Localizing Transcriptional Regulatory Elements at the Mouse Dlk1 Locus

Much effort has focused recently on determining the mechanisms that control the allele-specific expression of genes subject to genomic imprinting, yet imprinting regulation is only one aspect of configuring appropriate expression of these genes. Imprinting control mechanisms must interact with those regulating the tissue-specific expression pattern of each imprinted gene in a cluster. Proper expression of the imprinted Delta-like 1 (Dlk1) - Maternally expressed gene 3 (Meg3) gene pair is required for normal fetal development in mammals, yet the mechanisms that control tissue-specific expression of these genes are unknown. We have used a combination of in vivo and in vitro expression assays to localize cis-regulatory elements that may regulate Dlk1 expression in the mouse embryo. A bacterial artificial chromosome transgene encompassing the Dlk1 gene and 77 kb of flanking sequence conferred expression in most endogenous Dlk1-expressing tissues. In combination with previous transgenic data, these experiments localize the majority of Dlk1 cis-regulatory elements to a 41 kb region upstream of the gene. Cross-species sequence conservation was used to further define potential regulatory elements, several of which functioned as enhancers in a luciferase expression assay. Two of these elements were able to drive expression of a lacZ reporter transgene in Dlk1-expressing tissues in the mouse embryo. The sequence proximal to Dlk1 therefore contains at least two discrete regions that may regulate tissue-specificity of Dlk1 expression

Real-Time Science Operations to Support a Lunar Polar Volatiles Rover Mission

Future human exploration of the Moon will likely rely on in situ resource utilization (ISRU) to enable long duration lunar missions. Prior to utilizing ISRU on the Moon, the natural resources (in this case lunar volatiles) must be identified and characterized, and ISRU demonstrated on the lunar surface. To enable future uses of ISRU, NASA and the CSA are developing a lunar rover payload that can (1) locate near subsurface volatiles, (2) excavate and analyze samples of the volatile-bearing regolith, and (3) demonstrate the form, extractability and usefulness of the materials. Such investigations are important both for ISRU purposes and for understanding the scientific nature of these intriguing lunar volatile deposits. Temperature models and orbital data suggest near surface volatile concentrations may exist at briefly lit lunar polar locations outside persistently shadowed regions. A lunar rover could be remotely operated at some of these locations for the approx. 2-14 days of expected sunlight at relatively low cost. Due to the limited operational time available, both science and rover operations decisions must be made in real time, requiring immediate situational awareness, data analysis, and decision support tools. Given these constraints, such a mission requires a new concept of operations. In this paper we outline the results and lessons learned from an analog field campaign in July 2012 which tested operations for a lunar polar rover concept. A rover was operated in the analog environment of Hawaii by an off-site Flight Control Center, a rover navigation center in Canada, a Science Backroom at NASA Ames Research Center in California, and support teams at NASA Johnson Space Center in Texas and NASA Kennedy Space Center in Florida. We find that this type of mission requires highly efficient, real time, remotely operated rover operations to enable low cost, scientifically relevant exploration of the distribution and nature of lunar polar volatiles. The field demonstration illustrated the need for science operations personnel in constant communications with the flight mission operators and the Science Backroom to provide immediate and continual science support and validation throughout the mission. Specific data analysis tools are also required to enable immediate data monitoring, visualization, and decision making. The field campaign demonstrated that this novel methodology of real-time science operations is possible and applicable to providing important new insights regarding lunar polar volatiles for both science and exploration

Near-Infrared Monitoring of Volatiles in Frozen Lunar Simulants While Drilling

In Situ Resource Utilization (ISRU) focuses on using local resources for mission consumables. The approach can reduce mission cost and risk. Lunar polar volatiles, e.g. water ice, have been detected via remote sensing measurements and represent a potential resource for both humans and propellant. The exact nature of the horizontal and depth distribution of the ice remains to be documented in situ. NASA's Resource Prospector mission (RP) is intended to investigate the polar volatiles using a rover, drill, and the RESOLVE science package. RP component level hardware is undergoing testing in relevant lunar conditions (cryovacuum). In March 2015 a series of drilling tests were undertaken using the Honeybee Robotics RP Drill, Near-Infrared Volatile Spectrometer System (NIRVSS), and sample capture mechanisms (SCM) inside a 'dirty' thermal vacuum chamber at the NASA Glenn Research Center. The goal of these tests was to investigate the ability of NIRVSS to monitor volatiles during drilling activities and assess delivery of soil sample transfer to the SCMs in order to elucidate the concept of operations associated with this regolith sampling method

A multilevel examination of gender differences in the association between features of the school environment and physical activity among a sample of grades 9 to 12 students in Ontario, Canada

<p>Abstract</p> <p>Background</p> <p>Creating school environments that support student physical activity (PA) is a key recommendation of policy-makers to increase youth PA. Given males are more active than females at all ages, it has been suggested that investigating gender differences in the features of the environment that associate with PA may help to inform gender-focused PA interventions and reduce the gender disparity in PA. The purpose of this cross-sectional study was to explore gender differences in the association between factors of the school environment and students' time spent in PA.</p> <p>Methods</p> <p>Among a sample of 10781 female and 10973 male students in grades 9 to 12 from 76 secondary schools in Ontario, Canada, student- and school-level survey PA data were collected and supplemented with GIS-derived measures of the built environment within 1-km buffers of the 76 schools.</p> <p>Results</p> <p>Findings from the present study revealed significant differences in the time male and female students spent in PA as well as in some of the school- and student-level factors associated with PA. Results of the gender-specific multilevel analyses indicate schools should consider providing an alternate room for PA, especially for providing flexibility activities directed at female students. Schools should also consider offering daily physical education programming to male students in senior grades and providing PA promotion initiatives targeting obese male students.</p> <p>Conclusions</p> <p>Although most variation in male and female students' time spent in PA lies between students within schools, there is sufficient between-school variation to be of interest to practitioners and policy-makers. More research investigating gender differentials in environment factors associated with youth PA are warranted.</p

Sex differences in the clinical presentation and natural history of dilated cardiomyopathy

Background Biological sex has a diverse impact on the cardiovascular system. Its influence on dilated cardiomyopathy (DCM) remains unresolved. Objectives This study aims to investigate sex-specific differences in DCM presentation, natural history, and prognostic factors. Methods We conducted a prospective observational cohort study of DCM patients assessing baseline characteristics, cardiac magnetic resonance imaging, biomarkers, and genotype. The composite outcome was cardiovascular mortality or major heart failure (HF) events. Results Overall, 206 females and 398 males with DCM were followed for a median of 3.9 years. At baseline, female patients had higher left ventricular ejection fraction, smaller left ventricular volumes, less prevalent mid-wall myocardial fibrosis (23% vs 42%), and lower high-sensitivity cardiac troponin I than males (all P &lt; 0.05) with no difference in time from diagnosis, age at enrollment, N-terminal pro-B-type natriuretic peptide levels, pathogenic DCM genetic variants, myocardial fibrosis extent, or medications used for HF. Despite a more favorable profile, the risk of the primary outcome at 2 years was higher in females than males (8.6% vs 4.4%, adjusted HR: 3.14; 95% CI: 1.55-6.35; P = 0.001). Between 2 and 5 years, the effect of sex as a prognostic modifier attenuated. Age, mid-wall myocardial fibrosis, left ventricular ejection fraction, left atrial volume, N-terminal pro-B-type natriuretic peptide, high-sensitivity cardiac troponin I, left bundle branch block, and NYHA functional class were not sex-specific prognostic factors. Conclusions We identify a novel paradox in prognosis for females with DCM. Female DCM patients have a paradoxical early increase in major HF events despite less prevalent myocardial fibrosis and a milder phenotype at presentation. Future studies should interrogate the mechanistic basis for these sex differences

Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure

Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p&lt;0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (&lt;1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (&lt;1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure

Abstract: Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies