A point mutation in the AF-2 domain of thyroid hormone receptor alpha1 expressed after CRE mediated recombination partially recapitulates hypothyroidism.

Thyroid hormones act directly on transcription by binding to TRα1, TRβ1, TRβ2 nuclear receptors, regulating many aspects of post-natal development and homeostasis. To precisely analyze the implication of the widely expressed TRα1 isoform in this pleiotropic action, we have generated transgenic mice with a point mutation in the TRα1 coding sequence, which is expressed only after CRE/loxP mediated DNA recombination. The amino-acid change prevents interaction between TRα1 and histone acetyltransferase coactivators and the release of corepressors. Early expression of this dominant-negative receptor deeply affects post-natal development and adult homeostasis, recapitulating many aspects of congenital and adult hypothyroidism, except in tissues and cells where TRβ1 and TRβ2 are predominantly expressed. Both respective abundance and intrinsic properties of TRα1 and TRβ1/2 seems to govern specificity of action

The transforming acidic coiled coil (TACC1) protein modulates the transcriptional activity of the nuclear receptors TR and RAR

Background: The transcriptional activity of Nuclear hormone Receptors (NRs) is regulated by interaction with coactivator or corepressor proteins. Many of these cofactors have been shown to have a misregulated expression or to show a subcellular mislocalization in cancer cell lines or primary tumors. Therefore they can be factors involved in the process of oncogenesis. Results: We describe a novel NR coregulator, TACC1, which belongs to the Transforming Acidic Coiled Coil (TACC) family. The interaction of TACC1 with Thyroid Hormone Receptors (TR) and several other NRs has been shown in a yeast two-hybrid screen and confirmed by GST pulldown, colocalization and co-immunoprecipitation experiments. TACC1 interacts preferentially with unliganded NRs. In F9 cells, endogenous TACC1 localized in the chromatin-enriched fraction of the nucleus and interacted with Retinoid Acid Receptors (RAR alpha) in the nucleus. TACC1 depletion in the cell led to decreased RAR alpha and TR alpha ligand-dependent transcriptional activity and to delocalization of TR from the nucleus to the cytoplasm. Conclusions: From these experimental studies we propose that TACC1 might be a scaffold protein building up a transcriptional complex around the NRs we studied. This function of TACC1 might account for its involvement in several forms of tumour development

GC-Content evolution in bacterial genomes: The biased gene conversion hypothesis expands

The characterization of functional elements in genomes relies on the identification of the footprints of natural selection. In this quest, taking into account neutral evolutionary processes such as mutation and genetic drift is crucial because these forces can generate patterns that may obscure or mimic signatures of selection. In mammals, and probably in many eukaryotes, another such confounding factor called GC-Biased Gene Conversion (gBGC) has been documented. This mechanism generates patterns identical to what is expected under selection for higher GC-content, specifically in highly recombining genomic regions. Recent results have suggested that a mysterious selective force favouring higher GC-content exists in Bacteria but the possibility that it could be gBGC has been excluded. Here, we show that gBGC is probably at work in most if not all bacterial species. First we find a consistent positive relationship between the GC-content of a gene and evidence of intra-genic recombination throughout a broad spectrum of bacterial clades. Second, we show that the evolutionary force responsible for this pattern is acting independently from selection on codon usage, and could potentially interfere with selection in favor of optimal AU-ending codons. A comparison with data from human populations shows that the intensity of gBGC in Bacteria is comparable to what has been reported in mammals. We propose that gBGC is not restricted to sexual Eukaryotes but also widespread among Bacteria and could therefore be an ancestral feature of cellular organisms. We argue that if gBGC occurs in bacteria, it can account for previously unexplained observations, such as the apparent non-equilibrium of base substitution patterns and the heterogeneity of gene composition within bacterial genomes. Because gBGC produces patterns similar to positive selection, it is essential to take this process into account when studying the evolutionary forces at work in bacterial genomes

Entre discrimination et autocensure. Les carrières des femmes dans l'enseignement supérieur et la recherche.

Rapport de recherche au Ministère National de la Recherche et de la Technologie et à l'Inra.Ce rapport présente les principaux résultats d'un programme de recherche pluridisciplinaire consacré aux ressorts de la carrière des femmes dans l'enseignement supérieur et la recherche

Association between Repeated Unpredictable Chronic Mild Stress (UCMS) Procedures with a High Fat Diet: A Model of Fluoxetine Resistance in Mice

Major depressive disorder is a debilitating disease. Unfortunately, treatment with antidepressants (ADs) has limited therapeutic efficacy since resistance to AD is common. Research in this field is hampered by the lack of a reliable natural animal model of AD resistance. Depression resistance is related to various factors, including the attendance of cardiovascular risk factors and past depressive episodes. We aimed to design a rodent model of depression resistance to ADs, associating cardiovascular risk factors with repeated unpredicted chronic mild stress (UCMS). Male BALB/c mice were given either a regular (4% fat) or a high fat diet (45% fat) and subjected to two 7-week periods of UCMS separated by 6 weeks. From the second week of each UCMS procedure, vehicle or fluoxetine (10 mg/kg, i.p.) was administrated daily. The effects of the UCMS and fluoxetine in both diet conditions were assessed using physical (coat state and body weight) and behavioural tests (the reward maze test and the splash test). The results demonstrate that during the second procedure, UCMS induced behavioural changes, including coat state degradation, disturbances in self-care behaviour (splash test) and anhedonia (reward maze test) and these were reversed by fluoxetine in the regular diet condition. In contrast, the high-fat diet regimen prevented the AD fluoxetine from abolishing the UCMS-induced changes. In conclusion, by associating UCMS—an already validated animal model of depression—with high-fat diet regimen, we designed a naturalistic animal model of AD resistance related to a sub-nosographic clinical entity of depression

Objectively measured total sedentary time and pattern of sedentary accumulation in older adults: associations with incident cardiovascular disease and all-cause mortality

BACKGROUND: We examined associations of total duration and pattern of accumulation of objectively measured sedentary behavior (SB) with incident cardiovascular disease (CVD) and all-cause mortality among older adults. METHODS: Total sedentary time and 8 sedentary accumulation pattern metrics were extracted from accelerometer data of 3 991 Whitehall II study participants aged 60–83 years in 2012–2013. Incident CVD and all-cause mortality were ascertained up to March 2019. RESULTS: Two hundred and ninety-nine CVD cases and 260 deaths were recorded over a mean (standard deviation [SD]) follow-up of 6.2 (1.3) and 6.4 (0.8) years, respectively. Adjusting for sociodemographic and behavioral factors, 1-SD (100.2 minutes) increase in total sedentary time was associated with 20% higher CVD risk (hazard ratio [95% confidence interval]: 1.20 [1.05–1.37]). More fragmented SB was associated with reduced CVD risk (eg, 0.86 [0.76–0.97] for 1-SD [6.2] increase in breaks per sedentary hour). Associations were not evident once health-related factors and moderate-to-vigorous physical activity (MVPA) were considered. For all-cause mortality, associations with more fragmented SB (eg, 0.73 [0.59–0.91] for breaks per sedentary hour) were found only among the youngest older group (<74 years; p for interaction with age < .01) independently from all covariates. CONCLUSIONS: In this study, no associations of total sedentary time and sedentary accumulation patterns with incident CVD and all-cause mortality were found in the total sample once MVPA was considered. Our findings of reduced mortality risk with less total and more fragmented SB independent from MVPA among individuals <74 years need to be replicated to support the recent recommendations to reduce and fragment SB

Hantavirus Pulmonary Syndrome, French Guiana

A systematic serological survey of patients suffering from symptoms suggestive of Hantavirus pulmonary syndrome allowed us to identify a native case in French Guiana. Partial molecular characterization of the implicated hantavirus revealed its close relationship with the Bolivian Rio Mamore virus. We tentatively named it Maripa virus

VPS51 biallelic variants cause microcephaly with brain malformations: A confirmatory report

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