Covichem: A biochemical severity risk score of COVID-19 upon hospital admission

Clinical and laboratory predictors of COVID-19 severity are now well described and combined to propose mortality or severity scores. However, they all necessitate saturable equipment such as scanners, or procedures difficult to implement such as blood gas measures. To provide an easy and fast COVID-19 severity risk score upon hospital admission, and keeping in mind the above limits, we sought for a scoring system needing limited invasive data such as a simple blood test and co-morbidity assessment by anamnesis. A retrospective study of 303 patients (203 from Bordeaux University hospital and an external independent cohort of 100 patients from Paris Pitié-Salpêtrière hospital) collected clinical and biochemical parameters at admission. Using stepwise model selection by Akaike Information Criterion (AIC), we built the severity score Covichem. Among 26 tested variables, 7: obesity, cardiovascular conditions, plasma sodium, albumin, ferritin, LDH and CK were the independent predictors of severity used in Covichem (accuracy 0.87, AUROC 0.91). Accuracy was 0.92 in the external validation cohort (89% sensitivity and 95% specificity). Covichem score could be useful as a rapid, costless and easy to implement severity assessment tool during acute COVID-19 pandemic waves

Force Generation upon T Cell Receptor Engagement

T cells are major players of adaptive immune response in mammals. Recognition of an antigenic peptide in association with the major histocompatibility complex at the surface of an antigen presenting cell (APC) is a specific and sensitive process whose mechanism is not fully understood. The potential contribution of mechanical forces in the T cell activation process is increasingly debated, although these forces are scarcely defined and hold only limited experimental evidence. In this work, we have implemented a biomembrane force probe (BFP) setup and a model APC to explore the nature and the characteristics of the mechanical forces potentially generated upon engagement of the T cell receptor (TCR) and/or lymphocyte function-associated antigen-1 (LFA-1). We show that upon contact with a model APC coated with antibodies towards TCR-CD3, after a short latency, the T cell developed a timed sequence of pushing and pulling forces against its target. These processes were defined by their initial constant growth velocity and loading rate (force increase per unit of time). LFA-1 engagement together with TCR-CD3 reduced the growing speed during the pushing phase without triggering the same mechanical behavior when engaged alone. Intracellular Ca2+ concentration ([Ca2+]i) was monitored simultaneously to verify the cell commitment in the activation process. [Ca2+]i increased a few tens of seconds after the beginning of the pushing phase although no strong correlation appeared between the two events. The pushing phase was driven by actin polymerization. Tuning the BFP mechanical properties, we could show that the loading rate during the pulling phase increased with the target stiffness. This indicated that a mechanosensing mechanism is implemented in the early steps of the activation process. We provide here the first quantified description of force generation sequence upon local bidimensional engagement of TCR-CD3 and discuss its potential role in a T cell mechanically-regulated activation process

From an initial data to a global solution of the nonlinear Schrödinger equation: a building process

International audienceThe purpose of this work is to construct a continuous map from the homogeneous Besov space B^02,4(R^2) in the set G of initial data in B^02,4(R^2) which gives birth to global solution of the mass critical non linear Schrödinger equation in the space L^4(R^1+2). We use the fact that solutions of scale which are different enough almost do not interact; the main point is that we determine a condition about the size of the scale which depends continuously on the data

Deciphering pathogenic mechanisms underlying human calcium channelopathies

International audienceThese last years, our group has characterized several calcium channel mutations linked to neurological diseases. We have investigated the pathogenic mechanisms underlying channelopathies, especially for mutations in T-type/Cav3 genes recently discovered. Importantly, such studies provide in turn new clues to identify how these channels are activated, regulated, and how they contribute to physiology. Of note, some of these mutations lead to gain of channel activity, especially Cav3.2 mutations linked to Primary Aldosteronism (Daniil et al 2016, EBioMedicine. 13:225-236). Other mutations, i.e. mutations in the Cav3.1 subunit, are associated to new forms of cerebellar dysfunction, including Autosomal-Dominant Cerebellar Ataxia (Coutelier et al 2015, Am J Hum Genet. 97(5):726-37). Recently, we have also described gain of function mutations in the Cav3.1 subunit. These mutations are linked to Childhood-onset cerebellar atrophy (ChCA), a neurodevelopmental condition associated with cerebellar ataxia and defect in cognitive development (Chemin et al 2018, Brain. 141(7):1998-2013). These mutations markedly impair T-type channel inactivation and promote a larger window current fully inhibited by TTA-P2, a selective T-type channel blocker. These findings reveal that aberrant increased activity of Cav3.1 channels could markedly alter CNS development and suggest that such condition is amenable to treatment

Differential induction of carcinogen metabolizing enzymes in a transgenic mouse model of fulminant hepatitis

The objective of this work is to examine the possible modulation of carcinogen metabolism (activation by cytochrome P450s and detoxification by conjugation via glutathione S-transferases [GST]) in relation to hepatitis B virus (HBV)-associated liver injury. In HBV transgenic mouse lineage 107.5, the hepatitis B surface antigen (HBsAg) is expressed at noncytopathic concentrations but after injection of an HBsAg-specific, major histocompatibility complex (MHC) class I restricted cytotoxic T-lymphocyte (CTL) clone, the mice develop a severe acute necroinflammatory liver disease that reaches maximum severity within 3 days and gradually subsides during the next 2 to 3 weeks. In this model, using immunohistochemical analysis, we observed an increase of P450s (CYP1A and 2A5), both involved in aflatoxin B1, metabolism, but minor changes or no changes for others (2B, 2C, 2E, 3A). There was a fivefold decrease in the total liver P450 microsomal content 3 days' post-CTL injection with the result that the relative proportion of CYP2A5 and 1A compared with other P450s is increased. Individual microsomal P450 enzyme contents estimated by Western blotting; Northern blot analysis of liver CYP messenger RNA (mRNA) levels as well as in vitro metabolism of specific substrates for different P450 isoenzymes were consistent with the immunohistochemical data. Immunohistochemical staining with antibodies to cytosolic pi class GST was increased 1 and 3 days postinjection followed by a progressive decrease at later time points (the same phenomenon was observed to a lesser extent for GST α). The activity of hepatic cytosols toward substrates specific for different subclasses of GST (mu, pi, α) showed that while GST mu was not changed in the CTL-injected HBV transgenic mice, GST pi and, to a lesser extent, α were increased as compared with controls. These results suggest that liver cell injury induced by a process of acute fulminant-like hepatitis can lead to the induction of some carcinogen metabolizing enzymes notably, Cyp 1A, 2A5 and GST pi in the mouse