IgG4 Valency Modulates the Pathogenicity of Anti-Neurofascin-155 IgG4 in Autoimmune Nodopathy

Altres ajuts: Agence Nationale pour la Recherche; Association Française contre les Myopathies (23593).Background and Objective s : IgG4 autoantibodies to neurofascin-155 (Nfasc155) are associated with a subgroup of patients with chronic inflammatory demyelinating polyneuropathy (CIDP), currently named autoimmune nodopathy. We previously demonstrated that those antibodies alter conduction along myelinated axons by inducing Nfasc155 depletion and paranode destruction. In blood, IgG4 have the potency to exchange their moiety with other unrelated IgG4 through a process called Fab-arm exchange (FAE). This process results in functionally monovalent antibodies and may affect the pathogenicity of autoantibodies. Here, we examined this issue and whether FAE is beneficial or detrimental for Nfasc155 autoimmune nodopathy. Methods : The bivalency and monospecificity of anti-Nfasc155 were examined by sandwich ELISA in 10 reactive patients, 10 unreactive CIDP patients, and 10 healthy controls. FAE was induced in vitro using reduced glutathione and unreactive IgG4, and the ratio of the : light chain was monitored. To determine the pathogenic potential of bivalent anti-Nfasc155 IgG4, autoantibodies derived from patients were enzymatically cleaved into monovalent Fab and bivalent F(ab')2 or swapped with unreactive IgG4 and then were injected in neonatal animals. Results : Monospecific bivalent IgG4 against Nfasc155 were detected in the serum of all reactive patients, indicating that a fraction of IgG4 have not undergone FAE in situ. These IgG4 were, nonetheless, capable of engaging into FAE with unreactive IgG4 in vitro, and this decreased the levels of monospecific antibodies and modulated the ratio of the : light chain. When injected in animals, monovalent anti-Nfasc155 Fab did not alter the formation of paranodes; by contrast, both native anti-Nfasc155 IgG4 and F(ab')2 fragments strongly impaired paranode formation. The promotion of FAE with unreactive IgG4 also strongly diminished the pathogenic potential of anti-Nfasc155 IgG4 in animals and decreased IgG4 clustering on Schwann cells. Discussion : Our findings demonstrate that monospecific and bivalent anti-Nfasc155 IgG4 are detected in patients and that those autoantibodies are the pathogenic ones. The transformation of anti-Nfasc155 IgG4 into monovalent Fab or functionally monovalent IgG4 through FAE strongly decreases paranodal alterations. Bivalency thus appears crucial for Nfasc155 clustering and paranode destruction

Pebble abrasion during fluvial transport: Experimental results and implications for the evolution of the sediment load along rivers

International audienceIn actively eroding landscapes, fluvial abrasion modifies the characteristics of the sediment carried by rivers and consequently has a direct impact on the ability of mountain rivers to erode their bedrock and on the characteristics and volume of the sediment exported from upland catchments. In this experimental study, we use a novel flume replicating hydrodynamic conditions prevailing in mountain rivers to investigate the role played by different controlling variables on pebble abrasion during fluvial transport. Lithology controls abrasion rates and processes, with differences in abrasion rates exceeding two orders of magnitude. Attrition as well as breaking and splitting are efficient processes in reducing particle size. Mass loss by attrition increases with particle velocity but is weakly dependent on particle size. Fragment production is enhanced by the use of large particles, high impact velocities and the presence of joints. Based on our experimental results, we extrapolate a preliminary generic relationship between pebble attrition rate and transport stage (τ*/τ*c), where τ* = fluvial Shields stress and τ*c = critical Shields stress for incipient pebble motion. This relationship predicts that attrition rates are independent of transport stage for (τ*/τ*c) ≤ 3 and increase linearly with transport stage beyond this value. We evaluate the extent to which abrasion rates control downstream fining in several different natural settings. A simplified model predicts that the most resistant lithologies control bed load flux and fining ratio and that the concavity of transport-limited river profiles should rarely exceed 0.25 in the absence of deposition and sorting

Predominant floodplain over mountain weathering of Himalayan sediments (Ganga basin)

Author Posting. © The Author(s), 2011. This is the author's version of the work. It is posted here by permission of Elsevier B.V. for personal use, not for redistribution. The definitive version was published in Geochimica et Cosmochimica Acta 84 (2012): 410-432, doi:10.1016/j.gca.2012.02.001.We present an extensive river sediment dataset covering the Ganga basin from the Himalayan front downstream to the Ganga mainstream in Bangladesh. These sediments were mainly collected over several monsoon seasons and include depth profiles of suspended particles in the river water column. Mineral sorting is the first order control on the chemical composition of river sediments. Taking into account this variability we show that sediments become significantly depleted in mobile elements during their transit through the floodplain. By comparing sediments sampled at the Himalayan front with sediments from the Ganga mainstream in Bangladesh it is possible to budget weathering in the floodplain. Assuming a steady state weathering regime in the floodplain, the weathering of Himalayan sediments in the Gangetic floodplain releases ca. (189 ± 92)109 and (69 ± 22)109 moles/yr of carbonate bound Ca and Mg to the dissolved load, respectively. Silicate weathering releases (53 ± 18)109 and (42 ± 13)109 moles/yr of Na and K while the release of silicate Mg and Ca is substantially lower, between ca. 0 and 20109 moles/yr. Additionally, we show that sediment hydration, [H2O+], is a sensitive tracer of silicate weathering that can be used in continental detrital environments, such as the Ganga basin. Both [H2O+] content and the D/H isotopic composition of sediments increases during floodplain transfer in response to mineral hydrolysis and neoformations associated to weathering reactions. By comparing the chemical composition of river sediments across the floodplain with the composition of the eroded Himalayan source rocks, we suggest that the floodplain is the dominant location of silicate weathering for Na, K and [H2O+]. Overall this work emphasizes the role of the Gangetic floodplain in weathering Himalayan sediments. It also demonstrates how detrital sediments can be used as weathering tracers if mineralogical and chemical sorting effects are properly taken into account.This work was supported by INSU program “Relief de la Terre” and ANR Calimero. Valier Galy was supported by the U.S. National Science Fundation (Grant OCE-0851015)

Growth factors in multiple myeloma: a comprehensive analysis of their expression in tumor cells and bone marrow environment using Affymetrix microarrays

<p>Abstract</p> <p>Background</p> <p>Multiple myeloma (MM) is characterized by a strong dependence of the tumor cells on their microenvironment, which produces growth factors supporting survival and proliferation of myeloma cells (MMC). In the past few years, many myeloma growth factors (MGF) have been described in the literature. However, their relative importance and the nature of the cells producing MGF remain unidentified for many of them.</p> <p>Methods</p> <p>We have analysed the expression of 51 MGF and 36 MGF receptors (MGFR) using Affymetrix microarrays throughout normal plasma cell differentiation, in MMC and in cells from the bone marrow (BM) microenvironment (CD14, CD3, polymorphonuclear neutrophils, stromal cells and osteoclasts).</p> <p>Results</p> <p>4/51 MGF and 9/36 MGF-receptors genes were significantly overexpressed in plasmablasts (PPC) and BM plasma cell (BMPC) compared to B cells whereas 11 MGF and 11 MGFR genes were overexpressed in BMPC compared to PPC. 3 MGF genes (AREG, NRG3, Wnt5A) and none of the receptors were significantly overexpressed in MMC versus BMPC. Furthermore, 3/51 MGF genes were overexpressed in MMC compared to the the BM microenvironment whereas 22/51 MGF genes were overexpressed in one environment subpopulation compared to MMC.</p> <p>Conclusions</p> <p>Two major messages arise from this analysis 1) The majority of MGF genes is expressed by the bone marrow environment. 2) Several MGF and their receptors are overexpressed throughout normal plasma cell differentiation. This study provides an extensive and comparative analysis of MGF expression in plasma cell differentiation and in MM and gives new insights in the understanding of intercellular communication signals in MM.</p

Processus constitutifs de l'état de stress post-traumatique (implication des réponses psychologiques et biologiques précoces)

MONTPELLIER-BU Médecine UPM (341722108) / SudocMONTPELLIER-BU Médecine (341722104) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Apathy in Obsessive-Compulsive Disorder and Its Psychological Correlates: Comparison With Individuals With Schizophrenia

International audienceObjective: Apathy, defined as reduced goal-directed behavior, is a frequent symptom in mental and neurological disorders but has been poorly studied in individuals with obsessive-compulsive disorder (OCD). The primary aim of this study was to examine levels of apathy between individuals with OCD, healthy control subjects, and individuals with schizophrenia, a mental disorder with high levels of apathy. The second aim was to assess whether the psychological factors that have been previously shown as underlying apathy in other mental disorders were associated with apathy in patients with OCD.Methods: This exploratory study included 25 individuals with OCD, 24 individuals with schizophrenia, and 24 healthy control subjects. Apathy was assessed using the Lille Apathy Rating Scale. Measures of depression, sensibility to punishment and reward, defeatist performance beliefs, and cognitive functioning were also assessed.Results: Individuals diagnosed with OCD and schizophrenia scored significantly higher than healthy control subjects on the apathy total score. Levels of apathy among OCD patients were mainly associated with depression but also dysexecutive functioning and defeatist beliefs.Conclusions: These findings suggest that motivational deficits could play a central role in disability caused by OCD. Similar to other mental disorders, various psychological factors, including depression, defeatist beliefs, and dysexecutive functioning, are involved in apathetic manifestations. However, the fact that depression is the variable most associated with apathy indicates that apathetic symptoms in patients with OCD must be considered mainly as secondary rather than primary symptoms

Descriptcion de una nueva especie del genero Doxocopa Hübner, 1819, del Choco ecuatoriano

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Diminished capacity to make treatment decision for COVID-19 vaccination in schizophrenia

International audienceRecent evidence suggests that people with schizophrenia are at high risk for severe COVID-19 and should be prioritized for vaccination. However, impaired decision-making capacities could negatively affect the uptake of COVID-19 vaccination in this population. Capacity to consent to COVID-19 vaccination was assessed in 80 outpatients with schizophrenia. Using the MacArthur Competence Assessment Tool for Treatment, 56.3% of the sample were classified as having diminished capacity to consent to the vaccination. Diminished capacity to consent to COVID-19 vaccination was associated with lower vaccination rates, poorer cognition and higher level of psychotic symptoms. Developing interventions for enhancing informed consent for vaccination is urgent within this population

Evidence for a Great Medieval Earthquake (A.D. 1100) in Central Himalaya, Nepal.

International audiencehe Himalayan orogen has produced three thrust earthquakes with moment magnitude (Mw) 7.8 to 8.5 during the past century, yet no surface ruptures associated with these great earthquakes have been documented. Here, we present paleoseismic evidence from east central Nepal that, since ~700 A.D., a single earthquake ruptured the Frontal Thrust fault at ~1100 A.D., with a surface displacement of ~17 (+5/–3) meters and a lateral extent and size that could have exceeded 240 kilometers and ~Mw 8.8, respectively. Ruptures associated with Mw <8.2 events would contribute to the frontal Himalayas folding but would stop before reaching the surface. These findings could require substantial modifications to current regional seismic hazard models

Success of tardive electroconvulsive therapy sessions after loxapine-induced malignant syndrome in the context of very poor metabolisation

International audienceWe report the success of tardive electroconvulsive therapy in a case of loxapine malignant syndrome with catatonia. Loxapine and its metabolites were measured in biological samples by liquid chromatography coupled to tandem mass spectrometry. Genes were studied by sequencing and quantitative polymerase chain reaction (PCR). Plasmatic drug concentrations showed a supratherapeutic concentration of loxapine with a very low 8-hydroxyloxapine/loxapine ratio (range from 0.32 to 0.66, normal value>2 for 100mg) and a very long elimination half-life of loxapine (half-life>140h, normal value from 1 to 4hours). We tried to explain this kinetics by exploring the main pharmacogenes implicated in the metabolism of loxapine. No genetic abnormality for CYP1A2 was observed. The study of associated treatments showed the potential contribution of valproate. Pharmacokinetics and pharmacogenetics investigations revealed a blockade of the CYP1A2 metabolic pathway without genetic abnormalities, probably due to valproate co-medication. Toxicological monitoring of loxapine and its metabolites helped to explain the persistence of symptoms and to adapt the therapeutic management