Long-time behavior of the Stokes-transport system in a channel

The coupling between the transport equation for the density and the Stokes equation is considered in a periodic channel. More precisely, the density is advected by pure transport by a velocity field given by the Stokes equation with source force coming from the gravity due to differences in the density. Dirichlet boundary conditions are taken for the velocity field on the bottom and top of the channel, and periodic conditions in the horizontal variable. We prove that the affine stratified density profile is stable under small perturbations in Sobolev spaces and prove convergence of the density to another limiting stratified density profile for large time with an explicit algebraic decay rate. Moreover, we are able to precisely identify the limiting profile as the decreasing vertical rearrangement of the initial density. Finally, we study boundary layers formation to precisely characterize the long-time behavior beyond the constant limiting profile and enlighten the optimal decay rate.Comment: 69 page

Use of geochemical signatures, including rare earth elements, in mosses and lichens to assess spatial integration and the influence of forest environment

In order to assess the influence of local environment and spatial integration of Trace Metals (TM) by biomonitors, Al, As, Cd, Cr, Cs, Cu, Fe, Mn, Ni, Pb, Sb, Sn, V and Zn and some rare earth element (REE) concentrations have been measured in lichens and mosses collected in three French forest sites located in three distinct mountainous areas, as well as in the local soil and bedrock, and in both bulk deposition (BD) and throughfall (TF). Similar enrichment factors (EF) were calculated using lichens and mosses and local bedrock for most elements, except for Cs, Mn, Ni, Pb, and Cu which were significantly (KW, p < 0.05) more enriched in mosses. Similar REE ratios were measured in soils, bedrock, lichens and mosses at each study sites, indicating a regional integration of atmospheric deposition by both biomonitors. Both TM signature and REE composition of mosses revealed that this biomonitor is highly influenced by throughfall composition, and reflect atmospheric deposition interaction with the forest canopy. This explained the higher enrichment measured in mosses for elements which concentration in deposition were influenced by the canopy, either due to leaching (Mn), direct uptake (Ni), or dry deposition dissolution (Pb, Cu, Cs)

Subclinical hepatitis E virus infection in laboratory ferrets in the UK

Ferrets are widely used for experimental modelling of viral infections. However, background disease in ferrets could potentially confound intended experimental interpretation. Here we report the detection of a subclinical infection of ferret hepatitis E virus (FRHEV) within a colony sub-group of female laboratory ferrets that had been enrolled on an experimental viral infection study (non-hepatitis). Lymphoplasmacytic cuffing of periportal spaces was identified on histopathology but was negative for the RNA and antigens of the administered virus. Follow-up viral metagenomic analysis conducted on liver specimens revealed sequences attributed to FRHEV and these were confirmed by reverse-transcriptase polymerase chain reaction. Further genomic analysis revealed contiguous sequences spanning 79-95 % of the FRHEV genome and that the sequences were closely related to those reported previously in Europe. Using in situ hybridization by RNAScope, we confirmed the presence of HEV-specific RNA in hepatocytes. The HEV open reading frame 2 (ORF2) protein was also detected by immunohistochemistry in the hepatocytes and the biliary canaliculi. In conclusion, the results of our study provide evidence of background infection with FRHEV in laboratory ferrets. As this infection can be subclinical, we recommend routine monitoring of ferret populations using virological and liver function tests to avoid incorrect causal attribution of any liver disease detected in in vivo studies

Sublethal necroptosis signaling promotes inflammation and liver cancer

It is currently not well known how necroptosis and necroptosis responses manifest in vivo. Here, we uncovered a molecular switch facilitating reprogramming between two alternative modes of necroptosis signaling in hepatocytes, fundamentally affecting immune responses and hepatocarcinogenesis. Concomitant necrosome and NF-κB activation in hepatocytes, which physiologically express low concentrations of receptor-interacting kinase 3 (RIPK3), did not lead to immediate cell death but forced them into a prolonged "sublethal" state with leaky membranes, functioning as secretory cells that released specific chemokines including CCL20 and MCP-1. This triggered hepatic cell proliferation as well as activation of procarcinogenic monocyte-derived macrophage cell clusters, contributing to hepatocarcinogenesis. In contrast, necrosome activation in hepatocytes with inactive NF-κB-signaling caused an accelerated execution of necroptosis, limiting alarmin release, and thereby preventing inflammation and hepatocarcinogenesis. Consistently, intratumoral NF-κB-necroptosis signatures were associated with poor prognosis in human hepatocarcinogenesis. Therefore, pharmacological reprogramming between these distinct forms of necroptosis may represent a promising strategy against hepatocellular carcinoma

Intestinal B-cells license metabolic T-cell activation in NASH microbiota/antigen-independently and contribute to fibrosis by IgA-FcR signalling

BACKGROUND & AIMS The progression of nonalcoholic steatohepatitis (NASH) to fibrosis and hepatocellular carcinoma (HCC) is aggravated by auto-aggressive T cells. The gut-liver axis contributes to NASH, but the mechanisms involved and the consequences for NASH-induced fibrosis and liver cancer remain unknown. We investigated the role of gastrointestinal B cells in the development of NASH, fibrosis and NASH-induced HCC. METHODS C57BL/6J wild-type (WT), B cell-deficient and different immunoglobulin-deficient or transgenic mice were fed distinct NASH diets (for example, choline-deficient high-fat diet, CD-HFD) or chow diet for 6 or 12 months, whereafter NASH, fibrosis, and NASH-induced HCC were assessed and analysed. Specific pathogen-free/germ-free WT and μMT mice (containing B cells only in the gastrointestinal tract) were fed a CD-HFD, and treated with an anti-CD20 antibody, whereafter NASH and fibrosis were assessed. Tissue biopsy samples from patients with NAFL, NASH and cirrhosis were analysed to correlate the secretion of immunoglobulins to clinicopathological features. Flow cytometry, immunohistochemistry and scRNA-Seq analysis were performed in liver and gastrointestinal tissue for immune cells in mice and humans. RESULTS Activated intestinal B cells were increased in mouse and human NASH samples and licensed metabolic T-cell activation to induce NASH independently of antigen-specificity and gut microbiota. Genetic or therapeutic depletion of systemic or gastrointestinal B cells prevented or reverted NASH and liver fibrosis. IgA secretion was necessary for fibrosis induction by activating CD11b+CCR2+F4/80+CD11c-FCGR1+ hepatic myeloid cells through an IgA-FcR signalling axis. Similarly, patients with NASH had increased numbers of activated intestinal B-cells and showed a positive correlation between IgA levels and activated FcRγ+ hepatic myeloid cells as well extent of liver fibrosis. CONCLUSIONS Intestinal B cells and the IgA-FcR signalling axis represent potential therapeutic targets for treating NASH. IMPACT AND IMPLICATIONS Nonalcoholic steatohepatitis (NASH) is a chronic inflammatory condition on the rise and can lead to hepatocellular carcinoma (HCC), the 3rd most common cause of cancer-related death worldwide. Currently, there is no effective treatment for this progressive disease that correlates with a marked risk of HCC mortality and carries a substantial healthcare burden. To date, among all the solid tumours, especially in HCC, the incidence and mortality rates are almost the same, making it crucial to find curative treatments for chronic diseases, such as NASH, which highly predispose to tumorigenesis. We have previously shown that NASH is an auto-aggressive condition aggravated, amongst others, by T cells. Therefore, we hypothesized that B cells might have a role in disease induction and progression. Our present work highlights that B cells have a dual role in NASH pathogenesis, being implicated in the activation of auto-aggressive T cells and the development of fibrosis via activation of monocyte-derived macrophages by secreted immunoglobulins (e.g., IgA). Furthermore, we could show that the absence of B cells prevented HCC development. B-cell intrinsic signalling pathways, secreted immunoglobulins, and interactions of B cells with other immune cells are potential targets in combinatorial NASH therapies against inflammation and fibrosis

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Thérapie cellulaire des maladies respiratoires (utilisation de la voie aérienne pour l'implantation de cellules souches)

Une destruction progressive et irréversible de l'épithélium des voies aériennes est observée chez les patients atteints de maladies respiratoires. Une stratégie de thérapie cellulaire consisterait à utiliser des cellules souches pour coloniser les zones épithéliales lésées et réparer l'épithélium. Les premiers travaux de thérapie cellulaire respiratoire ont porté sur l'administration systémique de cellules souches adultes chez des souris irradiées. Ces études ont conduit à des résultats modestes et controversés à cause des méthodes de détection par fluorescence. L objectif de ce projet était de développer une stratégie de thérapie cellulaire visant l épithélium, tout en évitant l irradiation des souris et l utilisation de la fluorescence. Des cellules souches embryonnaires et des cellules souches mésenchymateuses ont été injectées en intratrachéal chez des souris présentant des lésions épithéliales dans les voies aériennes. Ces lésions étaient induites par l injection préalable d un détergent, le polidocanol. Des méthodes quantitatives ont montré que 0.4 à 5,5 % des cellules souches survivent dans les voies aériennes lésées. Cette survie s avère dépendante de l état de différenciation des cellules et de la présence de lésions. Une méthode biochimique a permis de détecter des cellules souches dans la lumière de la trachée et des bronches. 7 jours après l'injection de détergent, lorsque l'épithélium est spontanément régénéré, des cellules souches administrées ont été localisées dans les voies aériennes. Ces résultats confortent l'utilisation de la voie aérienne dans le développement d'une stratégie de thérapie cellulaire pour les pathologies respiratoires avec des lésions épithéliales telles que la mucoviscidose.Over the past decade, interest has increased in the use of stem cells from bone marrow to optimize lung repair after systemic administration in irradiated mice. These studies lead to limited and controversial results because of fluorescent detection methods. The objective of our work was to develop a stem cell based strategy while avoiding animal irradiation and controversial detection methods. Embryonic and mesenchymal stem cells were intratracheally injected in a murine model with acute epithelial airway injury. Epithelial injury was induced by intratracheal detergent administration. Quantitative methods showed that 0.4 to 5.5% stem cells survived specifically in the injured airway, whereas no differentiated cells survived in injured airway. Importantly, stem cells did not survive in healthy airway. With biochemical staining, mesenchymal stem cells were detected in injured trachea lumen and bronchi. 7 days after detergent administration while airway epithelium was totally repared, stem cells were located in regenerated bronchia. With this experimental design, we demonstrated the feasibility of intratracheal cell delivery for airway diseases with acute epithelial airway injury.NANTES-BU Médecine pharmacie (441092101) / SudocSudocFranceF

Long-time behavior of the Stokes-transport system in a channel

69 pagesThe coupling between the transport equation for the density and the Stokes equation is considered in a periodic channel. More precisely, the density is advected by pure transport by a velocity field given by the Stokes equation with source force coming from the gravity due to differences in the density. Dirichlet boundary conditions are taken for the velocity field on the bottom and top of the channel, and periodic conditions in the horizontal variable. We prove that the affine stratified density profile is stable under small perturbations in Sobolev spaces and prove convergence of the density to another limiting stratified density profile for large time with an explicit algebraic decay rate. Moreover, we are able to precisely identify the limiting profile as the decreasing vertical rearrangement of the initial density. Finally, we study boundary layers formation to precisely characterize the long-time behavior beyond the constant limiting profile and enlighten the optimal decay rate

Enhanced prognostic stratification of neoadjuvant treated lung squamous cell carcinoma by computationally-guided tumor regression scoring

INTRODUCTION The amount of residual tumor burden after neoadjuvant chemotherapy is an important prognosticator, but for non-small cell lung carcinoma (NSCLC), no official regression scoring system is yet established. Computationally derived histological regression scores could provide unbiased and quantitative readouts to complement the clinical assessment of treatment response. METHODS Histopathologic tumor regression was microscopically assessed on whole cases in a neoadjuvant chemotherapy-treated cohort (NAC, n = 55 patients) of lung squamous cell carcinomas (LSCC). For each patient, the slide showing the least pathologic regression was selected for subsequent computational analysis and histological features were quantified: percentage of vital tumor cells (cTu.Percentage), total surface covered by vital tumor cells (cTu.Area), area of the largest vital tumor fragment (cTu.Size.max), and total number of vital tumor fragments (cTu.Fragments). A chemo-naïve LSCC cohort (CN, n = 104) was used for reference. For 23 of the 55 patients [$^{18}$F]-Fluorodeoxyglucose (FDG) PET/CT measurements of maximum standard uptake value (SUV$_{max}$), background subtracted lesion activity (BSL) and background subtracted volume (BSV) were correlated with pathologic regression. Survival analysis was carried out using Cox regression and receiver operating characteristic (ROC) curve analysis using a 3-years cutoff. RESULTS All computational regression parameters significantly correlated with relative changes of BSV FDG PET/CT values after neoadjuvant chemotherapy. ROC curve analysis of histological parameters of NAC patients showed that cTu.Percentage was the most accurate prognosticator of overall survival (ROC curve AUC = 0.77, p-value = 0.001, Cox regression HR = 3.6, p = 0.001, variable cutoff < = 30 %). CONCLUSIONS This study demonstrates the prognostic relevance of computer-derived histopathologic scores. Additionally, the analysis carried out on slides displaying the least pathologic regression correlated with overall pathologic response and PET/CT values. This might improve the objective histopathologic assessment of tumor response in neoadjuvant setting

Prognostic Immune Cell Profiling of Malignant Pleural Effusion Patients by Computerized Immunohistochemical and Transcriptional Analysis

Malignant pleural effusion (MPE) is a severe condition of advanced tumors without effective therapy. We used digitalized immunohistochemical and transcriptional approaches to investigate the prognostic influence of immune cells and expression variance of associated immunomodulatory molecules in MPE. Cytology tissue microarrays were constructed from MPE cell blocks of 155 patients with five tumor entities. Immune cells lineage markers were quantified by computational cytopathology on immunohistochemistry. mRNA expression analysis of nine lineage markers and 17 immunomodulators was performed by NanoString. Immunohistochemically quantified high B cells to leukocytes ratio (hazard ratio (HR) = 0.70, p-value = 0.043) and low neutrophils to leukocytes ratio (HR = 1.78, p-value = 0.003) were favorable prognosticators for overall survival independent of tumor entity. Correspondingly, patients with high B cells but low neutrophils gene expression signature showed longer median overall survival of 500 days (HR = 2.29, p-value = 0.009). Regarding targetable molecule expressions, lung adenocarcinomas were characterized by high PD-L1, but mesothelioma by high LAG-3. Ovarian carcinoma was least immunogenic. Independent of tumor entity, the condition of the immune system in MPE liquids is able to provide additional prognostic cytologic information. Combined analysis of lineage specific markers and related immunomodulators may direct immune-based therapeutic decisions