Lack of Tgfbr1 and Acvr1b synergistically stimulates myofibre hypertrophy and accelerates muscle regeneration

In skeletal muscle, transforming growth factor-β (TGF-β) family growth factors, TGF-β1 and myostatin, are involved in atrophy and muscle wasting disorders. Simultaneous interference with their signalling pathways may improve muscle function; however, little is known about their individual and combined receptor signalling. Here, we show that inhibition of TGF-β signalling by simultaneous muscle-specific knockout of TGF-β type I receptors Tgfbr1 and Acvr1b in mice, induces substantial hypertrophy, while such effect does not occur by single receptor knockout. Hypertrophy is induced by increased phosphorylation of Akt and p70S6K and reduced E3 ligases expression, while myonuclear number remains unaltered. Combined knockout of both TGF-β type I receptors increases the number of satellite cells, macrophages and improves regeneration post cardiotoxin-induced injury by stimulating myogenic differentiation. Extra cellular matrix gene expression is exclusively elevated in muscle with combined receptor knockout. Tgfbr1 and Acvr1b are synergistically involved in regulation of myofibre size, regeneration, and collagen deposition

Metagenome-based diversity analyses suggest a significant contribution of non-cyanobacterial lineages to carbonate precipitation in modern microbialites

Frontiers in Microbiology 6 (2015): 797 This Document is Protected by copyright and was first published by Frontiers. All rights reserved. It is reproduced with permissionCyanobacteria are thought to play a key role in carbonate formation due to their metabolic activity, but other organisms carrying out oxygenic photosynthesis (photosynthetic eukaryotes) or other metabolisms (e.g., anoxygenic photosynthesis, sulfate reduction), may also contribute to carbonate formation. To obtain more quantitative information than that provided by more classical PCR-dependent methods, we studied the microbial diversity of microbialites from the Alchichica crater lake (Mexico) by mining for 16S/18S rRNA genes in metagenomes obtained by direct sequencing of environmental DNA. We studied samples collected at the Western (AL-W) and Northern (AL-N) shores of the lake and, at the latter site, along a depth gradient (1, 5, 10, and 15 m depth). The associated microbial communities were mainly composed of bacteria, most of which seemed heterotrophic, whereas archaea were negligible. Eukaryotes composed a relatively minor fraction dominated by photosynthetic lineages, diatoms in AL-W, influenced by Si-rich seepage waters, and green algae in AL-N samples. Members of the Gammaproteobacteria and Alphaproteobacteria classes of Proteobacteria, Cyanobacteria, and Bacteroidetes were the most abundant bacterial taxa, followed by Planctomycetes, Deltaproteobacteria (Proteobacteria), Verrucomicrobia, Actinobacteria, Firmicutes, and Chloroflexi. Community composition varied among sites and with depth. Although cyanobacteria were the most important bacterial group contributing to the carbonate precipitation potential, photosynthetic eukaryotes, anoxygenic photosynthesizers and sulfate reducers were also very abundant. Cyanobacteria affiliated to Pleurocapsales largely increased with depth. Scanning electron microscopy (SEM) observations showed considerable areas of aragonite-encrusted Pleurocapsa-like cyanobacteria at microscale. Multivariate statistical analyses showed a strong positive correlation of Pleurocapsales and Chroococcales with aragonite formation at macroscale, and suggest a potential causal link. Despite the previous identification of intracellularly calcifying cyanobacteria in Alchichica microbialites, most carbonate precipitation seems extracellular in this systemWe are grateful to Eleonor Cortés for help and good company during the field trip and to Eberto Novelo for helpful discussions at the UNAM lab. This research was funded by the European Research Council Grants ProtistWorld (PI PL-G., Grant Agreement no. 322669) and CALCYAN (PI KB, Grant Agreement no. 307110) under the European Union’s Seventh Framework Program and the RTP Génomique environnementale of the CNRS (project MetaStrom, PI DM

Sex-Related Differences in Lactotroph Tumor Aggressiveness Are Associated With a Specific Gene-Expression Signature and Genome Instability

Sex-related differences have been reported in various cancers, in particular men with lactotroph tumors have a worse prognosis than women. While the underlying mechanism of this sexual dimorphism remains unclear, it has been suggested that a lower estrogen receptor alpha expression may drive the sex differences observed in aggressive and malignant lactotroph tumors that are resistant to dopamine agonists. Based on this observation, we aimed to explore the molecular importance of the estrogen pathway through a detailed analysis of the transcriptomic profile of lactotroph tumors from 20 men and 10 women. We undertook gene expression analysis of the selected lactotroph tumors following their pathological grading using the five-tiered classification. Chromosomic alterations were further determined in 13 tumors. Functional analysis showed that there were differences between tumors from men and women in gene signatures associated with cell morphology, cell growth, cell proliferation, development, and cell movement. Hundred-forty genes showed an increased or decreased expression with a minimum 2-fold change. A large subset of those genes belonged to the estrogen receptor signaling pathway, therefore confirming the potent role of this pathway in lactotroph tumor sex-associated aggressiveness. Genes belonging to the X chromosome, such as CTAG2, FGF13, and VEGF-D, were identified as appealing candidates with a sex-linked dysregulation in lactotroph tumors. Through our comparative genomic hybridization analyses (CGH), chromosomic gain, in particular chromosome 19p, was found only in tumors from men, while deletion of chromosome 11 was sex-independent, as it was found in most (5/6) of the aggressive and malignant tumors. Comparison of transcriptomic and CGH analysis revealed four genes (CRB3, FAM138F, MATK, and STAP2) located on gained regions of chromosome 19 and upregulated in lactotroph tumors from men. MATK and STAP2 are both implicated in cell growth and are reported to be associated with the estrogen signaling pathway. Our work confirms the proposed involvement of the estrogen signaling pathway in favoring the increased aggressiveness of lactotroph tumors in men. More importantly, we highlight a number of ER-related candidate genes and further identify a series of target molecules with sex-specific expression that could contribute to the aggressive behavior of lactotroph tumors in men

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P < 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

Etude des conséquences physiopathologiques résultant de l'invalidation du gène de prédisposition aux Néoplasies Endocrines Multiples de type 1 (NEM1) gràce à la génération de modèles murins

Les Néoplasies Endocrines Multiples de type 1 (NEM1) constituent un syndrome héréditaire lié à l'inactivation du gène suppresseur de tumeurs MEN1. Afin de comprendre les fonctions de ce gène et son rôle dans la pathologie tumorale, nous avons généré et étudié plusieurs modèles murins où ce gène est invalidé. L'analyse des embryons Men1 nullizygotes a révélé une létalité à mi-gestation associée à des anomalies du cœur, du foie et du tube neural. L'étude des souris hétérozygotes a montré qu'elles développaient le spectre complet des tumeurs endocrines majeures retrouvées chez les patients atteints de NEM1. Enfin, l'invalidation du gène spécifiquement dans les cellules- du pancréas conduit à l'apparition précoce d'insulinomes présentant toutes les étapes de la progression tumorale. En conclusion, ces modèles et les cellules dérivées, obtenus durant ma thèse, constituent des outils puissants pour l'étude des fonctions du gène MEN1 et des conséquences de son inactivation dans les NEM1.LYON1-BU.Sciences (692662101) / SudocSudocFranceF

A multiscale approach of fatigue and shakedown for notched structures

The aim of this paper is to analyse the fatigue phenomena in the presence of stress gradients. It is well-known that most fatigue criteria fail to predict the lifetime of components in the presence of high stress concentrations or stress gradients, as it is the case in the neighbourhood of cracks, holes notches and encountered for example in riveted or threaded structures. Proposed is a numerical approach in the framework of the high cycle fatigue domain in order to give a qualitative answer. The work starts from the numerical computation of macroscopic loading corresponding to some fatigue experiments on specimens with an inclusion of metallic grains embedded in a macroscopic matrix. The computed fields are then analysed in terms of the HCF (high cycle fatigue) criterion [1], which is based on the estimation of the shakedown limit at the grain scale. The infinite lifetime prediction is based on the assumption that fatigue occurs if at least one grain fails, i.e. reaches plastic shakedown. The predictions at mesoscopic and macroscopic scales are close if the macroscopic stress distribution is homogeneous. However in the case of the stress gradient, lifetime predicted at the macroscopic scale is underestimated when compared to the predictions made at the mesoscopic scale. Another result is that the gap between microscopic and macroscopic predictions obtained from these numerical computations can roughly be estimated by a diminution of stress of the same order of magnitude as found in the experiments and phenomenological observations

The Microenvironment of Pituitary Tumors—Biological and Therapeutic Implications

International audienceThe tumor microenvironment (TME) includes resident and infiltrative non-tumor cells, as well as blood and lymph vessels, extracellular matrix molecules, and numerous soluble factors, such as cytokines and chemokines. While the TME is now considered to be a prognostic tool and a therapeutic target for many cancers, little is known about its composition in pituitary tumors. This review summarizes our current knowledge of the TME within pituitary tumors and the strong interest in TME as a therapeutic target. While we cover the importance of angiogenesis and immune infiltrating cells, we also address the role of the elusive folliculostellate cells, the emerging literature on pituitary tumor-associated fibroblasts, and the contribution of extracellular matrix components in these tumors. The cases of human pituitary tumors treated with TME-targeting therapies are reviewed and emerging concepts of vascular normalization and combined therapies are presented. Together, this snapshot overview of the current literature pinpoints not only the underestimated role of TME components in pituitary tumor biology, but also the major promise it may offer for both prognosis and targeted therapeutics

Biological and Therapeutic Implications of the Tumor Microenvironment in Pituitary Adenomas

International audienceAbstract Pituitary adenomas (PAs) are neoplasms derived from the endocrine cells of the anterior pituitary gland. Most frequently, they are benign tumors, but may sometimes display an aggressive course, and in some cases metastasize. Their biology, including their wide range of behavior, is only partly understood. In terms of therapeutic targeting, most PAs are easily treated with available medical treatments, surgery, and sometimes radiotherapy. Nevertheless, gonadotroph adenomas lack medical therapeutic options, and treatment of aggressive PAs and pituitary carcinomas remains challenging. Here, we present an overview of the implications of the tumor microenvironment in PAs, reviewing its composition and function, as well as published cases that have been treated thus far using tumor microenvironment–targeting therapies. Additionally, we discuss emerging views, such as the concept of nonangiogenic tumors, and present perspectives regarding treatments that may represent future potential therapeutic options. Tumor-infiltrating lymphocytes, tumor-associated macrophages, folliculostellate cells, tumor-associated fibroblasts, angiogenesis, as well as the extracellular matrix and its remodeling, all have complex roles in the biology of PAs. They have been linked to hormone production/secretion, size, invasion, proliferation, progression/recurrence, and treatment response in PAs. From a therapeutic perspective, immune-checkpoint inhibitors and bevacizumab have already shown a degree of efficacy in aggressive PAs and pituitary carcinomas, and the use of numerous other tumor microenvironment-targeting therapies can be foreseen. In conclusion, similar to other cancers, understanding the tumor microenvironment improves our understanding of PA biology beyond genetics and epigenetics, and constitutes an important tool for developing future therapies

Resilience of freshwater communities of small microbial eukaryotes undergoing severe drought events

Small and shallow aquatic ecosystems such as ponds and streams constitute a significant proportion of continental surface waters, especially in temperate zones. In comparison with bigger lakes and rivers, they harbor higher biodiversity but they also exhibit reduced buffering capacity face to environmental shifts, such that climate global change can affect them in a more drastic way. For instance, many temperate areas are predicted to undergo droughts with increasing frequency in the near future, which may lead to the temporal desiccation of streams and ponds. In this work, we monitored temporal dynamics of planktonic communities of microbial eukaryotes (cell size range: 0.2-5 mu m)in one brook and one pond that experienced recurrent droughts from 1 to 5 consecutive months during a temporal survey carried out monthly for 2 years based on high-throughput 18S rDNA metabarcoding. During drought-induced desiccation events, protist communities present in the remaining dry sediment, though highly diverse, differed radically from their planktonic counterparts. However, after water refill, the aquatic protist assemblages recovered their original structure within a month. This rapid recovery indicates that these eukaryotic communities are resilient to droughts, most likely via the entrance in dormancy. This property is essential for the long-term survival and functional stability of small freshwater ecosystems

Exploring the MEN1 dependent modulation of caspase 8 and caspase 3 in human pancreatic and murine embryo fibroblast cells

International audienceAbstract MEN1 mutation causes pancreatic neuroendocrine neoplasia and benign malignancies of the parathyroid, the adrenal cortex and pituitary gland. The transcriptional activity of its product menin promotes the expression of genes deputed to several cellular mechanism including cell death. Here, we focused on its implication in the activation of the initiator and executioner caspases after staurosporine mediated cell death in 2D and 3D human and murine cell models. The administration of staurosporine, a well-known inducer of apoptotic cell death, caused a significant reduction of BON1, QGP1 and HPSC2.2 cell viability. The transient knockdown of MEN1, performed by using a specific siRNA, caused a significant down-regulation of CDKN1A and TP53 transcripts. The treatment with 1 µM of staurosporine caused also a significant down-regulation of MEN1 and was able to restore the basal expression of TP53 only in QGP1 cells. Transient or permanent MEN1 inactivation caused a decrease of caspase 8 activity in BON1, HPSC2.2 cells and MEN1 −/− MEFs treated with staurosporine. Caspase 3/7 activity was suppressed after administration of staurosporine in MEN1 knocked down HPSC2.2 and MEN1 −/− MEFs as well. The cleaved caspase 8 and caspase 3 decreased in human cells after MEN1 knockdown and in MEN1 −/− MEFs. The treatment with staurosporine caused a reduction of the size of MEN1 + / + MEFs spheroids. Instead, MEN1 −/− MEFs spheroids did not show any significant reduction of their size. In conclusion, MEN1 controls the activity of the initiator caspase 8 and the executioner caspase 3 in human and murine cells. Restoring of a functional MEN1 and interfering with the apoptotic mechanism could represent a future strategy for the treatment of MEN1 -related malignancies