EpiphaNet: An Interactive Tool to Support Biomedical Discoveries

Background. EpiphaNet (http://epiphanet.uth.tmc.edu) is an interactive knowledge discovery system, which enables researchers to explore visually sets of relations extracted from MEDLINE using a combination of language processing techniques. In this paper, we discuss the theoretical and methodological foundations of the system, and evaluate the utility of the models that underlie it for literature‐based discovery. In addition, we present a summary of results drawn from a qualitative analysis of over six hours of interaction with the system by basic medical scientists. Results: The system is able to simulate open and closed discovery, and is shown to generate associations that are both surprising and interesting within the area of expertise of the researchers concerned. Conclusions: EpiphaNet provides an interactive visual representation of associations between concepts, which is derived from distributional statistics drawn from across the spectrum of biomedical citations in MEDLINE. This tool is available online, providing biomedical scientists with the opportunity to identify and explore associations of interest to them

The Putative Role of Resveratrol in SIRT-1 Mediated Modulation of the Vitamin D Pathway

The nuclear vitamin D receptor (VDR) modulates gene transcription in 1,25-dihydroxyvitamin D (1,25D) target tissues such as kidney, colon, and bone. The 1,25D hormone is derived from vitamin D in the skin or from the diet, and binds to and activates the VDR. We have previously shown that resveratrol, an antioxidant found in the skin of red grapes, has the ability to activate the VDR signaling pathway. Moreover, cells treated with both resveratrol and 1,25D resulted in an additive or even synergistic stimulation of VDR-mediated transcription compared to cells treated with 1,25D alone. Based on these initial results, experiments were designed to test the significance of mutations in the hormone-binding domain of VDR. Identical hormone treatments were applied to “wild-type” (non-mutated) and single point VDR mutations. 1,25D displayed a significant drop in activity caused by these mutations, while the ability of resveratrol to activate VDR was only modestly attenuated. One possible interpretation of these results is that resveratrol may affect VDR activity indirectly, perhaps via the ability of resveratrol to activate SIRT1, an enzyme which has been shown to deacetylate (and thereby activate) other nuclear receptors such as the liver X receptor (LXR). In support of this hypothesis, radiolabeled 1,25D displacement assays revealed an increase in bound radiolabeled 1,25D only in the presence of resveratrol, suggesting that direct binding of resveratrol to VDR is unlikely. Additionally, we observed increased transcriptional activity in response to resveratrol in a subset of other nuclear receptors, including the liver X receptor (LXR), which is closely related to VDR and is known to be deacetylated by SIRT1. Finally, we tested receptor-mediated transcriptional activity in a system containing VDR in the absence and presence of overexpressed SIRT1. Transcriptional activity was higher in cells expressing SIRT1, and synergistic activity of 1,25D combined with resveratrol was observed. We are currently conducting additional experiments employing the VDR/SIRT1 assay in multiple cellular contexts. In conclusion, this study elucidates, for the first time, a potential novel pathway for crosstalk between two nutritionally derived lipids, vitamin D and resveratrol

Optimal vitamin D spurs serotonin : 1,25-dihydroxyvitamin D represses serotonin reuptake transport (SERT) and degradation (MAO-A) gene expression in cultured rat serotonergic neuronal cell lines

Background: Diminished brain levels of two neurohormones, 5-hydroxytryptamine (5-HT; serotonin) and 1,25-dihydroxyvitamin D3 (1,25D; active vitamin D metabolite), are proposed to play a role in the atypical social behaviors associated with psychological conditions including autism spectrum disorders and depression. We reported previously that 1,25D induces expression of tryptophan hydroxylase-2 (TPH2), the initial and rate-limiting enzyme in the biosynthetic pathway to 5-HT, in cultured rat serotonergic neuronal cells. However, other enzymes and transporters in the pathway of tryptophan metabolism had yet to be examined with respect to the actions of vitamin D. Herein, we probed the response of neuronal cells to 1,25D by quantifying mRNA expression of serotonin synthesis isozymes, TPH1 and TPH2, as well as expression of the serotonin reuptake transporter (SERT), and the enzyme responsible for serotonin catabolism, monoamine oxidase-A (MAO-A). We also assessed the direct production of serotonin in cell culture in response to 1,25D. Results: Employing quantitative real-time PCR, we demonstrate that TPH-1/-2 mRNAs are 28- to 33-fold induced by 10 nM 1,25D treatment of cultured rat serotonergic neuronal cells (RN46A-B14), and the enhancement of TPH2 mRNA by 1,25D is dependent on the degree of neuron-like character of the cells. In contrast, examination of SERT, the gene product of which is a target for the SSRI-class of antidepressants, and MAO-A, which encodes the predominant catabolic enzyme in the serotonin pathway, reveals that their mRNAs are 51–59% repressed by 10 nM 1,25D treatment of RN46AB14 cells. Finally, serotonin concentrations are significantly enhanced (2.9-fold) by 10 nM 1,25D in this system. Conclusions: These results are consistent with the concept that vitamin D maintains extracellular fluid serotonin concentrations in the brain, thereby offering an explanation for how vitamin D could influence the trajectory and development of neuropsychiatric disorders. Given the profile of gene regulation in cultured RN46A-B14 serotonergic neurons, we conclude that 1,25D acts not only to induce serotonin synthesis, but also functions at an indirect, molecular-genomic stage to mimic SSRIs and MAO inhibitors, likely elevating serotonin in the CNS. These data suggest that optimal vitamin D status may contribute to improving behavioral pathophysiologies resulting from dysregulation of serotonergic neurotransmission

Формирование эмоциональной культуры как компонента инновационной культуры студентов

Homozygosity has long been associated with rare, often devastating, Mendelian disorders1 and Darwin was one of the first to recognise that inbreeding reduces evolutionary fitness2. However, the effect of the more distant parental relatedness common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity, ROH), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power3,4. Here we use ROH to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts and find statistically significant associations between summed runs of homozygosity (SROH) and four complex traits: height, forced expiratory lung volume in 1 second (FEV1), general cognitive ability (g) and educational attainment (nominal p<1 × 10−300, 2.1 × 10−6, 2.5 × 10−10, 1.8 × 10−10). In each case increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing convincing evidence for the first time that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples5,6, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein (LDL) cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection7, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been

Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels.

Elevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci and colocalization with gene expression in 47 tissues implicated the kidney and liver as the main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in the liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A transactivated the promoter of ABCG2, encoding a major urate transporter, in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardiometabolic traits.The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. Variant annotation was supported by software resources provided via the Caché Campus program of the InterSystems GmbH to Alexander Teumer

Novel Approach Identifies SNPs in SLC2A10 and KCNK9 with Evidence for Parent-of-Origin Effect on Body Mass Index

Marja-Liisa Lokki työryhmien Generation Scotland Consortium, LifeLines Cohort Study ja GIANT Consortium jäsenPeer reviewe

Differential and shared genetic effects on kidney function between diabetic and non-diabetic individuals

A large-scale GWAS provides insight on diabetes-dependent genetic effects on the glomerular filtration rate, a common metric to monitor kidney health in disease.Reduced glomerular filtration rate (GFR) can progress to kidney failure. Risk factors include genetics and diabetes mellitus (DM), but little is known about their interaction. We conducted genome-wide association meta-analyses for estimated GFR based on serum creatinine (eGFR), separately for individuals with or without DM (nDM = 178,691, nnoDM = 1,296,113). Our genome-wide searches identified (i) seven eGFR loci with significant DM/noDM-difference, (ii) four additional novel loci with suggestive difference and (iii) 28 further novel loci (including CUBN) by allowing for potential difference. GWAS on eGFR among DM individuals identified 2 known and 27 potentially responsible loci for diabetic kidney disease. Gene prioritization highlighted 18 genes that may inform reno-protective drug development. We highlight the existence of DM-only and noDM-only effects, which can inform about the target group, if respective genes are advanced as drug targets. Largely shared effects suggest that most drug interventions to alter eGFR should be effective in DM and noDM.</p

Nutraceuticals and the Skin: Roles in Health and Disease

ca. 200 words; this text will present the book in all promotional forms (e.g. flyers). Please describe the book in straightforward and consumer-friendly terms. [The skin is the largest organ of the body and serves as a barrier between the inner and external environments. As such, any problems in the skin can have serious effects on systemic health and well-being. Several studies have established that both nutritional and dietary factors play an important role in the maintenance of normal skin integrity, and can execute a causative, preventative and/or treatment role in a number of skin related conditions. Nutritional factors have been studied for their involvement in skin ageing, acne, inflammation and several chronic immune-mediated disorders such as atopic dermatitis, psoriasis, diabetes, obesity, wounds and various types of skin cancer. The skin condition, in turn, can affect nutritional choices and subsequent nutritional and health status. There are a multitude of mechanisms by which nutraceuticals can counteract adverse skin conditions. Consumption of a diet rich in nutrients and vitamins (nutraceuticals and antioxidants), particularly those derived from fruits and vegetables, not only supports health in general, but also skin maintenance and repair in particular. Epidemiological evidence links consumption of these diets with prevention and mitigation of disease progression. For example, nutraceuticals with anti-oxidative or metal chelating properties are being actively evaluated as natural tools to modulate, prevent or inhibit oxidative processes or modulate advanced glycation end products. However, many other properties of dietary compounds with relevance to skin remain to be characterized. For this Special Issue of Nutrients, we have compiled invited manuscripts describing original research, or reviewing scientific literature examining the role of diets and/or specific nutraceuticals in the prevention and treatment of skin disorders. These articles describe the beneficial effects of plant extracts and plant-derived compounds and their ability to ameliorate diverse skin-related conditions including UV damage, aging, atopic dermatitis, psoriasis, and skin cancer. A comprehensive article summarizes the results of current clinical trials on nutraceuticals for various skin afflicitons. Finally, the outcome and research methods used for studies on nutraceuticals and skin function, and their compliance with European regulations is analyzed. Taken together, this compilation of articles provides an up-to-date view of research into the application of nutraceuticals for skin health, for the researcher and anyone interested in the application of natural, plant-derived agents for treatment of skin disease.