Inflammation and Epstein-Barr Virus Infection Are Common Features of Myasthenia Gravis Thymus: Possible Roles in Pathogenesis

The thymus plays a major role in myasthenia gravis (MG). Our recent finding of a persistent Epstein-Barr (EBV) virus infection in some MG thymuses, combined with data showing that the thymus is in a proinflammatory state in most patients, supports a viral contribution to the pathogenesis of MG. Aim of this study was to gain further evidence for intrathymic chronic inflammation and EBV infection in MG patients. Transcriptional profiling by low density array and real-time PCR showed overexpression of genes involved in inflammatory and immune response in MG thymuses. Real-time PCR for EBV genome, latent (EBER1, EBNA1, LMP1) and lytic (BZLF1) transcripts, and immunohistochemistry for LMP1 and BZLF1 proteins confirmed an active intrathymic EBV infection, further supporting the hypothesis that EBV might contribute to onset or perpetuation of the autoimmune response in MG. Altogether, our results support a role of inflammation and EBV infection as pathogenic features of MG thymus

A New Thiopurine S-Methyltransferase Haplotype Associated With Intolerance to Azathioprine

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Past Antarctic ice sheet dynamics (PAIS) and implications for future sea-level change

Coauthors from the PAIS community Aisling M. Dolan, University of Leeds, Leeds, UK Alan K. Cooper, U.S. Geological Survey Emeritus, Menlo Park, USA Alessandra Venuti, Istituto Nazionale di Geofisica e Vulcanologia, Rome, Italy Amy Leventer, Colgate University, Hamilton, NY, USA Andrea Bergamasco, C.N.R. (National Research Council) ISMAR, Venice, Italy Carolina Acosta Hospitaleche, CONICET, División Paleontología Vertebrados, Museo de La Plata (Facultad de Ciencias Naturales y Museo, UNLP) La Plata, Argentina Carolina Acosta Hospitaleche, CONICET – División Paleontología Vertebrados, Museo de La Plata, Facultad de Ciencias Naturales y Museo, UNLP; La Plata, Argentina Catalina Gebhardt, Alfred Wegener Institute Helmholtz Centre of Polar and Marine Research, Bremerhaven, Germany Christine S. Siddoway, Colorado College, Colorado Springs, USA Christopher C. Sorlien, Earth Research Institute, University of California, Santa Barbara, Santa Barbara, California, USA David Harwood, University of Nebraska-Lincoln, Lincoln, Nebraska, USA David Pollard, Pennsylvania State University, University Park, Pennsylvania, USA David J. Wilson, Department of Earth Sciences, University College London, London, UK Denise K. Kulhanek, Texas A&M University, College Station, TX, United States Dominic A. Hodgson, British Antarctic Survey, Cambridge, UK Edward G.W. Gasson, University of Bristol, UK Fausto Ferraccioli, NERC/British Antarctic Survey, Cambridge, UK Fernando Bohoyo, Instituto Geológico y Minero de España, Madrid, Spain Francesca Battaglia, University of Venice Cá Foscari, Italy Frank O. Nitsche, Lamont-Doherty Earth Observatory of Columbia University, Palisades, USA Georgia R. Grant, GNS Science Wellington, New Zealand Gerhard Kuhn, Alfred-Wegener-Institut Helmholtz-Zentrum für Polar- und Meeresforschung, Bremerhaven, Germany Guy J.G. Paxman, Lamont-Doherty Earth Observatory, Columbia University, New York, USA Ian D. Goodwin, Climate Change Research Centre, University of New South Wales, Sydney, Australia Isabel Sauermilch, University of Tasmania, Institute for Marine and Antarctic Studies, Australia Jamey Stutz, Antarctic Research Centre at Victoria University of Wellington, New Zealand Jan Sverre Laberg, Department of Geosciences, UiT The Arctic University of Norway, NO-9037 Tromsø, Norway Javier N. Gelfo, CONICET – UNLP, División Paleontología Vertebrados, Museo de La Plata, Argentina Johann P. Klages, Alfred Wegener Institute Helmholtz Center for Polar and Marine Research, Bremerhaven, Germany Julia S. Wellner, University of Houston, Houston, USA Karsten Gohl, Alfred Wegener Institute Helmholtz Centre for Polar and Marine Research, Bremerhaven, Germany Laura Crispini, University of Genova (DISTAV, Genova, Italy) Leanne K. Armand, Australian National University, Canberra, Australia. Marcelo A. Reguero, Instituto Antártico Argentino, B1650HMK, San Martín, Buenos Aires, Argentina Marcelo A. Reguero, Instituto Antártico Argentino, Buenos Aires, Argentina Marco Taviani, Institute of Marine Sciences (ISMAR), National Research Council (CNR), 40129, Bologna, Italy and Biology Department, Woods Hole Oceanographic Institution, 02543, Woods Hole, USA Martin J. Siegert, Imperial College London, London, UK Marvin A. Speece, Montana Technological University, Butte, USA Mathieu Casado, Alfred Wegener Institute Helmholtz Centre for Polar and Marine Research, Potsdam, Germany Michele Rebesco, OGS, Trieste, Italy Mike Weber, University of Bonn, Institute for Geosciences, Department of Geochemistry and Petrology, 53115 Bonn, Germany Minoru Ikehara, Kochi University, Japan Nicholas R. Golledge, Antarctic Research Centre Victoria University of Wellington, Wellington 6140, New Zealand Nigel Wardell, OGS, Trieste, Italy Paolo Montagna, Institute of Polar Sciences, National Research Council, Bologna, Italy Peter J. Barrett, Antarctic Research Centre, Victoria University of Wellington, Wellington, New Zealand. Peter K. Bijl, Utrecht University, Utrecht, The Netherlands Philip E. O’Brien, Macquarie University, Sydney, Australia Philip J. Bart, Louisiana State University, Baton Rouge, USA Raffaella Tolotti, University of Genoa, Genoa, Italy Reed P. Scherer, Northern Illinois University, DeKalb, IL, USA Renata G. Lucchi, National Institute of Oceanography and Applied Geophysics (OGS), Sgonico-Trieste, Italy Riccardo Geletti, National Institute of Oceanography and Applied Geophysics – OGS, Trieste, Italy Richard C.A. Hindmarsh, British Antarctic Survey & Durham University, Cambridge & Durham, United Kingdom Richard H. Levy, GNS Science and Victoria University of Wellington, Lower Hutt and Wellington, New Zealand Robert B. Dunbar, Stanford University, Stanford, California, USA Robert D. Larter, British Antarctic Survey, Cambridge, UK Robert M. Mckay, Antarctic Research Centre, Victoria University of Wellington, Wellington, New Zealand R. Selwyn Jones, Monash University (Melbourne, Australia) Sandra Passchier, Montclair State University, Montclair, USA Sean P.S. Gulick, University of Texas at Austin, Austin, Texas Sidney R. Hemming, Columbia University, New York, USA Stefanie Brachfeld, Montclair State University, New Jersey, USA Suzanne OConnell, Wesleyan University, Middletown, CT, USA Trevor Williams, International Ocean Discovery Program, Texas A&M University, College Station, USA Ursula Röhl, MARUM, University of Bremen, Bremen, Germany Yasmina M. Martos, NASA Goddard Space Flight Center, Greenbelt, MD, USA & University of Maryland College Park, MD, USAThe legacy of the Scientific Committee on Antarctic Research’s (SCAR) PAIS strategic research programme includes not only breakthrough scientific discoveries, but it is also the story of a long-standing deep collaboration amongst different multi-disciplinary researchers from many nations, to share scientific infrastructure and data, facilities, and numerical models, in order to address high priority questions regarding the evolution and behaviour of the Antarctic ice sheets (AIS). The PAIS research philosophy is based on data-data and data-model integration and intercomparison, and the development of ‘ice-to-abyss’ data transects and paleo-environmental, extending from the ice sheet interior to the deep sea. PAIS strives to improve understanding of AIS dynamics and to reduce uncertainty in model simulations of future ice loss and global sea level change, by studying warm periods of the geological past that are relevant to future climate scenarios. The multi-disciplinary approach fostered by PAIS represents its greatest strength. Eight years after the start of this programme, PAIS achievements have been high-profile and impactful, both in terms of field campaigns that collected unique data sets and samples, and in terms of scientific advances concerning past AIS dynamics, that have measurably improved understanding of ice sheet sensitivity in response to global warming. Here we provide an overview and synthesis of the new knowledge generated by the PAIS Programme and its implications for anticipating and managing the impacts of global sea-level rise.TN acknowledges support from MBIE Antarctic Science Platform contract ANTA1801

VAV1 and BAFF, via NFκB pathway, are genetic risk factors for myasthenia gravis

Objective To identify novel genetic loci that predispose to early‐onset myasthenia gravis (EOMG) applying a two‐stage association study, exploration, and replication strategy. Methods Thirty‐four loci and one confirmation loci, human leukocyte antigen (HLA)‐DRA, were selected as candidate genes by team members of groups involved in different research aspects of MG. In the exploration step, these candidate genes were genotyped in 384 EOMG and 384 matched controls and significant difference in allele frequency were found in eight genes. In the replication step, eight candidate genes and one confirmation loci were genotyped in 1177 EOMG patients and 814 controls, from nine European centres. Results Allele frequency differences were found in four novel loci: CD86, AKAP12, VAV1, B‐cell activating factor (BAFF), and tumor necrosis factor‐alpha (TNF‐α), and these differences were consistent in all nine cohorts. Haplotype trend test supported the differences in allele frequencies between cases and controls. In addition, allele frequency difference in female versus male patients at HLA‐DRA and TNF‐α loci were observed. Interpretation The genetic associations to EOMG outside the HLA complex are novel and of interest as VAV1 is a key signal transducer essential for T‐ and B‐cell activation, and BAFF is a cytokine that plays important roles in the proliferation and differentiation of B‐cells. Moreover, we noted striking epistasis between the predisposing VAV1 and BAFF haplotypes; they conferred a greater risk in combination than alone. These, and CD86, share the same signaling pathway, namely nuclear factor‐kappaB (NFκB), thus implicating dysregulation of proinflammatory signaling in predisposition to EOMG

Past Antarctic ice sheet dynamics (PAIS) and implications for future sea-level change

The legacy of the Scientific Committee on Antarctic Research’s (SCAR) PAIS strategic research programme includes not only breakthrough scientific discoveries, but it is also the story of a long-standing deep collaboration amongst different multi-disciplinary researchers from many nations, to share scientific infrastructure and data, facilities, and numerical models, in order to address high priority questions regarding the evolution and behaviour of the Antarctic ice sheets (AIS). The PAIS research philosophy is based on data-data and data-model integration and intercomparison, and the development of ‘ice-to-abyss’ data transects and paleo-environmental, extending from the ice sheet interior to the deep sea. PAIS strives to improve understanding of AIS dynamics and to reduce uncertainty in model simulations of future ice loss and global sea level change, by studying warm periods of the geological past that are relevant to future climate scenarios. The multi-disciplinary approach fostered by PAIS represents its greatest strength. Eight years after the start of this programme, PAIS achievements have been high-profile and impactful, both in terms of field campaigns that collected unique data sets and samples, and in terms of scientific advances concerning past AIS dynamics, that have measurably improved understanding of ice sheet sensitivity in response to global warming. Here we provide an overview and synthesis of the new knowledge generated by the PAIS Programme and its implications for anticipating and managing the impacts of global sea-level rise

Past Antarctic ice sheet dynamics (PAIS) and implications for future sea-level change

The legacy of the Scientific Committee on Antarctic Research’s (SCAR) PAIS strategic research programme includes not only breakthrough scientific discoveries, but it is also the story of a long-standing deep collaboration amongst different multi-disciplinary researchers from many nations, to share scientific infrastructure and data, facilities, and numerical models, in order to address high priority questions regarding the evolution and behaviour of the Antarctic ice sheets (AIS). The PAIS research philosophy is based on data-data and data-model integration and intercomparison, and the development of ‘ice-to-abyss’ data transects and paleo-environmental, extending from the ice sheet interior to the deep sea. PAIS strives to improve understanding of AIS dynamics and to reduce uncertainty in model simulations of future ice loss and global sea level change, by studying warm periods of the geological past that are relevant to future climate scenarios. The multi-disciplinary approach fostered by PAIS represents its greatest strength. Eight years after the start of this programme, PAIS achievements have been high-profile and impactful, both in terms of field campaigns that collected unique data sets and samples, and in terms of scientific advances concerning past AIS dynamics, that have measurably improved understanding of ice sheet sensitivity in response to global warming. Here we provide an overview and synthesis of the new knowledge generated by the PAIS Programme and its implications for anticipating and managing the impacts of global sea-level rise

VAV 1 and BAFF , via NF κB pathway, are genetic risk factors for myasthenia gravis

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Clinical and Molecular Spectrum of Myotonia and Periodic Paralyses Associated With Mutations in SCN4A in a Large Cohort of Italian Patients

Background: Four main clinical phenotypes have been traditionally described in patients mutated in SCN4A, including sodium-channel myotonia (SCM), paramyotonia congenita (PMC), Hypokaliemic type II (HypoPP2), and Hyperkaliemic/Normokaliemic periodic paralysis (HyperPP/NormoPP); in addition, rare phenotypes associated with mutations in SCN4A are congenital myasthenic syndrome and congenital myopathy. However, only scarce data have been reported in literature on large patient cohorts including phenotypes characterized by myotonia and episodes of paralysis. Methods: We retrospectively investigated clinical and molecular features of 80 patients fulfilling the following criteria: (1) clinical and neurophysiological diagnosis of myotonia, or clinical diagnosis of PP, and (2) presence of a pathogenic SCN4A gene variant. Patients presenting at birth with episodic laryngospasm or congenital myopathy-like phenotype with later onset of myotonia were considered as neonatal SCN4A. Results: PMC was observed in 36 (45%) patients, SCM in 30 (37.5%), Hyper/NormoPP in 7 (8.7%), HypoPP2 in 3 (3.7%), and neonatal SCN4A in 4 (5%). The median age at onset was significantly earlier in PMC than in SCM (p < 0.01) and in Hyper/NormoPP than in HypoPP2 (p = 0.02). Cold-induced myotonia was more frequently observed in PMC (n = 34) than in SCM (n = 23) (p = 0.04). No significant difference was found in age at onset of episodes of paralysis among PMC and PP or in frequency of permanent weakness between PP (n = 4), SCM (n = 5), and PMC (n = 10). PP was more frequently associated with mutations in the S4 region of the NaV1.4 channel protein compared to SCM and PMC (p < 0.01); mutations causing PMC were concentrated in the C-terminal region of the protein, while SCM-associated mutations were detected in all the protein domains. Conclusions: Our data suggest that skeletal muscle channelopathies associated with mutations in SCN4A represent a continuum in the clinical spectrum