Human Luteinizing Hormone and Chorionic Gonadotropin Display Biased Agonism at the LH and LH/CG Receptors.

Human luteinizing hormone (LH) and chorionic gonadotropin (hCG) have been considered biologically equivalent because of their structural similarities and their binding to the same receptor; the LH/CGR. However, accumulating evidence suggest that LH/CGR differentially responds to the two hormones triggering differential intracellular signaling and steroidogenesis. The mechanistic basis of such differential responses remains mostly unknown. Here, we compared the abilities of recombinant rhLH and rhCG to elicit cAMP, β-arrestin 2 activation, and steroidogenesis in HEK293 cells and mouse Leydig tumor cells (mLTC-1). For this, BRET and FRET technologies were used allowing quantitative analyses of hormone activities in real-time and in living cells. Our data indicate that rhLH and rhCG differentially promote cell responses mediated by LH/CGR revealing interesting divergences in their potencies, efficacies and kinetics: rhCG was more potent than rhLH in both HEK293 and mLTC-1 cells. Interestingly, partial effects of rhLH were found on β-arrestin recruitment and on progesterone production compared to rhCG. Such a link was further supported by knockdown experiments. These pharmacological differences demonstrate that rhLH and rhCG act as natural biased agonists. The discovery of novel mechanisms associated with gonadotropin-specific action may ultimately help improve and personalize assisted reproduction technologies

Impact of anatase and rutile titanium dioxide nanoparticles on uptake carriers and efflux pumps in Caco-2 gut epithelial cells

International audienceTiO2 microparticles are widely used in food products, where they are added as a white food colouring agent. This food additive contains a significant amount of nanoscale particles; still the impact of TiO2 nanoparticles (TiO2-NPs) on gut cells is poorly documented. Our study aimed at evaluating the impact of rutile and anatase TiO2-NPs on the main functions of enterocytes, i.e. nutrient absorption driven by solute-liquid carriers (SLC transporters) and protection against other xenobiotics driven by efflux pumps from the ATP-binding cassette (ABC) family. We show that acute exposure of Caco-2 cells to both anatase (12 nm) and rutile (20 nm) TiO2-NPs induce early upregulation of a battery of efflux pumps and nutrient transporters. In addition they cause overproduction of reactive oxygen species and misbalance redox repair systems, without inducing cell mortality or DNA damage. Taken together, these data suggest that TiO2-NPs may increase the functionality of gut epithelial cells, particularly their property to form a protective barrier against exogenous toxicants and to absorb nutrients

Arcobacter butzleri: Underestimated Enteropathogen

Molecular methods applied to 2,855 strains of Campylobacter-like organisms received from a surveillance network of Campylobacter infections in France identified 29 Arcobacter butzleri infections. This species ranks fourth for Campylobacteraceae isolation and appears to have the same pathogenic potential as the other species in the genus

Direct impact of COVID-19 by estimating disability-adjusted life years at national level in France in 2020

Background: The World Health Organization declared a pandemic of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), on March 11, 2020. The standardized approach of disability-adjusted life years (DALYs) allows for quantifying the combined impact of morbidity and mortality of diseases and injuries. The main objective of this study was to estimate the direct impact of COVID-19 in France in 2020, using DALYs to combine the population health impact of infection fatalities, acute symptomatic infections and their post-acute consequences, in 28 days (baseline) up to 140 days, following the initial infection. Methods: National mortality, COVID-19 screening, and hospital admission data were used to calculate DALYs based on the European Burden of Disease Network consensus disease model. Scenario analyses were performed by varying the number of symptomatic cases and duration of symptoms up to a maximum of 140 days, defining COVID-19 deaths using the underlying, and associated, cause of death. Results: In 2020, the estimated DALYs due to COVID-19 in France were 990 710 (1472 per 100 000), with 99% of burden due to mortality (982 531 years of life lost, YLL) and 1% due to morbidity (8179 years lived with disability, YLD), following the initial infection. The contribution of YLD reached 375%, assuming the duration of 140 days of post-acute consequences of COVID-19. Post-acute consequences contributed to 49% of the total morbidity burden. The contribution of YLD due to acute symptomatic infections among people younger than 70 years was higher (67%) than among people aged 70 years and above (33%). YLL among people aged 70 years and above, contributed to 74% of the total YLL. Conclusions: COVID-19 had a substantial impact on population health in France in 2020. The majority of population health loss was due to mortality. Men had higher population health loss due to COVID-19 than women. Post-acute consequences of COVID-19 had a large contribution to the YLD component of the disease burden, even when we assume the shortest duration of 28 days, long COVID burden is large. Further research is recommended to assess the impact of health inequalities associated with these estimates

Regulation of Postsynaptic Function by the Dementia-Related ESCRT-III Subunit CHMP2B

The charged multivesicular body proteins (Chmp1–7) are an evolutionarily conserved family of cytosolic proteins that transiently assembles into helical polymers that change the curvature of cellular membrane domains. Mutations in human CHMP2B cause frontotemporal dementia, suggesting that this protein may normally control some neuron-specific process. Here, we examined the function, localization, and interactions of neuronal Chmp2b. The protein was highly expressed in mouse brain and could be readily detected in neuronal dendrites and spines. Depletion of endogenous Chmp2b reduced dendritic branching of cultured hippocampal neurons, decreased excitatory synapse density in vitro and in vivo, and abolished activity-induced spine enlargement and synaptic potentiation. To understand the synaptic effects of Chmp2b, we determined its ultrastructural distribution by quantitative immuno-electron microscopy and its biochemical interactions by coimmunoprecipitation and mass spectrometry. In the hippocampus in situ, a subset of neuronal Chmp2b was shown to concentrate beneath the perisynaptic membrane of dendritic spines. In synaptoneurosome lysates, Chmp2b was stably bound to a large complex containing other members of the Chmp family, as well as postsynaptic scaffolds. The supramolecular Chmp assembly detected here corresponds to a stable form of the endosomal sorting complex required for transport-III (ESCRT-III), a ubiquitous cytoplasmic protein complex known to play a central role in remodeling of lipid membranes. We conclude that Chmp2b-containing ESCRT-III complexes are also present at dendritic spines, where they regulate synaptic plasticity. We propose that synaptic ESCRT-III filaments may function as a novel element of the submembrane cytoskeleton of spines

The follicle-stimulating hormone signaling network in gonadal cells.

International audienceFSH (follicle-stimulating hormone) is a master endocrine regulator of somatic cells of the gonads that support gametogenesis. In the male, FSH dictates the Sertoli cell proliferation rate prior to puberty, then maintains their main biological roles as nurturing cells and physical support to spermatogenesis throughout life. In the female, FSH is instrumental in processing the terminal differentiation phase of folliculogenesis that progressively drives the ovarian follicle to ovulation. The biological function of FSH is transduced by a membrane receptor, the FSH receptor (FSHR). Deciphering the molecular bases of the developmental switch in FSH biological activities is required to gain insights into FSH-induced signaling pathways. This quest has led to the identification of a complex interconnected signaling network affected by testicular paracrine factors, implying not only protein post-translational modifications but also regulation by microRNA and chromatin remodeling. In the female, the emphasis is now placed on deciphering the complex functional relationships between the LHCGR (luteinizing hormone/choriogonadotropin hormone receptor) and the FSHR that trigger intertwined signaling networks in the same granulosa cell type. Breakthroughs in the organization and dynamic functioning of the FSH-induced signaling network are expected to identifying novel regulatory processes and therapeutic strategies for infertilities and contraception

Focal myositis

International audienceObjective To better define in a cohort study the clinical and pathologic features of focal myositis (FM). Methods With the use of the usual clinicopathologic definition, each confirmed case of FM in the Lyon University Hospital's myopathologic database between 2000 and 2016 was retrieved. Clinical, pathologic, imaging, serologic, and therapeutic data were collected. When data were missing but feasible, appropriate pathologic analyses were performed. Results Of the 924 patients included in the database, 37 (4%) had confirmed FM (14 female, 23 male patients). The main symptoms were pain (n = 30, 81%), muscular mass (n = 16, 43%), erythema at the site of FM (n = 12, 32%), and fever (n = 9, 24%). Serum creatine kinase was normal in most patients (81%); serum immune abnormalities were frequent (inflammatory syndrome in sera [39%], dysglobulinemia [52%], and anti-nuclear antibody positivity [29%]). In addition to confirming previously reported findings, pathologic analyses found significant rates of vasculitis (68%) and fasciitis (73%). Here, FM appeared frequently to be associated with other diseases such as immune-mediated inflammatory disease (IMID; 32%), neoplasia (24%), and radiculopathy (11%). Regarding outcomes, 64% of the cases had received immunosuppressive drugs, and the relapse rate was 41%. Conclusion The present study suggests that FM is not as innocuous as previously believed, particularly considering the associated disorders. Notably, patients with FM should receive careful IMID and neoplasia screening

Two Negative Allosteric Modulators (NAMS) display biased activities on FSH-induced β-arrestin recruitment at the FSH-R

National audienc