Whole-genome sequencing of African Americans implicates differential genetic architecture in inflammatory bowel disease

Whether or not populations diverge with respect to the genetic contribution to risk of specific complex diseases is relevant to understanding the evolution of susceptibility and origins of health disparities. Here, we describe a large-scale whole-genome sequencing study of inflammatory bowel disease encompassing 1,774 affected individuals and 1,644 healthy control Americans with African ancestry (African Americans). Although no new loci for inflammatory bowel disease are discovered at genome-wide significance levels, we identify numerous instances of differential effect sizes in combination with divergent allele frequencies. For example, the major effect at PTGER4 fine maps to a single credible interval of 22 SNPs corresponding to one of four independent associations at the locus in European ancestry individuals but with an elevated odds ratio for Crohn disease in African Americans. A rare variant aggregate analysis implicates C

Ethical use of animal models in musculoskeletal research.

The use of animals in research is under increasing scrutiny from the general public, funding agencies, and regulatory authorities. Our ability to continue to perform in-vivo studies in laboratory animals will be critically determined by how researchers respond to this new reality. This Perspectives article summarizes recent and ongoing initiatives within ORS and allied organizations to ensure that musculoskeletal research is performed to the highest ethical standards. It goes on to present an overview of the practical application of the 3Rs (reduction, refinement, and replacement) into experimental design and execution, and discusses recent guidance with regard to improvements in the way in which animal data are reported in publications. The overarching goal of this review is to challenge the status quo, to highlight the absolute interdependence between animal welfare and rigorous science, and to provide practical recommendations and resources to allow clinicians and scientists to optimize the ways in which they undertake preclinical studies involving animals. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:740-751, 2017

Large-scale sequencing identifies multiple genes and rare variants associated with Crohn's disease susceptibility

Genome-wide association studies (GWASs) have identified hundreds of loci associated with Crohn's disease (CD). However, as with all complex diseases, robust identification of the genes dysregulated by noncoding variants typically driving GWAS discoveries has been challenging. Here, to complement GWASs and better define actionable biological targets, we analyzed sequence data from more than 30,000 patients with CD and 80,000 population controls. We directly implicate ten genes in general onset CD for the first time to our knowledge via association to coding variation, four of which lie within established CD GWAS loci. In nine instances, a single coding variant is significantly associated, and in the tenth, ATG4C, we see additionally a significantly increased burden of very rare coding variants in CD cases. In addition to reiterating the central role of innate and adaptive immune cells as well as autophagy in CD pathogenesis, these newly associated genes highlight the emerging role of mesenchymal cells in the development and maintenance of intestinal inflammation.Large-scale sequence-based analyses identify novel risk variants and susceptibility genes for Crohn's disease, and implicate mesenchymal cell-mediated intestinal homeostasis in disease etiology.Cellular mechanisms in basic and clinical gastroenterology and hepatolog

Large-scale sequencing identifies multiple genes and rare variants associated with Crohn’s disease susceptibility

peer reviewe

Physical Exercise Training but Not Metformin Attenuates Albuminuria and Shedding of ACE2 in Type 2 Diabetic db/db Mice

Angiotensin II (Ang II), a potent vasoconstrictor cleaved from Ang I, is responsible for renal damage in diabetes. Angiotensin converting enzyme 2 (ACE2) is highly expressed in the kidney and has been shown to be renoprotective by degrading Ang II to Ang-(1-7). A Disintegrin and Metalloproteinases (ADAMs) were recently identified as an ectodomain sheddases of transmembrane proteins. ADAM17 mediated shedding of renal ACE2 could contribute to the pathogenesis of diabetic nephropathy. In our previous study, rosiglitazone treatment normalized hyperglycemia and improved renal injury by preventing ACE2 shedding. The aim of this study is to test the hypothesis that improved glucose homeostasis with exercise and/or metformin attenuates albuminuria, renal ADAM17 protein and prevents shedding of ACE2 in db/db mice. Seven week old normal and db/db mice were subjected to physical exercise training and/or metformin treatment (150 mg/kg/day) for 10 weeks. Exercised mice ran on a mouse forced exercise walking wheel system for 1 hr a day for 7 days a week at a speed of 8 meters/minute. At juvenile stages (6 week old), db/db mice demonstrated higher levels of blood glucose, urinary albumin and ACE2 excretion. Urinary ACE2 is enzymatically active and 20 kDa shorter as demonstrated by immunoblotting. Renal ADAM17 and ACE2 protein levels were significantly upregulated in db/db mice compared to non-diabetic controls. In diabetic kidney, upregulated ADAM17 and ACE2 proteins co-localized in the tubular cortex. However, physical exercise training significantly attenuated blood glucose, urinary albumin and ACE2 excretion of db/db mice throughout the study period, whereas metformin treatment was effective in lowering hyperglycemia only in the initial stages of diabetes. The increased renal ADAM17 protein levels in db/db diabetic mice were normalized by exercise training but not by metformin. In addition, exercise training reduced plasma triglycerides and enhanced insulin levels of db/db mice. The combination of exercise and metformin was effective against lowering plasma glucagon. Results demonstrated a significant association between blood glucose, urinary albumin, plasma insulin, glucagon and triglycerides with urinary ACE2 excretion. In conclusion, co-localization of ADAM17 with ACE2 suggests a possible interaction in diabetic kidney. Exercise training with or without metformin prevented shedding of renal ACE2 by attenuating ADAM17 protein. Elevated plasma insulin by exercise could be responsible for improved glucose homeostasis, at least in partial. Urinary ACE2 could serve as a prognostic tool in the progression of kidney damage and its attenuation by exercise may partially contribute to its renal protection

Importance of Safety of International Female Students at Pittsburg State University

Safety is an important factor to be considered especially for international female students studying in colleges. This could be due to more female students going to colleges today than ever before. Also parents living in other countries will be worrying about the safety of their daughters if they are attending late evening classes. If this safety problem is not addressed properly for international female. Students, it would really make a serious concern for the university. It’s a basic need for the females to showcase themselves with higher education and make their mark on society. Providing proper safety for international female students will help gain confidence and send their daughters to study. Whatever the reason, safety is a growing concern that must be addressed by college campuses, particularly by administrators. In order for the college administrators to address safety concerns, they must be aware of the types of safety issues present on their campus. The international female students present in Pittsburg State University are facing safety concerns while attending late evening sessions. This is because students attending late evening classes don’t have transportation to commute between their home apartment and the technology center. Though the university provides all the students with several safety measures like on-campus university police, emergency poles to click on during necessary times, it does not provide transportation for international female students attending classes after 6:30 pm in the evening. In order to address the problem, the proposed research study will try to answer the following research questions: How and to what extent safety is a concern for international female students, attending late evening classes at Pittsburg State University? The proposed research will use mixed method to study to analyze the safety issues faced by international female students who are attending late evening sessions at PSU. The data will be collected from international female students by means of survey and face to face interviews. The details such as number of international female students attending late evening sessions, number of students with lack of transportation after attending late evening sessions will be conducted during class break times. With necessary approvals from the international office, the survey and interviews will be conducted. The gathered data will be drafted for the analysis. The analyzed data will be displayed in tabular and statistical report.https://digitalcommons.pittstate.edu/posters_2015/1041/thumbnail.jp

Implementation of m-Health for Asthma Management in India

Mobile Health (mHealth) in evidence-based patient care is a fast-growing technology that is yet to be adapted in the healthcare setting for managing asthma. This research thesis aims to understand the determinant factors that can be recognized as drivers and barriers for mHealth implementation for asthma.  The literature review chapter outlined the aspects of wicked problems in implementing innovation, and the study of implementation science explained in relevant to the implementation of mHealth in the healthcare system. The selected framework is based on the implementation outcome and addressed all four categories of human organizational levels. A qualitative case study was carried out in metropolitan cities of India, and a purposive sampling method is applied to choose the engaged pulmonologist & healthcare providers.  The empirical findings are categorized into themes using thematic analysis and identified the barriers and drivers under five themes, such as Technology, Human Factor, System, Literacy and Process.  The aspects under the theme technology include integrating IoT systems and data platforms, pre-testing, and adaptability. In contrast, the human factor’s theme revolves around the patient behaviour and attitude, emotions and beliefs on the technology. The aspects under the system and literacy theme mainly suggest that health literacy and language play a significant role. The results of these empirical studies have not previously been explored in the literature. And finally, the process theme indicates that the doctors play an essential role as an opinion leader and implementation leader in driving the implementation efforts. The analysis concludes that the determinant factors acting as barrier and driver are more under the human factors, technology and system aspects. These factors need to be considered when implementing the mHealth intervention for asthma management, and the role of healthcare practitioners engaging in the implementation process is foreseen as a potential driving factor for the successful outcome and technology acceptance by the patients

A Low Threshold Voltage Ultradynamic Voltage Scaling SRAM Write Assist Technique for High-Speed Applications

With the percentage of embedded SRAM increasing in SoC chips, low-power design such as the near-threshold SRAM technique are getting increasing attention to reduce the entire chip energy consumption. However, the descending operating voltage will lead to longer write latency and a higher failure rate. In this paper, we present a novel low Vth ultradynamic voltage scaling (UDVS) 9T subthreshold SRAM cell to improve the write ability of SRAM cells. The proposed Low Vth UDVS SRAM cell is demonstrated with a low threshold voltage speed-up transistor and an ultradynamic voltage scaling circuit implemented in 16 nm low-leakage CMOS technology. This wide supply range was made possible by a combination of circuits optimized for both subthreshold and abovethreshold regimes. This write assist technique can be operated selectively to provide write capability at very low voltage levels while avoiding excessive power overhead. The simulation findings reveal that with 16 nm technology, the write ability is improved by 33% over the normal case at 0.9 V supply voltage