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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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

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

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

International audienc

Early and middle Miocene ice sheet dynamics in the Ross Sea: Results from integrated core-log-seismic interpretation

Oscillations in ice sheet extent during early and middle Miocene are intermittently preserved in the sedimentary record from the Antarctic continental shelf, with widespread erosion occurring during major ice sheet advances, and open marine deposition during times of ice sheet retreat. Data from seismic reflection surveys and drill sites from Deep Sea Drilling Project Leg 28 and International Ocean Discovery Program Expedition 374, located across the present-day middle continental shelf of the central Ross Sea (Antarctica), indicate the presence of expanded early to middle Miocene sedimentary sections. These include the Miocene climate optimum (MCO ca. 17–14.6 Ma) and the middle Miocene climate transition (MMCT ca. 14.6–13.9 Ma). Here, we correlate drill core records, wireline logs and reflection seismic data to elucidate the depositional architecture of the continental shelf and reconstruct the evolution and variability of dynamic ice sheets in the Ross Sea during the Miocene. Drill-site data are used to constrain seismic isopach maps that document the evolution of different ice sheets and ice caps which influenced sedimentary processes in the Ross Sea through the early to middle Miocene. In the early Miocene, periods of localized advance of the ice margin are revealed by the formation of thick sediment wedges prograding into the basins. At this time, morainal bank complexes are distinguished along the basin margins suggesting sediment supply derived from marine-terminating glaciers. During the MCO, biosiliceous-bearing sediments are regionally mapped within the depocenters of the major sedimentary basin across the Ross Sea, indicative of widespread open marine deposition with reduced glacimarine influence. At the MMCT, a distinct erosive surface is interpreted as representing large-scale marine-based ice sheet advance over most of the Ross Sea paleo-continental shelf. The regional mapping of the seismic stratigraphic architecture and its correlation to drilling data indicate a regional transition through the Miocene from growth of ice caps and inland ice sheets with marine-terminating margins, to widespread marine-based ice sheets extending across the outer continental shelf in the Ross Sea