Clinical progress and pharmacology of small molecule bromodomain inhibitors

Bromodomains have emerged as an exciting target class for drug discovery over the past decade. Research has primarily focused on the bromodomain and extra terminal (BET) family of bromodomains, which has led to the development of multiple small molecule inhibitors and an increasing number of clinical assets. The excitement centred on the clinical potential of BET inhibition has stimulated intense interest in the broader family and the growing number of non-BET bromodomain chemical probes has facilitated phenotypic investigations, implicating these targets in a variety of disease pathways including cancer, inflammation, embryonic development and neurological disorders

Computational Biology and Bioinformatics in Nigeria

Over the past few decades, major advances in the field of molecular biology, coupled with advances in genomic technologies, have led to an explosive growth in the biological data generated by the scientific community. The critical need to process and analyze such a deluge of data and turn it into useful knowledge has caused bioinformatics to gain prominence and importance. Bioinformatics is an interdisciplinary research area that applies techniques, methodologies, and tools in computer and information science to solve biological problems. In Nigeria, bioinformatics has recently played a vital role in the advancement of biological sciences. As a developing country, the importance of bioinformatics is rapidly gaining acceptance, and bioinformatics groups comprised of biologists, computer scientists, and computer engineers are being constituted at Nigerian universities and research institutes. In this article, we present an overview of bioinformatics education and research in Nigeria. We also discuss professional societies and academic and research institutions that play central roles in advancing the discipline in Nigeria. Finally, we propose strategies that can bolster bioinformatics education and support from policy makers in Nigeria, with potential positive implications for other developing countries. © 2014 Fatumo et al.SAF was supported by H3ABioNet NABDA Node, Abuja, Nigeria with NIH Common Fund Award/NHGRI Grant Number U41HG006941 and Genetic Epidemiology Group at Wellcome Trust Sanger Institute.Published versio

Effects of a cognitive acceleration program in a low socio-economic high school in regional Australia

This paper presents research on the effects of a cognitive acceleration intervention in science lessons on low socio-economic students in a government high school in regional Western Australia. Thinking Science Australia is a program currently being implemented in Australian junior high school classes. The research was conducted over two years as a case study in one school with students as they entered high school in Year 8 (n = 71). Findings show that significant cognitive gains were made, with concomitant improvement in the state-wide testing in science when participating students were in Year 9, aged 13 and 14. Teachers reported changes to the ways they teach and described the challenges in implementing the intervention program

Atomistic modeling of nanowires, small-scale fatigue damage in cast magnesium, and materials for MEMS.

Lightweight and miniaturized weapon systems are driving the use of new materials in design such as microscale materials and ultra low-density metallic materials. Reliable design of future weapon components and systems demands a thorough understanding of the deformation modes in these materials that comprise the components and a robust methodology to predict their performance during service or storage. Traditional continuum models of material deformation and failure are not easily extended to these new materials unless microstructural characteristics are included in the formulation. For example, in LIGA Ni and Al-Si thin films, the physical size is on the order of microns, a scale approaching key microstructural features. For a new potential structural material, cast Mg offers a high stiffness-to-weight ratio, but the microstructural heterogeneity at various scales requires a structure-property continuum model. Processes occurring at the nanoscale and microscale develop certain structures that drive material behavior. The objective of the work presented in this report was to understand material characteristics in relation to mechanical properties at the nanoscale and microscale in these promising new material systems. Research was conducted primarily at the University of Colorado at Boulder to employ tightly coupled experimentation and simulation to study damage at various material size scales under monotonic and cyclic loading conditions. Experimental characterization of nano/micro damage will be accomplished by novel techniques such as in-situ environmental scanning electron microscopy (ESEM), 1 MeV transmission electron microscopy (TEM), and atomic force microscopy (AFM). New simulations to support experimental efforts will include modified embedded atom method (MEAM) atomistic simulations at the nanoscale and single crystal micromechanical finite element simulations. This report summarizes the major research and development accomplishments for the LDRD project titled 'Atomistic Modeling of Nanowires, Small-scale Fatigue Damage in Cast Magnesium, and Materials for MEMS'. This project supported a strategic partnership between Sandia National Laboratories and the University of Colorado at Boulder by providing funding for the lead author, Ken Gall, and his students, while he was a member of the University of Colorado faculty

The digital divide: Patterns, policy and scenarios for connecting the ‘final few’ in rural communities across Great Britain

The Internet can bestow significant benefits upon those who use it. The prima facie case for an urban-rural digital divide is widely acknowledged, but detailed accounts of the spatial patterns of digital communications infrastructure are rarely reported. In this paper we present original analysis of data published by the UK telecommunications regulator, Ofcom, and identify and reflect on the entrenched nature of the urban-rural digital divide in Great Britain. Drawing upon illustrative case vignettes we demonstrate the implications of digital exclusion for personal and business lives in rural, and in particular remote rural, areas. The ability of the current UK policy context to effectively address the urban-rural digital divide is reviewed and scenarios for improving digital connectivity amongst the ‘final few’, including community-led broadband, satellite broadband and mobile broadband, are considered. A call is made for digital future proofing in telecommunications policy, without which the already faster urban areas will get ‘faster, fastest’ leaving rural areas behind and an increasingly entrenched urban-rural divide

The Ascent of the Abundant: How Mutational Networks Constrain Evolution

Evolution by natural selection is fundamentally shaped by the fitness landscapes in which it occurs. Yet fitness landscapes are vast and complex, and thus we know relatively little about the long-range constraints they impose on evolutionary dynamics. Here, we exhaustively survey the structural landscapes of RNA molecules of lengths 12 to 18 nucleotides, and develop a network model to describe the relationship between sequence and structure. We find that phenotype abundance—the number of genotypes producing a particular phenotype—varies in a predictable manner and critically influences evolutionary dynamics. A study of naturally occurring functional RNA molecules using a new structural statistic suggests that these molecules are biased toward abundant phenotypes. This supports an “ascent of the abundant” hypothesis, in which evolution yields abundant phenotypes even when they are not the most fit

Influenza A H5N1 Immigration Is Filtered Out at Some International Borders

Geographic spread of highly pathogenic influenza A H5N1, the bird flu strain, appears a necessary condition for accelerating the evolution of a related human-to-human infection. As H5N1 spreads the virus diversifies in response to the variety of socioecological environments encountered, increasing the chance a human infection emerges. Genetic phylogenies have for the most part provided only qualitative evidence that localities differ in H5N1 diversity. For the first time H5N1 variation is quantified across geographic space.We constructed a statistical phylogeography of 481 H5N1 hemagglutinin genetic sequences from samples collected across 28 Eurasian and African localities through 2006. The MigraPhyla protocol showed southern China was a source of multiple H5N1 strains. Nested clade analysis indicated H5N1 was widely dispersed across southern China by both limited dispersal and long distance colonization. The UniFrac metric, a measure of shared phylogenetic history, grouped H5N1 from Indonesia, Japan, Thailand and Vietnam with those from southeastern Chinese provinces engaged in intensive international trade. Finally, H5N1's accumulative phylogenetic diversity was greatest in southern China and declined beyond. The gradient was interrupted by areas of greater and lesser phylogenetic dispersion, indicating H5N1 migration was restricted at some geopolitical borders. Thailand and Vietnam, just south of China, showed significant phylogenetic clustering, suggesting newly invasive H5N1 strains have been repeatedly filtered out at their northern borders even as both countries suffered recurring outbreaks of endemic strains. In contrast, Japan, while successful in controlling outbreaks, has been subjected to multiple introductions of the virus.The analysis demonstrates phylogenies can provide local health officials with more than hypotheses about relatedness. Pathogen dispersal, the functional relationships among disease ecologies across localities, and the efficacy of control efforts can also be inferred, all from viral genetic sequences alone

Correlation between driving-related skill and alcohol use in young-adults from six European countries: the TEN-D by Night Project

<p>Abstract</p> <p>Background</p> <p>Only few studies with small experimental samples investigated the impact of psychoactive substances on driving performance. We conducted a multicenter international cross-sectional study to evaluate the correlation between alcohol use and driving-related skill as measured by brake reaction time (RT).</p> <p>Methods</p> <p>Before and after the entrance into randomly selected recreational sites from six European countries, all subjects aged 16-35 years, owning a driver license, were asked to compile a structured socio-demographic questionnaire and measure RT (SimuNomad3 driving simulator), breath alcohol concentration (BAC; Drager Alcoltest), and drug use (Oratect III saliva test, only at the exit). Mixed regression modeling was used to evaluate the independent association between RT and alcohol concentration or drug use.</p> <p>Results</p> <p>Before the entrance into the recreational site, 4534 subjects completed all assessments and composed the final sample. Their mean age was 23.1 ± 4.2y; 68.3% were males; 54.7% had BAC > 0 g/L (assumed alcoholics); 7.5% declared illegal drug assumption (mostly cannabis). After the exit, 3019 also completed the second assessment: 71.7% showed BAC > 0 g/L. Controlling for age, gender, educational level, occupation, driver license years, and drug use, BAC was positively associated with RT, achieving significance, however, only when BAC was higher than 0.49 g/L. Significant interaction terms were found between BAC and female gender or drug use, with highest RTs (> 1 sec.) recorded among drug users with BAC > = 1 g/L.</p> <p>Conclusions</p> <p>This field study confirms previous experimental data on the negative impact of alcohol use on driving-related skill, supporting regulations and educational campaigns aimed at discouraging driving after consumption of psychoactive substances.</p

On the development logic of city-regions: inter- versus intra-city mobility in England and Wales

This paper combines an allometric urban model with a hierarchical clustering method in order to investigate the effects of distance and spatial scale on the geography of transport-led agglomerative strategies implemented to address comparative regional economic underperformance. The study is undertaken in the context of the urban system in England and Wales by constructing agglomerated city-regions using city units defined at different spatial scales. As is shown, a greater importance than is currently given lies in local and intra-city mobility as compared with longer distance transport schemes promoted using agglomeration theory principles. This signals a need for prioritization of mobility improvements at smaller intra-urban distances coupled with long-term densification efforts as integral to the performance of longer distance inter-city pairings