A Predictive Model of the Oxygen and Heme Regulatory Network in Yeast

Deciphering gene regulatory mechanisms through the analysis of high-throughput expression data is a challenging computational problem. Previous computational studies have used large expression datasets in order to resolve fine patterns of coexpression, producing clusters or modules of potentially coregulated genes. These methods typically examine promoter sequence information, such as DNA motifs or transcription factor occupancy data, in a separate step after clustering. We needed an alternative and more integrative approach to study the oxygen regulatory network in Saccharomyces cerevisiae using a small dataset of perturbation experiments. Mechanisms of oxygen sensing and regulation underlie many physiological and pathological processes, and only a handful of oxygen regulators have been identified in previous studies. We used a new machine learning algorithm called MEDUSA to uncover detailed information about the oxygen regulatory network using genome-wide expression changes in response to perturbations in the levels of oxygen, heme, Hap1, and Co2+. MEDUSA integrates mRNA expression, promoter sequence, and ChIP-chip occupancy data to learn a model that accurately predicts the differential expression of target genes in held-out data. We used a novel margin-based score to extract significant condition-specific regulators and assemble a global map of the oxygen sensing and regulatory network. This network includes both known oxygen and heme regulators, such as Hap1, Mga2, Hap4, and Upc2, as well as many new candidate regulators. MEDUSA also identified many DNA motifs that are consistent with previous experimentally identified transcription factor binding sites. Because MEDUSA's regulatory program associates regulators to target genes through their promoter sequences, we directly tested the predicted regulators for OLE1, a gene specifically induced under hypoxia, by experimental analysis of the activity of its promoter. In each case, deletion of the candidate regulator resulted in the predicted effect on promoter activity, confirming that several novel regulators identified by MEDUSA are indeed involved in oxygen regulation. MEDUSA can reveal important information from a small dataset and generate testable hypotheses for further experimental analysis. Supplemental data are included

A systematic review of the reporting of Data Monitoring Committees' roles, interim analysis and early termination in pediatric clinical trials

<p>Abstract</p> <p>Background</p> <p>Decisions about interim analysis and early stopping of clinical trials, as based on recommendations of Data Monitoring Committees (DMCs), have far reaching consequences for the scientific validity and clinical impact of a trial. Our aim was to evaluate the frequency and quality of the reporting on DMC composition and roles, interim analysis and early termination in pediatric trials.</p> <p>Methods</p> <p>We conducted a systematic review of randomized controlled clinical trials published from 2005 to 2007 in a sample of four general and four pediatric journals. We used full-text databases to identify trials which reported on DMCs, interim analysis or early termination, and included children or adolescents. Information was extracted on general trial characteristics, risk of bias, and a set of parameters regarding DMC composition and roles, interim analysis and early termination.</p> <p>Results</p> <p>110 of the 648 pediatric trials in this sample (17%) reported on DMC or interim analysis or early stopping, and were included; 68 from general and 42 from pediatric journals. The presence of DMCs was reported in 89 of the 110 included trials (81%); 62 papers, including 46 of the 89 that reported on DMCs (52%), also presented information about interim analysis. No paper adequately reported all DMC parameters, and nine (15%) reported all interim analysis details. Of 32 trials which terminated early, 22 (69%) did not report predefined stopping guidelines and 15 (47%) did not provide information on statistical monitoring methods.</p> <p>Conclusions</p> <p>Reporting on DMC composition and roles, on interim analysis results and on early termination of pediatric trials is incomplete and heterogeneous. We propose a minimal set of reporting parameters that will allow the reader to assess the validity of trial results.</p

Keeping the blood flowing—plasminogen activator genes and feeding behavior in vampire bats

The blood feeding vampire bats emerged from New World leaf-nosed bats that fed on fruit and insects. Plasminogen activator, a serine protease that regulates blood coagulation, is known to be expressed in the saliva of Desmodus rotundus (common vampire bat) and is thought to be a key enzyme for the emergence of blood feeding in vampire bats. To better understand the evolution of this biological function, we studied the plasminogen activator (PA) genes from all vampire bat species in light of their feeding transition to bird and subsequently mammalian blood. We include the rare species Diphylla ecaudata and Diaemus youngi, where plasminogen activator had not previously been studied and demonstrate that PA gene duplication observed in Desmodus is not essential to the vampire phenotype, but relates to the emergence of predominant mammalian blood feeding in this species. Plasminogen activator has evolved through gene duplication, domain loss, and sequence evolution leading to change in fibrin-specificity and susceptibility to plasminogen activator inhibitor-1. Before undertaking this study, only the four plasminogen activator isoforms from Desmodus were known. The evolution of vampire bat plasminogen activators can now be linksed phylogenetically to the transition in feeding behavior among vampire bat species from bird to mammalian blood

Can Phone-Based Motivational Interviewing Improve Medication Adherence to Antiplatelet Medications After a Coronary Stent Among Racial Minorities? A Randomized Trial

BACKGROUND: Minorities have lower adherence to cardiovascular medications and have worst cardiovascular outcomes post coronary stent placement OBJECTIVE: The aim of this study is to compare the efficacy of phone-delivered Motivational Interviewing (MINT) to an educational video at improving adherence to antiplatelet medications among insured minorities. DESIGN: This was a randomized study. PARTICIPANTS: We identified minorities with a recently placed coronary stent from an administrative data set by using a previously validated algorithm. INTERVENTIONS: MINT subjects received quarterly phone calls and the DVD group received a one-time mailed video. MAIN MEASURES: Outcome variables were collected at baseline and at 12-month post-stent, using surveys and administrative data. The primary outcome was antiplatelet (clopidogrel and prasugrel) adherence measured by Medication Possession Ratio (MPR) and self- reported adherence (Morisky score). We also measured appropriate adherence defined as an MPR ≥ 0.80. KEY RESULTS: We recruited 452 minority subjects with a new coronary stent (44 % Hispanics and 56 % Black). The patients had a mean age of 69.5 ± 8.8, 58 % were males, 78 % had an income lower than $30,000 per year and only 22 % had achieved high school education or higher. The MPR for antiplatelet medications was 0.77 for the MINT group compared to 0.70 for the DVD group (p < 0.05). The percentage of subjects with adequate adherence to their antiplatelet medication was 64 % in the MINT group and 50 % in the DVD group (p < 0.01). Self-reported adherence at 12 months was higher in the MINT group compared to the DVD group (p < 0.01). Results were similar among drug-eluting stent (DES) recipients. CONCLUSIONS: Among racial minorities, a phone-based motivational interview is effective at improving adherence to antiplatelet medications post coronary stent placement. Phone-based MINT seems to be a promising and cost-effective strategy to modify risk behaviors among minority populations at high cardiovascular risk

Migrant Women's Utilization of Prenatal Care: A Systematic Review

Our objectives were to determine whether migrant women in Western industrialized countries have higher odds of inadequate prenatal care (PNC) compared to receiving-country women and to summarize factors that are associated with inadequate PNC among migrant women in these countries. We conducted searches of electronic databases (MEDLINE, EMBASE, and PsycINFO), reference lists, known experts, and an existing database of the Reproductive Outcomes And Migration international research collaboration for articles published between January, 1995 and April, 2010. Title and abstract review and quality appraisal were conducted independently by 2 reviewers using established criteria, with consensus achieved through discussion. In this systematic review of 29 studies, the majority of studies demonstrated that migrant women were more likely to receive inadequate PNC than receiving-country women, with most reporting moderate to large effect sizes. Rates of inadequate PNC among migrant women varied widely by country of birth. Only three studies explored predictors of inadequate PNC among migrant women. These studies found that inadequate PNC among migrant women was associated with being less than 20 years of age, multiparous, single, having poor or fair language proficiency, education less than 5 years, an unplanned pregnancy, and not having health insurance. We concluded that migrant women as a whole were more likely to have inadequate PNC and the magnitude of this risk differed by country of origin. Few studies addressed predictors of PNC utilization in migrant women and this limits our ability to provide effective PNC in this population. © 2012 Springer Science+Business Media, LLC.SCOPUS: re.jinfo:eu-repo/semantics/publishe