Detection of coccolithophore blooms with biogeochemical‐argo floats

Coccolithophores (calcifying phytoplankton) form extensive blooms in temperate and subpolar oceans as evidenced from ocean-color satellites. This study examines the potential to detect coccolithophore blooms with BioGeoChemical-Argo (BGC-Argo) floats, autonomous ocean profilers equipped with bio-optical and physicochemical sensors. We first matched float data to ocean-color satellite data of calcite concentration to select floats that sampled coccolithophore blooms. We identified two floats in the Southern Ocean, which measured the particulate beam attenuation coefficient (c(p)) in addition to two core BGC-Argo variables, Chlorophyll-a concentration ([Chl-a]) and the particle backscattering coefficient (b(bp)). We show that coccolithophore blooms can be identified from floats by distinctively high values of (1) the b(bp)/c(p) ratio, a proxy for the refractive index of suspended particles, and (2) the b(bp)/[Chl-a] ratio, measurable by any BGC-Argo float. The latter thus paves the way to global investigations of environmental control of coccolithophore blooms and their role in carbon export. Plain Language Summary Coccolithophores are a group of phytoplankton that form an armor of calcite plates. Coccolithophores may form intense blooms which can be identified from space by so-called ocean-color satellites, providing global images of the color of the surface ocean. BioGeoChemical-Argo (BGC-Argo) floats, robots profiling down to 2,000 m with a variety of physicochemical and bio-optical sensors, present an increasingly attractive and cost-effective platform to study phytoplankton blooms and their impact on oceanic biogeochemical cycles. We show that coccolithophore blooms can be detected by BGC-Argo floats with high confidence, hence providing a new way to study them at the global scale as well as their role in sinking carbon. Key Points We matched profiling float trajectories with ocean-color satellite observations of coccolithophore blooms Two simple bio-optical indices permitted successful identification of coccolithophore blooms from floats in the Southern Ocean A method for identifying coccolithophore blooms at the global scale is proposed using regional thresholds of bio-optical float measurement

Interlaboratory study for coral Sr/Ca and other element/Ca ratio measurements

The Sr/Ca ratio of coral aragonite is used to reconstruct past sea surface temperature (SST). Twentyone laboratories took part in an interlaboratory study of coral Sr/Ca measurements. Results show interlaboratory bias can be significant, and in the extreme case could result in a range in SST estimates of 7°C. However, most of the data fall within a narrower range and the Porites coral reference material JCp- 1 is now characterized well enough to have a certified Sr/Ca value of 8.838 mmol/mol with an expanded uncertainty of 0.089 mmol/mol following International Association of Geoanalysts (IAG) guidelines. This uncertainty, at the 95% confidence level, equates to 1.5°C for SST estimates using Porites, so is approaching fitness for purpose. The comparable median within laboratory error is <0.5°C. This difference in uncertainties illustrates the interlaboratory bias component that should be reduced through the use of reference materials like the JCp-1. There are many potential sources contributing to biases in comparative methods but traces of Sr in Ca standards and uncertainties in reference solution composition can account for half of the combined uncertainty. Consensus values that fulfil the requirements to be certified values were also obtained for Mg/Ca in JCp-1 and for Sr/Ca and Mg/Ca ratios in the JCt-1 giant clam reference material. Reference values with variable fitness for purpose have also been obtained for Li/Ca, B/Ca, Ba/Ca, and U/Ca in both reference materials. In future, studies reporting coral element/Ca data should also report the average value obtained for a reference material such as the JCp-1

In-depth characterization of CD24(high)CD38(high) transitional human B cells reveals different regulatory profiles

International audienc

Genome-wide whole blood transcriptome profiling in a large European cohort of systemic sclerosis patients

Objectives The analysis of annotated transcripts from genome-wide expression studies may help to understand the pathogenesis of complex diseases, such as systemic sclerosis (SSc). We performed a whole blood (WB) transcriptome analysis on RNA collected in the context of the European PRECISESADS project, aiming at characterising the pathways that differentiate SSc from controls and that are reproducible in geographically diverse populations. Methods Samples from 162 patients and 252 controls were collected in RNA stabilisers. Cases and controls were divided into a discovery (n=79+163; Southern Europe) and validation cohort (n=83+89; Central-Western Europe). RNA sequencing was performed by an Illumina assay. Functional annotations of Reactome pathways were performed with the Functional Analysis of Individual Microarray Expression (FAIME) algorithm. In parallel, immunophenotyping of 28 circulating cell populations was performed. We tested the presence of differentially expressed genes/pathways and the correlation between absolute cell counts and RNA transcripts/FAIME scores in regression models. Results significant in both populations were considered as replicated. Results Overall, 15 224 genes and 1277 functional pathways were available; of these, 99 and 225 were significant in both sets. Among replicated pathways, we found a deregulation in type-I interferon, Toll-like receptor cascade, tumour suppressor p53 protein function, platelet degranulation and activation. RNA transcripts or FAIME scores were jointly correlated with cell subtypes with strong geographical differences; neutrophils were the major determinant of gene expression in SSc-WB samples. Conclusions We discovered a set of differentially expressed genes/pathways validated in two independent sets of patients with SSc, highlighting a number of deregulated processes that have relevance for the pathogenesis of autoimmunity and SSc

OP0137 GENOME-WIDE WHOLE-BLOOD TRANSCRIPTOME PROFILING IN A LARGE EUROPEAN COHORT OF SYSTEMIC SCLEROSIS PATIENTS

Background:The analysis of annotated transcripts from genome-wide expression studies data is of paramount importance to understand the molecular phenomena underlying the occurrence of complex diseases, such as systemic sclerosis (SSc).Objectives:To perform whole-blood transcriptome and pathway analysis on whole-blood (WB) RNA collected in two cohorts of European SSc patients. Via a discovery and validation strategy we aimed at characterizing the molecular pathways that differentiate SSc from controls and that are reproducible in geographically diverse populations.Methods:WB samples from 252 controls and 162 SSc patients were collected in RNA stabilizers. Patients were divided into a discovery (n=79; Southern Europe) and validation cohort (n=83; Central-Western Europe). RNA sequencing was performed by an Illumina assay. Functional annotations of Reactome pathways were performed with the FAIME algorithm. In parallel, a immunophenotyping analysis on 28 circulating cell populations was assessed. We then tested: the presence of differentially expressed genes or pathways and the correlation between absolute cell counts and RNA transcripts/FAIME scores in regression models. Results significant in both populations were considered as replicated.Results:A total of 15224 genes and 1277 related functional pathways were available for analysis. Among these, 99 genes and 225 pathways were significant in both sets. The heatmap in figure shows the relative expression of replicated pathways and the distribution of cases and controls (red and green bars). Among the significant pathways we found a deregulation in: type-I IFN, TLR-cascade and signalling, function of the tumor suppressor p53 protein, platelet degranulation and activation. Correlation analysis showed that the count of several cell subtypes is jointly associated with RNA transcripts or FAIME scores with strong differences in relation to the geographical origin of samples; neutrophils emerged as the major determinant of gene expression in SSc-whole-blood samples.Conclusion:We discovered a set of differentially expressed genes and pathways that could be validated in two independent sets of SSc patients highlighting a number of deregulated molecular processes that have relevance for the pathogenesis of autoimmunity and SSc.Acknowledgments:This work was supported by EU/EFPIA/Innovative Medicines Initiative Joint Undertaking PRECISESADS grant No. 115565.Disclosure of Interests:Lorenzo Beretta Grant/research support from: Pfizer, Guillermo Barturen: None declared, Barbara Vigone: None declared, Chiara Bellocchi: None declared, Nicolas Hunzelmann: None declared, Ellen Delanghe: None declared, László Kovács: None declared, Ricard Cervera: None declared, Maria Gerosa: None declared, Rafaela Ortega Castro: None declared, Isabel Almeida: None declared, Divi Cornec: None declared, Carlo Chizzolini Consultant of: Boehringer Ingelheim, Roche, Jacques-Olivier Pers: None declared, Zuzanna Makowska Employee of: Bayer AG, Anne buttgereit Employee of: Bayer AG, Ralf Lesche Employee of: Bayer, Martin Kerick: None declared, Marta Alarcon-Riquelme: None declared, Javier Martin Ibanez: None declare

High-content multimodal analysis supports the IL-7/IL-7 receptor axis as a relevant therapeutic target in primary Sjögren's syndrome

Objective: While the involvement of IL-7/IL-7R axis in pSS has been described in relation to T cells, little is known about the contribution of this pathway in relationship with other immune cells, and its implication in autoimmunity. Using high-content multiomics data, we aimed at characterizing IL-7R expressing cells and the involvement of IL-7/IL-7R pathway in pSS pathophysiology. Methods: An IL-7 signature established using RNA-sequencing of human PBMCs incubated with IL-7 was applied to 304 pSS patients, and on RNA-Seq datasets from tissue biopsies. High-content immunophenotyping using flow and imaging mass cytometry was developed to characterize peripheral and in situ IL-7R expression. Results: We identified a blood 4-gene IL-7 module (IKZF4, KIAA0040, PGAP1 and SOS1) associated with anti-SSA/Ro positiveness in patients as well as disease activity, and a tissue 5-gene IL-7 module (IL7R, PCED1B, TNFSF8, ADAM19, MYBL1) associated with infiltration severity. We confirmed expression of IL-7R on T cells subsets, and further observed upregulation of IL-7R on double-negative (DN) B cells, and especially DN2 B cells. IL-7R expression was increased in pSS compared to sicca patients with variations seen according to the degree of infiltration. When expressed, IL-7R was mainly found on epithelial cells, CD4+ and CD8+ T cells, switched memory B cells, DN B cells and M1 macrophages. Conclusion: This exhaustive characterization of the IL-7/IL-7R pathway in pSS pathophysiology established that two IL-7 gene modules discriminate pSS patients with a high IL-7 axis involvement. Their use could guide the implementation of an anti-IL-7R targeted therapy in a precision medicine approach. © 2023 Elsevier Lt

Decoding drivers of carbon flux attenuation in the oceanic biological pump

The biological pump supplies carbon to the oceans’ interior, driving long-term carbon sequestration and providing energy for deep-sea ecosystems1,2. Its efficiency is set by transformations of newly formed particles in the euphotic zone, followed by vertical flux attenuation via mesopelagic processes3. Depth attenuation of the particulate organic carbon (POC) flux is modulated by multiple processes involving zooplankton and/or microbes4,5. Nevertheless, it continues to be mainly parameterized using an empirically derived relationship, the ‘Martin curve’6. The derived power-law exponent is the standard metric used to compare flux attenuation patterns across oceanic provinces7,8. Here we present in situ experimental findings from C-RESPIRE9, a dual particle interceptor and incubator deployed at multiple mesopelagic depths, measuring microbially mediated POC flux attenuation. We find that across six contrasting oceanic regimes, representing a 30-fold range in POC flux, degradation by particle-attached microbes comprised 7–29 per cent of flux attenuation, implying a more influential role for zooplankton in flux attenuation. Microbial remineralization, normalized to POC flux, ranged by 20-fold across sites and depths, with the lowest rates at high POC fluxes. Vertical trends, of up to threefold changes, were linked to strong temperature gradients at low-latitude sites. In contrast, temperature played a lesser role at mid- and high-latitude sites, where vertical trends may be set jointly by particle biochemistry, fragmentation and microbial ecophysiology. This deconstruction of the Martin curve reveals the underpinning mechanisms that drive microbially mediated POC flux attenuation across oceanic provinces

Interferon and B-cell Signatures Inform Precision Medicine in Lupus Nephritis

Introduction: Current therapeutic management of lupus nephritis (LN) fails to induce long-term remission in over 50% of patients, highlighting the urgent need for additional options. Methods: We analyzed differentially expressed genes (DEGs) in peripheral blood from patients with active LN (n = 41) and active nonrenal lupus (n = 62) versus healthy controls (HCs) (n = 497) from the European PRECISESADS project (NTC02890121), and dysregulated gene modules in a discovery (n = 26) and a replication (n = 15) set of active LN cases. Results: Replicated gene modules qualified for correlation analyses with serologic markers, and regulatory network and druggability analysis. Unsupervised coexpression network analysis revealed 20 dysregulated gene modules and stratified the active LN population into 3 distinct subgroups. These subgroups were characterized by low, intermediate, and high interferon (IFN) signatures, with differential dysregulation of the “B cell” and “plasma cells/Ig” modules. Drugs annotated to the IFN network included CC-motif chemokine receptor 1 (CCR1) inhibitors, programmed death-ligand 1 (PD-L1) inhibitors, and irinotecan; whereas the anti-CD38 daratumumab and proteasome inhibitor bortezomib showed potential for counteracting the “plasma cells/Ig” signature. In silico analysis demonstrated the low-IFN subgroup to benefit from calcineurin inhibition and the intermediate-IFN subgroup from B-cell targeted therapies. High-IFN patients exhibited greater anticipated response to anifrolumab whereas daratumumab appeared beneficial to the intermediate-IFN and high-IFN subgroups. Conclusion: IFN upregulation and B and plasma cell gene dysregulation patterns revealed 3 subgroups of LN, which may not necessarily represent distinct disease phenotypes but rather phases of the inflammatory processes during a renal flare, providing a conceptual framework for precision medicine in LN. © 2024 International Society of Nephrolog

Primary Sj\uf6gren\u27s Disease: a review of unmet need, outcome measures, therapeutic advances and health economic impacts. Lessons from the NEw Clinical Endpoints in primary Sj\uf6gren\u27s Syndrome: an Interventional Trial based on stratifYing patients (NECESSITY) Innovative Health Initiative (IHI)

\ua9 2025 The Authors. Primary Sj\uf6gren\u27s disease (pSjD) is an autoimmune rheumatic disease involving exocrine glands and associated with high symptom burden (dryness, fatigue, pain), systemic features and salivary gland dysfunction. B-cell hyperactivity is common, with an increased risk of mucosa-associated lymphoid tissue lymphoma. This review describes the unmet need, scientific validity of outcome measures, optimisation of clinical trial design, therapeutic advances and how clinical improvement relates to health-related quality of life, additional quality-adjusted life years and economic benefit in pSjD. It derives from the EU-funded Necessity IHI Academic-Industry collaborative Consortium project while also drawing on work by the European Alliance of Associations for Rheumatology Sj\uf6gren\u27s task force and others. The NECESSITY Consortium, formed within the framework of the Innovative Health Initiative (IHI), comprises 20 academic partners, 1 patient group partner and 4 industry partners (NECESSITY; https://necessity-h2020.eu). Patient leaders have been closely involved, with expert advice obtained from the European Medicines Agency and the United States Food and Drug Administration during the development phase of a new outcome measure, the Sj\uf6gren\u27s Tool for Assessing Response composite response criteria. This tool is now undergoing validation through the NECESSITY IHI clinical trial and industry-sponsored trials

Identification of a new VHL exon and complex splicing alterations in familial erythrocytosis or von Hippel-Lindau disease

Chuvash polycythemia is an autosomal recessive form of erythrocytosis associated with a homozygous p.Arg200Trp mutation in the von Hippel-Lindau (VHL) gene. Since this discovery, additional VHL mutations have been identified in patients with congenital erythrocytosis, in a homozygous or compound-heterozygous state. VHL is a major tumor suppressor gene, mutations in which were first described in patients presenting with VHL disease, which is characterized by the development of highly vascularized tumors. Here, we identify a new VHL cryptic exon (termed E1′) deep in intron 1 that is naturally expressed in many tissues. More importantly, we identify mutations in E1′ in 7 families with erythrocytosis (1 homozygous case and 6 compound-heterozygous cases with a mutation in E1′ in addition to a mutation in VHL coding sequences) and in 1 large family with typical VHL disease but without any alteration in the other VHL exons. In this study, we show that the mutations induced a dysregulation of VHL splicing with excessive retention of E1′ and were associated with a downregulation of VHL protein expression. In addition, we demonstrate a pathogenic role for synonymous mutations in VHL exon 2 that altered splicing through E2-skipping in 5 families with erythrocytosis or VHL disease. In all the studied cases, the mutations differentially affected splicing, correlating with phenotype severity. This study demonstrates that cryptic exon retention and exon skipping are new VHL alterations and reveals a novel complex splicing regulation of the VHL gene. These findings open new avenues for diagnosis and research regarding the VHL-related hypoxia-signaling pathway