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The ability to determine full-length nucleotide composition of individual RNA molecules is essential for understanding the architecture and function of a transcriptome. However, experimental approaches capable of capturing the sequences of both 5' and 3' termini of the same transcript remain scarce. In the present study, simultaneous 5' and 3' end sequencing (SEnd-seq)-a high-throughput and unbiased method that simultaneously maps transcription start and termination sites with single-nucleotide resolution-is presented. Using this method, a comprehensive view of the Escherichia coli transcriptome was obtained, which displays an unexpected level of complexity. SEnd-seq notably expands the catalogue of transcription start sites and termination sites, defines unique transcription units and detects prevalent antisense RNA. Strikingly, the results of the present study unveil widespread overlapping bidirectional terminators located between opposing gene pairs. Furthermore, it has been shown that convergent transcription is a major contributor to highly efficient bidirectional termination both in vitro and in vivo. This finding highlights an underappreciated role of RNA polymerase conflicts in shaping transcript boundaries and suggests an evolutionary strategy for modulating transcriptional output by arranging gene orientation.

Allostatic load reflects the cumulative effects of stressful experiences

Mesenchymal stem/stromal cells (MSCs) are self-renewing multipotent

Soon after exposure to genotoxic reagents, mammalian cells inhibit transcription to prevent collisions with repair machinery and to mount a proper DNA damage response. However, mechanisms underlying early transcriptional inhibition are poorly understood. In this report, we show that site-specific acetylation of super elongation complex (SEC) subunit AFF1 by p300 reduces its interaction with other SEC components and impairs P-TEFb-mediated C-terminal domain phosphorylation of RNA polymerase II both in vitro and in vivo. Reexpression of wild-type AFF1, but not an acetylation mimic mutant, restores SEC component recruitment and target gene expression in AFF1 knockdown cells. Physiologically, we show that, upon genotoxic exposure, p300-mediated AFF1 acetylation is dynamic and strongly correlated with concomitant global down-regulation of transcription-and that this can be reversed by over-expression of an acetylation-defective AFF1 mutant. Therefore, we describe a mechanism of dynamic transcriptional regulation involving p300-mediated acetylation of a key elongation factor during genotoxic stress.

Numerous challenges have impeded HIV-1 vaccine development. Among these is the lack of a convenient small animal model in which to study antibody elicitation and efficacy. We describe a chimeric Rhabdo-Immunodeficiency virus (RhIV) murine model that recapitulates key features of HIV-1 entry, tropism and antibody sensitivity. RhIVs are based on vesicular stomatitis viruses (VSV), but viral entry is mediated by HIV-1 Env proteins from diverse HIV-1 strains. RhIV infection of transgenic mice expressing human CD4 and CCR5, exclusively on mouse CD4+ cells, at levels mimicking those on human CD4+ T-cells, resulted in acute, resolving viremia and CD4+ T-cell depletion. RhIV infection elicited protective immunity, and antibodies to HIV-1 Env that were primarily non-neutralizing and had modest protective efficacy following passive transfer. The RhIV model enables the convenient in vivo study of HIV-1 Env-receptor interactions, antiviral activity of antibodies and humoral responses against HIV-1 Env, in a genetically manipulatable host.

Network biology has the capability to integrate, represent, interpret, and model complex biological systems by collectively accommodating biological omics data, biological interactions and associations, graph theory, statistical measures, and visualizations. Biological networks have recently been shown to be very useful for studies that decipher biological mechanisms and disease etiologies and for studies that predict therapeutic responses, at both the molecular and system levels. In this review, we briefly summarize the general framework of biological network studies, including data resources, network construction methods, statistical measures, network topological properties, and visualization tools. We also introduce several recent biological network applications and methods for the studies of rare diseases.

Pumas are the most widely distributed felid in the Western Hemisphere. Increasingly, however, human persecution and habitat loss are isolating puma populations. To explore the genomic consequences of this isolation, we assemble a draft puma genome and a geographically broad panel of resequenced individuals. We estimate that the lineage leading to present-day North American pumas diverged from South American lineages 300-100 thousand years ago. We find signatures of close inbreeding in geographically isolated North American populations, but also that tracts of homozygosity are rarely shared among these populations, suggesting that assisted gene flow would restore local genetic diversity. The genome of a Florida panther descended from translocated Central American individuals has long tracts of homozygosity despite recent outbreeding. This suggests that while translocations may introduce diversity, sustaining diversity in small and isolated populations will require either repeated translocations or restoration of landscape connectivity. Our approach provides a framework for genome-wide analyses that can be applied to the management of similarly small and isolated populations.

Chronic low-level lead exposure alters cognitive function in young

BACKGROUND Alzheimer's disease (AD) is a multifactorial