Considerations in the search for epistasis.

Epistasis refers to changes in the effect on phenotype of a unit of genetic information, such as a single nucleotide polymorphism or a gene, dependent on the context of other genetic units. Such interactions are both biologically plausible and good candidates to explain observations which are not fully explained by an additive heritability model. However, the search for epistasis has so far largely failed to recover this missing heritability.

Discovering non-additive heritability using additive GWAS summary statistics.

LD score regression (LDSC) is a method to estimate narrow-sense heritability from genome-wide association study (GWAS) summary statistics alone, making it a fast and popular approach. In this work, we present interaction-LD score (i-LDSC) regression: an extension of the original LDSC framework that accounts for interactions between genetic variants. By studying a wide range of generative models in simulations, and by re-analyzing 25 well-studied quantitative phenotypes from 349,468 individuals in the UK Biobank and up to 159,095 individuals in BioBank Japan, we show that the inclusion of a -interaction score (i.

Leveraging the genetic correlation between traits improves the detection of epistasis in genome-wide association studies.

Epistasis, commonly defined as the interaction between genetic loci, is known to play an important role in the phenotypic variation of complex traits. As a result, many statistical methods have been developed to identify genetic variants that are involved in epistasis, and nearly all of these approaches carry out this task by focusing on analyzing one trait at a time. Previous studies have shown that jointly modeling multiple phenotypes can often dramatically increase statistical power for association mapping.

Intra-Tumoral Nerve-Tracing in a Novel Syngeneic Model of High-Grade Serous Ovarian Carcinoma.

Dense tumor innervation is associated with enhanced cancer progression and poor prognosis. We observed innervation in breast, prostate, pancreatic, lung, liver, ovarian, and colon cancers. Defining innervation in high-grade serous ovarian carcinoma (HGSOC) was a focus since sensory innervation was observed whereas the normal tissue contains predominantly sympathetic input.

Effects of extreme high flow events on macroinvertebrate communities in Vermont streams.

Heavy precipitation events and subsequent high flows are occurring with greater frequency and intensity, which could have substantial implications for biomonitoring programs that typically evaluate changes in biological condition due to stressors at local and watershed scales. In this study we evaluated response and recovery of macroinvertebrate communities at nine reference quality streams located in multiple watersheds throughout Vermont to flooding from Tropical Storm (TS) Irene in 2011. At each site, the Vermont Department of Environmental Conservation (VT DEC) had collected macroinvertebrate data on an annual basis from 2009-2013.

Limitations of trait-based approaches for stressor assessment: The case of freshwater invertebrates and climate drivers.

The appeal of trait-based approaches for assessing environmental vulnerabilities arises from the potential insight they provide into the mechanisms underlying the changes in populations and community structure. Traits can provide ecologically based explanations for observed responses to environmental changes, along with predictive power gained by developing relationships between traits and environmental variables. Despite these potential benefits, questions remain regarding the utility and limitations of these approaches, which we explore focusing on the following questions: (a) How reliable are predictions of biotic responses to changing conditions based on single trait-environment relationships? (b) What factors constrain detection of single trait-environment relationships, and how can they be addressed? (c) Can we use information on meta-community processes to reveal conditions when assumptions underlying trait-based studies are not met? We address these questions by reviewing published literature on aquatic invertebrate communities from stream ecosystems.

A REVIEW OF WATER QUALITY RESPONSES TO AIR TEMPERATURE AND PRECIPITATION CHANGES 1: FLOW, WATER TEMPERATURE, SALTWATER INTRUSION.

Anticipated future increases in air temperature and regionally variable changes in precipitation will have direct and cascading effects on U.S. water quality.

Continuous nonenzymatic cross-replication of DNA strands with activated DNA oligonucleotides.

Continuous enzyme-free replication of oligonucleotides is central for open-ended evolution experiments that mimic the origin of life. Here, we studied a reaction system, whereby two 24mer DNA templates cross-catalyzed each other's synthesis from four 12mer DNA fragments, two of which were activated with the condensing agent 1-ethyl-3-(3-dimethylamino-propyl)carbodiimide (EDC). We circumvented the problem of product inhibition by melting the stable product duplexes for their reuse as templates in the following ligation step.

Sleep and major depressive disorder: a review of non-pharmacological chronotherapeutic treatments for unipolar depression.

Depression is a significant public health issue, made worse by the absence of response to antidepressant medications by many patients. Given the high degree of overlap between sleep and circadian complaints and depression, chronotherapies are a promising avenue for novel, effective, and fast-acting treatments for depression. A critical literature review was conducted of bright light therapy (BLT) as a treatment for unipolar depression.

A REVIEW OF WATER QUALITY RESPONSES TO AIR TEMPERATURE AND PRECIPITATION CHANGES 2: NUTRIENTS, ALGAL BLOOMS, SEDIMENT, PATHOGENS.

In this paper we review the published, scientific literature addressing the response of nutrients, sediment, pathogens and cyanobacterial blooms to historical and potential future changes in air temperature and precipitation. The goal is to document how different attributes of water quality are sensitive to these drivers, to characterize future risk, to inform management responses and to identify research needs to fill gaps in our understanding. Results suggest that anticipated future changes present a risk of water quality and ecosystem degradation in many U.

BAF250a Expression in Atypical Endometriosis and Endometriosis-Associated Ovarian Cancer.

Background And Objective: Atypical endometriosis (AE) is thought to be a precursor lesion to the ovarian cancer subtypes associated with endometriosis, namely, endometrioid and clear cell carcinomas. ARID1A encodes a nuclear protein (BAF250a) governing chromatin remodeling, and mutations in ARID1A have been found in 30% to 50% of clear cell and endometrioid ovarian cancers. As BAF250a expression loss by immunohistochemistry (IHC) has been documented in the endometriosis precursor lesions closely associated with these ovarian cancers subtypes, our goal was to further study the association between BAF250a expression in cases of AE with and without an associated cancer.

Ovarian hormones and propensity to drug relapse: a review.

Sex differences have been reported in various phases of substance abuse, including relapse. In general, women show greater propensity to drug relapse than men, owing perhaps to divergent withdrawal experiences and increased reactivity to internal (emotional) and external (drug-associated) cues. Animal research tends to parallel human findings, revealing enhanced reinstatement of drug administration in females than males.

The HR/LR model: Further evidence as an animal model of sensation seeking.

Sensation seeking is a personality trait characterized by risk-taking and the desire to experience novel stimuli. Evidence suggests that sensation seeking may increase an individual's psychological and neurobiological vulnerabilities to drug abuse. One potential animal model of human sensation seeking is high response to novelty in rats.

Lack of estradiol modulation of sleep deprivation-induced c-Fos in the rat brain.

Women recover from sleep deprivation more efficiently than men, but the mechanism for this difference is unknown. Effects of estrogen on sleep suggest that it could play a role, but the brain targets on which estrogen may act to have this effect have not been identified. Sleep deprivation increases levels of the immediate-early gene protein c-Fos in selected brain regions, but it is unknown whether estrogen modulates this response.

Food restriction enhances peak corticosterone levels, cocaine-induced locomotor activity, and DeltaFosB expression in the nucleus accumbens of the rat.

Chronic stress has been known to potentiate addictive behaviours in both human addicts and experimental animals. In the present study, chronic mild food restriction was used as a stressor to investigate its effect on the locomotor simulant effects of cocaine as well as FosB expression in the nucleus accumbens and caudate putamen. Chronic mild food restriction enhanced the locomotor response to the first cocaine injection, such that chronically food restricted animals showed a significant increase in activity upon an initial administration of 15 mg/kg of cocaine, an effect which only became apparent in control animals after repeated injections.

High efficacy and low toxicity of weekly docetaxel given as first-line treatment for metastatic breast cancer.

Background: Docetaxel is one of the most effective antitumor agents currently available for the treatment of metastatic breast cancer (MBC). This phase II multicenter study prospectively analyzed the efficacy and toxicity of docetaxel given on a weekly schedule as first-line treatment of metastatic breast cancer.

Patients And Methods: All patients received docetaxel, 35 mg/m(2) weekly for 6 weeks, followed by 2 weeks of rest.

Corticosterone modulates autonomic responses and adaptation of central immediate-early gene expression to repeated restraint stress.

We have tested the role of elevated corticosterone in modulating the responses to either a single (acute) or chronic (repeated daily) restraint stress. Male rats were adrenalectomised, and received subcutaneous corticosterone pellets that resulted in either low (ca. 60 ng/ml) or higher (ca.

Development and validation of a self-efficacy scale for use in British patients with rheumatoid arthritis (RASE).

Objective: Current arthritis self-efficacy scales have attracted some criticism. Therefore, the aim of this study was to develop and validate a measure of self-efficacy for use in British rheumatoid arthritis patients [Rheumatoid Arthritis Self-efficacy (RASE) scale].

Methods: Phase I: item generation of self-management strategies by rheumatology professionals and patients to create a pilot RASE.

Electrical stimulation therapy in the treatment of cigarette smoking.

In this study electrical stimulation therapy (EST) is explored as a possible new treatment for smoking cessation within a randomized controlled trial. The investigation follows reports of several authors that electrical stimulation applied to specific acupuncture points is effective in treating a variety of drug dependencies, including cigarette smoking. Three key features of treatment (electrical stimulation, frequency modulation, and electrode placement), were investigated in a 2 x 2 x 2 factorial design, resulting in eight treatment combinations.

Multiple immediate-early gene expression during physiological and endocrine adaptation to repeated stress.

This study had three objectives: (i) to determine whether there were individual differences in the activation and adaptation of a range of immediate-early genes to repeated restraint stress, (ii) to monitor physiological responses (endocrine, cardiovascular and core temperature) and their adaptation with repeated presentations of the stressor, and (iii) to determine whether any of these indices were altered by dehydroepiandrosterone, an anti-glucocorticoid steroid known to be reduced in humans by stress. Four groups of male rats were implanted subcutaneously with either dehydroepiandrosterone or control (paraffin) pellets. They were then subjected to either a single or 14 days of restraint (60 min/day) or transferred to the testing room (unstressed).

Distribution of ionotropic glutamate receptor subunit immunoreactivity in the suprachiasmatic nucleus and intergeniculate leaflet of the hamster.

Glutamate is thought to mediate the effects of light on the circadian pacemaker contained in the suprachiasmatic nucleus. Glutamate can reset this pacemaker both in vivo and in vitro while glutamate antagonists can reduce photically induced phase shifts in activity rhythms and c-fos expression in the suprachiasmatic nucleus. Most behavioural and gene expression experiments investigating circadian rhythms use hamsters, but the majority of the anatomical data on the presence and distribution of selected glutamate receptor subunits in the suprachiasmatic nucleus has been collected from rat.