Postpartum depression (PPD) appears at two peak periods: early-onset prior to 2 months after delivery and late-onset (2 months after delivery and beyond). The aim of our study is to evaluate the ...different genetic factors associated with early- and late-onset PPD. With the French multicenter interaction of gene and environment of depression during postpartum (IGEDEPP) cohort, we conducted a genome-wide association study (GWAS) on 234 women with early-onset PPD and 223 women with late-onset PPD, as well as 1,204 controls with no history of lifetime depression. We performed post-GWAS analyses: functional mapping and annotation of GWAS results using MAGMA thanks to Functional Mapping and Annotation of Genome-Wide Association Studies (FUMA), expression quantitative trait loci (QTL) analyses, mapping using data from the PsychENCODE and GTEx, and polygenic risk score (PRS) analysis based on published GWAS. We found two new significant candidate loci for early-onset PPD, rs6436132 in
PTPRN
gene on chromosome 2 and rs184644645 in
RAD18
on chromosome 14, respectively, and one region of interest with five significant associated SNPs in chromosome 20 for late-onset PPD. Variant rs6436132 is the most significant associated with early-onset PPD, and it is a QTL that significantly modifies the expression and splicing of the
PTPRN
gene in different brain tissues. We also found an enrichment of uterus tissue in the early expression of PPD genes. PRS analysis showed a genetic overlap between both early and late-onset PPD and major depressive disorder, but only early-onset PPD overlaps with bipolar disorder. Our study presents two GWAS separately, highlighting two candidate loci for early-onset PPD and one different region of interest for late-onset PPD. These results have important consequences in our understanding of these disorders, especially since our data reinforce the hormonal pathophysiological hypotheses for early-onset PPD.
Uveal melanoma (UM) is the most common cancer of the eye. The loss of chromosome 3 (M3) is associated with a high risk of metastases. M3 tumors are more infiltrated by T-lymphocytes than low-risk ...disomic-3 (D3) tumors, contrasting with other tumor types in which T cell infiltration correlates with better prognosis. Whether these T cells represent an antitumor response and how these T cells would be primed in the eye are both unknown. Herein, we characterized the T cells infiltrating primary UMs. CD8+ and Treg cells were more abundant in M3 than in D3 tumors. CD39+PD-1+CD8+ T cells were enriched in M3 tumors, suggesting specific responses to tumor antigen (Ag) as confirmed using HLA-A2:Melan-A tetramers. scRNAseq-VDJ analysis of T cells evidenced high numbers of proliferating CD39+PD1+CD8+ clonal expansions, suggesting in situ antitumor Ag responses. TCRseq and tumor-Ag tetramer staining characterized the recirculation pattern of the antitumor responses in M3 and D3 tumors. Thus, tumor-Ag responses occur in localized UMs, raising the question of the priming mechanisms in the absence of known lymphatic drainage.
The intestinal microbiota contributes to the global wellbeing of their host by their fundamental role in the induction and maintenance of a healthy immune system. Commensal bacteria shape the mucosal ...immune system by influencing the proportion and the activation state of anti-inflammatory regulatory T cells (Treg) by metabolites that are still only partially unravelled. Microbiota members such as Clostridiales provide a transforming growth factor β (TGFβ)-rich environment that promotes the accumulation of Treg cells in the gut. The intestinal epithelial cells (IECs) take a central part in this process, as they are a major source of TGFβ1 upon bacterial colonisation. In this study, we investigated which gut commensal bacteria were able to regulate the TGFB1 human promoter in IECs using supernatants from cultured bacteria. We reported that Firmicutes and Fusobacteria supernatants were the most potent TGFB1 modulators in HT-29 cells. Furthermore, we demonstrated that butyrate was the main metabolite in bacterial supernatants accounting for TGFβ1 increase. This butyrate-driven effect was independent of the G-protein coupled receptors GPR41, GPR43 and GPR109a, the transporter MCT1 as well as the transcription factors NF-κB and AP-1 present on TGFB1 promoter. Interestingly, HDAC inhibitors were inducing a similar TGFB1 increase suggesting that butyrate acted through its HDAC inhibitor properties. Finally, our results showed that SP1 was the main transcription factor mediating the HDAC inhibitor effect of butyrate on TGFB1 expression. This is, to our knowledge, the first characterisation of the mechanisms underlying TGFB1 regulation in IEC by commensal bacteria derived butyrate.
Autoantibodies directed against the N-methyl-D-aspartate receptor (NMDAR-Ab) are pathogenic immunoglobulins detected in patients suffering from NMDAR encephalitis. NMDAR-Ab alter the receptor ...membrane trafficking, synaptic transmission and neuronal network properties, leading to patients' neurological and psychiatric symptoms. Patients often have very little neuronal damage but rapid and massive (treatment-responsive) brain dysfunctions related to unknown early mechanism of NMDAR-Ab. Our understanding of this early molecular cascade remains surprisingly fragmented. Here, we used a combination of single molecule-based imaging of membrane proteins to unveil the spatio-temporal action of NMDAR-Ab onto live hippocampal neurons. We first demonstrate that different clones of NMDAR-Ab primarily affect extrasynaptic -and not synaptic- NMDAR. In the first minutes, NMDAR-Ab increase extrasynaptic NMDAR membrane dynamics, de-clustering its surface interactome. NMDAR-Ab also rapidly reshuffle all membrane proteins located at the extrasynaptic compartment. Consistent with this alteration of multiple proteins, NMDAR-Ab effects were not mediated through the sole interaction between NMDAR and EphB2 receptor. At the long-term, NMDAR-Ab reduce NMDAR synaptic pool by slowing down receptor membrane dynamics in a cross-linking independent manner. Remarkably, exposing only extrasynaptic NMDAR to NMDAR-Ab was sufficient to produce their full-blown effect on synaptic receptors. Collectively, we demonstrate that NMDAR-Ab first impair extrasynaptic proteins, and then the synaptic ones. These data shed thus new, and unsuspected, lights on the mode of action of NMDAR-Ab and likely to our understanding of (extra)synaptopathies.
The anaerobic bacterium
is significantly associated with human colorectal cancer (CRC) and is considered a significant contributor to the disease. The mechanisms underlying the promotion of ...intestinal tumor formation by
have only been partially uncovered. Here, we showed that
releases a metabolite into the microenvironment that strongly activates NF-κB in intestinal epithelial cells via the ALPK1/TIFA/TRAF6 pathway. Furthermore, we showed that the released molecule had the biological characteristics of ADP-heptose. We observed that
induction of this pathway increased the expression of the inflammatory cytokine IL-8 and two anti-apoptotic genes known to be implicated in CRC,
and
. Finally, it promoted the survival of CRC cells and reduced 5-fluorouracil chemosensitivity
. Taken together, our results emphasize the importance of the ALPK1/TIFA pathway in
induced-CRC pathogenesis, and identify the role of ADP-H in this process.
While Brachypodium distachyon (Brachypodium) is an emerging model for grasses, no expression atlas or gene coexpression network is available. Such tools are of high importance to provide insights ...into the function of Brachypodium genes.
We present a detailed Brachypodium expression atlas, capturing gene expression in its major organs at different developmental stages. The data were integrated into a large-scale coexpression database (www.gene2function.de), enabling identification of duplicated pathways and conserved processes across 10 plant species, thus allowing genome-wide inference of gene function.
We highlight the importance of the atlas and the platform through the identification of duplicated cell wall modules, and show that a lignin biosynthesis module is conserved across angiosperms. We identified and functionally characterised a putative ferulate 5-hydroxylase gene through overexpression of it in Brachypodium, which resulted in an increase in lignin syringyl units and reduced lignin content of mature stems, and led to improved saccharification of the stem biomass.
Our Brachypodium expression atlas thus provides a powerful resource to reveal functionally related genes, which may advance our understanding of important biological processes in grasses.
Water quality measures for inland and coastal waters are available as discrete samples from professional and volunteer water quality monitoring programs and higher-frequency, near-continuous data ...from automated in situ sensors. Water quality parameters also are estimated from model outputs and remote sensing. The integration of these data, via data assimilation, can result in a more holistic characterization of these highly dynamic ecosystems, and consequently improve water resource management. It is becoming common to see combinations of these data applied to answer relevant scientific questions. Yet, methods for scaling water quality data across regions and beyond, to provide actionable knowledge for stakeholders, have emerged only recently, particularly with the availability of satellite data now providing global coverage at high spatial resolution. In this paper, data sources and existing data integration frameworks are reviewed to give an overview of the present status and identify the gaps in existing frameworks. We propose an integration framework to provide information to user communities through the the Group on Earth Observations (GEO) AquaWatch Initiative. This aims to develop and build the global capacity and utility of water quality data, products, and information to support equitable and inclusive access for water resource management, policy and decision making.
The commensal bacteria that make up the gut microbiota impact the health of their host on multiple levels. In particular, the interactions taking place between the microbe-associated molecule ...patterns (MAMPs) and pattern recognition receptors (PRRs), expressed by intestinal epithelial cells (IECs), are crucial for maintaining intestinal homeostasis. While numerous studies showed that TLRs and NLRs are involved in the control of gut homeostasis by commensal bacteria, the role of additional innate immune receptors remains unclear. Here, we seek for novel MAMP-PRR interactions involved in the beneficial effect of the commensal bacterium Akkermansia muciniphila on intestinal homeostasis. We show that A. muciniphila strongly activates NF-κB in IECs by releasing one or more potent activating metabolites into the microenvironment. By using drugs, chemical and gene-editing tools, we found that the released metabolite(s) enter(s) epithelial cells and activate(s) NF-κB via an ALPK1, TIFA and TRAF6-dependent pathway. Furthermore, we show that the released molecule has the biological characteristics of the ALPK1 ligand ADP-heptose. Finally, we show that A. muciniphila induces the expression of the MUC2, BIRC3 and TNFAIP3 genes involved in the maintenance of the intestinal barrier function and that this process is dependent on TIFA. Altogether, our data strongly suggest that the commensal A. muciniphila promotes intestinal homeostasis by activating the ALPK1/TIFA/TRAF6 axis, an innate immune pathway exclusively described so far in the context of Gram-negative bacterial infections.
Flight behavior of insecticide-resistant and susceptible malaria mosquitoes approaching deltamethrin-treated nets was examined using a wind tunnel. Behavior was linked to resulting health status ...(dead or alive) using comparisons between outcomes from free-flight assays and standard World Health Organization (WHO) bioassays. There was no difference in response time, latency time to reach the net, or spatial distribution in the wind tunnel between treatments. Unaffected resistant mosquitoes spent less time close to (< 30 cm) treated nets. Nettings that caused high knockdown or mortality in standard WHO assays evoked significantly less mortality in the wind tunnel; there was no excitorepellent effect in mosquitoes making contact with the nettings in free flight. This study shows a new approach to understanding mosquito behavior near insecticidal nets. The methodology links free-flight behavior to mosquito health status on exposure to nets. The results suggest that behavioral assays can provide important insights for evaluation of insecticidal effects on disease vectors.
Distraction is a classic anxiety management strategy in preoperative setting with children: distracting activities take children's attention away from threatening clues. What is less clear is the ...differential effectiveness of this technique depending on the task, and the degree of children engagement with the distracting task. The present work examined the role of flow (state of intense concentration and absorption in the distracting task) on children's preoperative anxiety.
Anxiety and flow in a distracting activity were measured in a sample of 100 children (3 to 10 years-old), at two critical moments of the preoperative period prior to ambulatory surgery under general anesthesia (phase 1: up to separation from the parents; phase 2: up to general anesthesia). Common negative postoperative outcomes were also measured.
As expected, the analysis showed a negative association between the mean level of flow in the distracting activity during waiting periods and the preoperative anxiety of children at critical moments in the two phases (although there was no effect on postoperative recovery).
These findings demonstrate the importance of considering the degree of engagement in the distracting activity to understand the effectiveness of this strategy. The results may help provide guidance for better clinical application of this method.
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