelli, F., Liberatore, G., Sorosina, M., Osiceanu, A. M., Esposito, F., Mascia, E., Santoro, S., Pavan, G., Colombo, B., Moiola, L., Martinelli, V., Comi, Giancarlo, and Martinelli boneschi, F.

Subjects
0301 basic medicine, Male, Time Factors, Pharmacogenomic Variants, Genome-wide association study, Bioinformatics, Receptors, Metabotropic Glutamate, Pharmacogenetic Study, 0302 clinical medicine, Immunologic Factor, Receptors, Kainic Acid, Multiple Sclerosi, Pharmacogenetic, Middle Aged, Phenotype, Treatment Outcome, Italy, Pharmacogenomic Variant, Molecular Medicine, Female, Case-Control Studie, Human, Adult, Multiple Sclerosis, Time Factor, Adolescent, Genotype, Cell Adhesion Molecules, Neuronal, Quantitative Trait Loci, Quantitative trait locus, Biology, Peripheral blood mononuclear cell, Polymorphism, Single Nucleotide, 03 medical and health sciences, Young Adult, Genetic, Genetics, medicine, Humans, Immunologic Factors, Allele, Pharmacology, Multiple sclerosis, Gene Expression Profiling, Interferon-beta, medicine.disease, Pharmacogenomic Testing, Gene expression profiling, 030104 developmental biology, Pharmacogenetics, Case-Control Studies, Immunology, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

The aim of the study is the identification of genetic factors that influence the long-term response to interferon-β (IFNβ) (4-year follow-up). We performed a genome-wide association study in 337 IFNβ-treated Italian multiple sclerosis patients at the extreme of treatment response, and we meta-analyzed association effects, integrating results with pathway analysis, gene-expression profiling of IFNβ-stimulated peripheral blood mononuclear cells from 20 healthy controls (HC) and expression quantitative locus (eQTL) analyses. From meta-analysis, 43 markers were associated at P

Published
2015

48. AMDA 2.13: A major update for automated cross-platform microarray data analysis

Author

Paola Ricciardi-Castagnoli, Ottavio Beretta, Federico Vitulli, Dimos Kapetis, Ferdinando Clarelli, Nicole Kerlero de Rosbo, Maria Foti, Francesca Zolezzi, Kapetis, D, Clarelli, F, Vitulli, F, de Rosbo, N, Beretta, O, Foti, M, Castagnoli, P, and Zolezzi, F

Subjects
Microarray, Computer science, open-source software, Computational biology, Bioinformatics, analytical pipeline, General Biochemistry, Genetics and Molecular Biology, Database normalization, User-Computer Interface, Cross-platform, Statistical analysis, automation, Oligonucleotide Array Sequence Analysis, Microarray analysis techniques, business.industry, Gene Expression Profiling, MED/04 - PATOLOGIA GENERALE, Genomics, Automation, Identification (information), DNA microarray, business, microarray, Software, Biotechnology, data analysi
Abstract

Microarray platforms require analytical pipelines with modules for data pre-processing including data normalization, statistical analysis for identification of differentially expressed genes, cluster analysis, and functional annotation. We previously developed the Automated Microarray Data Analysis (AMDA, version 2.3.5) pipeline to process Affymetrix 3′ IVT GeneChips. The availability of newer technologies that demand open-source tools for microarray data analysis has impelled us to develop an updated multi-platform version, AMDA 2.13. It includes additional quality control metrics, annotation-driven (annotation grade of Affymetrix NetAffx) and signal-driven (Inter-Quartile Range) gene filtering, and approaches to experimental design. To enhance understanding of biological data, differentially expressed genes have been mapped into KEGG pathways. Finally, a more stable and user-friendly interface was designed to integrate the requirements for different platforms. AMDA 2.13 allows the analysis of Affymetrix (cartridges and plates) and whole transcript probe design (Gene 1.0/1.1 ST and Exon 1.0 ST GeneChips), Illumina Bead Arrays, and one-channel Agilent 4×44 arrays. Relative to early versions, it supports various experimental designs and delivers more insightful biological understanding and up-to-date annotations.

Published
2011

49. Impact of multiple sclerosis risk loci in postinfectious neurological syndromes

Author

Ferdinando Clarelli, Silvia Peroni, Laura Ferrè, Silvia Santoro, Andrea Cortese, Giancarlo Comi, Angelo Gugliemi, Filippo Martinelli-Boneschi, Riccardo Currò, Elisabetta Mascia, Giulia Berzero, Enrico Marchioni, Massimo Filippi, Federica Esposito, Elisa Vegezzi, Ilaria Callegari, Melissa Sorosina, Martinelli-Boneschi, F., Curro, R., Santoro, S., Berzero, G., Sorosina, M., Ferre, L., Mascia, E., Peroni, S., Comi, G., Gugliemi, A., Vegezzi, E., Callegari, I., Filippi, M., Cortese, A., Esposito, F., Clarelli, F., and Marchioni, E.

Subjects
Adult, Male, medicine.medical_specialty, Multiple Sclerosis, Genotype, Myelitis, Single-nucleotide polymorphism, Disease, Postinfectious neurological syndrome, Multiple sclerosis, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Genetics, Humans, 030212 general & internal medicine, Genetic variability, Alleles, Acquired demyelinating disease, business.industry, Retrospective cohort study, General Medicine, Syndrome, Middle Aged, medicine.disease, Magnetic Resonance Imaging, 3. Good health, Neurology, Female, Neurology (clinical), Differential diagnosis, business, 030217 neurology & neurosurgery, Cohort study, Weighted genetic risk score
Abstract

Background: The genetic component of multiple sclerosis (MS) is now set to 200 autosomal common variants. However, it is unclear how genetic knowledge be clinically used in the differential diagnosis between MS and other inflammatory conditions like adult-onset postinfectious neurological syndromes (PINS). The aim of this study was to investigate whether PINS and MS have a shared genetic background using an updated polygenic risk scores. Methods: Eighty-eight PINS patients have been consecutively recruited between 1996 and 2016 at Mondino Foundation of Pavia, diagnosed according to clinical, MRI and CSF findings and followed-up for several years. Patients were typed using Illumina array, and genotypes imputed using the 1000 Genomes Project reference panel. A weighted genetic risk score (wGRS) has been calculated based on autosomal MS risk loci derived from large-scale studies, and an HLA genetic burden (HLAGB) was also calculated on loci associated to MS. Results: PINS occurred as an episode of myelitis in 44% of patients, encephalomyelitis in 44%, and encephalitis in remaining cases, with an involvement of peripheral nervous system in 41% of patients. Mean age of onset was 50.1 years, and female:male ratio was 1.4. Patients were followed-up for a mean of 7.2 years, and at last visit 55% had a low disability grade (mRS 0–1). Disease was monophasic in 67% of patients, relapsing in 18% and chronic-progressive in 15%. The wGRS of PINS cases was comparable to 370 healthy controls, while significantly lower compared to 907 bout-onset MS (BOMS) cases (wGRS= 20.9 vs 21.2; p

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50. Vitamin D affects the risk of disease activity in multiple sclerosis.

Author

Giordano A, Clarelli F, Pignolet B, Mascia E, Sorosina M, Misra K, Ferrè L, Bucciarelli F, Manouchehrinia A, Moiola L, Martinelli V, Rocca MA, Liblau R, Filippi M, and Esposito F

Subjects
Humans, Male, Female, Adult, Middle Aged, Genome-Wide Association Study, Multiple Sclerosis blood, Multiple Sclerosis genetics, Vitamin D blood, Vitamin D analogs & derivatives, Mendelian Randomization Analysis, Multiple Sclerosis, Relapsing-Remitting blood, Multiple Sclerosis, Relapsing-Remitting genetics, Genetic Predisposition to Disease
Abstract

Background: Vitamin D (VitD) affects the risk of multiple sclerosis (MS), but the impact on disease activity is controversial. We assessed whether VitD is associated with the No-Evidence of Disease Activity-3 (NEDA-3) status at 2 years from disease-modifying treatment (DMT) start, and whether this association is causal or the result of confounding factors. Furthermore, we explored if a genetic predisposition to higher VitD levels affects the risk of disease activity., Methods: 230 untreated relapsing-remitting MS patients underwent serum 25-OH-vitamin-D measurement, and the association between seasonally adjusted VitD and disease activity was tested. Modelling a Polygenic Risk Score from a Genome-Wide Association Study on ~400 000 individuals, we studied the impact of genetic predisposition to higher VitD on the NEDA-3 status in 1408 independent MS patients. Two-sample Mendelian randomisation (MR) was used to assess causality., Results: Lower baseline VitD was associated with decreased probability of NEDA-3 at 2 years (p=0.019). Particularly, VitD levels <20 ng/mL conferred an over twofold risk of disease activity (OR 2.36, 95% CI 1.30 to 3.88, p=0.0037). Genetic predisposition to higher VitD levels was associated with delayed age at MS onset (p=0.018) and with a higher probability of NEDA-3 status (p=0.034). MR confirmed causality between VitD and the risk of disease activity (p=0.041)., Conclusions: VitD levels before DMT start affect the risk of disease activity in MS. Genetic predisposition to higher VitD levels confers a lower risk of disease activity and is associated with delayed MS onset. Our work prompts future prospective studies regarding VitD supplementation and lifestyle interventions to hamper disease activity in MS., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2025. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Published
2025
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