Naturally Occurring Osmolyte, Trehalose Induces Functional Conformation in an Intrinsically Disordered Activation Domain of Glucocorticoid Receptor

Intrinsically disordered (ID) regions are frequently found in the activation domains of many transcription factors including nuclear hormone receptors. It is believed that these ID regions promote molecular recognition by creating large surfaces suitable for interactions with their specific protein binding partners, which is a critical component of gene regulation by transcription factors. It has been hypothesized that conditional folding of these activation domains may be a prerequisite for their efficient interaction with specific coregulatory proteins, and subsequent transcriptional activity leading to the regulation of target gene(s). In this study, we tested whether a naturally occurring osmolyte, trehalose can promote functionally ordered conformation in glucocorticoid receptor's major activation function domain, AF1, which is found to exist as an ID protein, and requires an efficient interaction with coregulatory proteins for optimal activity. Our data show that trehalose induces an ordered conformation in AF1 such that its interaction with steroid receptor coactivator-1 (SRC-1), a critical coregulator of glucocorticoid receptor's activity, is greatly enhanced

Antenatal allopurinol for reduction of birth asphyxia induced brain damage (ALLO-Trial); a randomized double blind placebo controlled multicenter study

<p>Abstract</p> <p>Background</p> <p>Hypoxic-ischaemic encephalopathy is associated with development of cerebral palsy and cognitive disability later in life and is therefore one of the fundamental problems in perinatal medicine. The xanthine-oxidase inhibitor allopurinol reduces the formation of free radicals, thereby limiting the amount of hypoxia-reperfusion damage. In case of suspected intra-uterine hypoxia, both animal and human studies suggest that maternal administration of allopurinol immediately prior to delivery reduces hypoxic-ischaemic encephalopathy.</p> <p>Methods/Design</p> <p>The proposed trial is a randomized double blind placebo controlled multicenter study in pregnant women at term in whom the foetus is suspected of intra-uterine hypoxia.</p> <p>Allopurinol 500 mg IV or placebo will be administered antenatally to the pregnant woman when foetal hypoxia is suspected. Foetal distress is being diagnosed by the clinician as an abnormal or non-reassuring foetal heart rate trace, preferably accompanied by either significant ST-wave abnormalities (as detected by the STAN-monitor) or an abnormal foetal blood scalp sampling (pH < 7.20).</p> <p>Primary outcome measures are the amount of S100B (a marker for brain tissue damage) and the severity of oxidative stress (measured by isoprostane, neuroprostane, non protein bound iron and hypoxanthine), both measured in umbilical cord blood. Secondary outcome measures are neonatal mortality, serious composite neonatal morbidity and long-term neurological outcome. Furthermore pharmacokinetics and pharmacodynamics will be investigated.</p> <p>We expect an inclusion of 220 patients (110 per group) to be feasible in an inclusion period of two years. Given a suspected mean value of S100B of 1.05 ug/L (SD 0.37 ug/L) in the placebo group this trial has a power of 90% (alpha 0.05) to detect a mean value of S100B of 0.89 ug/L (SD 0.37 ug/L) in the 'allopurinol-treated' group (z-test_2-sided). Analysis will be by intention to treat and it allows for one interim analysis.</p> <p>Discussion</p> <p>In this trial we aim to answer the question whether antenatal allopurinol administration reduces hypoxic-ischaemic encephalopathy in neonates exposed to foetal hypoxia.</p> <p>Trial registration number</p> <p>Clinical Trials, protocol registration system: NCT00189007</p

Exploration of Shared Genetic Architecture Between Subcortical Brain Volumes and Anorexia Nervosa

In MRI scans of patients with anorexia nervosa (AN), reductions in brain volume are often apparent. However, it is unknown whether such brain abnormalities are influenced by genetic determinants that partially overlap with those underlying AN. Here, we used a battery of methods (LD score regression, genetic risk scores, sign test, SNP effect concordance analysis, and Mendelian randomization) to investigate the genetic covariation between subcortical brain volumes and risk for AN based on summary measures retrieved from genome-wide association studies of regional brain volumes (ENIGMA consortium, n = 13,170) and genetic risk for AN (PGC-ED consortium, n = 14,477). Genetic correlations ranged from − 0.10 to 0.23 (all p > 0.05). There were some signs of an inverse concordance between greater thalamus volume and risk for AN (permuted p = 0.009, 95% CI: [0.005, 0.017]). A genetic variant in the vicinity of ZW10, a gene involved in cell division, and neurotransmitter and immune system relevant genes, in particular DRD2, was significantly associated with AN only after conditioning on its association with caudate volume (pFDR = 0.025). Another genetic variant linked to LRRC4C, important in axonal and synaptic development, reached significance after conditioning on hippocampal volume (pFDR = 0.021). In this comprehensive set of analyses and based on the largest available sample sizes to date, there was weak evidence for associations between risk for AN and risk for abnormal subcortical brain volumes at a global level (that is, common variant genetic architecture), but suggestive evidence for effects of single genetic markers. Highly powered multimodal brain- and disorder-related genome-wide studies are needed to further dissect the shared genetic influences on brain structure and risk for AN

Post-orogenic shoshonitic magmas of the Yzerfontein pluton, South Africa: the 'smoking gun' of mantle melting and crustal growth during Cape granite genesis?

The post-orogenic Yzerfontein pluton, in the Saldania Belt of South Africa was constructed through numerous injections of shoshonitic magmas. Most magma compositions are adequately modelled as products of fractionation, but the monzogranites and syenogranites may have a separate origin. A separate high-Mg mafic series has a less radiogenic mantle source. Fine-grained magmatic enclaves in the intermediate shoshonitic rocks are autoliths. The pluton was emplaced between 533 ± 3 and 537 ± 3 Ma (LASF-ICP-MS U–Pb zircon), essentially synchronously with many granitic magmas of the Cape Granite Suite (CGS). Yzerfontein may represent a high-level expression of the mantle heat source that initiated partial melting of the local crust and produced the CGS granitic magmas, late in the Saldanian Orogeny. However, magma mixing is not evident at emplacement level and there are no magmatic kinships with the I-type granitic rocks of the CGS. The mantle wedge is inferred to have been enriched during subduction along the active continental margin. In the late- to post-orogenic phase, the enriched mantle partially melted to produce heterogeneous magma batches, exemplified by those that formed the Yzerfontein pluton, which was further hybridized through minor assimilation of crustal materials. Like Yzerfontein, the small volumes of mafic rocks associated with many batholiths, worldwide, are probably also lowvolume, high-level expressions of crustal growth through the emplacement of major amounts of mafic magma into the deep crust.IS

Limited influence of subducted continental material on mineralogy and elemental geochemistry of primitive magmas from Indonesia-Australia collision zone

Melt inclusions within forsterite-rich olivine crystals in two mixed magmas from the Indonesia–Australia collision zone provide information on the primary melts formed within this tectonic environment. Although whole rock Sr, Nd and Pb isotope data show a strong influence of subducted continental material, the melt inclusion major and trace element compositions are only subtly different from typical subduction-related magmas. The presence of low-Ca olivine crystals with inclusions of aluminous spinel in one sample can be explained by localised reactions during influx of hot basaltic magma in a partially crystallised magma chamber. The mineralogy of the samples is similar to that of other mixed arc magmas. Major and trace element data for reheated melt inclusions show subtle distinctions compared to non-collisional magmas in terms of CaO/Al2O3, Th/Nb and Sr/Y ratios, reflecting partial melting processes during slab to wedge transfer of subducted continental material. Magmas influenced by the subduction of continental material are therefore very similar to normal subduction-related magmas, apart from their radiogenic isotope signature. Magmas with crustal isotope ratios and highly unusual (e.g. peraluminous) geochemical compositions must therefore be formed by other processes, such as upper crustal contamination