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Survival of plasma cells is regulated by B-cell maturation antigen (BCMA), a membrane-bound receptor activated by its agonist ligands BAFF and APRIL. Here we report that γ-secretase directly cleaves BCMA, without prior truncation by another protease. This direct shedding is facilitated by the short length of BCMA’s extracellular domain. In vitro , γ-secretase reduces BCMA-mediated NF-κB activation. In addition, γ-secretase releases soluble BCMA (sBCMA) that acts as a decoy neutralizing APRIL. In vivo , inhibition of γ-secretase enhances BCMA surface expression in plasma cells and increases their number in the bone marrow. Furthermore, in multiple sclerosis, sBCMA levels in spinal fluid are elevated and associated with intracerebral IgG production; in systemic lupus erythematosus, sBCMA levels in serum are elevated and correlate with disease activity. Together, shedding of BCMA by γ-secretase controls plasma cells in the bone marrow and yields a potential biomarker for B-cell involvement in human autoimmune diseases. B-cell maturation antigen (BCMA) regulates the survival of B cells and is essential for the maintenance of long-lived plasma cells. Here, the authors show that γ-secretase directly sheds BCMA from the cell surface and therefore regulates the number of plasma cells.

The BAFF-APRIL system is crucial for the pathogenesis of systemic lupus erythematosus (SLE) by promoting B cell survival, differentiation and the maintenance of humoral autoimmunity. Here, we investigated the relationship of BCMA expression on B cell subsets with its ligands BAFF and APRIL, together with soluble BCMA, and with clinical and serologic variables in a cohort of 100 SLE patients (86 under conventional and 14 under belimumab therapy) and 30 healthy controls (HCs) using multicolor flow cytometry and ELISA. We found that BCMA expression in SLE patients was significantly increased on all B cell subsets compared to HCs, with all examined components of the BAFF-APRIL system being upregulated. BCMA expression was significantly increased on switched and unswitched memory B cells compared to naïve B cells, both in HCs and SLE. BCMA expression on B cells correlated with plasmablast frequencies, serum anti-dsDNA antibodies and complement consumption, while soluble BCMA correlated with plasmablast frequency, highlighting its potential as a clinical biomarker. Belimumab treatment significantly reduced BCMA expression on most B cell subsets and soluble TACI and contributed to the inhibition of almost the entire BAFF-APRIL system and restoration of B cell homeostasis. These results provide insights into the complex dysregulation of the BAFF-APRIL system in SLE and highlight the therapeutic potential of targeting its components, particularly BCMA, in addition to its use as a biomarker for disease activity.

Survival of plasma cells is regulated by B-cell maturation antigen (BCMA), a membrane-bound receptor activated by its agonist ligands BAFF and APRIL. Here we report that γ-secretase directly cleaves BCMA, without prior truncation by another protease. This direct shedding is facilitated by the short length of BCMA's extracellular domain. In vitro, γ-secretase reduces BCMA-mediated NF-κB activation. In addition, γ-secretase releases soluble BCMA (sBCMA) that acts as a decoy neutralizing APRIL. In vivo, inhibition of γ-secretase enhances BCMA surface expression in plasma cells and increases their number in the bone marrow. Furthermore, in multiple sclerosis, sBCMA levels in spinal fluid are elevated and associated with intracerebral IgG production; in systemic lupus erythematosus, sBCMA levels in serum are elevated and correlate with disease activity. Together, shedding of BCMA by γ-secretase controls plasma cells in the bone marrow and yields a potential biomarker for B-cell involvement in human autoimmune diseases.

This study introduces CNRM‐ESM2‐1, the Earth system (ES) model of second generation developed by CNRM‐CERFACS for the sixth phase of the Coupled Model Intercomparison Project (CMIP6). CNRM‐ESM2‐1 offers a higher model complexity than the Atmosphere‐Ocean General Circulation Model CNRM‐CM6‐1 by adding interactive ES components such as carbon cycle, aerosols, and atmospheric chemistry. As both models share the same code, physical parameterizations, and grid resolution, they offer a fully traceable framework to investigate how far the represented ES processes impact the model performance over present‐day, response to external forcing and future climate projections. Using a large variety of CMIP6 experiments, we show that represented ES processes impact more prominently the model response to external forcing than the model performance over present‐day. Both models display comparable performance at replicating modern observations although the mean climate of CNRM‐ESM2‐1 is slightly warmer than that of CNRM‐CM6‐1. This difference arises from land cover‐aerosol interactions where the use of different soil vegetation distributions between both models impacts the rate of dust emissions. This interaction results in a smaller aerosol burden in CNRM‐ESM2‐1 than in CNRM‐CM6‐1, leading to a different surface radiative budget and climate. Greater differences are found when comparing the model response to external forcing and future climate projections. Represented ES processes damp future warming by up to 10% in CNRM‐ESM2‐1 with respect to CNRM‐CM6‐1. The representation of land vegetation and the CO2‐water‐stomatal feedback between both models explain about 60% of this difference. The remainder is driven by other ES feedbacks such as the natural aerosol feedback. Key Points This study introduces CNRM‐ESM2‐1 and describes its set‐up for CMIP6 Represented Earth system processes further impact the model response to external forcing than the model performance over present‐day Represented Earth system processes damp future warming by up to 10%

Toxicity testing and regulation of advanced materials at the nanoscale, i.e. nanosafety, is challenged by the growing number of nanomaterials and their property variants requiring assessment for potential human health impacts. The existing animal-reliant toxicity testing tools are onerous in terms of time and resources and are less and less in line with the international effort to reduce animal experiments. Thus, there is a need for faster, cheaper, sensitive and effective animal alternatives that are supported by mechanistic evidence. More importantly, there is an urgency for developing alternative testing strategies that help justify the strategic prioritization of testing or targeting the most apparent adverse outcomes, selection of specific endpoints and assays and identifying nanomaterials of high concern. The Adverse Outcome Pathway (AOP) framework is a systematic process that uses the available mechanistic information concerning a toxicological response and describes causal or mechanistic linkages between a molecular initiating event, a series of intermediate key events and the adverse outcome. The AOP framework provides pragmatic insights to promote the development of alternative testing strategies. This review will detail a brief overview of the AOP framework and its application to nanotoxicology, tools for developing AOPs and the role of toxicogenomics, and summarize various AOPs of relevance to inhalation toxicity of nanomaterials that are currently under various stages of development. The review also presents a network of AOPs derived from connecting all AOPs, which shows that several adverse outcomes induced by nanomaterials originate from a molecular initiating event that describes the interaction of nanomaterials with lung cells and involve similar intermediate key events. Finally, using the example of an established AOP for lung fibrosis, the review will discuss various in vitro tests available for assessing lung fibrosis and how the information can be used to support a tiered testing strategy for lung fibrosis. The AOPs and AOP network enable deeper understanding of mechanisms involved in inhalation toxicity of nanomaterials and provide a strategy for the development of alternative test methods for hazard and risk assessment of nanomaterials.

Severe influenza disease strikes otherwise healthy children and remains unexplained. We report compound heterozygous null mutations in IRF7, which encodes the transcription factor interferon regulatory factor 7, in an otherwise healthy child who suffered life-threatening influenza during primary infection. In response to influenza virus, the patient's leukocytes and plasmacytoid dendritic cells produced very little type I and III interferons (IFNs). Moreover, the patient's dermal fibroblasts and induced pluripotent stem cell (iPSC)–derived pulmonary epithelial cells produced reduced amounts of type I IFN and displayed increased influenza virus replication. These findings suggest that IRF7-dependent amplification of type I and III IFNs is required for protection against primary infection by influenza virus in humans. They also show that severe influenza may result from single-gene inborn errors of immunity.

Purpose In Martinique, there is an unmet need in EC management. Although the incidence rate is similar to that in mainland France, the mortality rate is higher, potentially due to the over-incidence of high-grade tumors. Recently, we reported CCNE1 amplification in 70% of these tumors which have a poor prognosis. This alteration has been observed in non-endometrioid subtypes of African American women. To elucidate the over-incidence of poor prognosis EC in Martinique, we aim to describe molecular profiles especially CCNE1 amplification of a cohort of all patient diagnosed between January 2023 and June 2024. Methods CCNE1 amplification status was determined using digital PCR. We also performed the analysis of POLE , MMR and TP53 to classified tumors in current molecular classification. A total of 55 patients were included in our study, revealing a different distribution of biomarkers than described in the literature. Results We reported an over-incidence of TP53 mutations and CCNE1 amplification. Conversely, the prevalence of POLE mutations was lower. In this study, non-endometrioid subtypes were particularly associated with CCNE1 amplification that is consistent with previous studies. The molecular classification observed in our cohort is consistent with findings in populations of African descent. The higher CCNE1 amplification rate mirrors those seen in these populations. Conclusion Given the ethnic origin of the Martinique population, these data suggest that CCNE1 amplification may be linked to African genetic heritage and could explain the over-incidence of non-endometrioid subtypes in these populations. Furthermore, our study contributes to addressing racial disparities in endometrial cancer outcomes by providing crucial insights into the genetic factors that may influence the prognosis of African-descended populations.

The prognosis of patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) remains unsatisfactory and, despite major advances in genomic studies, the biological mechanisms underlying chemoresistance are still poorly understood. We conducted for the first time a large-scale differential multi-omics investigation on DLBCL patient’s samples in order to identify new biomarkers that could early identify patients at risk of R/R disease and to identify new targets that could determine chemorefractoriness. We compared a well-characterized cohort of R/R versus chemosensitive DLBCL patients by combining label-free quantitative proteomics and targeted RNA sequencing performed on the same tissues samples. The cross-section of both data levels allowed extracting a sub-list of 22 transcripts/proteins pairs whose expression levels significantly differed between the two groups of patients. In particular, we identified significant targets related to tumor metabolism (Hexokinase 3), microenvironment (IDO1, CXCL13), cancer cells proliferation, migration and invasion (S100 proteins) or BCR signaling pathway (CD79B). Overall, this study revealed several extremely promising biomarker candidates related to DLBCL chemorefractoriness and highlighted some new potential therapeutic drug targets. The complete datasets have been made publically available and should constitute a valuable resource for the future research.

The subtropical oceanic gyre in the North Pacific Ocean is currently covered with tens of thousands of tonnes of floating plastic debris, dispersed over millions of square kilometres. A large fraction is composed of fishing nets and ropes while the rest is mostly composed of hard plastic objects and fragments, sometimes carrying evidence on their origin. In 2019, an oceanographic mission conducted in the area, retrieved over 6000 hard plastic debris items > 5 cm. The debris was later sorted, counted, weighed, and analysed for evidence of origin and age. Our results, complemented with numerical model simulations and findings from a previous oceanographic mission, revealed that a majority of the floating material stems from fishing activities. While recent assessments for plastic inputs into the ocean point to coastal developing economies and rivers as major contributors into oceanic plastic pollution, here we show that most floating plastics in the North Pacific subtropical gyre can be traced back to five industrialised fishing nations, highlighting the important role the fishing industry plays in the solution to this global issue.

Genes underneath signals from genome-wide association studies (GWAS) for kidney function are promising targets for functional studies, but prioritizing variants and genes is challenging. By GWAS meta-analysis for creatinine-based estimated glomerular filtration rate (eGFR) from the Chronic Kidney Disease Genetics Consortium and UK Biobank (n = 1,201,909), we expand the number of eGFRcrea loci (424 loci, 201 novel; 9.8% eGFRcrea variance explained by 634 independent signal variants). Our increased sample size in fine-mapping (n = 1,004,040, European) more than doubles the number of signals with resolved fine-mapping (99% credible sets down to 1 variant for 44 signals, ≤5 variants for 138 signals). Cystatin-based eGFR and/or blood urea nitrogen association support 348 loci (n = 460,826 and 852,678, respectively). Our customizable tool for Gene PrioritiSation reveals 23 compelling genes including mechanistic insights and enables navigation through genes and variants likely relevant for kidney function in human to help select targets for experimental follow-up. Identifying causal variants and genes in genome-wide association studies remains a challenge, an issue that is ameliorated with larger sample sizes. Here the authors meta-analyze kidney function genome-wide association studies to identify new loci and fine-map loci to home in on variants and genes involved in kidney function.