Showing papers by "Virginia Commonwealth University published in 2011"

Spatio-temporal transcriptome of the human brain

Abstract: Brain development and function depend on the precise regulation of gene expression. However, our understanding of the complexity and dynamics of the transcriptome of the human brain is incomplete. Here we report the generation and analysis of exon-level transcriptome and associated genotyping data, representing males and females of different ethnicities, from multiple brain regions and neocortical areas of developing and adult post-mortem human brains. We found that 86 per cent of the genes analysed were expressed, and that 90 per cent of these were differentially regulated at the whole-transcript or exon level across brain regions and/or time. The majority of these spatio-temporal differences were detected before birth, with subsequent increases in the similarity among regional transcriptomes. The transcriptome is organized into distinct co-expression networks, and shows sex-biased gene expression and exon usage. We also profiled trajectories of genes associated with neurobiological categories and diseases, and identified associations between single nucleotide polymorphisms and gene expression. This study provides a comprehensive data set on the human brain transcriptome and insights into the transcriptional foundations of human neurodevelopment.

Genome-wide association study identifies five new schizophrenia loci

Abstract: We examined the role of common genetic variation in schizophrenia in a genome-wide association study of substantial size: a stage 1 discovery sample of 21,856 individuals of European ancestry and a stage 2 replication sample of 29,839 independent subjects. The combined stage 1 and 2 analysis yielded genome-wide significant associations with schizophrenia for seven loci, five of which are new (1p21.3, 2q32.3, 8p23.2, 8q21.3 and 10q24.32-q24.33) and two of which have been previously implicated (6p21.32-p22.1 and 18q21.2). The strongest new finding (P = 1.6 x 10(-11)) was with rs1625579 within an intron of a putative primary transcript for MIR137 (microRNA 137), a known regulator of neuronal development. Four other schizophrenia loci achieving genome-wide significance contain predicted targets of MIR137, suggesting MIR137-mediated dysregulation as a previously unknown etiologic mechanism in schizophrenia. In a joint analysis with a bipolar disorder sample (16,374 affected individuals and 14,044 controls), three loci reached genome-wide significance: CACNA1C (rs4765905, P = 7.0 x 10(-9)), ANK3 (rs10994359, P = 2.5 x 10(-8)) and the ITIH3-ITIH4 region (rs2239547, P = 7.8 x 10(-9)).

OpenMx: An Open Source Extended Structural Equation Modeling Framework

Abstract: OpenMx is free, full-featured, open source, structural equation modeling (SEM) software. OpenMx runs within the R statistical programming environment on Windows, Mac OS–X, and Linux computers. The rationale for developing OpenMx is discussed along with the philosophy behind the user interface. The OpenMx data structures are introduced—these novel structures define the user interface framework and provide new opportunities for model specification. Two short example scripts for the specification and fitting of a confirmatory factor model are next presented. We end with an abbreviated list of modeling applications available in OpenMx 1.0 and a discussion of directions for future development.

Transformational Leadership and Performance Across Criteria and Levels: A Meta-Analytic Review of 25 Years of Research:

Abstract: Although transformational leadership has been studied extensively, the magnitude of the relationship between transformational leadership and follower performance across criterion types and levels of analysis remains unclear. Based on 117 independent samples over 113 primary studies, the current meta-analytic study showed that transformational leadership was positively related to individual-level follower performance across criterion types, with a stronger relationship for contextual performance than for task performance across most study settings. In addition, transformational leadership was positively related to performance at the team and organization levels. Moreover, both meta-analytic regression and relative importance analyses consistently showed that transformational leadership had an augmentation effect over transactional leadership (contingent reward) in predicting individual-level contextual performance and team-level performance. Contrary to our expectation, however, no augmentation effect of t...

Plasma Levels of Soluble CD14 Independently Predict Mortality in HIV Infection

Abstract: Methods. This nested case-control study included 74 subjects who died, 120 of whom developed cardiovascular disease and 81 of whom developed AIDS during the Strategies for Management of Anti-Retroviral Therapy (SMART) study with matched control subjects. Intestinal fatty acid binding protein (I-FABP), lipopolysaccharide (LPS), soluble CD14 (sCD14), endotoxin core antibody (EndoCAb), and 16S ribosomal DNA (rDNA) were measured in baseline plasma samples. Results. Subjects with the highest quartile of sCD14 levels had a 6-fold higher risk of death than did those in the lowest quartile (95% confidence interval, 2.2‐16.1; P,.001), with minimal change after adjustment for inflammatory markers, CD4 1 T cell count, and HIV RNA level. No other marker was significantly associated with clinical outcomes. I-FABP, LPS, and sCD14 were increased and EndoCAb was decreased in study subjects, compared with healthy volunteers. sCD14 level correlated with levels of IL-6, C-reactive protein, serum amyloid A and D-dimer. Conclusions. sCD14, a marker of monocyte response to LPS, is an independent predictor of mortality in HIV infection. Therapeutic attenuation of innate immune activation may improve survival in patients with HIV infection.

Effect of Vitamin E or Metformin for Treatment of Nonalcoholic Fatty Liver Disease in Children and Adolescents: The TONIC Randomized Controlled Trial

Abstract: Context Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in US children and adolescents and can present with advanced fibrosis or nonalcoholic steatohepatitis (NASH). No treatment has been established. Objective To determine whether children with NAFLD would improve from therapeutic intervention with vitamin E or metformin. Design, Setting, and Patients Randomized, double-blind, double-dummy, placebo-controlled clinical trial conducted at 10 university clinical research centers in 173 patients (aged 8-17 years) with biopsy-confirmed NAFLD conducted between September 2005 and March 2010. Interventions Daily dosing of 800 IU of vitamin E (58 patients), 1000 mg of metformin (57 patients), or placebo (58 patients) for 96 weeks. Main Outcome Measures The primary outcome was sustained reduction in alanine aminotransferase (ALT) defined as 50% or less of the baseline level or 40 U/L or less at visits every 12 weeks from 48 to 96 weeks of treatment. Improvements in histological features of NAFLD and resolution of NASH were secondary outcome measures. Results Sustained reduction in ALT level was similar to placebo (10/58; 17%; 95% CI, 9% to 29%) in both the vitamin E (15/58; 26%; 95% CI, 15% to 39%; P = .26) and metformin treatment groups (9/57; 16%; 95% CI, 7% to 28%; P = .83). The mean change in ALT level from baseline to 96 weeks was −35.2 U/L (95% CI, −56.9 to −13.5) with placebo vs −48.3 U/L (95% CI, −66.8 to −29.8) with vitamin E (P = .07) and −41.7 U/L (95% CI, −62.9 to −20.5) with metformin (P = .40). The mean change at 96 weeks in hepatocellular ballooning scores was 0.1 with placebo (95% CI, −0.2 to 0.3) vs −0.5 with vitamin E (95% CI, −0.8 to −0.3; P = .006) and −0.3 with metformin (95% CI, −0.6 to −0.0; P = .04); and in NAFLD activity score, −0.7 with placebo (95% CI, −1.3 to −0.2) vs −1.8 with vitamin E (95% CI, −2.4 to −1.2; P = .02) and −1.1 with metformin (95% CI, −1.7 to −0.5; P = .25). Among children with NASH, the proportion who resolved at 96 weeks was 28% with placebo (95% CI, 15% to 45%; 11/39) vs 58% with vitamin E (95% CI, 42% to 73%; 25/43; P = .006) and 41% with metformin (95% CI, 26% to 58%; 16/39; P = .23). Compared with placebo, neither therapy demonstrated significant improvements in other histological features. Conclusion Neither vitamin E nor metformin was superior to placebo in attaining the primary outcome of sustained reduction in ALT level in patients with pediatric NAFLD. Trial Registration clinicaltrials.gov Identifier: NCT00063635

Materials for Hydrogen Storage: Past, Present, and Future

Abstract: With a growing world population, an increasing standard of living in many developing countries, a limited supply of fossil fuels, and its adverse effect on the environment, the need for clean and sustainable energy has never been greater. Hydrogen, the simplest and most abundant element in the universe, has the potential to meet this energy need if numerous hurdles in its efficient and safe production, storage, and use in fuel cell vehicles can be overcome. This Perspective briefly discusses the status of hydrogen storage — past, present, and future.

The relation between emotional intelligence and job performance: A meta‐analysis

Abstract: This meta-analysis builds upon a previous meta-analysis by (1) including 65 per cent more studies that have over twice the sample size to estimate the relationships between emotional intelligence (EI) and job performance; (2) using more current meta-analytical studies for estimates of relationships among personality variables and for cognitive ability and job performance; (3) using the three-stream approach for classifying EI research; (4) performing tests for differences among streams of EI research and their relationships with personality and cognitive intelligence; (5) using latest statistical procedures such as dominance analysis; and (6) testing for publication bias. We classified EI studies into three streams: (1) ability-based models that use objective test items; (2) self-report or peer-report measures based on the four-branch model of EI; and (3) “mixed models” of emotional competencies. The three streams have corrected correlations ranging from 0.24 to 0.30 with job performance. The three streams correlated differently with cognitive ability and with neuroticism, extraversion, openness, agreeableness, and conscientiousness. Streams 2 and 3 have the largest incremental validity beyond cognitive ability and the Five Factor Model (FFM). Dominance analysis demonstrated that all three streams of EI exhibited substantial relative importance in the presence of FFM and intelligence when predicting job performance. Publication bias had negligible influence on observed effect sizes. The results support the overall validity of EI. Copyright © 2010 John Wiley & Sons, Ltd. Note: Correction added on 22 July 2010 after first publication online on 29 June 2010. The affiliations for Ronald H. Humphrey and Thomas H. Hawver have been corrected in this version of the article.

The outs and the ins of sphingosine-1-phosphate in immunity

Abstract: The potent lipid mediator sphingosine-1-phosphate (S1P) is produced inside cells by two closely related kinases, sphingosine kinase 1 (SPHK1) and SPHK2, and has emerged as a crucial regulator of immunity. Many of the actions of S1P in innate and adaptive immunity are mediated by its binding to five G protein-coupled receptors, designated S1PR1-5, but recent findings have also identified important roles for S1P as a second messenger during inflammation. In this Review, we discuss recent advances in our understanding of the roles of S1P receptors and describe the newly identified intracellular targets of S1P that are crucial for immune responses. Finally, we discuss the therapeutic potential of new drugs that target S1P signalling and functions.

Religion and spirituality.

Abstract: Many clients highly value religious and spiritual (R/S) commitments, and many psychotherapists have accommodated secular treatments to R/S perspectives. We meta-analyzed 51 samples from 46 studies (N = 3,290) that examined the outcomes of religious accommodative therapies and nonreligious spirituality therapies. Comparisons on psychological and spiritual outcomes were made to a control condition, an alternate treatment, or a subset of those studies that used a dismantling design (similar in theory and duration of treatment, but including religious contents). Patients in R/S psychotherapies showed greater improvement than those in alternate secular psychotherapies both on psychological (d =.26) and on spiritual (d = .41) outcomes. Religiously accommodated treatments outperformed dismantling-design alternative treatments on spiritual (d = .33) but not on psychological outcomes. Clinical examples are provided and therapeutic practices are recommended.

Cold plasma selectivity and the possibility of a paradigm shift in cancer therapy

Abstract: Plasma is an ionised gas that is typically generated in high-temperature laboratory conditions. However, recent progress in atmospheric plasmas has led to the creation of cold plasmas with ion temperature close to room temperature. Both in-vitro and in-vivo studies revealed that cold plasmas selectively kill cancer cells. We show that: (a) cold plasma application selectively eradicates cancer cells in vitro without damaging normal cells; and (b) significantly reduces tumour size in vivo. It is shown that reactive oxygen species metabolism and oxidative stress responsive genes are deregulated. The development of cold plasma tumour ablation has the potential of shifting the current paradigm of cancer treatment and enabling the transformation of cancer treatment technologies by utilisation of another state of matter.

Neuronal activity modifies the DNA methylation landscape in the adult brain

Abstract: It has been unclear how extensively neuronal DNA methylome is regulated by activity. In this resource article, the authors use next-generation sequencing methods and quantitatively compare the CpG methylation landscape of adult mouse dentate granule neurons in vivo before and after synchronous neuronal activation.

Engaging neuroscience to advance translational research in brain barrier biology

Abstract: A great many aspects of neuronal physiology and pathology involve or affect the brain barriers. Recent insights into the role of the blood–brain barrier during development, and advances in our understanding of how it affects neurological disorders, have led to closer links between the two topics.

The inflammasome promotes adverse cardiac remodeling following acute myocardial infarction in the mouse

Abstract: Acute myocardial infarction (AMI) initiates an intense inflammatory response that promotes cardiac dysfunction, cell death, and ventricular remodeling. The molecular events underlying this inflammatory response, however, are incompletely understood. In experimental models of sterile inflammation, ATP released from dying cells triggers, through activation of the purinergic P2X7 receptor, the formation of the inflammasome, a multiprotein complex necessary for caspase-1 activation and amplification of the inflammatory response. Here we describe the presence of the inflammasome in the heart in an experimental mouse model of AMI as evidenced by increased caspase-1 activity and cytoplasmic aggregates of the three components of the inflammasome—apoptosis speck-like protein containing a caspase-recruitment domain (ASC), cryopyrin, and caspase-1, localized to the granulation tissue and cardiomyocytes bordering the infarct. Cultured adult murine cardiomyocytes also showed the inducible formation of the inflammasome associated with increased cell death. P2X7 and cryopyrin inhibition (using silencing RNA or a pharmacologic inhibitor) prevented the formation of the inflammasome and limited infarct size and cardiac enlargement after AMI. The formation of the inflammasome in the mouse heart during AMI causes additional loss of functional myocardium, leading to heart failure. Modulation of the inflammasome may therefore represent a unique therapeutic strategy to limit cell death and prevent heart failure after AMI.

Therapeutic cancer vaccines: past, present, and future.

Abstract: Therapeutic vaccines represent a viable option for active immunotherapy of cancers that aim to treat late stage disease by using a patient's own immune system. The promising results from clinical trials recently led to the approval of the first therapeutic cancer vaccine by the U.S. Food and Drug Administration. This major breakthrough not only provides a new treatment modality for cancer management but also paves the way for rationally designing and optimizing future vaccines with improved anticancer efficacy. Numerous vaccine strategies are currently being evaluated both preclinically and clinically. This review discusses therapeutic cancer vaccines from diverse platforms or targets as well as the preclinical and clinical studies employing these therapeutic vaccines. We also consider tumor-induced immune suppression that hinders the potency of therapeutic vaccines, and potential strategies to counteract these mechanisms for generating more robust and durable antitumor immune responses.

Pulmonary Hypertension in Heart Failure With Preserved Ejection Fraction A Target of Phosphodiesterase-5 Inhibition in a 1-Year Study

Abstract: Background—The prevalence of heart failure with preserved ejection fraction is increasing. The prognosis worsens with pulmonary hypertension and right ventricular (RV) failure development. We targeted pulmonary hypertension and RV burden with the phosphodiesterase-5 inhibitor sildenafil. Methods and Results—Forty-four patients with heart failure with preserved ejection fraction (heart failure signs and symptoms, diastolic dysfunction, ejection fraction 50%, and pulmonary artery systolic pressure 40 mm Hg) were randomly assigned to placebo or sildenafil (50 mg thrice per day). At 6 months, there was no improvement with placebo, but sildenafil mediated significant improvements in mean pulmonary artery pressure (42.013.0%) and RV function, as suggested by leftward shift of the RV Frank-Starling relationship, increased tricuspid annular systolic excursion (69.019.0%) and ejection rate (17.08.3%), and reduced right atrial pressure (54.07.2%). These effects may have resulted from changes within the lung (reduced lung water content and improved alveolar-capillary gas conductance, 15.84.5%), the pulmonary vasculature (arteriolar resistance, 71.08.2%), and left-sided cardiac function (wedge pulmonary pressure, 15.73.1%; cardiac index, 6.00.9%; deceleration time, 13.01.9%; isovolumic relaxation time, 14.01.7%; septal mitral annulus velocity, 76.49.2%). Results were similar at 12 months. Conclusions—The multifaceted response to phosphodiesterase-5 inhibition in heart failure with preserved ejection fraction includes improvement in pulmonary pressure and vasomotility, RV function and dimension, left ventricular relaxation and distensibility (structural changes and/or ventricular interdependence), and lung interstitial water metabolism (wedge pulmonary pressure decrease improving hydrostatic balance and right atrial pressure reduction facilitating lung lymphatic drainage). These results enhance our understanding of heart failure with preserved ejection fraction and offer new directions for therapy. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT01156636. (Circulation. 2011;124:164-174.)

DNA methyltransferase 1, cytosine methylation, and cytosine hydroxymethylation in mammalian mitochondria

Abstract: Mitochondrial DNA (mtDNA) has been reported to contain 5-methylcytosine (5mC) at CpG dinucleotides, as in the nuclear genome, but neither the mechanism generating mtDNA methylation nor its functional significance is known. We now report the presence of 5-hydroxymethylcytosine (5hmC) as well as 5mC in mammalian mtDNA, suggesting that previous studies underestimated the level of cytosine modification in this genome. DNA methyltransferase 1 (DNMT1) translocates to the mitochondria, driven by a mitochondrial targeting sequence located immediately upstream of the commonly accepted translational start site. This targeting sequence is conserved across mammals, and the encoded peptide directs a heterologous protein to the mitochondria. DNMT1 is the only member of the three known catalytically active DNA methyltransferases targeted to the mitochondrion. Mitochondrial DNMT1 (mtDNMT1) binds to mtDNA, proving the presence of mtDNMT1 in the mitochondrial matrix. mtDNMT1 expression is up-regulated by NRF1 and PGC1α, transcription factors that activate expression of nuclear-encoded mitochondrial genes in response to hypoxia, and by loss of p53, a tumor suppressor known to regulate mitochondrial metabolism. Altered mtDNMT1 expression asymmetrically affects expression of transcripts from the heavy and light strands of mtDNA. Hence, mtDNMT1 appears to be responsible for mtDNA cytosine methylation, from which 5hmC is presumed to be derived, and its expression is controlled by factors that regulate mitochondrial function.

What is the source of chronic low back pain and does age play a role

Abstract: Objective. The objective of this study was to estimate the prevalence, mean age, and association of prevalence and age of lumbar internal disc disruption (IDD), facet joint pain (FJP), sacroiliac joint pain (SIJP), spinal and pelvic insufficiency fractures, interspinous ligament injury/Baastrup's Disease, and soft tissue irritation by fusion hardware. Design. The study's design was a retrospective chart review. Setting. The study was set in an academic spine center. Patients. A total of 378 cases from 358 patients were reviewed of which 170 cases from 156 patients who underwent diagnostic procedures were included. Interventions. Discography, dual diagnostic facet joint blocks, intra-articular sacroiliac joint injections, anesthetic injections of painful interspinous ligaments/opposing spinous processes/posterior fusion hardware, or percutaneous augmentation were performed. Outcome Measures. Prevalence and age were analyzed for each diagnosis group. Methods. Patients with recalcitrant low back pain underwent diagnostic procedures based on their clinical presentation until the pain source was identified. Results. The prevalence of internal disc disruption, facet joint pain and sacroiliac joint pain was 42%, 31%, and 18%, respectively. Patients with internal disc disruption were significantly younger than those with facet joint pain or sacroiliac joint pain. Increased age was associated with a decreased probability of internal disc disruption and increased probabilities of facet joint pain and sacroiliac joint pain as the source of low back pain until approximately age 70. Conclusion. Our data confirm the intervertebral disc as the most common etiology of chronic low back pain in adults. Based on our sample, the younger the patient, the more likely low back pain is discogenic in origin. Facetogenic or sacroiliac joint pain is more likely in older patients.

The five-factor model of personality traits and organizational citizenship behaviors: A meta-analysis.

Abstract: Using meta-analytic tests based on 87 statistically independent samples, we investigated the relationships between the five-factor model (FFM) of personality traits and organizational citizenship behaviors in both the aggregate and specific forms, including individual-directed, organization-directed, and change-oriented citizenship. We found that Emotional Stability, Extraversion, and Openness/Intellect have incremental validity for citizenship over and above Conscientiousness and Agreeableness, 2 well-established FFM predictors of citizenship. In addition, FFM personality traits predict citizenship over and above job satisfaction. Finally, we compared the effect sizes obtained in the current meta-analysis with the comparable effect sizes predicting task performance from previous meta-analyses. As a result, we found that Conscientiousness, Emotional Stability, and Extraversion have similar magnitudes of relationships with citizenship and task performance, whereas Openness and Agreeableness have stronger relationships with citizenship than with task performance. This lends some support to the idea that personality traits are (slightly) more important determinants of citizenship than of task performance. We conclude with proposed directions for future research on the relationships between FFM personality traits and specific forms of citizenship, based on the current findings.

What kinds of things are psychiatric disorders

Abstract: This essay explores four answers to the question 'What kinds of things are psychiatric disorders?' Essentialist kinds are classes whose members share an essence from which their defining features arise. Although elegant and appropriate for some physical (e.g. atomic elements) and medical (e.g. Mendelian disorders) phenomena, this model is inappropriate for psychiatric disorders, which are multi-factorial and 'fuzzy'. Socially constructed kinds are classes whose members are defined by the cultural context in which they arise. This model excludes the importance of shared physiological mechanisms by which the same disorder could be identified across different cultures. Advocates of practical kinds put off metaphysical questions about 'reality' and focus on defining classes that are useful. Practical kinds models for psychiatric disorders, implicit in the DSM nosologies, do not require that diagnoses be grounded in shared causal processes. If psychiatry seeks to tie disorders to etiology and underlying mechanisms, a model first proposed for biological species, mechanistic property cluster (MPC) kinds, can provide a useful framework. MPC kinds are defined not in terms of essences but in terms of complex, mutually reinforcing networks of causal mechanisms. We argue that psychiatric disorders are objectively grounded features of the causal structure of the mind/brain. MPC kinds are fuzzy sets defined by mechanisms at multiple levels that act and interact to produce the key features of the kind. Like species, psychiatric disorders are populations with central paradigmatic and more marginal members. The MPC view is the best current answer to 'What kinds of things are psychiatric disorders?'

Template-Free Synthesis of a Highly Porous Benzimidazole-Linked Polymer for CO2 Capture and H2 Storage

Abstract: A highly porous benzimidazole-linked polymer (SABET 1172 m2/g) exhibits very high gas selectivity CO2/N2 (70) and CO2/CH4 (10) and can store CO2 (19 wt %, 273 K, 1 bar) and H2 (1.9 wt %, 77 K, 1 bar) with Qst values of 26.7 and 7.9 kJ/mol, respectively.