Associations of General and Central Adiposity With Incident Diabetes in Chinese Men and Women.

Objective: We assess associations of general and central adiposity in middle age and of young adulthood adiposity with incident diabetes in adult Chinese and estimate the associated population burden of diabetes.

Research Design And Methods: The prospective China Kadoorie Biobank enrolled 512,891 adults 30-79 years of age from 10 localities across China during 2004-2008. During 9.

Elp3 and RlmN: A tale of two mitochondrial tail-anchored radical SAM enzymes in Toxoplasma gondii.

Radical S-adenosylmethionine (rSAM) enzymes use a 5'-deoxyadensyl 5'-radical to methylate a wide array of diverse substrates including proteins, lipids and nucleic acids. One such enzyme, Elongator protein-3 (TgElp3), is an essential protein in Toxoplasma gondii, a protozoan parasite that can cause life-threatening opportunistic disease. Unlike Elp3 homologues which are present in all domains of life, TgElp3 localizes to the outer mitochondrial membrane (OMM) via a tail-anchored trafficking mechanism in Toxoplasma.

Revisiting Image of the City in Cyberspace: Analysis of Spatial Twitter Messages During a Special Event.

This research investigated people's communication of urban space as reflected in Twitter messages (tweets) during the 2012 Super Bowl. The authors archived over 600,000 tweets related to the Super Bowl from January 23 through early February 6. The authors identified 78 Indianapolis-area places or routes named in the tweets.

Smoking, alcohol, and diet in relation to risk of pancreatic cancer in China: a prospective study of 0.5 million people.

In China, the incidence of pancreatic cancer (PC) has increased in recent decades. However, little is known about the relevance to PC risk of lifestyle and behavioral factors such as smoking, alcohol drinking, and diet. The China Kadoorie Biobank prospective study recruited 512,891 adults (210,222 men, 302,669 women) aged 30-79 (mean 52) years from 10 diverse areas during 2004-08.

Seasonal Changes in Functional Fitness and Neurocognitive Assessments in Youth Ice-Hockey Players.

Avery, M, Wattie, N, Holmes, M, and Dogra, S. Seasonal changes in functional fitness and neurocognitive assessments in youth ice-hockey players. J Strength Cond Res 32(11): 3143-3152, 2018-Deficits in balance and strength combined with differing rates of sensory and motor neural development may increase risk of sports-related injury in youth.

Genetic Association of Lipids and Lipid Drug Targets With Abdominal Aortic Aneurysm: A Meta-analysis.

Importance: Risk factors for abdominal aortic aneurysm (AAA) are largely unknown, which has hampered the development of nonsurgical treatments to alter the natural history of disease.

Objective: To investigate the association between lipid-associated single-nucleotide polymorphisms (SNPs) and AAA risk.

Design, Setting, And Participants: Genetic risk scores, composed of lipid trait-associated SNPs, were constructed and tested for their association with AAA using conventional (inverse-variance weighted) mendelian randomization (MR) and data from international AAA genome-wide association studies.

Association of CETP Gene Variants With Risk for Vascular and Nonvascular Diseases Among Chinese Adults.

Importance: Increasing levels of high-density lipoprotein (HDL) cholesterol through pharmacologic inhibition of cholesteryl ester transfer protein (CETP) is a potentially important strategy for prevention and treatment of cardiovascular disease (CVD).

Objective: To use genetic variants in the CETP gene to assess potential risks and benefits of lifelong lower CETP activity on CVD and other outcomes.

Design, Setting, And Participants: This prospective biobank study included 151 217 individuals aged 30 to 79 years who were enrolled from 5 urban and 5 rural areas of China from June 25, 2004, through July 15, 2008.

Correcting the Standard Errors of 2-Stage Residual Inclusion Estimators for Mendelian Randomization Studies.

Mendelian randomization studies use genotypes as instrumental variables to test for and estimate the causal effects of modifiable risk factors on outcomes. Two-stage residual inclusion (TSRI) estimators have been used when researchers are willing to make parametric assumptions. However, researchers are currently reporting uncorrected or heteroscedasticity-robust standard errors for these estimates.

Effect of Androgen Deprivation Therapy on Bone Mineral Density in a Prostate Cancer Cohort in New Zealand: A Pilot Study.

Introduction: Reduction in bone mineral density (BMD) is a common side effect of androgen deprivation therapy (ADT). We aimed to examine the cross-sectional and longitudinal variation in BMD and associated bone markers in patients with nonmetastatic prostate cancer (PCa) managed with and without ADT.

Methods: Bone mineral density of the total body, lumbar spine, femoral neck, ultradistal forearm, and one-third distal radius was measured in 88 patients with PCa without bone metastases at baseline and at 6 months.

Genetic Support for a Causal Role of Insulin Resistance on Circulating Branched-Chain Amino Acids and Inflammation.

Objective: Insulin resistance has deleterious effects on cardiometabolic disease. We used Mendelian randomization analyses to clarify the causal relationships of insulin resistance (IR) on circulating blood-based metabolites to shed light on potential mediators of the IR to cardiometabolic disease relationship.

Research Design And Methods: We used 53 single nucleotide polymorphisms associated with IR from a recent genome-wide association study (GWAS) to explore their effects on circulating lipids and metabolites.

Supraphysiologic control over HIV-1 replication mediated by CD8 T cells expressing a re-engineered CD4-based chimeric antigen receptor.

HIV is adept at avoiding naturally generated T cell responses; therefore, there is a need to develop HIV-specific T cells with greater potency for use in HIV cure strategies. Starting with a CD4-based chimeric antigen receptor (CAR) that was previously used without toxicity in clinical trials, we optimized the vector backbone, promoter, HIV targeting moiety, and transmembrane and signaling domains to determine which components augmented the ability of T cells to control HIV replication. This re-engineered CAR was at least 50-fold more potent in vitro at controlling HIV replication than the original CD4 CAR, or a TCR-based approach, and substantially better than broadly neutralizing antibody-based CARs.

Preclinical modeling highlights the therapeutic potential of hematopoietic stem cell gene editing for correction of SCID-X1.

Targeted genome editing in hematopoietic stem/progenitor cells (HSPCs) is an attractive strategy for treating immunohematological diseases. However, the limited efficiency of homology-directed editing in primitive HSPCs constrains the yield of corrected cells and might affect the feasibility and safety of clinical translation. These concerns need to be addressed in stringent preclinical models and overcome by developing more efficient editing methods.

Bone mineral density and risk of type 2 diabetes and coronary heart disease: A Mendelian randomization study.

Observational studies have demonstrated that increased bone mineral density is associated with a higher risk of type 2 diabetes (T2D), but the relationship with risk of coronary heart disease (CHD) is less clear. Moreover, substantial uncertainty remains about the causal relevance of increased bone mineral density for T2D and CHD, which can be assessed by Mendelian randomisation studies.  We identified 235 independent single nucleotide polymorphisms (SNPs) associated at <5×10 with estimated heel bone mineral density (eBMD) in 116,501 individuals from the UK Biobank study, accounting for 13.

Impact of Selection Bias on Estimation of Subsequent Event Risk.

Background: Studies of recurrent or subsequent disease events may be susceptible to bias caused by selection of subjects who both experience and survive the primary indexing event. Currently, the magnitude of any selection bias, particularly for subsequent time-to-event analysis in genetic association studies, is unknown.

Methods And Results: We used empirically inspired simulation studies to explore the impact of selection bias on the marginal hazard ratio for risk of subsequent events among those with established coronary heart disease.

Dyslipidaemia: Revealing the effect of CETP inhibition in cardiovascular disease.

Initial randomized trials of cholesteryl ester transfer protein (CETP) inhibitors were terminated early owing to adverse effects or futility. The REVEAL trial now shows the benefit of CETP inhibition in coronary heart disease. Despite raising HDL-cholesterol levels, the cardiovascular effect of CETP inhibitors is probably due to lowering of non-HDL-cholesterol levels.

Cost-effectiveness of antibiotic treatment of uncomplicated urinary tract infection in women: a comparison of four antibiotics.

Background: Urinary tract infections (UTIs) are one of the most common reasons for women to attend primary care. There are four different antibiotics currently recommended in England for treatment of uncomplicated UTI but little evidence on their comparative cost-effectiveness.

Aim: To assess the relative cost-effectiveness of the four antibiotics currently recommended in England for treatment of uncomplicated UTI in adult women.

Translational Control in the Latency of Apicomplexan Parasites.

Apicomplexan parasites Toxoplasma gondii and Plasmodium spp. use latent stages to persist in the host, facilitate transmission, and thwart treatment of infected patients. Therefore, it is important to understand the processes driving parasite differentiation to and from quiescent stages.

Genetic and epigenetic studies of adiposity and cardiometabolic disease.

Over 300 million adults are obese, but little is known about the impact of obesity on cardiovascular health. We discuss recent genetic and epigenetic studies of adiposity that indicate a causal role for general and central adiposity in cardiometabolic disease, and highlight potential mechanisms including insulin resistance and gene expression.

Comparison of Zinc Finger Nucleases Versus CRISPR-Specific Nucleases for Genome Editing of the Wiskott-Aldrich Syndrome Locus.

Primary immunodeficiencies, including Wiskott-Aldrich syndrome (WAS), are a main target for genome-editing strategies using specific nucleases (SNs) because a small number of corrected hematopoietic stem cells could cure patients. In this work, we have designed various WAS gene-specific CRISPR/Cas9 systems and compared their efficiency and specificity with homodimeric and heterodimeric WAS-specific zinc finger nucleases (ZFNs), using K-562 cells as a cellular model and plasmid nucleofection or integration-deficient lentiviral vectors (IDLVs) for delivery. The various CRISPR/Cas9 and ZFN SNs showed similar efficiency when using plasmid nucleofection for delivery.

Acyclic Quaternary Carbon Stereocenters via Enantioselective Transition Metal Catalysis.

Whereas numerous asymmetric methods for formation of quaternary carbon stereocenters in cyclic systems have been documented, the construction of acyclic quaternary carbon stereocenters with control of absolute stereochemistry remains a formidable challenge. This Review summarizes enantioselective methods for the construction of acyclic quaternary carbon stereocenters from achiral or chiral racemic reactants via transition metal catalysis.

EFFECTS OF A BAND LOOP ON LOWER EXTREMITY MUSCLE ACTIVITY AND KINEMATICS DURING THE BARBELL SQUAT.

Background: Medial knee collapse can signal an underlying movement issue that, if uncorrected, can lead to a variety of knee injuries. Placing a band around the distal thigh may act as a proprioceptive aid to minimize medial collapse of the knee during squats; however, little is known about EMG and biomechanics in trained and untrained individuals during the squat with an elastic band added.

Hypothesis/purpose: To investigate the effects of the TheraBand® Band Loop on kinematics and muscle activity of the lower extremity during a standard barbell back squat at different intensities in both trained and untrained individuals.

Young adulthood and adulthood adiposity in relation to incidence of pancreatic cancer: a prospective study of 0.5 million Chinese adults and a meta-analysis.

Background: Adult adiposity is positively associated with pancreatic cancer in Western populations. Little is known, however, about the association in China where many have lower body mass index (BMI) or about the relevance of young adulthood adiposity for pancreatic cancer in both Western and East Asian populations.

Methods: The China Kadoorie Biobank (CKB) recruited 512 891 adults aged 30-79 years during 2004-2008, recording 595 incident cases of pancreatic cancer during 8-year follow-up.

Therapeutic gene editing in CD34 hematopoietic progenitors from Fanconi anemia patients.

Gene targeting constitutes a new step in the development of gene therapy for inherited diseases. Although previous studies have shown the feasibility of editing fibroblasts from Fanconi anemia (FA) patients, here we aimed at conducting therapeutic gene editing in clinically relevant cells, such as hematopoietic stem cells (HSCs). In our first experiments, we showed that zinc finger nuclease (ZFN)-mediated insertion of a non-therapeutic EGFP-reporter donor in the "safe harbor" locus of FA-A lymphoblastic cell lines (LCLs), indicating that FANCA is not essential for the editing of human cells.

Education and coronary heart disease: mendelian randomisation study.

 To determine whether educational attainment is a causal risk factor in the development of coronary heart disease. Mendelian randomisation study, using genetic data as proxies for education to minimise confounding. The main analysis used genetic data from two large consortia (CARDIoGRAMplusC4D and SSGAC), comprising 112 studies from predominantly high income countries.

Genome editing for scalable production of alloantigen-free lentiviral vectors for gene therapy.

Lentiviral vectors (LV) are powerful and versatile vehicles for gene therapy. However, their complex biological composition challenges large-scale manufacturing and raises concerns for applications, because particle components and contaminants may trigger immune responses. Here, we show that producer cell-derived polymorphic class-I major histocompatibility complexes (MHC-I) are incorporated into the LV surface and trigger allogeneic T-cell responses.