Donepezil Effects on Mood in Patients with Schizophrenia and Schizoaffective Disorder

Donepezil, 5 mg/d for 6 wk then 10 mg/d for 6 wk, and placebo daily for 12 wk in a double-blind cross-over paradigm, was added to the therapeutic regimen of 13 patients with schizophrenia or schizoaffective disorders, clinically stable on atypical antipsychotic medications. Patients had varying degrees of depressive symptoms, ranging from no depression to clinically significant depression. There was no worsening or induction of depression in individual patients or the group as a whole. In addition there was a statistically significant antidepressant effect in the group as a whole during the donepezil condition and a clinically significant antidepressant effect in the patients with clinically significant depressive symptoms, although there were not enough depressed patients in the group to conclude that donepezil may have antidepressant effects. Thus, in this study, donepezil did not induce or worsen depressive symptoms in schizophrenic and schizoaffective disorder patients

Glycerophospholipid Profiles of Bats with White-Nose Syndrome

Pseudogymnoascus destructans is an ascomycetous fungus responsible for the disease dubbed white-nose syndrome (WNS) and massive mortalities of cave-dwelling bats. The fungus infects bat epidermal tissue, causing damage to integumentary cells and pilosebaceous units. Differences in epidermal lipid composition caused by P. destructans infection could have drastic consequences for a variety of physiological functions, including innate immune efficiency and water retention. While bat surface lipid and stratum corneum lipid composition have been described, the differences in epidermal lipid content between healthy tissue and P. destructans–infected tissue have not been documented. In this study, we analyzed the effect of wing damage from P. destructans infection on the epidermal polar lipid composition (glycerophospholipids [GPs] and sphingomyelin) of little brown bats (Myotis lucifugus). We hypothesized that infection would lead to lower levels of total lipid or higher oxidized lipid product proportions. Polar lipids from three damaged and three healthy wing samples were profiled by electrospray ionization tandem mass spectrometry. We found lower total broad lipid levels in damaged tissue, specifically etherlinked phospholipids, lysophospholipids, phosphatidylcholine, and phosphatidylethanolamine. Thirteen individual GP species from four broad GP classes were present in higher amounts in healthy tissue. Six unsaturated GP species were absent in damaged tissue. Our results confirm that P. destructans infection leads to altered lipid profiles. Clinical signs of WNS may include lower lipid levels and lower proportions of unsaturated lipids due to cellular and glandular damage."This project was funded by an Arkansas State Wildlife Grant, the National Speleological Society, the Graduate Program of Environmental Science at Arkansas State University (ASU), the US Fish and Wildlife Service, a Government of Canada Postdoctoral Fellowship (PDRF), the Natural Sciences and Engineering Research Council (NSERC; Canada), the German Academic Exchange Service (DAAD), and the Center for North American Bat Research and Conservation at Indiana State University. Instrument acquisition and method development at KLRC was supported by NSF grants MCB 0455318, MCB 0920663, and DBI 0521587; Kansas Networks of Biomedical Research Excellence (INBRE; National Institutes of Health grant P20 RR16475 from the INBRE program of the National Center for Research Resources); National Science Foundation Experimental Program to Stimulate Competitive Research grant EPS-0236913; Kansas Technology Enterprise Corporation; and Kansas State University."https://www.journals.uchicago.edu/doi/10.1086/68193

Angiogenic mRNA and microRNA Gene Expression Signature Predicts a Novel Subtype of Serous Ovarian Cancer

Ovarian cancer is the fifth leading cause of cancer death for women in the U.S. and the seventh most fatal worldwide. Although ovarian cancer is notable for its initial sensitivity to platinum-based therapies, the vast majority of patients eventually develop recurrent cancer and succumb to increasingly platinum-resistant disease. Modern, targeted cancer drugs intervene in cell signaling, and identifying key disease mechanisms and pathways would greatly advance our treatment abilities. In order to shed light on the molecular diversity of ovarian cancer, we performed comprehensive transcriptional profiling on 129 advanced stage, high grade serous ovarian cancers. We implemented a, re-sampling based version of the ISIS class discovery algorithm (rISIS: robust ISIS) and applied it to the entire set of ovarian cancer transcriptional profiles. rISIS identified a previously undescribed patient stratification, further supported by micro-RNA expression profiles, and gene set enrichment analysis found strong biological support for the stratification by extracellular matrix, cell adhesion, and angiogenesis genes. The corresponding “angiogenesis signature” was validated in ten published independent ovarian cancer gene expression datasets and is significantly associated with overall survival. The subtypes we have defined are of potential translational interest as they may be relevant for identifying patients who may benefit from the addition of anti-angiogenic therapies that are now being tested in clinical trials

Glutathione pathway gene variation and risk of autism spectrum disorders

Despite evidence that autism is highly heritable with estimates of 15 or more genes involved, few studies have directly examined associations of multiple gene interactions. Since inability to effectively combat oxidative stress has been suggested as a mechanism of autism, we examined genetic variation 42 genes (308 single-nucleotide polymorphisms (SNPs)) related to glutathione, the most important antioxidant in the brain, for both marginal association and multi-gene interaction among 318 case–parent trios from The Autism Genetic Resource Exchange. Models of multi-SNP interactions were estimated using the trio Logic Regression method. A three-SNP joint effect was observed for genotype combinations of SNPs in glutaredoxin, glutaredoxin 3 (GLRX3), and cystathione gamma lyase (CTH); OR = 3.78, 95% CI: 2.36, 6.04. Marginal associations were observed for four genes including two involved in the three-way interaction: CTH, alcohol dehydrogenase 5, gamma-glutamylcysteine synthetase, catalytic subunit and GLRX3. These results suggest that variation in genes involved in counterbalancing oxidative stress may contribute to autism, though replication is necessary

Polymorphism screening and haplotype analysis of the tryptophan hydroxylase gene (TPH1) and association with bipolar affective disorder in Taiwan

BACKGROUND: Disturbances in serotonin neurotransmission are implicated in the etiology of many psychiatric disorders, including bipolar affective disorder (BPD). The tryptophan hydroxylase gene (TPH), which codes for the enzyme catalyzing the rate-limiting step in serotonin biosynthetic pathway, is one of the leading candidate genes for psychiatric and behavioral disorders. In a preliminary study, we found that TPH1 intron7 A218C polymorphism was associated with BPD. This study was designed to investigate sequence variants of the TPH1 gene in Taiwanese and to test whether the TPH1 gene is a susceptibility factor for the BPD. METHODS: Using a systematic approach, we have searched the exons and promoter region of the TPH1 gene for sequence variants in Taiwanese Han and have identified five variants, A-1067G, G-347T, T3804A, C27224T, and A27237G. These five variants plus another five taken from the literature and a public database were examined for an association in 108 BPD patients and 103 controls; no association was detected for any of the 10 variants. RESULTS: Haplotype constructions using these 10 SNPs showed that the 3 most common haplotypes in both patients and controls were identical. One of the fourth common haplotype in the patient group (i.e. GGGAGACCCA) was unique and showed a trend of significance with the disease (P = 0.028). However, the significance was abolished after Bonferroni correction thus suggesting the association is weak. In addition, three haplotype-tagged SNPs (htSNPs) were selected to represent all haplotypes with frequencies larger than 2% in the Taiwanese Han population. The defined TPH1 htSNPs significantly reduce the marker number for haplotype analysis thus provides useful information for future association studies in our population. CONCLUSION: Results of this study did not support the role of TPH1 gene in BPD etiology. As the current studies found the TPH1 gene under investigation belongs to the peripheral serotonin system and may link to a cardiac dysfunction phenotype, a second TPH gene that functions predominantly in the brain (i.e., nTPH or TPH2) should be the target for the future association study

Association between Regulator of G Protein Signaling 9–2 and Body Weight

Regulator of G protein signaling 9–2 (RGS9–2) is a protein that is highly enriched in the striatum, a brain region that mediates motivation, movement and reward responses. We identified a naturally occurring 5 nucleotide deletion polymorphism in the human RGS9 gene and found that the mean body mass index (BMI) of individuals with the deletion was significantly higher than those without. A splicing reporter minigene assay demonstrated that the deletion had the potential to significantly decrease the levels of correctly spliced RGS9 gene product. We measured the weights of rats after virally transduced overexpression of RGS9–2 or the structurally related RGS proteins, RGS7, or RGS11, in the nucleus accumbens (NAc) and observed a reduction in body weight after overexpression of RGS9–2 but not RGS7 or 11. Conversely, we found that the RGS9 knockout mice were heavier than their wild-type littermates and had significantly higher percentages of abdominal fat. The constituent adipocytes were found to have a mean cross-sectional area that was more than double that of corresponding cells from wild-type mice. However, food intake and locomotion were not significantly different between the two strains. These studies with humans, rats and mice implicate RGS9–2 as a factor in regulating body weight.National Institute of Mental Health (U.S.) (R41MH78570 award)National Center for Research Resources (U.S.) (Rhode Island IDeA Network of Biomedical Research Excellence (RI-INBRE) Award P20RR016457-10

The Beaker phenomenon and the genomic transformation of northwest Europe

From around 2750 to 2500 bc, Bell Beaker pottery became widespread across western and central Europe, before it disappeared between 2200 and 1800 bc. The forces that propelled its expansion are a matter of long-standing debate, and there is support for both cultural diffusion and migration having a role in this process. Here we present genome-wide data from 400 Neolithic, Copper Age and Bronze Age Europeans, including 226 individuals associated with Beaker-complex artefacts. We detected limited genetic affinity between Beaker-complex-associated individuals from Iberia and central Europe, and thus exclude migration as an important mechanism of spread between these two regions. However, migration had a key role in the further dissemination of the Beaker complex. We document this phenomenon most clearly in Britain, where the spread of the Beaker complex introduced high levels of steppe-related ancestry and was associated with the replacement of approximately 90% of Britain’s gene pool within a few hundred years, continuing the east-to-west expansion that had brought steppe-related ancestry into central and northern Europe over the previous centuries

European and multi-ancestry genome-wide association meta-analysis of atopic dermatitis highlights importance of systemic immune regulation

Atopic dermatitis (AD) is a common inflammatory skin condition and prior genome-wide association studies (GWAS) have identified 71 associated loci. In the current study we conducted the largest AD GWAS to date (discovery N = 1,086,394, replication N = 3,604,027), combining previously reported cohorts with additional available data. We identified 81 loci (29 novel) in the European-only analysis (which all replicated in a separate European analysis) and 10 additional loci in the multi-ancestry analysis (3 novel). Eight variants from the multi-ancestry analysis replicated in at least one of the populations tested (European, Latino or African), while two may be specific to individuals of Japanese ancestry. AD loci showed enrichment for DNAse I hypersensitivity and eQTL associations in blood. At each locus we prioritised candidate genes by integrating multi-omic data. The implicated genes are predominantly in immune pathways of relevance to atopic inflammation and some offer drug repurposing opportunities.</p

Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer.

To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC