Ten years of the horse reference genome: insights into equine biology, domestication and population dynamics in the post-genome era.

The horse reference genome from the Thoroughbred mare Twilight has been available for a decade and, together with advances in genomics technologies, has led to unparalleled developments in equine genomics. At the core of this progress is the continuing improvement of the quality, contiguity and completeness of the reference genome, and its functional annotation. Recent achievements include the release of the next version of the reference genome (EquCab3.0) and generation of a reference sequence for the Y chromosome. Horse satellite-free centromeres provide unique models for mammalian centromere research. Despite extremely low genetic diversity of the Y chromosome, it has been possible to trace patrilines of breeds and pedigrees and show that Y variation was lost in the past approximately 2300 years owing to selective breeding. The high-quality reference genome has led to the development of three different SNP arrays and WGSs of almost 2000 modern individual horses. The collection of WGS of hundreds of ancient horses is unique and not available for any other domestic species. These tools and resources have led to global population studies dissecting the natural history of the species and genetic makeup and ancestry of modern breeds. Most importantly, the available tools and resources, together with the discovery of functional elements, are dissecting molecular causes of a growing number of Mendelian and complex traits. The improved understanding of molecular underpinnings of various traits continues to benefit the health and performance of the horse whereas also serving as a model for complex disease across species

Reduction of Injection-Related Risk Behaviors After Emergency Implementation of a Syringe Services Program During an HIV Outbreak

Objective: To describe injection-related HIV risk behaviors preimplementation and postimplementation of an emergency syringe services program (SSP) in Scott County, Indiana, after an HIV outbreak among persons who inject drugs (PWID). Design: Mixed methods retrospective pre–post intervention analysis. Methods: We analyzed routine SSP program data collected at first and most recent visit among clients with ≥2 visits, ≥7 days apart from April 4 to August 30, 2015, to quantify changes in injection-related risk behaviors. We also analyzed qualitative data collected from 56 PWID recruited in Scott County to understand factors contributing to these behaviors. Results: SSP clients included in our analysis (n = 148, 62% of all SSP clients) reported significant (P < 0.001) reductions over a median 10 weeks (range 1–23) in syringe sharing to inject (18%–2%) and divide drugs (19%–4%), sharing other injection equipment (eg, cookers) (24%–5%), and number of uses of the same syringe [2 (interquartile range: 1–4) to 1 (interquartile range: 1–1)]. Qualitative study participants described access to sterile syringes and safer injection education through the SSP, as explanatory factors for these reductions. Injection frequency findings were mixed, but overall suggested no change. The number of syringes returned by SSP clients increased from 0 at first visit to median 57. All qualitative study participants reported using sharps containers provided by the SSP. Conclusions: Analyses of an SSP program and in-depth qualitative interview data showed rapid reduction of injection-related HIV risk behaviors among PWID post-SSP implementation. Sterile syringe access as part of comprehensive HIV prevention is an important tool to control and prevent HIV outbreaks

Structures of MauG in complex with quinol and quinone MADH

MauG has been cocrystallized with methylamine dehydrogenase (MADH) with its TTQ cofactor in the o-quinol (TTQ(OQ)) and quinone (TTQ(OX)) forms and the structures of the resulting complexes have been solved. The TTQ(OQ) structure crystallized in either space group P2(1) or C2, while the TTQ(OX) structure crystallized in space group P1. The previously solved structure of MauG in complex with MADH bearing an incompletely formed TTQ cofactor (preMADH) also crystallized in space group P1, although with different unit-cell parameters. Despite the changes in crystal form, the structures are virtually identical, with only very minor changes at the protein-protein interface. The relevance of these structures with respect to the measured changes in affinity between MauG and various forms of MADH is discussed

Effect of Water Depth on Heart Rate and Core Temperature During Underwater Treadmill Walking

Exercising using an underwater treadmill (UTM) has become a popular modality; however, few studies have focused on the physiological demands of UTM walking at varying water depths. Thus, the objective of this study was to investigate changes in heart rate (HR) and core temperature (CT) values in college-aged males and females while exercising at different water immersion depths using an UTM. Twenty participants (age = 21.50 ± 2.19 years; height = 169.04 ± 10.85cm; weight = 75.56 ± 22.28kg) walked at water depths of 10cm below the xiphoid process and at the level of the superior iliac crest (I.C.). Each UTM session lasted 15 minutes, consisting of 5-minute bouts at 1, 2, and 3 mph. Polar HR monitors and ingestible thermoregulatory pills were used to measure HR and CT. Results indicated that HR at 1 (p = .305) and 2 mph (p = .864) were not significantly different between water depths. Heart rate was significantly higher at 3 mph (p = .003) at the I.C. water level. No significant differences were found in CT at 1 (p = .919), 2 (p = .392), or 3 mph (p = .310) during either immersion depth. As a result, higher immersion depths resulted in a lower average HR during higher intensity exercise due to the increased buoyancy effects and the reduced gravity environment of the water. Thus, exercising in higher immersion depths allows participants to exercise at a higher intensity with less overall stress placed on the lower extremities

Credible and Actionable Evidence Across Stakeholder Levels of the Cooperative Extension System

This article provides a look at the various levels within the Cooperative Extension System and the use of evidence within these levels. The authors examine the factors associated with credible evidence and the various levels. The impact of factors such as politics, science, stakeholder support, and expectations are discussed. The various levels within Extension are summarized in relation to evidence that is routinely requested or required for each. Lastly, the authors use information directly from Extension directors to provide a framework for the discussion

Development of the morpholino gene knockdown technique in Fundulus heteroclitus : a tool for studying molecular mechanisms in an established environmental model

Author Posting. © Elsevier B.V., 2008. This is the author's version of the work. It is posted here by permission of Elsevier B.V. for personal use, not for redistribution. The definitive version was published in Aquatic Toxicology 87 (2008): 289-295, doi:10.1016/j.aquatox.2008.02.010.A significant challenge in environmental toxicology is that many genetic and genomic tools available in laboratory models are not developed for commonly used environmental models. The Atlantic killifish (Fundulus heteroclitus) is one of the most studied teleost environmental models, yet few genetic or genomic tools have been developed for use in this species. The advancement of genetic and evolutionary toxicology will require that many of the tools developed in laboratory models be transferred into species more applicable to environmental toxicology. Antisense morpholino oligonucleotide (MO) gene knockdown technology has been widely utilized to study development in zebrafish and has been proven to be a powerful tool in toxicological investigations through direct manipulation of molecular pathways. To expand the utility of killifish as an environmental model, MO gene knockdown technology was adapted for use in Fundulus. Morpholino microinjection methods were altered to overcome the significant differences between these two species. Morpholino efficacy and functional duration were evaluated with molecular and phenotypic methods. A cytochrome P450-1A (CYP1A) MO was used to confirm effectiveness of the methodology. For CYP1A MO-injected embryos, a 70% reduction in CYP1A activity, a 86% reduction in total CYP1A protein, a significant increase in β-naphthoflavone-induced teratogenicity, and estimates of functional duration (50% reduction in activity 10 dpf, and 86% reduction in total protein 12 dpf) conclusively demonstrated that MO technologies can be used effectively in killifish and will likely be just as informative as they have been in zebrafish.This work was funded in part by the National Institute of Environmental Health Sciences through the Duke Superfund Basic Research Center (P42ES010356), the Boston University Superfund Basic Research Program (P42ES007381), and the Duke Integrated Toxicology and Environmental Health Program (ES-T32-0007031). Additional support was provided by a U.S. Environmental Protection Agency STAR fellowship awarded to C.R.F

Diradical intermediate within the context of tryptophan tryptophylquinone biosynthesis

Despite the importance of tryptophan (Trp) radicals in biology, very few radicals have been trapped and characterized in a physiologically meaningful context. Here we demonstrate that the diheme enzyme MauG uses Trp radical chemistry to catalyze formation of a Trp-derived tryptophan tryptophylquinone cofactor on its substrate protein, premethylamine dehydrogenase. The unusual six-electron oxidation that results in tryptophan tryptophylquinone formation occurs in three discrete two-electron catalytic steps. Here the exact order of these oxidation steps in the processive six-electron biosynthetic reaction is determined, and reaction intermediates are structurally characterized. The intermediates observed in crystal structures are also verified in solution using mass spectrometry. Furthermore, an unprecedented Trp-derived diradical species on premethylamine dehydrogenase, which is an intermediate in the first two-electron step, is characterized using high-frequency and -field electron paramagnetic resonance spectroscopy and UV-visible absorbance spectroscopy. This work defines a unique mechanism for radical-mediated catalysis of a protein substrate, and has broad implications in the areas of applied biocatalysis and understanding of oxidative protein modification during oxidative stress

Is it possible to separate the graft-versus-leukemia (GVL) effect against B cell acute lymphoblastic leukemia from graft-versus-host disease (GVHD) after hematopoietic cell transplant?

Hematopoietic cell transplant is a curative therapy for many pediatric patients with high risk acute lymphoblastic leukemia. Its therapeutic mechanism is primarily based on the generation of an alloreactive graft-versus-leukemia effect that can eliminate residual leukemia cells thus preventing relapse. However its efficacy is diminished by the concurrent emergence of harmful graft-versus-host disease disease which affects healthly tissue leading to significant morbidity and mortality. The purpose of this review is to describe the interventions that have been trialed in order to augment the beneficial graft-versus leukemia effect post-hematopoietic cell transplant while limiting the harmful consequences of graft-versus-host disease. This includes many emerging and promising strategies such a

Haploinsufficiency of SF3B2 causes craniofacial microsomia

Craniofacial microsomia (CFM) is the second most common congenital facial anomaly, yet its genetic etiology remains unknown. We perform whole-exome or genome sequencing of 146 kindreds with sporadic (n = 138) or familial (n = 8) CFM, identifying a highly significant burden of loss of function variants in SF3B2 (P = 3.8 × 10−10), a component of the U2 small nuclear ribonucleoprotein complex, in probands. We describe twenty individuals from seven kindreds harboring de novo or transmitted haploinsufficient variants in SF3B2. Probands display mandibular hypoplasia, microtia, facial and preauricular tags, epibulbar dermoids, lateral oral clefts in addition to skeletal and cardiac abnormalities. Targeted morpholino knockdown of SF3B2 in Xenopus results in disruption of cranial neural crest precursor formation and subsequent craniofacial cartilage defects, supporting a link between spliceosome mutations and impaired neural crest development in congenital craniofacial disease. The results establish haploinsufficient variants in SF3B2 as the most prevalent genetic cause of CFM, explaining ~3% of sporadic and ~25% of familial cases