Search tips
Search criteria

Results 1-17 (17)

Clipboard (0)

Select a Filter Below

Year of Publication
Document Types
1.  Chronic Treatment with Clenbuterol Modulates Endothelial Progenitor Cells and Circulating Factors in a Murine Model of Cardiomyopathy 
The purpose of this study was to determine the effects of chronic treatment with the beta 2 adrenergic receptor agonist clenbuterol on endothelial progenitor cells (EPC) in a well-characterized model of heart failure, the muscle LIM protein knockout (MLP−/−) mouse. MLP−/−mice were treated daily with clenbuterol (2 mg/kg) or saline subcutaneously for 6 weeks. Clenbuterol led to a 30% increase in CD31+ cells in the bone marrow of MLP−/− heart failure mice (p<0.004). Clenbuterol did not improve ejection fraction. Clenbuterol treatment in MLP−/− mice was associated with significant changes in the following circulating factors: tissue inhibitor of metalloproteinase-type 1, leukemia inhibitory factor 1, C-reactive protein, apolipoprotein A1, fibroblast growth factor 2, serum glutamic oxaloacetic transaminase, macrophage-derived chemokine, and monocyte chemoattractant protein-3. Clen-buterol treatment in the MLP−/− model of heart failure did not rescue heart function, yet did increase CD31+ cells in the bone marrow. This is the first evidence that a beta 2 agonist increases EPC proliferation in the bone marrow in a preclinical model of heart failure.
PMCID: PMC4066445  PMID: 20559986
Clenbuterol; Heart Failure; Muscle LIM Protein; Beta 2 Adrenergic Receptor; Endothelial Progenitor Cell
2.  Feasibility and acceptability of the DSM-5 Field Trial procedures in the Johns Hopkins Community Psychiatry Programs† 
The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) contains criteria for psychiatric diagnoses that reflect advances in the science and conceptualization of mental disorders and address the needs of clinicians. DSM-5 also recommends research on dimensional measures of cross-cutting symptoms and diagnostic severity, which are expected to better capture patients’ experiences with mental disorders. Prior to its May 2013 release, the American Psychiatric Association (APA) conducted field trials to examine the feasibility, clinical utility, reliability, and where possible, the validity of proposed DSM-5 diagnostic criteria and dimensional measures. The methods and measures proposed for the DSM-5 field trials were pilot tested in adult and child/adolescent clinical samples, with the goal to identify and correct design and procedural problems with the proposed methods before resources were expended for the larger DSM-5 Field Trials. Results allowed for the refinement of the protocols, procedures, and measures, which facilitated recruitment, implementation, and completion of the DSM-5 Field Trials. These results highlight the benefits of pilot studies in planning large multisite studies.
PMCID: PMC4047142  PMID: 24615761
DSM; methodology; epidemiology
3.  DNA Methylation in an Enhancer Region of the FADS Cluster Is Associated with FADS Activity in Human Liver 
PLoS ONE  2014;9(5):e97510.
Levels of omega-6 (n-6) and omega-3 (n-3), long chain polyunsaturated fatty acids (LcPUFAs) such as arachidonic acid (AA; 20∶4, n-6), eicosapentaenoic acid (EPA; 20∶5, n-3) and docosahexaenoic acid (DHA; 22∶6, n-3) impact a wide range of biological activities, including immune signaling, inflammation, and brain development and function. Two desaturase steps (Δ6, encoded by FADS2 and Δ5, encoded by FADS1) are rate limiting in the conversion of dietary essential 18 carbon PUFAs (18C-PUFAs) such as LA (18∶2, n-6) to AA and α-linolenic acid (ALA, 18∶3, n-3) to EPA and DHA. GWAS and candidate gene studies have consistently identified genetic variants within FADS1 and FADS2 as determinants of desaturase efficiencies and levels of LcPUFAs in circulating, cellular and breast milk lipids. Importantly, these same variants are documented determinants of important cardiovascular disease risk factors (total, LDL, and HDL cholesterol, triglycerides, CRP and proinflammatory eicosanoids). FADS1 and FADS2 lie head-to-head (5′ to 5′) in a cluster configuration on chromosome 11 (11q12.2). There is considerable linkage disequilibrium (LD) in this region, where multiple SNPs display association with LcPUFA levels. For instance, rs174537, located ∼15 kb downstream of FADS1, is associated with both FADS1 desaturase activity and with circulating AA levels (p-value for AA levels = 5.95×10−46) in humans. To determine if DNA methylation variation impacts FADS activities, we performed genome-wide allele-specific methylation (ASM) with rs174537 in 144 human liver samples. This approach identified highly significant ASM with CpG sites between FADS1 and FADS2 in a putative enhancer signature region, leading to the hypothesis that the phenotypic associations of rs174537 are likely due to methylation differences. In support of this hypothesis, methylation levels of the most significant probe were strongly associated with FADS1 and, to a lesser degree, FADS2 activities.
PMCID: PMC4026313  PMID: 24842322
4.  Antipsychotic Treatment Patterns and Aggressive Behavior Among Adolescents in Residential Facilities 
This study examined the association between acute aggressive behavior patterns of 145 adolescents in residential treatment facilities with use of and changes in antipsychotic medication for the chronic management of aggression. Seclusion/restraint (S/R) frequency over 12 months was used to categorize youth into none, low, moderate, and high S/R groups. Data were analyzed using longitudinal mixed effects logistic regression models that allowed for intra-subject variability over time. The high and moderate S/R groups were significantly more likely to receive antipsychotics, get higher doses, and have changes in medication compared with the none S/R group. Increases in antipsychotic dose were associated with a lower likelihood of changes in antipsychotic medication over time. Despite persistent antipsychotic use at higher doses, youth in the high and moderate S/R groups continued to be secluded/restrained frequently. The findings question the adequacy of these medications in managing aggressive behavior.
PMCID: PMC3637837  PMID: 23319375
5.  Human Umbilical Cord Blood for Transplantation Therapy in Myocardial Infarction 
Cell-based therapy is a promising therapy for myocardial infarction. Endogenous repair of the heart muscle after myocardial infarction is a challenge because adult cardiomyocytes have a limited capacity to proliferate and replace damaged cells. Pre-clinical and clinical evidence has shown that cell based therapy may promote revascularization and replacement of damaged myocytes after myocardial infarction. Adult stem cells can be harvested from different sources including bone marrow, skeletal myoblast, and human umbilical cord blood cells. The use of these cells for the repair of myocardial infarction presents various advantages over other sources of stem cells. Among these are easy harvesting, unlimited differentiation capability, and robust angiogenic potential. In this review, we discuss the milestone findings and the most recent evidence demonstrating the therapeutic efficacy and safety of the transplantation of human umbilical cord blood cells as a stand-alone therapy or in combination with gene therapy, highlighting the importance of optimizing the timing, dose and delivery methods, and a better understanding of the mechanisms of action that will guide the clinical entry of this innovative treatment for ischemic disorders, specifically myocardial infarction.
PMCID: PMC3845524  PMID: 24307973
Myocardial infarction; Cardiomyocytes; Umbilical cord blood; Angiogenesis; Gene therapy
6.  Science games and the development of scientific possible selves 
Serious scientific games, especially those that include a virtual apprenticeship component, provide players with realistic experiences in science. This article discusses how science games can influence learning about science and the development of science-oriented possible selves through repeated practice in professional play and through social influences (e.g., peer groups). We first review the theory of possible selves (Markus and Nurius 1986) and discuss the potential of serious scientific games for influencing the development of scientific possible selves. As part of our review, we present a forensic game that inspired our work. Next we present a measure of scientific possible selves and assess its reliability and validity with a sample of middle-school students (N=374). We conclude by discussing the promise of science games and the development of scientific possible selves on both the individual and group levels as a means of inspiring STEM careers among adolescents.
PMCID: PMC3587663  PMID: 23483731
scientific possible selves; self-concept; science games; career development; science identity; transformative identity
7.  The Impact of a Science Education Game on Students’ Learning and Perception of Inhalants as Body Pollutants 
This study investigated the knowledge gains and attitude shifts attributable to a unique online science education game, Uncommon Scents. The game was developed to teach middle school students about the biological consequences of exposure to toxic chemicals in an environmental science context, as well as the risks associated with abusing these chemicals as inhalants. Middle school students (n = 444) grades six through eight participated in the study consisting of a pre-test, three game-play sessions, and a delayed post-test. After playing the game, students demonstrated significant gains in science content knowledge, with game usability ratings emerging as the strongest predictor of post-test content knowledge scores. The intervention also resulted in a shift to more negative attitudes toward inhalants, with the most negative shift occurring among eighth grade students and post-test knowledge gains as the strongest predictor of attitude change across all grade levels. These findings suggest that the environmental science approach used in Uncommon Scents is an efficacious strategy for delivering both basic science content and influencing perceived harm relating to the inhalation of toxic chemicals from common household products.
PMCID: PMC3733386  PMID: 23926416
Game-based learning; Science-based drug education; Environmental education; Toxic chemicals; Body pollution; Attitudes toward inhalants; Video game
8.  Clinical, Molecular and Genetic Changes in Response to a Left Ventricular Assist Device 
The use of left ventricular assist devices (LVADs) in treating patients with end stage heart failure has increased significantly in recent years, both as a bridge to transplant and as destination therapy in those who are ineligible for cardiac transplantation. This increase is based largely on the results of several recently completed clinical trials with the new second generation continuous flow devices that showed significant improvement in survival, functional capacity, and quality of life. Additional information on the use of the first generation and second generation LVADs has come from a recently released report spanning the years 2006–2009, from The Interagency Registry for Mechanical Circulatory Support (INTERMACS), a National Heart Lung and Blood Institute sponsored collaboration between the United States Food and Drug Administration (FDA), the Center for Medicare and Medicaid (CMS) and the scientific community (1). This paper provides a review of the latest clinical trials and data from the INTERMACS registry with tight integration of the landmark molecular, cellular and genomic research that accompanies the reverse remodeling of the human heart in response to the LVAD and functional recovery that has been reported in a subset of these patients.
PMCID: PMC3381801  PMID: 21292124
Ventricular assist device; clinical trials; microarray; miRNA; gene expression; calcium; beta-adrenergic; integrins
9.  Teaching the Biological Consequences of Alcohol Abuse through an Online Game: Impacts among Secondary Students 
CBE Life Sciences Education  2012;11(1):94-102.
A multimedia game was designed to serve as a dual-purpose intervention that aligned with National Science Content Standards, while also conveying knowledge about the consequences of alcohol consumption for a secondary school audience. A tertiary goal was to positively impact adolescents' attitudes toward science through career role-play experiences within the game. In a pretest/delayed posttest design, middle and high school students, both male and female, demonstrated significant gains on measures of content knowledge and attitudes toward science. The best predictors of these outcomes were the players' ratings of the game's usability and satisfaction with the game. The outcomes suggest that game interventions can successfully teach standards-based science content, target age-appropriate health messages, and impact students' attitudes toward science.
PMCID: PMC3292064  PMID: 22383621
We report the first comprehensive analysis of gene expression differences by sex and age in left ventricular samples from 102 patients with dilated cardiomyopathy.
Gene expression data (HG-U133A gene chip, Affymetrix) were analyzed from 30 females and 72 males from 3 separate centers. Over 1,800 genes displayed sexual dimorphism in the heart (adjusted p-value <0.05). A significant number of these genes were highly represented in gene ontology pathways involved in ion transport and G-protein-coupled receptor signaling. Localization of these genes revealed enrichment on both the sex chromosomes as well as chromosomes 3, 4, and 14. The second goal of this study was to determine the effect of age on gene expression. Within the female cohort, over 140 genes were differentially expressed in the under 55 age group compared to age group above 55 years of age. These genes were highly represented in gene ontology pathways involved in DNA damage. In contrast, zero genes in the male cohort under age 55 met statistical significance when compared to the group over 55.
Gene expression in dilated cardiomyopathy displayed evidence of sexual dimorphism similar to other somatic tissues and age dimorphism within the female cohort.
PMCID: PMC3090727  PMID: 20031553
Heart failure; Sex; Aging; Genes
11.  Environment-responsive transcription factors bind subtelomeric elements and regulate gene silencing 
Chromosome position analysis of ChIP-chip data revealed that several carbon source and stress-responsive yeast transcription factors conditionally bind subtelomeric X elements.Integration of several microarray gene expression data sets showed that, in this context, the factors conditionally control the boundaries and strength of subtelomeric silencing.Regulation of silencing by a fatty acid-responsive factor was found to be dependent on Sir2p and independent of Hda1p.These findings provide a critical link for establishing the mechanisms by which telomere biology is coordinated with other cellular processes including responses to environmental stimuli, aging and adaptation.
It is well established that environmental conditions modulate gene expression through local binding of a variety of conditionally active transcription factors, each responsive to specific environmental cues. However, another prevalent mechanism of gene regulation in eukaryotic cells is the long-range control of groups of genes by chromatin modifications or other position-dependent mechanisms. One such phenomenon, gene silencing, is an important and evolutionarily conserved mode of regulation that controls expression of subtelomeric genes. These genes are enriched for stress response and metabolic genes and their regulation is controlled by the spreading of silencing molecules from chromosome ends (telomeres) into subtelomeric regions. Levels of subtelomeric silencing have been linked to cellular lifespan, and study of the regulation of silencing is fundamental to our understanding of human aging. The spread of silencing in subtelomeric regions is discontinuous, and is controlled by various genomic elements that can either relay and enhance silencing from telomeres (proto-silencing) or create boundaries that protect some genomic regions from silencing. In yeast, every subtelomeric region contains an X element that proto-silences centromere-proximal genes, and also insulates telomere-proximal genes from silencing.
In this paper, we identify a regulatory mechanism to control X element-mediated proto-silencing and insulating activities in response to environmental cues. The mechanism was identified using chromosome position analysis of microarray-based chromatin immunoprecipitation (ChIP-chip) data for environment-responsive TFs and genome-wide gene expression data under the same conditions. The mechanism involves the conditional association of environment-responsive transcription factors to X elements. The binding at X elements results in regulation of proto-silencing of centromere-proximal genes, or insulation of telomere-proximal genes (depending on the factor) in response to environmental stimuli related to stress response and metabolism. One example is shown below (Figure 4B). Transcription factor, Oaf1p, conditionally binds X elements in the presence of fatty acids and enhances proto-silencing specifically under this condition. Oaf1p and several other factors implicated here are known to control adjacent genes at intrachromosomal positions, suggesting their dual functionality in both gene-specific transcriptional regulation, and long-range position-dependent mechanism. Investigation of this mechanism during the response to fatty acid exposure showed that conditional proto-silencing activity is dependent on Sir2p, a molecule known to be involved in subtelomeric silencing related to aging. This study reveals a path cells can use to coordinate subtelomeric silencing related to aging with cellular environment, and with the activities of other cellular processes.
Subtelomeric chromatin is subject to evolutionarily conserved complex epigenetic regulation and is implicated in numerous aspects of cellular function including formation of heterochromatin, regulation of stress response pathways and control of lifespan. Subtelomeric DNA is characterized by the presence of specific repeated segments that serve to propagate silencing or to protect chromosomal regions from spreading epigenetic control. In this study, analysis of genome-wide chromatin immunoprecipitation and expression data, suggests that several yeast transcription factors regulate subtelomeric silencing in response to various environmental stimuli through conditional association with proto-silencing regions called X elements. In this context, Oaf1p, Rox1p, Gzf1p and Phd1p control the propagation of silencing toward centromeres in response to stimuli affecting stress responses and metabolism, whereas others, including Adr1p, Yap5p and Msn4p, appear to influence boundaries of silencing, regulating telomere-proximal genes in Y′ elements. The factors implicated here are known to control adjacent genes at intrachromosomal positions, suggesting their dual functionality. This study reveals a path for the coordination of subtelomeric silencing with cellular environment, and with activities of other cellular processes.
PMCID: PMC3049408  PMID: 21206489
chromatin; proto-silencer; Sir2; subtelomeric silencing; X element
12.  Depot-medroxyprogesterone Acetate and Combined Oral Contraceptive Use and Cervical Neoplasia among Women with Oncogenic Human Papillomavirus Infection 
Examine the relationship of depot-medroxyprogesterone acetate (DMPA) and combined oral contraceptive (COC) use with cervical intraepithelial neoplasia (CIN).
Study Design
Two case-control studies of women who presented for gynecological care and underwent cytologic and human papillomavirus (HPV) testing were performed. The first included oncogenic HPV-positive women grouped based on histology: negative(n=152), CIN1(n=133), and ≥CIN2-3(n=173). For the second, two groups were identified: negative HPV/negative histology(n=107) and positive oncogenic HPV/negative histology(n=152).
Among oncogenic HPV-positive women, DMPA use was inversely associated with ≥CIN2-3 (adjusted odds ratio[ORadj]=0.4;95% confidence interval[CI]=0.2–1.1) and CIN1 (ORadj=0.1;95% CI=0.01–0.6); COC use was not associated with either. Among histologically negative women, DMPA use was associated with oncogenic HPV (ORadj=4.7;95% CI=1.4–15.8).
Among women with oncogenic HPV, hormonal contraceptive use was not associated with an increased risk of ≥CIN2-3. Longer-term DMPA use may attenuate the colposcopic and histologic features of CIN as women reporting such use were more likely than others to have cervical oncogenic HPV without evidence of CIN.
PMCID: PMC2713031  PMID: 19375566
CIN; hormonal contraception; DMPA; Oncogenic HPV infection
13.  DraGnET: Software for storing, managing and analyzing annotated draft genome sequence data 
BMC Bioinformatics  2010;11:100.
New "next generation" DNA sequencing technologies offer individual researchers the ability to rapidly generate large amounts of genome sequence data at dramatically reduced costs. As a result, a need has arisen for new software tools for storage, management and analysis of genome sequence data. Although bioinformatic tools are available for the analysis and management of genome sequences, limitations still remain. For example, restrictions on the submission of data and use of these tools may be imposed, thereby making them unsuitable for sequencing projects that need to remain in-house or proprietary during their initial stages. Furthermore, the availability and use of next generation sequencing in industrial, governmental and academic environments requires biologist to have access to computational support for the curation and analysis of the data generated; however, this type of support is not always immediately available.
To address these limitations, we have developed DraGnET (Draft Genome Evaluation Tool). DraGnET is an open source web application which allows researchers, with no experience in programming and database management, to setup their own in-house projects for storing, retrieving, organizing and managing annotated draft and complete genome sequence data. The software provides a web interface for the use of BLAST, allowing users to perform preliminary comparative analysis among multiple genomes. We demonstrate the utility of DraGnET for performing comparative genomics on closely related bacterial strains. Furthermore, DraGnET can be further developed to incorporate additional tools for more sophisticated analyses.
DraGnET is designed for use either by individual researchers or as a collaborative tool available through Internet (or Intranet) deployment. For genome projects that require genome sequencing data to initially remain proprietary, DraGnET provides the means for researchers to keep their data in-house for analysis using local programs or until it is made publicly available, at which point it may be uploaded to additional analysis software applications. The DraGnET home page is available at and includes example files for examining the functionalities, a link for downloading the DraGnET setup package and a link to the DraGnET source code hosted with full documentation on SourceForge.
PMCID: PMC3098051  PMID: 20175920
14.  Value of Clinician Assessment of Hemodynamics in Advanced Heart Failure: The ESCAPE Trial 
Circulation. Heart failure  2008;1:170-177.
We determined whether estimated hemodynamics from history and physical examination (H&P) reflect invasive measurements and predict outcomes in advanced heart failure (HF). The role of the H&P in medical decision making has declined in favor of diagnostic tests, perhaps due to lack of evidence for utility.
Methods and Results
We compared H&P estimates of filling pressures and cardiac index with invasive measurements in 194 patients in the ESCAPE trial. H&P estimates were compared with 6-month outcomes in 388 patients enrolled in ESCAPE. Measured right atrial pressure (RAP) was <8 mm Hg in 82% of patients with RAP estimated from jugular veins as <8 mm Hg, and was >12 mm Hg in 70% of patients when estimated as >12 mm Hg. From the H&P, only estimated RAP ≥12 mm Hg (odds ratio [OR] 4.6; P<0.001) and orthopnea ≥2 pillows (OR 3.6; P<0.05) were associated with pulmonary capillary wedge pressure (PCWP) ≥30 mm Hg. Estimated cardiac index did not reliably reflect measured cardiac index (P=0.09), but “cold” versus “warm” profile was associated with lower median measured cardiac index (1.75 vs. 2.0 L/min/m2; P=0.004). In Cox regression analysis, discharge “cold” or “wet” profile conveyed a 50% increased risk of death or rehospitalization.
In advanced HF, the presence of orthopnea and elevated jugular venous pressure are useful to detect elevated PCWP, and a global assessment of inadequate perfusion (“cold” profile) is useful to detect reduced cardiac index. Hemodynamic profiles estimated from the discharge H&P identify patients at increased risk of early events.
PMCID: PMC2724723  PMID: 19675681
history and physical examination; hemodynamics; heart failure
15.  Zinc Finger Database (ZiFDB): a repository for information on C2H2 zinc fingers and engineered zinc-finger arrays 
Nucleic Acids Research  2008;37(Database issue):D279-D283.
Zinc fingers are the most abundant DNA-binding motifs encoded by eukaryotic genomes and one of the best understood DNA-recognition domains. Each zinc finger typically binds a 3-nt target sequence, and it is possible to engineer zinc-finger arrays (ZFAs) that recognize extended DNA sequences by linking together individual zinc fingers. Engineered zinc-finger proteins have proven to be valuable tools for gene regulation and genome modification because they target specific sites in a genome. Here we describe ZiFDB (Zinc Finger Database;, a web-accessible resource that compiles information on individual zinc fingers and engineered ZFAs. To enhance its utility, ZiFDB is linked to the output from ZiFiT—a software package that assists biologists in finding sites within target genes for engineering zinc-finger proteins. For many molecular biologists, ZiFDB will be particularly valuable for determining if a given ZFA (or portion thereof) has previously been constructed and whether or not it has the requisite DNA-binding activity for their experiments. ZiFDB will also be a valuable resource for those scientists interested in better understanding how zinc-finger proteins recognize target DNA.
PMCID: PMC2686427  PMID: 18812396
16.  An Online, Interactive Approach to Teaching Neuroscience to Adolescents 
CBE— Life Sciences Education  2006;5(2):137-143.
Most of today's students are skilled in instant messaging, Web browsing, online games, and blogs. These have become part of the social landscape and have changed how we learn and where we learn. The question becomes how to harness the attractiveness and ubiquity of electronic venues toward the goal of teaching neuroscience. At the Rice University Center for Technology in Teaching and Learning, a central focus is the creation of innovative materials that appeal to middle school students. A recent project was undertaken through a Science Education Drug Abuse Partnership Award (R25 DA15063) from the National Institute on Drug Abuse to inform adolescents about the neurobiology of substance abuse and the current research dealing with a class of drugs known as club drugs. Problem-based learning, multimedia pedagogy, and the National Science Content Standards were integrated to produce The Reconstructors™, an episodic series available via the World Wide Web at A field test of students from five schools assessed the retention of content after “playing” The Reconstructors™ series titled Nothing to Rave About. Gain scores indicated that middle school students' knowledge about club drugs and the basic neuroscience concepts that explain their effects improved significantly.
PMCID: PMC1618520  PMID: 17012204
17.  A comparative study of discriminating human heart failure etiology using gene expression profiles 
BMC Bioinformatics  2005;6:205.
Human heart failure is a complex disease that manifests from multiple genetic and environmental factors. Although ischemic and non-ischemic heart disease present clinically with many similar decreases in ventricular function, emerging work suggests that they are distinct diseases with different responses to therapy. The ability to distinguish between ischemic and non-ischemic heart failure may be essential to guide appropriate therapy and determine prognosis for successful treatment. In this paper we consider discriminating the etiologies of heart failure using gene expression libraries from two separate institutions.
We apply five new statistical methods, including partial least squares, penalized partial least squares, LASSO, nearest shrunken centroids and random forest, to two real datasets and compare their performance for multiclass classification. It is found that the five statistical methods perform similarly on each of the two datasets: it is difficult to correctly distinguish the etiologies of heart failure in one dataset whereas it is easy for the other one. In a simulation study, it is confirmed that the five methods tend to have close performance, though the random forest seems to have a slight edge.
For some gene expression data, several recently developed discriminant methods may perform similarly. More importantly, one must remain cautious when assessing the discriminating performance using gene expression profiles based on a small dataset; our analysis suggests the importance of utilizing multiple or larger datasets.
PMCID: PMC1224853  PMID: 16120216

Results 1-17 (17)