Androgen regulation of axon growth and neurite extension in motoneurons

Androgens act on the CNS to affect motor function through interaction with a widespread distribution of intracellular androgen receptors (AR). This review highlights our work on androgens and process outgrowth in motoneurons, both in vitro and in vivo. The actions of androgens on motoneurons involve the generation of novel neuronal interactions that are mediated by the induction of androgen-dependent neurite or axonal outgrowth. Here, we summarize the experimental evidence for the androgenic regulation of the extension and regeneration of motoneuron neurites in vitro using cultured immortalized motoneurons, and axons in vivo using the hamster facial nerve crush paradigm. We place particular emphasis on the relevance of these effects to SBMA and peripheral nerve injurie

Glaciovolcanic evidence for a polythermal Neogene East Antarctic Ice Sheet

A paradigm has existed for more than 30 years that the basal thermal regime of the East Antarctic Ice Sheet in Victoria Land made a fundamental transition from wet-based to cold-based either at ca. 14 Ma or after ca. 2.5 Ma. The basal thermal regime is important because it determines the potential for unstable behavior in an ice sheet. We have studied the environmental characteristics of subglacially erupted volcanic centers scattered along 800 km of the Ross Sea fl ank of the Transantarctic Mountains. The volcanoes preserve evidence for the coeval paleo-ice thicknesses and contain features diagnostic of both wet-based and cold-based ice conditions. By dating the sequences we are able to demonstrate that the basal thermal regime varied spatially and with time between ca. 12 Ma and present. It was polythermal overall and probably comprised a coarse temperature patchwork of frozen-bed and thawed-bed ice, similar to the East Antarctic Ice Sheet today. Thus, an important shift is required in the prevailing paradigm describing its temporal evolution

ORIO (Online Resource for Integrative Omics): a web-based platform for rapid integration of next generation sequencing data

Abstract Established and emerging next generation sequencing (NGS)-based technologies allow for genome-wide interrogation of diverse biological processes. However, accessibility of NGS data remains a problem, and few user-friendly resources exist for integrative analysis of NGS data from different sources and experimental techniques. Here, we present Online Resource for Integrative Omics (ORIO; https://orio.niehs.nih.gov/), a web-based resource with an intuitive user interface for rapid analysis and integration of NGS data. To use ORIO, the user specifies NGS data of interest along with a list of genomic coordinates. Genomic coordinates may be biologically relevant features from a variety of sources, such as ChIP-seq peaks for a given protein or transcription start sites from known gene models. ORIO first iteratively finds read coverage values at each genomic feature for each NGS dataset. Data are then integrated using clustering-based approaches, giving hierarchical relationships across NGS datasets and separating individual genomic features into groups. In focusing its analysis on read coverage, ORIO makes limited assumptions about the analyzed data; this allows the tool to be applied across data from a variety of experiments and techniques. Results from analysis are presented in dynamic displays alongside user-controlled statistical tests, supporting rapid statistical validation of observed results. We emphasize the versatility of ORIO through diverse examples, ranging from NGS data quality control to characterization of enhancer regions and integration of gene expression information. Easily accessible on a public web server, we anticipate wide use of ORIO in genome-wide investigations by life scientists

Heterogeneous polymerase fidelity and mismatch repair bias genome variation and composition

Mutational heterogeneity must be taken into account when reconstructing evolutionary histories, calibrating molecular clocks, and predicting links between genes and disease. Selective pressures and various DNA transactions have been invoked to explain the heterogeneous distribution of genetic variation between species, within populations, and in tissue-specific tumors. To examine relationships between such heterogeneity and variations in leading- and lagging-strand replication fidelity and mismatch repair, we accumulated 40,000 spontaneous mutations in eight diploid yeast strains in the absence of selective pressure. We found that replicase error rates vary by fork direction, coding state, nucleosome proximity, and sequence context. Further, error rates and DNA mismatch repair efficiency both vary by mismatch type, responsible polymerase, replication time, and replication origin proximity. Mutation patterns implicate replication infidelity as one driver of variation in somatic and germline evolution, suggest mechanisms of mutual modulation of genome stability and composition, and predict future observations in specific cancers

Questionnaire-Based Polyexposure Assessment Outperforms Polygenic Scores for Classification of Type 2 Diabetes in a Multiancestry Cohort

OBJECTIVE Environmental exposures may have greater predictive power for type 2 diabetes than polygenic scores (PGS). Studies examining environmental risk factors, however, have included only individuals with European ancestry, limiting the applicability of results. We conducted an exposome-wide association study in the multiancestry Personalized Environment and Genes Study to assess the effects of environmental factors on type 2 diabetes. RESEARCH DESIGN AND METHODS Using logistic regression for single-exposure analysis, we identified exposures associated with type 2 diabetes, adjusting for age, BMI, household income, and self-reported sex and race. To compare cumulative genetic and environmental effects, we computed an overall clinical score (OCS) as a weighted sum of BMI and prediabetes, hyperten-sion, and high cholesterol status and a polyexposure score (PXS) as a weighted sum of 13 environmental variables. Using UK Biobank data, we developed a multiancestry PGS and calculated it for participants. RESULTS We found 76 significant associations with type 2 diabetes, including novel associations of asbestos and coal dust exposure. OCS, PXS, and PGS were significantly associated with type 2 diabetes. PXS had moderate power to determine associations, with larger effect size and greater power and reclassification improvement than PGS. For all scores, the results differed by race. CONCLUSIONS Our findings in a multiancestry cohort elucidate how type 2 diabetes odds can be at-tributed to clinical, genetic, and environmental factors and emphasize the need for exposome data in disease-risk association studies. Race-based differences in predictive scores highlight the need for genetic and exposome-wide studies in diverse populations. EmR2TaFJ

Symptom Phenotypes in Pulmonary Arterial Hypertension: The PAH “Symptome”

Women with pulmonary arterial hypertension (PAH) experience multiple symptoms, including dyspnea, fatigue, and sleep disturbance, that impair their health‐related quality of life (HRQOL). However, we know little about phenotypic subgroups of patients with PAH with similar, concurrent, multiple symptoms. The objectives of this study were to define the “symptome” by symptom cluster phenotypes and compare characteristics such as biomarkers, cardiac structure and function (echocardiography), functional capacity (6‐min walk distance), and HRQOL between the groups. This cross‐sectional study included 60 women with PAH. Subjects completed an assessment battery: Pulmonary Arterial Hypertension Symptom Scale, Pittsburgh Sleep Quality Index, Multidimensional Dyspnea Profile, Patient‐Reported Outcomes Measurement Information System (PROMIS®) Physical Function, PROMIS® Sleep‐Related Impairment, and the emPHasis‐10. Subjects also underwent transthoracic echocardiography, phlebotomy, 6‐min walk distance, and actigraphy. The three symptoms of dyspnea, fatigue, and sleep disturbance were used to define the symptom clusters. Other PAH symptoms, plasma and serum biomarkers, cardiac structure and function (echocardiography), exercise capacity (6‐min walk distance), sleep (actigraphy), and HRQOL were compared across phenotypes. The mean age was 50 ± 18 years, 51% were non‐ Hispanic white, 32% were non‐Hispanic Black and 40% had idiopathic PAH. Cluster analysis identified Mild (n = 28, 47%), Moderate (n = 20, 33%), and Severe Symptom Cluster Phenotypes (n = 12, 20%). There were no differences for age, race, or PAH etiology between the phenotypes. WHO functional class (p \u3c 0.001), norepinephrine levels (p = 0.029), right atrial pressure (p = 0.001), physical function (p \u3c 0.001), sleep onset latency (p = 0.040), and HRQOL (p \u3c 0.001) all differed significantly across phenotypes. We identified three distinctive symptom cluster phenotypes (Mild, Moderate, and Severe) for women with PAH that also differed by PAH‐related symptoms, physical function, right atrial pressure, norepinephrine levels, and HRQOL. These phenotypes could suggest targeted interventions to improve symptoms and HRQOL in those most severely affected

INO80 Facilitates Pluripotency Gene Activation in Embryonic Stem Cell Self-Renewal, Reprogramming, and Blastocyst Development

The master transcription factors play integral roles in the pluripotency transcription circuitry of embryonic stem cells (ESCs). How they selectively activate expression of the pluripotency network while simultaneously repressing genes involved in differentiation is not fully understood. Here we define a requirement for the INO80 complex, a SWI/SNF family chromatin remodeler, in ESC self-renewal, somatic cell reprogramming, and blastocyst development. We show that Ino80, the chromatin remodeling ATPase, co-occupies pluripotency gene promoters with the master transcription factors, and its occupancy is dependent on Oct4 and Wdr5. At the pluripotency genes, Ino80 maintains open chromatin architecture and licenses recruitment of Mediator and RNA Polymerase II for gene activation. Our data reveal an essential role for INO80 in the expression of the pluripotency network, and illustrate the coordination among chromatin remodeler, transcription factor, and histone modifying enzyme in the regulation of the pluripotent state