Discovery of active enhancers through bidirectional expression of short transcripts

Abstract Background Long-range regulatory elements, such as enhancers, exert substantial control over tissue-specific gene expression patterns. Genome-wide discovery of functional enhancers in different cell types is important for our understanding of genome function as well as human disease etiology. Results In this study, we developed an in silico approach to model the previously reported phenomenon of transcriptional pausing, accompanied by divergent transcription, at active promoters. We then used this model for large-scale prediction of non-promoter-associated bidirectional expression of short transcripts. Our predictions were significantly enriched for DNase hypersensitive sites, histone H3 lysine 27 acetylation (H3K27ac), and other chromatin marks associated with active rather than poised or repressed enhancers. We also detected modest bidirectional expression at binding sites of the CCCTC-factor (CTCF) genome-wide, particularly those that overlap H3K27ac. Conclusions Our findings indicate that the signature of bidirectional expression of short transcripts, learned from promoter-proximal transcriptional pausing, can be used to predict active long-range regulatory elements genome-wide, likely due in part to specific association of RNA polymerase with enhancer regions

Cross-Modal Health State Estimation

Individuals create and consume more diverse data about themselves today than any time in history. Sources of this data include wearable devices, images, social media, geospatial information and more. A tremendous opportunity rests within cross-modal data analysis that leverages existing domain knowledge methods to understand and guide human health. Especially in chronic diseases, current medical practice uses a combination of sparse hospital based biological metrics (blood tests, expensive imaging, etc.) to understand the evolving health status of an individual. Future health systems must integrate data created at the individual level to better understand health status perpetually, especially in a cybernetic framework. In this work we fuse multiple user created and open source data streams along with established biomedical domain knowledge to give two types of quantitative state estimates of cardiovascular health. First, we use wearable devices to calculate cardiorespiratory fitness (CRF), a known quantitative leading predictor of heart disease which is not routinely collected in clinical settings. Second, we estimate inherent genetic traits, living environmental risks, circadian rhythm, and biological metrics from a diverse dataset. Our experimental results on 24 subjects demonstrate how multi-modal data can provide personalized health insight. Understanding the dynamic nature of health status will pave the way for better health based recommendation engines, better clinical decision making and positive lifestyle changes.Comment: Accepted to ACM Multimedia 2018 Conference - Brave New Ideas, Seoul, Korea, ACM ISBN 978-1-4503-5665-7/18/1

Orbital Solutions and Absolute Elements of the Short-Period Eclipsing Binary ES Librae

We have obtained new differential UBV photoelectric photometry and radial velocities of both components of the short-period eclipsing binary ES Lib. The system has a circular orbit with a period of 0.883040928 days and is seen at an inclination of 70.1°. With the Wilson-Devinney analysis program, we obtained a simultaneous solution of our photometric and spectroscopic observations that resulted in masses of M1 = 2.30 ± 0.03 M⊙ and M2 = 0.97 ± 0.01 M⊙ and the equal-volume radii of R1 = 2.69 ± 0.02 R⊙ and R2 = 1.83 ± 0.01 R⊙ for the primary and secondary, respectively. The secondary is oversized and overluminous for its mass. The effective temperatures of the primary and secondary are 8500 K (fixed) and 5774 ± 57 K, respectively. Despite the very large temperature difference, our photometric and spectroscopic data indicate that ES Lib is not semidetached but rather require it to be in an overcontact state, where both components exceed their critical Roche lobes. Given its nonthermal equilibrium state, if the overcontact solution correctly characterizes the system, the change from being semidetached to overcontact may have occurred recently. While the asymmetry of the light curves can be modeled well with a large, hot starspot or a large, cool one on the secondary component, we prefer the latter interpretation because cool spots are a typical feature on many contact binaries

The PAndAS field of streams: Stellar structures in the milky way halo toward andromeda and triangulum

We reveal the highly structured nature of the Milky Way (MW) stellar halo within the footprint of the Pan-Andromeda Archaeological Survey (PAndAS) photometric survey from blue main sequence (MS) and MS turn-off stars. We map no fewer than five stellar structures within a heliocentric range of 5-30 kpc. Some of these are known (the Monoceros Ring, the Pisces/Triangulum globular cluster stream), but we also uncover three well-defined stellar structures that could be, at least partly, responsible for the so-called Triangulum/Andromeda and Triangulum/Andromeda 2 features. In particular, we trace a new faint stellar stream located at a heliocentric distance of 17 kpc. With a surface brightness of Σ V 32-32.5 mag arcsec-2, it follows an orbit that is almost parallel to the Galactic plane north of M31 and has so far eluded surveys of the MW halo as these tend to steer away from regions dominated by the Galactic disk. Investigating our follow-up spectroscopic observations of PAndAS, we serendipitously uncover a radial velocity signature from stars that have colors and magnitudes compatible with the stream. From the velocity of eight likely member stars, we show that this stellar structure is dynamically cold, with an unresolved velocity dispersion that is lower than 7.1 km s-1 at the 90% confidence level. Along with the width of the stream (300-650 pc), its dynamics point to a dwarf-galaxy-accretion origin. The numerous stellar structures we can map in the MW stellar halo between 5 and 30 kpc and their varying morphology is a testament to the complex nature of the stellar halo at these intermediate distances

Genetic Analysis of Hematological Parameters in Incipient Lines of the Collaborative Cross

Hematological parameters, including red and white blood cell counts and hemoglobin concentration, are widely used clinical indicators of health and disease. These traits are tightly regulated in healthy individuals and are under genetic control. Mutations in key genes that affect hematological parameters have important phenotypic consequences, including multiple variants that affect susceptibility to malarial disease. However, most variation in hematological traits is continuous and is presumably influenced by multiple loci and variants with small phenotypic effects. We used a newly developed mouse resource population, the Collaborative Cross (CC), to identify genetic determinants of hematological parameters. We surveyed the eight founder strains of the CC and performed a mapping study using 131 incipient lines of the CC. Genome scans identified quantitative trait loci for several hematological parameters, including mean red cell volume (Chr 7 and Chr 14), white blood cell count (Chr 18), percent neutrophils/lymphocytes (Chr 11), and monocyte number (Chr 1). We used evolutionary principles and unique bioinformatics resources to reduce the size of candidate intervals and to view functional variation in the context of phylogeny. Many quantitative trait loci regions could be narrowed sufficiently to identify a small number of promising candidate genes. This approach not only expands our knowledge about hematological traits but also demonstrates the unique ability of the CC to elucidate the genetic architecture of complex traits

Minority youth, crime, conflict, and belonging in Australia

In recent decades, the size and diversity of the minority population of contemporary western societies has increased significantly. To the critics of immigration, minority youth have been increasingly linked to crime, criminal gangs, anti-social behaviour, and riots. In this article, we draw on fieldwork conducted in Sydney, Australia's largest and most ethnically diverse city, to probe aspects of the criminality, anti-social behaviour, national identity, and belonging of ethnic minority youth in Australia. We conclude that the evidence on minority youth criminality is weak and that the panic about immigrant youth crime and immigrant youth gangs is disproportionate to the reality, drawing on and in turn creating racist stereotypes, particularly with youth of 'Middle Eastern appearance'. A review of the events leading up to the Sydney Cronulla Beach riots of December 2005 suggests that the underlying cause of the riots were many years of international, national, and local anti-Arab, anti-Muslim media discourse, and political opportunism, embedded in changing but persistent racist attitudes and practises. Our argument is that such inter-ethnic conflict between minority and majority youth in Sydney is the exception, not the rule. Finally, we draw on a hitherto unpublished survey of youth in Sydney to explore issues of national identity and belonging among young people of diverse ethnic and religious background. We conclude that minority youth in Sydney do not live 'parallel lives' but contradictory, inter-connected cosmopolitan lives. They are connected to family and local place, have inter-ethnic friendships but are often disconnected to the nation and the flag. © 2009 Springer Science+Business Media B.V

Transgressing the moral economy: Wheelerism and management of the nationalised coal industry in Scotland

This article illuminates the links between managerial style and political economy in post-1945 Britain, and explores the origins of the 1984–1985 miners' strike, by examining in longer historical context the abrasive attitudes and policies of Albert Wheeler, Scottish Area Director of the National Coal Board (NCB). Wheeler built on an earlier emphasis on production and economic criteria, and his micro-management reflected pre-existing centralising tendencies in the industries. But he was innovative in one crucial aspect, transgressing the moral economy of the Scottish coalfield, which emphasised the value of economic security and changes by joint industrial agreement

Imaging in population science: cardiovascular magnetic resonance in 100,000 participants of UK Biobank - rationale, challenges and approaches

PMCID: PMC3668194SEP was directly funded by the National Institute for Health Research Cardiovascular Biomedical Research Unit at Barts. SN acknowledges support from the Oxford NIHR Biomedical Research Centre and from the Oxford British Heart Foundation Centre of Research Excellence. SP and PL are funded by a BHF Senior Clinical Research fellowship. RC is supported by a BHF Research Chair and acknowledges the support of the Oxford BHF Centre for Research Excellence and the MRC and Wellcome Trust. PMM gratefully acknowledges training fellowships supporting his laboratory from the Wellcome Trust, GlaxoSmithKline and the Medical Research Council

Sequence-tagged sites (STSs) spanning 4p16.3 and the Huntington disease candidate region

The generation of sequence-tagged sites (STSs) has been proposed as a unifying approach to correlating the disparate results generated by genetic and various physical techniques being used to map the human genome. We have developed an STS map to complement the existing physical and genetic maps of 4p16.3, the region containing the Huntington disease gene. A total of 18 STSs span over 4 Mb of 4p16.3, with an average spacing of about 250 kb. Eleven of the STSs are located within the primary candidate HD region of 2.5 Mb between D4S126 and D4S168. The availability of STSs makes the corresponding loci accessible to the general community without the need for distribution of cloned DNA. These STSs should also provide the means to isolate yeast artificial chromosome clones spanning the HD candidate region.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/30062/1/0000432.pd

Engineering the Controlled Assembly of Filamentous Injectisomes in E. coli K-12 for Protein Translocation into Mammalian Cells.

Bacterial pathogens containing type III protein secretion systems (T3SS) assemble large needle-like protein complexes in the bacterial envelope, called injectisomes, for translocation of protein effectors into host cells. The application of these molecular syringes for the injection of proteins into mammalian cells is hindered by their structural and genomic complexity, requiring multiple polypeptides encoded along with effectors in various transcriptional units (TUs) with intricate regulation. In this work, we have rationally designed the controlled expression of the filamentous injectisomes found in enteropathogenic Escherichia coli (EPEC) in the nonpathogenic strain E. coli K-12. All structural components of EPEC injectisomes, encoded in a genomic island called the locus of enterocyte effacement (LEE), were engineered in five TUs (eLEEs) excluding effectors, promoters and transcriptional regulators. These eLEEs were placed under the control of the IPTG-inducible promoter Ptac and integrated into specific chromosomal sites of E. coli K-12 using a marker-less strategy. The resulting strain, named synthetic injector E. coli (SIEC), assembles filamentous injectisomes similar to those in EPEC. SIEC injectisomes form pores in the host plasma membrane and are able to translocate T3-substrate proteins (e.g., translocated intimin receptor, Tir) into the cytoplasm of HeLa cells reproducing the phenotypes of intimate attachment and polymerization of actin-pedestals elicited by EPEC bacteria. Hence, SIEC strain allows the controlled expression of functional filamentous injectisomes for efficient translocation of proteins with T3S-signals into mammalian cells