Specifications and programs for computer software validation

Three software products developed during the study are reported and include: (1) FORTRAN Automatic Code Evaluation System, (2) the Specification Language System, and (3) the Array Index Validation System

Fortran Automatic Code Evaluation System (FACES)

Software package takes as input FORTRAN program which may contain many modules (subroutines and functions). Main parts: (1) FORTRAN front end gathers information about input program and (2) set of routines organized as diagnostic package evaluates information and prints warning messages concerning actual or potential errors

Utilization of a fuel cell power plant for the capture and conversion of gob well gas. Final report, June--December, 1995

A preliminary study has been made to determine if a 200 kW fuel cell power plant operating on variable quality coalbed methane can be placed and successfully operated at the Jim Walter Resources No. 4 mine located in Tuscaloosa County, Alabama. The purpose of the demonstration is to investigate the effects of variable quality (50 to 98% methane) gob gas on the output and efficiency of the power plant. To date, very little detail has been provided concerning the operation of fuel cells in this environment. The fuel cell power plant will be located adjacent to the No. 4 mine thermal drying facility rated at 152 M British thermal units per hour. The dryer burns fuel at a rate of 75,000 cubic feet per day of methane and 132 tons per day of powdered coal. The fuel cell power plant will provide 700,000 British thermal units per hour of waste heat that can be utilized directly in the dryer, offsetting coal utilization by approximately 0.66 tons per day and providing an avoided cost of approximately $20 per day. The 200 kilowatt electrical power output of the unit will provide a utility cost reduction of approximately$3,296 each month. The demonstration will be completely instrumented and monitored in terms of gas input and quality, electrical power output, and British thermal unit output. Additionally, real-time power pricing schedules will be applied to optimize cost savings. 28 refs., 35 figs., 13 tabs

Demonstration of the enrichment of medium quality gas from gob wells through interactive well operating practices. Final report, June--December, 1995

Methane released to the atmosphere during coal mining operations is believed to contribute to global warming and represents a waste of a valuable energy resource. Commercial production of pipeline-quality gob well methane through wells drilled from the surface into the area above the gob can, if properly implemented, be the most effective means of reducing mine methane emissions. However, much of the gas produced from gob wells is vented because the quality of the gas is highly variable and is often below current natural gas pipeline specifications. Prior to the initiation of field-testing required to further understand the operational criteria for upgrading gob well gas, a preliminary evaluation and assessment was performed. An assessment of the methane gas in-place and producible methane resource at the Jim Walter Resources, Inc. No. 4 and No. 5 Mines established a potential 15-year supply of 60 billion cubic feet of mien methane from gob wells, satisfying the resource criteria for the test site. To understand the effect of operating conditions on gob gas quality, gob wells producing pipeline quality (i.e., < 96% hydrocarbons) gas at this site will be operated over a wide range of suction pressures. Parameters to be determined will include absolute methane quantity and methane concentration produced through the gob wells; working face, tailgate and bleeder entry methane levels in the mine; and the effect on the economics of production of gob wells at various levels of methane quality. Following this, a field demonstration will be initiated at a mine where commercial gob gas production has not been attempted. The guidelines established during the first phase of the project will be used to design the production program. The economic feasibility of various utilization options will also be tested based upon the information gathered during the first phase. 41 refs., 41 figs., 12 tabs

Variability in Working Memory Performance Explained by Epistasis vs Polygenic Scores in the ZNF804A Pathway

Importance: We investigated the variation in neuropsychological function explained by risk alleles at the psychosis susceptibility gene ZNF804A and its interacting partners using single nucleotide polymorphisms (SNPs), polygenic scores, and epistatic analyses. Of particular importance was the relative contribution of the polygenic score vs epistasis in variation explained. Objectives To (1) assess the association between SNPs in ZNF804A and the ZNF804A polygenic score with measures of cognition in cases with psychosis and (2) assess whether epistasis within the ZNF804A pathway could explain additional variation above and beyond that explained by the polygenic score. Design, Setting, and Participants: Patients with psychosis (n = 424) were assessed in areas of cognitive ability impaired in schizophrenia including IQ, memory, attention, and social cognition. We used the Psychiatric GWAS Consortium 1 schizophrenia genome-wide association study to calculate a polygenic score based on identified risk variants within this genetic pathway. Cognitive measures significantly associated with the polygenic score were tested for an epistatic component using a training set (n = 170), which was used to develop linear regression models containing the polygenic score and 2-SNP interactions. The best-fitting models were tested for replication in 2 independent test sets of cases: (1) 170 individuals with schizophrenia or schizoaffective disorder and (2) 84 patients with broad psychosis (including bipolar disorder, major depressive disorder, and other psychosis). Main Outcomes and Measures: Participants completed a neuropsychological assessment battery designed to target the cognitive deficits of schizophrenia including general cognitive function, episodic memory, working memory, attentional control, and social cognition. Results: Higher polygenic scores were associated with poorer performance among patients on IQ, memory, and social cognition, explaining 1% to 3% of variation on these scores (range, P = .01 to .03). Using a narrow psychosis training set and independent test sets of narrow phenotype psychosis (schizophrenia and schizoaffective disorder), broad psychosis, and control participants (n = 89), the addition of 2 interaction terms containing 2 SNPs each increased the R2 for spatial working memory strategy in the independent psychosis test sets from 1.2% using the polygenic score only to 4.8% (P = .11 and .001, respectively) but did not explain additional variation in control participants. Conclusions and Relevance: These data support a role for the ZNF804A pathway in IQ, memory, and social cognition in cases. Furthermore, we showed that epistasis increases the variation explained above the contribution of the polygenic score

Enhancing discovery of genetic variants for posttraumatic stress disorder through integration of quantitative phenotypes and trauma exposure information

Background Posttraumatic stress disorder (PTSD) is heritable and a potential consequence of exposure to traumatic stress. Evidence suggests that a quantitative approach to PTSD phenotype measurement and incorporation of lifetime trauma exposure (LTE) information could enhance the discovery power of PTSD genome-wide association studies (GWASs). Methods A GWAS on PTSD symptoms was performed in 51 cohorts followed by a fixed-effects meta-analysis (N = 182,199 European ancestry participants). A GWAS of LTE burden was performed in the UK Biobank cohort (N = 132,988). Genetic correlations were evaluated with linkage disequilibrium score regression. Multivariate analysis was performed using Multi-Trait Analysis of GWAS. Functional mapping and annotation of leading loci was performed with FUMA. Replication was evaluated using the Million Veteran Program GWAS of PTSD total symptoms. Results GWASs of PTSD symptoms and LTE burden identified 5 and 6 independent genome-wide significant loci, respectively. There was a 72% genetic correlation between PTSD and LTE. PTSD and LTE showed largely similar patterns of genetic correlation with other traits, albeit with some distinctions. Adjusting PTSD for LTE reduced PTSD heritability by 31%. Multivariate analysis of PTSD and LTE increased the effective sample size of the PTSD GWAS by 20% and identified 4 additional loci. Four of these 9 PTSD loci were independently replicated in the Million Veteran Program. Conclusions Through using a quantitative trait measure of PTSD, we identified novel risk loci not previously identified using prior case-control analyses. PTSD and LTE have a high genetic overlap that can be leveraged to increase discovery power through multivariate methods

Circulating microRNAs in sera correlate with soluble biomarkers of immune activation but do not predict mortality in ART treated individuals with HIV-1 infection: A case control study

Introduction: The use of anti-retroviral therapy (ART) has dramatically reduced HIV-1 associated morbidity and mortality. However, HIV-1 infected individuals have increased rates of morbidity and mortality compared to the non-HIV-1 infected population and this appears to be related to end-organ diseases collectively referred to as Serious Non-AIDS Events (SNAEs). Circulating miRNAs are reported as promising biomarkers for a number of human disease conditions including those that constitute SNAEs. Our study sought to investigate the potential of selected miRNAs in predicting mortality in HIV-1 infected ART treated individuals. Materials and Methods: A set of miRNAs was chosen based on published associations with human disease conditions that constitute SNAEs. This case: control study compared 126 cases (individuals who died whilst on therapy), and 247 matched controls (individuals who remained alive). Cases and controls were ART treated participants of two pivotal HIV-1 trials. The relative abundance of each miRNA in serum was measured, by RTqPCR. Associations with mortality (all-cause, cardiovascular and malignancy) were assessed by logistic regression analysis. Correlations between miRNAs and CD4+ T cell count, hs-CRP, IL-6 and D-dimer were also assessed. Results: None of the selected miRNAs was associated with all-cause, cardiovascular or malignancy mortality. The levels of three miRNAs (miRs -21, -122 and -200a) correlated with IL-6 while miR-21 also correlated with D-dimer. Additionally, the abundance of miRs -31, -150 and -223, correlated with baseline CD4+ T cell count while the same three miRNAs plus miR- 145 correlated with nadir CD4+ T cell count. Discussion: No associations with mortality were found with any circulating miRNA studied. These results cast doubt onto the effectiveness of circulating miRNA as early predictors of mortality or the major underlying diseases that contribute to mortality in participants treated for HIV-1 infection

The glial growth factors deficiency and synaptic destabilization hypothesis of schizophrenia

BACKGROUND: A systems approach to understanding the etiology of schizophrenia requires a theory which is able to integrate genetic as well as neurodevelopmental factors. PRESENTATION OF THE HYPOTHESIS: Based on a co-localization of loci approach and a large amount of circumstantial evidence, we here propose that a functional deficiency of glial growth factors and of growth factors produced by glial cells are among the distal causes in the genotype-to-phenotype chain leading to the development of schizophrenia. These factors include neuregulin, insulin-like growth factor I, insulin, epidermal growth factor, neurotrophic growth factors, erbB receptors, phosphatidylinositol-3 kinase, growth arrest specific genes, neuritin, tumor necrosis factor alpha, glutamate, NMDA and cholinergic receptors. A genetically and epigenetically determined low baseline of glial growth factor signaling and synaptic strength is expected to increase the vulnerability for additional reductions (e.g., by viruses such as HHV-6 and JC virus infecting glial cells). This should lead to a weakening of the positive feedback loop between the presynaptic neuron and its targets, and below a certain threshold to synaptic destabilization and schizophrenia. TESTING THE HYPOTHESIS: Supported by informed conjectures and empirical facts, the hypothesis makes an attractive case for a large number of further investigations. IMPLICATIONS OF THE HYPOTHESIS: The hypothesis suggests glial cells as the locus of the genes-environment interactions in schizophrenia, with glial asthenia as an important factor for the genetic liability to the disorder, and an increase of prolactin and/or insulin as possible working mechanisms of traditional and atypical neuroleptic treatments