Discovery of Sexual Dimorphisms in Metabolic and Genetic Biomarkers

Metabolomic profiling and the integration of whole-genome genetic association data has proven to be a powerful tool to comprehensively explore gene regulatory networks and to investigate the effects of genetic variation at the molecular level. Serum metabolite concentrations allow a direct readout of biological processes, and association of specific metabolomic signatures with complex diseases such as Alzheimer's disease and cardiovascular and metabolic disorders has been shown. There are well-known correlations between sex and the incidence, prevalence, age of onset, symptoms, and severity of a disease, as well as the reaction to drugs. However, most of the studies published so far did not consider the role of sexual dimorphism and did not analyse their data stratified by gender. This study investigated sex-specific differences of serum metabolite concentrations and their underlying genetic determination. For discovery and replication we used more than 3,300 independent individuals from KORA F3 and F4 with metabolite measurements of 131 metabolites, including amino acids, phosphatidylcholines, sphingomyelins, acylcarnitines, and C6-sugars. A linear regression approach revealed significant concentration differences between males and females for 102 out of 131 metabolites (p-values<3.8 x 10(-4); Bonferroni-corrected threshold). Sex-specific genome-wide association studies (GWAS) showed genome-wide significant differences in beta-estimates for SNPs in the CPS1 locus (carbamoyl-phosphate synthase 1, significance level: p<3.8 x 10(-10); Bonferroni-corrected threshold) for glycine. We showed that the metabolite profiles of males and females are significantly different and, furthermore, that specific genetic variants in metabolism-related genes depict sexual dimorphism. Our study provides new important insights into sex-specific differences of cell regulatory processes and underscores that studies should consider sex-specific effects in design and interpretation

The effects of a 6-week strength training on critical velocity, anaerobic running distance, 30-m sprint and yo-yo intermittent running test performances in male soccer players

The objectives of this study were to examine the effects of a moderate intensity strength training on changes in critical velocity (CV), anaerobic running distance (D'), sprint performance and Yo-Yo intermittent running test (Yo-Yo IR1) performances. Methods: two recreational soccer teams were divided in a soccer training only group (SO; n = 13) and a strength and soccer training group (ST; n = 13). Both groups were tested for values of CV, D', Yo-Yo IR1 distance and 30-m sprint time on two separate occasions (pre and post intervention). The ST group performed a concurrent 6-week upper and lower body strength and soccer training, whilst the SO group performed a soccer only training. Results: after the re-test of all variables, the ST demonstrated significant improvements for both, YoYo IR1 distance (p = 0.002) and CV values (p<0.001) with no significant changes in the SO group. 30-m sprint performance were slightly improved in the ST group with significantly decreased performance times identified in the SO group (p<0.001). Values for D' were slightly reduced in both groups (ST -44.5 m, 95% CI = -90.6 to 1.6; SO -42.6 m, 95% CI = -88.7 to 3.5). Conclusions: combining a 6-week moderate strength training with soccer training significantly improves CV, Yo-Yo IR1 whilst moderately improving 30-m sprint performances in non-previously resistance trained male soccer players. Critical Velocity can be recommended to coaches as an additional valid testing tool in soccer

A HIF-independent, CD133-mediated mechanism of cisplatin resistance in glioblastoma cells

Purpose Glioblastoma Multiforme (GBM) is the commonest brain tumour in adults. A population of cells, known as cancer stem cells (CSCs), is thought to mediate chemo/radiotherapy resistance. CD133 is a cell surface marker to identify and isolate CSCs. However, its functional significance and the relevant microenvironment in which to study CD133 remain unknown. We examined the influence of hypoxia on CD133 expression and the potential functional significance of CD133 in glioblastoma chemoresistance. Methods Gene expression was analysed by qRT-PCR. siRNA technique was used to downregulate genes and confirmed by flow cytometry. IC50 values was evaluated with the Alamar blue assay. Results CD133 expression was upregulated in hypoxia in 2D and 3D models. There was increased resistance to chemotherapeutics, cisplatin, temozolomide and etoposide, in cells cultured in hypoxia compared to normoxia. siRNA knockdown of either HIF1a or HIF2a resulted in reduced CD133 mRNA expression with HIF2a having a more prolonged effect on CD133 expression. HIF2a downregulation sensitized GBM cells to cisplatin to a greater extent than HIF1a but CD133 knockdown had a much more marked effect on cisplatin sensitisation than knockdown of either of the HIFs suggesting a HIF-independent mechanism of cisplatin resistance mediated via CD133. The same mechanism was not involved in temozolomide resistance since downregulation of HIF1a but not HIF2a or CD133 sensitized GBM cells to temozolomide. Conclusion Knowledge of the mechanisms involved in the novel hypoxia-induced CD133-mediated resistance to cisplatin observed might lead to identification of new strategies that enable more effective use of current therapeutic agents

Characterizing the morbid genome of ciliopathies

Background Ciliopathies are clinically diverse disorders of the primary cilium. Remarkable progress has been made in understanding the molecular basis of these genetically heterogeneous conditions; however, our knowledge of their morbid genome, pleiotropy, and variable expressivity remains incomplete. Results We applied genomic approaches on a large patient cohort of 371 affected individuals from 265 families, with phenotypes that span the entire ciliopathy spectrum. Likely causal mutations in previously described ciliopathy genes were identified in 85% (225/265) of the families, adding 32 novel alleles. Consistent with a fully penetrant model for these genes, we found no significant difference in their “mutation load” beyond the causal variants between our ciliopathy cohort and a control non-ciliopathy cohort. Genomic analysis of our cohort further identified mutations in a novel morbid gene TXNDC15, encoding a thiol isomerase, based on independent loss of function mutations in individuals with a consistent ciliopathy phenotype (Meckel-Gruber syndrome) and a functional effect of its deficiency on ciliary signaling. Our study also highlighted seven novel candidate genes (TRAPPC3, EXOC3L2, FAM98C, C17orf61, LRRCC1, NEK4, and CELSR2) some of which have established links to ciliogenesis. Finally, we show that the morbid genome of ciliopathies encompasses many founder mutations, the combined carrier frequency of which accounts for a high disease burden in the study population. Conclusions Our study increases our understanding of the morbid genome of ciliopathies. We also provide the strongest evidence, to date, in support of the classical Mendelian inheritance of Bardet-Biedl syndrome and other ciliopathies

Heterochromatin Protein 1β (HP1β) has distinct functions and distinct nuclear distribution in pluripotent versus differentiated cells

Background: Pluripotent embryonic stem cells (ESCs) have the unique ability to differentiate into every cell type and to self-renew. These characteristics correlate with a distinct nuclear architecture, epigenetic signatures enriched for active chromatin marks and hyperdynamic binding of structural chromatin proteins. Recently, several chromatin-related proteins have been shown to regulate ESC pluripotency and/or differentiation, yet the role of the major heterochromatin proteins in pluripotency is unknown. Results: Here we identify Heterochromatin Protein 1β (HP1β) as an essential protein for proper differentiation, and, unexpectedly, for the maintenance of pluripotency in ESCs. In pluripotent and differentiated cells HP1β is differentially localized and differentially associated with chromatin. Deletion of HP1β, but not HP1aα, in ESCs provokes a loss of the morphological and proliferative characteristics of embryonic pluripotent cells, reduces expression of pluripotency factors and causes aberrant differentiation. However, in differentiated cells, loss of HP1β has the opposite effect, perturbing maintenance of the differentiation state and facilitating reprogramming to an induced pluripotent state. Microscopy, biochemical fractionation and chromatin immunoprecipitation reveal a diffuse nucleoplasmic distribution, weak association with chromatin and high expression levels for HP1β in ESCs. The minor fraction of HP1β that is chromatin-bound in ESCs is enriched within exons, unlike the situation in differentiated cells, where it binds heterochromatic satellite repeats and chromocenters. Conclusions: We demonstrate an unexpected duality in the role of HP1β: it is essential in ESCs for maintaining pluripotency, while it is required for proper differentiation in differentiated cells. Thus, HP1β function both depends on, and regulates, the pluripotent state

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

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Multi‐scale studies of 3d printed Mn–Na–W/SiO2 catalyst for oxidative coupling of methane

This work presents multi-scale approaches to investigate 3D printed structured Mn–Na–W/SiO_{2} atalysts used for the oxidative coupling of methane (OCM) reaction. The performance of the 3D printed catalysts has been compared to their conventional analogues, packed beds of pellets and powder. The physicochemical properties of the 3D printed catalysts were investigated using scanning electron microscopy, nitrogen adsorption and X-ray diffraction (XRD). Performance and durability tests of the 3D printed catalysts were conducted in the laboratory and in a miniplant under real reaction conditions. In addition, synchrotron-based X-ray diffraction computed tomography technique (XRD-CT) was employed to obtain cross sectional maps at three different positions selected within the 3D printed catalyst body during the OCM reaction. The maps revealed the evolution of catalyst active phases and silica support on spatial and temporal scales within the interiors of the 3D printed catalyst under operating conditions. These results were accompanied with SEM-EDS analysis that indicated a homogeneous distribution of the active catalyst particles across the silica support

Combinatorial hydrogel library enables identification of materials that mitigate the foreign body response in primates

The foreign body response is an immune-mediated reaction that can lead to the failure of implanted medical devices and discomfort for the recipient. There is a critical need for biomaterials that overcome this key challenge in the development of medical devices. Here we use a combinatorial approach for covalent chemical modification to generate a large library of variants of one of the most widely used hydrogel biomaterials, alginate. We evaluated the materials in vivo and identified three triazole-containing analogs that substantially reduce foreign body reactions in both rodents and, for at least 6 months, in non-human primates. The distribution of the triazole modification creates a unique hydrogel surface that inhibits recognition by macrophages and fibrous deposition. In addition to the utility of the compounds reported here, our approach may enable the discovery of other materials that mitigate the foreign body response.Leona M. and Harry B. Helmsley Charitable Trust (3-SRA-2014-285-M-R)United States. National Institutes of Health (EB000244)United States. National Institutes of Health (EB000351)United States. National Institutes of Health (DE013023)United States. National Institutes of Health (CA151884)United States. National Institutes of Health (P41EB015871-27)National Cancer Institute (U.S.) (P30-CA14051