Thyroid hormone and vitamin D regulate VGF expression and promoter activity

The Siberian hamster (Phodopus sungorus) survives winter by decreasing food intake and catabolizing abdominal fat reserves, resulting in a sustained, profound loss of body weight. Hypothalamic tanycytes are pivotal for this process. In these cells, short-winter photoperiods upregulate deiodinase 3, an enzyme that regulates thyroid hormone availability, and downregulate genes encoding components of retinoic acid (RA) uptake and signaling. The aim of the current studies was to identify mechanisms by which seasonal changes in thyroid hormone and RA signaling from tanycytes might ultimately regulate appetite and energy expenditure. proVGF is one of the most abundant peptides in the mammalian brain, and studies have suggested a role for VGF-derived peptides in the photoperiodic regulation of body weight in the Siberian hamster. In silico studies identified possible thyroid and vitamin D response elements in the VGF promoter. Using the human neuroblastoma SH-SY5Y cell line, we demonstrate that RA increases endogenous VG expression (P!0.05) and VGF promoter activity (P!0.0001). Similarly, treatment with 1,25-ihydroxyvitamin D3 increased endogenous VGF mRNA expression (P!0.05) and VGF promoter activity (P!0.0001),whereas triiodothyronine (T3) decreased both (P!0.01 and P!0.0001). Finally, intrahypothalamic administration of T3 blocked the short day-induced increase in VGF expression in the dorsomedial posterior arcuate nucleus of Siberian hamsters. Thus, we conclude that VGF expression is a likely target of photoperiod-induced changes in tanycyte-derived signals and is potentially a regulator of seasonal changes in appetite and energy expenditure

Hypothalamic ventricular ependymal thyroid hormone deiodinases are an important element of circannual timing in the siberian hamster (Phodopus sungorus)

Exposure to short days (SD) induces profound changes in the physiology and behaviour of Siberian hamsters, including gonadal regression and up to 30% loss in body weight. In a continuous SD environment after approximately 20 weeks, Siberian hamsters spontaneously revert to a long day (LD) phenotype, a phenomenon referred to as the photorefractory response. Previously we have identified a number of genes that are regulated by short photoperiod in the neuropil and ventricular ependymal (VE) cells of the hypothalamus, although their importance and contribution to photoperiod induced physiology is unclear. In this refractory model we hypothesised that the return to LD physiology involves reversal of SD expression levels of key hypothalamic genes to their LD values and thereby implicate genes required for LD physiology. Male Siberian hamsters were kept in either LD or SD for up to 39 weeks during which time SD hamster body weight decreased before increasing, after more than 20 weeks, back to LD values. Brain tissue was collected between 14 and 39 weeks for in situ hybridization to determine hypothalamic gene expression. In VE cells lining the third ventricle, expression of nestin, vimentin, Crbp1 and Gpr50 were down-regulated at 18 weeks in SD photoperiod, but expression was not restored to the LD level in photorefractory hamsters. Dio2, Mct8 and Tsh-r expression were altered by SD photoperiod and were fully restored, or even exceeded values found in LD hamsters in the refractory state. In hypothalamic nuclei, expression of Srif and Mc3r mRNAs was altered at 18 weeks in SD, but were similar to LD expression values in photorefractory hamsters. We conclude that in refractory hamsters not all VE cell functions are required to establish LD physiology. However, thyroid hormone signalling from ependymal cells and reversal of neuronal gene expression appear to be essential for the SD refractory response

Conservative interventions for urinary incontinence in women: an overview of Cochrane systematic reviews

This is the protocol for a review and there is no abstract. The objectives are as follows:  To synthesise Cochrane reviews of conservative interventions, as described above, for the prevention or treatment of female urinary incontinence.Output Type: Protoco

Evolutive Unification in Composite Active Galactic Nuclei

In this paper we explore an evolutionary Unified scenario involving super massive black hole and starburst with outflow, that seems capable of explaining most of the observational properties of at least part of AGNs. Our suggestion is explored inside the expectations of the Starburst model close associated with the AGN where the NLR, BLR and BAL region are produced in part by the outflow process with shells and in compact supernova remnants. The outflow process in BAL QSOs with extreme IR and Fe II emission is studied. In addition, the Fe II poblem regarding the BLR of AGN is analysed. Neither the correlations between the BAL, IR emission, FeII intensity and the intrinsic properties of the AGN are clearly understood. We suggest here that the behaviour of the BAL, IR and FeII emission in AGNs can be understood inside an evolutionary and composite model for AGNs. In our model, strong BAL systems and Fe II emission are present (and intense) in young IR objects. Orientation/ obscuration effects take the role of a second parameter providing the segregation between Sy1/Sy2 and BLRG/NLRG.Comment: 14 pages, 6 figures (submitted MNRAS

Antibody-mediated inhibition of the FGFR1c isoform induces a catabolic lean state in Siberian hamsters

Hypothalamic tanycytes are considered to function as sensors of peripheral metabolism [1]. To facilitate this role, they express a wide range of receptors, including fibroblast growth factor receptor 1 (FGFR1). Using a monoclonal antibody (IMC-H7) that selectively antagonizes the FGFR1c isoform [2], we investigated possible actions of FGFR1c in a natural animal model of adiposity, the Siberian hamster. Infusion of IMC-H7 into the third ventricle suppressed appetite and increased energy expenditure. Likewise, peripheral treatment with IMC-H7 decreased appetite and body weight and increased energy expenditure and fat oxidation. A greater reduction in body weight and caloric intake was observed in response to IMC-H7 during the long-day fat state as compared to the short-day lean state. This enhanced response to IMC-H7 was also observed in calorically restricted hamsters maintained in long days, suggesting that it is the central photoperiodic state rather than the peripheral adiposity that determines the response to FGFR1c antagonism. Hypothalamic thyroid hormone availability is controlled by deiodinase enzymes (DIO2 and DIO3) expressed in tanycytes and is the key regulator of seasonal cycles of energy balance [3 and 4]. Therefore, we determined the effect of IMC-H7 on hypothalamic expression of these deiodinase enzymes. The reductions in food intake and body weight were always associated with decreased expression of DIO2 in the hypothalamic ependymal cell layer containing tanycytes. These data provide further support for the notion the tanycytes are an important component of the mechanism by which the hypothalamus integrates central and peripheral signals to regulate energy intake and expenditure

Spatial variability of fluvial blanket peat erosion rates for the 21st Century modelled using PESERA-PEAT

Many peatlands across the world suffer from degradation. Blanket peatlands are found mainly in high latitude oceanic areas and subpolar islands. Exacerbated erosion of blanket peatlands is common particularly where they have been disturbed by human influence or where climate has become more marginal for their functioning. A recently developed fluvial blanket peat erosion model, PESERA-PEAT was applied across 845 km2 of blanket peatlands in the North Pennines of northern England. The aim was to evaluate the spatial and temporal variability of erosion rates under climate change and land management scenarios. Climate change data to the end of the 21st Century, derived from UKCP09 median emission projections aligned to the UK Met Office’s historical meteorological dataset, were downscaled to 100 m cells. Land management scenarios were developed which included intensified and extensified grazing, artificial drainage and prescribed burning. The modelling results showed that under current management, 21st Century climate change would slightly increase the overall fluvial erosion rates for the study region from the climatic baseline (2.2 t ha-1 yr-1) to the 2080s (2.3 t ha-1 yr-1 ). However, the predicted response to climate change was spatially very variable. Predicted erosion rates decreased at locations that are currently wet and cold while they increased in some warmer and drier locations by more than 50%. Summer desiccation was found to become more important for the study region under climate change. Thus, predicted autumn sediment yields became the biggest component of the annual budget by the 2080s. Less intensive management was shown to reduce blanket peat erosion but potentially enhance wildfire severity. The results demonstrated that land management change will be useful in mitigating the impact of 21st Century climate change on the amount and spatial pattern of blanket peat erosion. The results of our study can be used within blanket peatland regions to inform spatially-targeted management strategies

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.