Fatty acid nitroalkenes ameliorate glucose intolerance and pulmonary hypertension in high-fat diet-induced obesity

Aims Obesity is a risk factor for diabetes and cardiovascular diseases, with the incidence of these disorders becoming epidemic. Pathogenic responses to obesity have been ascribed to adipose tissue (AT) dysfunction that promotes bioactive mediator secretion from visceral AT and the initiation of pro-inflammatory events that induce oxidative stress and tissue dysfunction. Current understanding supports that suppressing pro-inflammatory and oxidative events promotes improved metabolic and cardiovascular function. In this regard, electrophilic nitro-fatty acids display pleiotropic anti-inflammatory signalling actions. Methods and results It was hypothesized that high-fat diet (HFD)-induced inflammatory and metabolic responses, manifested by loss of glucose tolerance and vascular dysfunction, would be attenuated by systemic administration of nitrooctadecenoic acid (OA-NO2). Male C57BL/6j mice subjected to a HFD for 20 weeks displayed increased adiposity, fasting glucose, and insulin levels, which led to glucose intolerance and pulmonary hypertension, characterized by increased right ventricular (RV) end-systolic pressure (RVESP) and pulmonary vascular resistance (PVR). This was associated with increased lung xanthine oxidoreductase (XO) activity, macrophage infiltration, and enhanced expression of pro-inflammatory cytokines. Left ventricular (LV) end-diastolic pressure remained unaltered, indicating that the HFD produces pulmonary vascular remodelling, rather than LV dysfunction and pulmonary venous hypertension. Administration of OA-NO2 for the final 6.5 weeks of HFD improved glucose tolerance and significantly attenuated HFD-induced RVESP, PVR, RV hypertrophy, lung XO activity, oxidative stress, and pro-inflammatory pulmonary cytokine levels. Conclusions These observations support that the pleiotropic signalling actions of electrophilic fatty acids represent a therapeutic strategy for limiting the complex pathogenic responses instigated by obesity.Fil: Kelley, Eric E.. University of Pittsburgh; Estados UnidosFil: Baust, Jeff. University of Pittsburgh; Estados UnidosFil: Bonacci, Gustavo Roberto. University of Pittsburgh; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Golin Bisello, Franca. University of Pittsburgh; Estados UnidosFil: Devlin, Jason E.. University of Pittsburgh; Estados UnidosFil: Croix, Claudette M. St.. University of Pittsburgh; Estados UnidosFil: Watkins, Simon C.. University of Pittsburgh; Estados UnidosFil: Gor, Sonia. University of Pittsburgh; Estados UnidosFil: Cantu Medellin, Nadiezhda. University of Pittsburgh; Estados UnidosFil: Weidert, Eric R.. University of Pittsburgh; Estados UnidosFil: Frisbee,Jefferson C.. University of Virginia; Estados UnidosFil: Gladwin, Mark T.. University of Pittsburgh; Estados UnidosFil: Champion, Hunter C.. University of Pittsburgh; Estados UnidosFil: Freeman, Bruce A.. University of Pittsburgh; Estados UnidosFil: Khoo, Nicholas K.H.. University of Pittsburgh; Estados Unido

Complex exon-intron marking by histone modifications is not determined solely by nucleosome distribution

It has recently been shown that nucleosome distribution, histone modifications and RNA polymerase II (Pol II) occupancy show preferential association with exons (“exon-intron marking”), linking chromatin structure and function to co-transcriptional splicing in a variety of eukaryotes. Previous ChIP-sequencing studies suggested that these marking patterns reflect the nucleosomal landscape. By analyzing ChIP-chip datasets across the human genome in three cell types, we have found that this marking system is far more complex than previously observed. We show here that a range of histone modifications and Pol II are preferentially associated with exons. However, there is noticeable cell-type specificity in the degree of exon marking by histone modifications and, surprisingly, this is also reflected in some histone modifications patterns showing biases towards introns. Exon-intron marking is laid down in the absence of transcription on silent genes, with some marking biases changing or becoming reversed for genes expressed at different levels. Furthermore, the relationship of this marking system with splicing is not simple, with only some histone modifications reflecting exon usage/inclusion, while others mirror patterns of exon exclusion. By examining nucleosomal distributions in all three cell types, we demonstrate that these histone modification patterns cannot solely be accounted for by differences in nucleosome levels between exons and introns. In addition, because of inherent differences between ChIP-chip array and ChIP-sequencing approaches, these platforms report different nucleosome distribution patterns across the human genome. Our findings confound existing views and point to active cellular mechanisms which dynamically regulate histone modification levels and account for exon-intron marking. We believe that these histone modification patterns provide links between chromatin accessibility, Pol II movement and co-transcriptional splicing

Assessment of Strike of Adult Killer Whales by an OpenHydro Tidal Turbine Blade

Report to DOE on an analysis to determine the effects of a potential impact to an endangered whale from tidal turbines proposed for deployment in Puget Sound

Introductory programming: a systematic literature review

As computing becomes a mainstream discipline embedded in the school curriculum and acts as an enabler for an increasing range of academic disciplines in higher education, the literature on introductory programming is growing. Although there have been several reviews that focus on specific aspects of introductory programming, there has been no broad overview of the literature exploring recent trends across the breadth of introductory programming. This paper is the report of an ITiCSE working group that conducted a systematic review in order to gain an overview of the introductory programming literature. Partitioning the literature into papers addressing the student, teaching, the curriculum, and assessment, we explore trends, highlight advances in knowledge over the past 15 years, and indicate possible directions for future research

DeLLITE Depression in late life: an intervention trial of exercise. Design and recruitment of a randomised controlled trial

<p>Abstract</p> <p>Background</p> <p>Physical activity shows potential in combating the poor outcomes associated with depression in older people. Meta-analyses show gaps in the research with poor trial design compromising certainty in conclusions and few programmes showing sustained effects.</p> <p>Methods/design</p> <p>The Depression in Late Life: an Intervention Trial of Exercise (DeLLITE) is a 12 month randomised controlled trial of a physical activity intervention to increase functional status in people aged 75 years and older with depressive symptoms. The intervention involves an individualised activity programme based on goal setting and progression of difficulty of activities delivered by a trained nurse during 8 home visits over 6 months. The control group received time matched home visits to discuss social contacts and networks. Baseline, 6 and 12 months measures were assessed in face to face visits with the primary outcome being functional status (SPPB, NEADL). Secondary outcomes include depressive symptoms (Geriatric Depression Scale), quality of life (SF-36), physical activity (AHS Physical Activity Questionnaire) and falls (self report).</p> <p>Discussion</p> <p>Due to report in 2008 the DeLLITE study has recruited 70% of those eligible and tests the efficacy of a home based, goal setting physical activity programme in improving function, mood and quality of life in older people with depressive symptomatology. If successful in improving function and mood this trial could prove for the first time that there are long term health benefit of physical activity, independent of social activity, in this high risk group who consume excess health related costs.</p> <p>Trial registration</p> <p>Australian and New Zealand Clinical Trials Register ACTRN12605000475640</p

The Y-Chromosome Tree Bursts into Leaf: 13,000 High-Confidence SNPs Covering the Majority of Known Clades

Many studies of human populations have used the male-specific region of the Y chromosome (MSY) as a marker, but MSY sequence variants have traditionally been subject to ascertainment bias. Also, dating of haplogroups has relied on Y-specific short tandem repeats (STRs), involving problems of mutation rate choice, and possible long-term mutation saturation. Next-generation sequencing can ascertain single nucleotide polymorphisms (SNPs) in an unbiased way, leading to phylogenies in which branch-lengths are proportional to time, and allowing the times-to-most-recent-common-ancestor (TMRCAs) of nodes to be estimated directly. Here we describe the sequencing of 3.7 Mb of MSY in each of 448 human males at a mean coverage of 51x, yielding 13,261 high-confidence SNPs, 65.9% of which are previously unreported. The resulting phylogeny covers the majority of the known clades, provides date estimates of nodes, and constitutes a robust evolutionary framework for analyzing the history of other classes of mutation. Different clades within the tree show subtle but significant differences in branch lengths to the root. We also apply a set of 23 Y-STRs to the same samples, allowing SNP- and STR-based diversity and TMRCA estimates to be systematically compared. Ongoing purifying selection is suggested by our analysis of the phylogenetic distribution of nonsynonymous variants in 15 MSY single-copy genes

ISBS 2018 AUCKLAND CONFERENCE SPRINZ-HPSNZ-AUT MILLENNIUM APPLIED PROGRAMME

An interactive afternoon of sessions delivered by High Performance Sport New Zealand (HPSNZ) and AUT SPRINZ Biomechanists, Performance Analysts and other biomechanics relevant sport facing practitioners. The 11 sessions are at AUT Millennium (AUTM), which is a satellite site of AUT University and the Auckland training hub for many HPSNZ supported sports such as athletics, sailing, and swimming. These sports and others (cycling, rowing, snow sports etc.) will be represented in the line-up. The applied sessions involve practical demonstrations of aspects of analysis and/or tools used to deliver in the field to directly positively impact athletes performances on the world stage. Following these engaging sessions there will be tasting of New Zealand wine, allowing for further discussion and networking. Sir Graeme Avery will be acknowledged for his contribution to sport science. Mike Stanley is AUT Millennium Chief Executive & NZ Olympic Committee President will explain the partners in the facility. AUT Millennium is a charitable trust established to help New Zealanders live longer and healthier lives, and to enjoy and excel in sport through the provision of world-class facilities, services, research and education. Founded in 2002 as Millennium Institute of Sport and Health (MISH) by Sir Stephen Tindall and Sir Graeme Avery as a premium health and fitness facility for both athletes and the public alike. Partnered with AUT University in 2009, forming AUT Millennium, to expand research and education in the sporting sector. Professor Barry Wilson is an Adjunct Professor with SPRINZ at Auckland University of Technology and will be outlining the research and student opportunities. Martin Dowson is the General Manager Athlete Performance Support at High Performance Sport New Zealand and has overall responsibility for the programme. Simon Briscoe, AUT Millennium Applied Session Coordinator, is the head of the Performance and Technique Analysis discipline within HPSNZ. Simon is coordinating the applied sessions along with technical support from Dr Allan Carman, Research Fellow, AUT SPRINZ. Jodi Cossor and Matt Ingram will provide a demonstration of a multidisciplinary approach driven by biomechanical analysis for Paralympic swimmers. Justin Evans and Sarah-Kate Millar will provide a practical session assessing the athletes rowing stroke to assist the coach on technical changes. This session will demonstrate various rowing traits and how the biomechanist and coach can work together to optimise boat speed. Mike Schofield and Kim Hébert-Losier will provide a session looking at shotput and the evidence based approach to coaching. Dr Craig Harrison and Professor John Cronin will provide examples from the AUTM Athlete Development programme. Kim Simperingham and Jamie Douglas who work with high performance rugby athletes will outline sprinting mechanics in practice. Dr Bruce Hamilton, Fiona Mather, Justin Ralph and Rone Thompson will demonstrate the approach of HPSNZ and Cycling NZ performance health teams in the use of some specific tools for prevention of injury and optimisation of performance. Kelly Sheerin, Denny Wells and Associate Professor Thor Besier will provide examples of using IMU and motion capture methods for running and basketball biomechanics research, education and service. Dr Rodrigo Bini and Associate Professor Andrew Kilding will show how linking of biomechanics and physiology improves injury prevention and performance enhancement. Robert Tang, Andre de Jong and Farhan Tinwala discuss select projects developed by Goldmine, HPSNZ’s in-house engineering team, and how these innovations have enabled unprecedented levels of biomechanics feedback. Cameron Ross and Paul McAlpine demonstrate the technology being used at the Snow Sports NZ training centre in Cadrona to enhance load monitoring of athletes. This application allows greater insight into training performances and biomechanical loads than has been previously possible in the training environment. AUT Millennium tour guides are coordinated by Josh McGeown and include Enora Le Flao, Dustin Oranchuk, Erika Ikeda, Jono Neville, Aaron Uthoff, Andrew Pichardo, Farhan Tinwala, Shelley Diewald, Renata Bastos Gottgtroy, Jessica Yeoman, Casey Watkins, Eric Harbour, Anja Zoellner, Alyssa Joy Spence, Victor Lopez Jr, and Albert Chang

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes