Effect of natural genetic variation on enhancer selection and function.

The mechanisms by which genetic variation affects transcription regulation and phenotypes at the nucleotide level are incompletely understood. Here we use natural genetic variation as an in vivo mutagenesis screen to assess the genome-wide effects of sequence variation on lineage-determining and signal-specific transcription factor binding, epigenomics and transcriptional outcomes in primary macrophages from different mouse strains. We find substantial genetic evidence to support the concept that lineage-determining transcription factors define epigenetic and transcriptomic states by selecting enhancer-like regions in the genome in a collaborative fashion and facilitating binding of signal-dependent factors. This hierarchical model of transcription factor function suggests that limited sets of genomic data for lineage-determining transcription factors and informative histone modifications can be used for the prioritization of disease-associated regulatory variants

Affinity and dose of TCR engagement yield proportional enhancer and gene activity in CD4+ T cells.

Affinity and dose of T cell receptor (TCR) interaction with antigens govern the magnitude of CD4+ T cell responses, but questions remain regarding the quantitative translation of TCR engagement into downstream signals. We find that while the response of mouse CD4+ T cells to antigenic stimulation is bimodal, activated cells exhibit analog responses proportional to signal strength. Gene expression output reflects TCR signal strength, providing a signature of T cell activation. Expression changes rely on a pre-established enhancer landscape and quantitative acetylation at AP-1 binding sites. Finally, we show that graded expression of activation genes depends on ERK pathway activation, suggesting that an ERK-AP-1 axis plays an important role in translating TCR signal strength into proportional activation of enhancers and genes essential for T cell function

A Content Analysis of Psychological Resilience Among First Responders and the General Population

The current study examined how first responders and the general population described the concept of resilience. Categories of resilience were coded a priori using Stemler’s content analysis. For the general population, positive coping was the most frequently occurring category followed by social support and adaptability. The next most frequently occurring terms were societal resources and personal competence. Consistent with the general population, first responders described resilience most frequently with positive coping. Social support was the next most frequently occurring category, followed by personal competence, perseverance, emotional regulation, and physical fitness. Although both the general population and first responder participants highlighted the importance of having a support network, first responders suggested that dealing with traumatic experiences was more of an individual process, and seeking professional help was not common practice. Implications for mental health professionals and future directions for research are offered.ECU Open Access Publishing Support Fun

Evidence of a North Atlantic right whale calf (Eubalaena glacialis) born in northeastern U.S. waters

Author Posting. © The Author(s), 2008. This is the author's version of the work. It is posted here by permission of John Wiley & Sons for personal use, not for redistribution. The definitive version was published in Marine Mammal Science 25 (2009): 462-477, doi:10.1111/j.1748-7692.2008.00261.x.The general temporal and geographical patterns of North Atlantic right whale (Eubalaena glacialis) calving events have been clarified during the last quarter century of research (Kraus and Rolland 2007). Right whales give birth to a single calf every three to five years after a twelve- to thirteen-month gestation period (Best 1994; Kraus and Hatch 2001). Most calves are born between December and March in the coastal waters of the southeastern U.S., the only known calving ground for this species (Kraus et al. 2007; Winn et al. 1986). Although historical whaling records suggest that there were once two winter calving grounds, one off the southeastern U.S. and the other off northwestern Africa, it appears that only the former is still used today (Notarbartolo di Sciara et al. 1998; Reeves and Mitchell 1986; 1988). In the late winter, right whales leave the calving grounds and migrate to their foraging grounds off the northeastern U.S. and Canadian Maritimes. North Atlantic right whales can be found in Cape Cod and Massachusetts Bays throughout the late winter and early spring (Hamilton and Mayo 1990; Mayo and Marx 1990; Schevill et al. 1986), in the Great South Channel during mid-spring to early summer (Kenney et al. 1995), and in the Bay of Fundy (Kraus et al. 1982) and on the Scotian Shelf (Mitchell et al. 1986; Stone et al. 1988) during the summer and fall. Some individuals (mostly pregnant females and juveniles) return to the calving grounds off the southeastern U.S. in December and January, but the location of the rest of the population during those months is currently unknown (although recent evidence suggests that right whales are present in the Gulf of Maine and on the Scotian Shelf throughout the winter (Mellinger et al. 2007; T. Cole pers comm. ; S. Van Parijs pers comm. )

Simultaneous identification of Chlamydia trachomatis, Neisseria gonorrhoeae, Mycoplasma genitalium, and Trichomonas vaginalis ‒ multicenter evaluation of the Alinity m STI assay

Abstract Objectives Accurate and rapid diagnosis of sexually transmitted infections (STIs) is essential for timely administration of appropriate treatment and reducing the spread of the disease. We examined the performance of the new Alinity m STI assay, a qualitative real-time multiplex PCR test for simultaneous identification of Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG), Mycoplasma genitalium (MG), and Trichomonas vaginalis (TV) run on the fully automated Alinity m platform. Methods This international, multicenter study evaluated the accuracy, reproducibility, and clinical performance of the Alinity m STI assay compared to commonly used STI assays in a large series of patient samples encountered in clinical practice. Results The Alinity m STI assay identified accurately and precisely single and mixed pathogens from an analytical panel of specimens. The Alinity m STI assay demonstrated high overall agreement rates with comparator STI assays (99.6% for CT [n=2,127], 99.2% for NG [n=2,160], 97.1% for MG [n=491], and 99.4% for TV [n=313]). Conclusions The newly developed Alinity m STI assay accurately detects the 4 sexually transmitted target pathogens in various collection devices across clinically relevant specimen types, regardless of single or mixed infection status

Development and clinical validation of the Genedrive point-of-care test for qualitative detection of hepatitis C virus

Objective: Recently approved direct acting antivirals provide transformative therapies for chronic hepatitis C virus (HCV) infection. The major clinical challenge remains to identify the undiagnosed patients worldwide, many of whom live in low-income and middle-income countries, where access to nucleic acid testing remains limited. The aim of this study was to develop and validate a point-of-care (PoC) assay for the qualitative detection of HCV RNA. Design: We developed a PoC assay for the qualitative detection of HCV RNA on the PCR Genedrive instrument. We validated the Genedrive HCV assay through a case–control study comparing results with those obtained with the Abbott RealTime HCV test. Results: The PoC assay identified all major HCV genotypes, with a limit of detection of 2362 IU/mL (95% CI 1966 to 2788). Using 422 patients chronically infected with HCV and 503 controls negative for anti-HCV and HCV RNA, the Genedrive HCV assay showed 98.6% sensitivity (95% CI 96.9% to 99.5%) and 100% specificity (95% CI 99.3% to 100%) to detect HCV. In addition, melting peak ratiometric analysis demonstrated proof-of-principle for semiquantification of HCV. The test was further validated in a real clinical setting in a resource-limited country. Conclusion: We report a rapid, simple, portable and accurate PoC molecular test for HCV, with sensitivity and specificity that fulfils the recent FIND/WHO Target Product Profile for HCV decentralised testing in low-income and middle-income countries. This Genedrive HCV assay may positively impact the continuum of HCV care from screening to cure by supporting real-time treatment decisions