Molecular Dynamic Simulations of CRISPR and HIV

In the United States, there were 37,600 new HIV infections in 2014, with an estimated 1.1 million people living with the disease in 2015, according to the CDC. HIV targets the cell receptor CD4 and chemocine coreceptors CCR5 or CXCR5. Some individuals possess a mutation within CCR5 that causes a resistance to HIV-1. One HIV+ patient in Berlin, Timothy Brown, developed an immunity to the virus after a bone marrow transplant from a donor who possessed this CCR5 mutation. After this coincidence, researchers attempted a variety of gene therapies, such as zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and Cas9. CRISPR/Cas9 is a promising new tool that scientists have been using to do direct editing of genomes with more ease and specificity than ever before. CRISPR stands for cluster of regularly interspaced palindromic repeats, which are segments of RNA that are found in many prokaryotes to defend the organism against viral infections and unwanted gene transfers. Cas is a gene cluster that mediates the response to the RNA encoded in the CRISPR segments. Cas are designated by the protein complex responsible for interference. Together, these molecules identify a segment of target RNA, extract it, and replace it with another segment. They make up part of the adaptive immune system of eukaryotic cells. This research hopes to create a predictive model by analyzing the existing gene therapy data from previous studies, and using numerical molecular dynamic simulation software to glean more information about those results. Previously published studies discuss how gene therapies such as ZFN and CRISPR are used to modify either the host genome or the viral genome3, and then experiments are performed to determine whether this therapy is effective at preventing viral infection. By analyzing the bonding characteristics of different strands of RNA, it may be possible to predict which RNA segments make the best candidates for gene therapies that will confer resistance to HIV infection

Ultra-High Temperature Metallic Seal/Energizer Development for Aero Propulsion and Gas Turbine Applications

The industry is requiring seals to operate at higher and higher temperatures. Traditional static seal designs and materials experience stress relaxation, losing their ability to maintain contact with moving flanges. Ultra High Temperature seal development program is a multiphase program with incremental increases in seal operating temperatures

Design of an unmanned Martian polar exploration system

The design of an unmanned Martian polar exploration system is presented. The system elements include subsystems for transportation of material from earth to Mars, study of the Martian north pole, power generation, and communications. Early next century, three Atlas 2AS launch vehicles will be used to insert three Earth-Mars transfer vehicles, or buses, into a low-energy transfer orbit. Capture at Mars will be accomplished by aerobraking into a circular orbit. Each bus contains four landers and a communications satellite. Six of the twelve total landers will be deployed at 60 deg intervals along 80 deg N, and the remaining six landers at 5 deg intervals along 30 deg E from 65 deg N to 90 deg N by a combination of retrorockets and parachutes. The three communications satellites will be deployed at altitudes of 500 km in circular polar orbits that are 120 deg out of phase. These placements maximize the polar coverage of the science and communications subsystems. Each lander contains scientific equipment, two microrovers, power supplies, communications equipment, and a science computer. The lander scientific equipment includes a microweather station, seismometer, thermal probe, x-ray spectrometer, camera, and sounding rockets. One rover, designed for short-range (less than 2 km) excursions from the lander, includes a mass spectrometer for mineral analysis, an auger/borescope system for depth profiling, a deployable thermal probe, and charge coupled device cameras for terrain visualization/navigation. The second rover, designed for longer-range (2-5 km) excursions from the lander, includes radar sounding/mapping equipment, a seismometer, and laser ranging devices. Power for all subsystems is supplied by a combination of solar cells, Ni-H batteries, and radioisotope thermoelectric generators. Communications are sequenced from rovers, sounding rockets, and remote sensors to the lander, then to the satellites, through the Deep Space Network to and from earth

Prevention of Lower Urinary Tract Symptoms Research Consortium focus group Study of Habits, Attitudes, Realities, and Experiences of Bladder health

AimThe study purpose is to explore adolescent and adult women’s experiences, perceptions, beliefs, knowledge and behaviours related to bladder health across the life course using a socioecological perspective. Lower urinary tract symptoms affect between 20-40% of young adult to middle-aged women, with symptoms increasing in incidence and severity with aging. There is limited evidence to address bladder health promotion and prevention of dysfunction. This first study of the Prevention of Lower Urinary Tract Symptoms (PLUS) Research Consortium is designed to address gaps in existing qualitative research in this area.DesignThis focus group study will be implemented across seven geographically diverse United States research centres using a semi-structured focus group guide informed by a conceptual framework based on the socioecological model.MethodsThe study was approved in July 2017. A total of 44 focus groups composed of 6-8 participants representing six different age categories (ranging from 11 to over 65 years) will be completed. We aim to recruit participants with diverse demographic and personal characteristics including race, ethnicity, education, socioeconomic status, urban/rural residence, physical/health conditions, and urinary symptom experience. Six of the focus groups will be conducted in Spanish and translated into English. Focus group transcripts will undergo content analysis and data interpretation to identify and classify themes and articulate emerging themes.DiscussionThis foundational qualitative study seeks to develop an evidence base to inform future research on bladder health promotion in adolescent and adult women.ImpactThis study has the potential to provide new insights and understanding into adolescent and adult women’s lived experience of bladder health, the experience of lower urinary symptoms and knowledge and beliefs across the life course.ç ®ç æ ¬ç  ç©¶ç ç ®ç æ ¯ä» ç¤¾ä¼ ç æ å­¦ç è§ åº¦,æ ¢è®¨é å° å¹´å æ å¹´å¥³æ §å ¨äººç è¿ ç¨ ä¸­ä¸ è è ±å ¥åº·ç ¸å ³ç ç» éª ã è§ å¿µã 信念ã ç ¥è¯ å è¡ ä¸ºã ä¸ å°¿è·¯ç ç ¶å½±å 20-40%ç 中é å¹´å¥³æ §,é ç å¹´é¾ ç å¢ é ¿,ç ç ¶ç å ç ç å 严é ç¨ åº¦é ½å ¨å¢ é ¿ã å ³äº ä¿ è¿ è è ±å ¥åº·å é¢ é ²å è ½é ç¢ ç è¯ æ ®æ é ã æ ¬æ¬¡é¢ é ²ä¸ å°¿è·¯ç ç ¶(PLUS)ç  ç©¶è ç ç ç  ç©¶æ ¯é¦ ä¸ªå ³äº æ­¤æ ¹é ¢ç ç  ç©¶,æ ¨å ¨è§£å ³ç °æ ç å® æ §ç  ç©¶å ¨è¿ æ ¹é ¢ç å·®è· ã è®¾è®¡è¯¥é¡¹ç ¦ç ¹å° ç» ç  ç©¶å° å ¨ä¸ ä¸ªä¸ å ä½ ç½®ç ç¾ å ½ç  ç©¶ä¸­å¿ è¿ è¡ ,ä»¥å ºäº ç¤¾ä¼ ç æ 模å æ¦ å¿µæ¡ æ ¶ç å ç» æ å ç ç ¦ç ¹å° ç» æ å 为æ 导ã æ ¹æ³ è¯¥ç  ç©¶äº 2017å¹´7æ è ·å¾ æ ¹å ã ç ±6-8å 代表6ä¸ªä¸ å å¹´é¾ ç±»å «(ä» 11å² å °65å² ä»¥ä¸ )ç å ä¸ è ç» æ å ±44ä¸ªç ¦ç ¹å° ç» ã æ 们计å æ å ä¸ å äººå £å ä¸ªäººç ¹å¾ ç å ä¸ è ,ä¾ å¦ ç§ æ ã ç§ æ æ¸ æº ã æ è ²ç» å ã ç¤¾ä¼ ç» æµ å °ä½ ã å ä¹¡å± æ° ã èº«ä½ /å ¥åº·ç ¶å µå æ³ å°¿ç³»ç» ç ç ¶ç» å ã å ­ä¸ªç ¦ç ¹å° ç» ç ç  ç©¶å° ä»¥è¥¿ç ­ç è¯­è¿ è¡ ,å¹¶ç¿»è¯ æ è ±è¯­ã ç ¦ç ¹å° ç» ç èª æ ¬å° è¢«ç ¨äº å 容å æ å æ °æ ®è§£é ,ä»¥ç¡®å® å å ç±»ä¸»é¢ ,并é æ æ °å ºç °ç ä¸»é¢ ã è®¨è®ºè¿ é¡¹å ºç¡ æ §ç å® æ §ç  ç©¶æ ¨å ¨ä¸ºæ é« æ ªæ ¥é å° å¹´å æ å¹´å¦ å¥³ç è è ±å ¥åº·ç ç  ç©¶æ ä¾ è¯ æ ®å ºç¡ ã å½±å è¿ é¡¹ç  ç©¶æ å ¯è ½æ ä¾ å ³äº é å° å¹´å æ å¹´å¦ å¥³ç è è ±å ¥åº·ç ç æ´»ç» éª ,ç» éª ç ä¸ å°¿è·¯ç ç ¶å ç ¥è¯ å ç æ³ ç 人ç è¿ ç¨ ä¸­æ °ç è§ è§£å ç 解ãPeer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/151981/1/jan14148_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151981/2/jan14148.pd

Blinded by Simplicity: Locating the Social Dimension in Software Development Process Literature

The software development process is a complex human, intellectual and labor-intensive activity and human related factors have shown to be the most significant contributors to software system failures. Lacking the ability to identify or quantify these factors, software practitioners will not learn from the failures caused by them. Although, social factors give rise to high failure rates in software development projects they tend to be ignored. Business continues as usual. The inability for software engineers to attain a holistic and inclusive approach will leave the social dimension out and undermine the realization of a fully sustainable software development process.This paper builds on the master’s thesis with the same title completed in December 2019 at Stockholm University. The thesis demonstrates how research literature on software development processes addresses (or not) the social dimension of sustainability from a holistic point of view. The results indicate that the practice of dealing holistically with complexity including the social dimension is still underdeveloped. Further research is suggested regarding the development of adequate supporting tools, social skills, and managerial attitudes and behaviors

SUCLA2 mutations cause global protein succinylation contributing to the pathomechanism of a hereditary mitochondrial disease

Mitochondrial acyl-coenzyme A species are emerging as important sources of protein modification and damage. Succinyl-CoA ligase (SCL) deficiency causes a mitochondrial encephalomyopathy of unknown pathomechanism. Here, we show that succinyl-CoA accumulates in cells derived from patients with recessive mutations in the tricarboxylic acid cycle (TCA) gene succinyl-CoA ligase subunit-beta (SUCLA2), causing global protein hyper-succinylation. Using mass spectrometry, we quantify nearly 1,000 protein succinylation sites on 366 proteins from patient-derived fibroblasts and myotubes. Interestingly, hyper-succinylated proteins are distributed across cellular compartments, and many are known targets of the (NAD(+))-dependent desuccinylase SIRT5. To test the contribution of hyper-succinylation to disease progression, we develop a zebrafish model of the SCL deficiency and find that SIRT5 gain-of-function reduces global protein succinylation and improves survival. Thus, increased succinyl-CoA levels contribute to the pathology of SCL deficiency through post-translational modifications. The pathomechanism of succinyl-CoA ligase (SCL) deficiency, a hereditary mitochondrial disease, is not fully understood. Here, the authors show that increased succinyl-CoA levels contribute to SCL pathology by causing global protein hyper-succinylation.Peer reviewe

Wednesday Convocation

Program listing performers and works performe

Mediator and cohesin connect gene expression and chromatin architecture

Transcription factors control cell-specific gene expression programs through interactions with diverse coactivators and the transcription apparatus. Gene activation may involve DNA loop formation between enhancer-bound transcription factors and the transcription apparatus at the core promoter, but this process is not well understood. Here we report that mediator and cohesin physically and functionally connect the enhancers and core promoters of active genes in murine embryonic stem cells. Mediator, a transcriptional coactivator, forms a complex with cohesin, which can form rings that connect two DNA segments. The cohesin-loading factor Nipbl is associated with mediator–cohesin complexes, providing a means to load cohesin at promoters. DNA looping is observed between the enhancers and promoters occupied by mediator and cohesin. Mediator and cohesin co-occupy different promoters in different cells, thus generating cell-type-specific DNA loops linked to the gene expression program of each cell.National Institutes of Health (U.S.) (Fellowship)Canadian Institutes of Health Research (Research Fellowship)National Institutes of Health (U.S.) (Grant R01 HG002668

The Impact of Multifunctional Genes on "Guilt by Association" Analysis

Many previous studies have shown that by using variants of “guilt-by-association”, gene function predictions can be made with very high statistical confidence. In these studies, it is assumed that the “associations” in the data (e.g., protein interaction partners) of a gene are necessary in establishing “guilt”. In this paper we show that multifunctionality, rather than association, is a primary driver of gene function prediction. We first show that knowledge of the degree of multifunctionality alone can produce astonishingly strong performance when used as a predictor of gene function. We then demonstrate how multifunctionality is encoded in gene interaction data (such as protein interactions and coexpression networks) and how this can feed forward into gene function prediction algorithms. We find that high-quality gene function predictions can be made using data that possesses no information on which gene interacts with which. By examining a wide range of networks from mouse, human and yeast, as well as multiple prediction methods and evaluation metrics, we provide evidence that this problem is pervasive and does not reflect the failings of any particular algorithm or data type. We propose computational controls that can be used to provide more meaningful control when estimating gene function prediction performance. We suggest that this source of bias due to multifunctionality is important to control for, with widespread implications for the interpretation of genomics studies