CONTINUUM DISLOCATION DYNAMICS MODELING OF THE DEFORMATION OF FCC SINGLE CRYSTALS

A continuum dislocation dynamics model was developed for simulation of the deformation of Face Centred Cubic (FCC) single crystals. In this model, dislocations are described by a set of vector fields, one per slip system, whose evolution is governed by curl-type kinetic equations describing the transport of dislocation lines. These kinetic equations are closed by specifying the velocity field in terms of a mobility law in which the driving force is obtained by solving the Cauchy¡¯s equilibrium equation for stress. The coupled kinetic equations and crystal mechanics equations are numerically solved in a staggered fashion using a custom finite element approach featuring the use of Galerkin and Least Squares finite element methods for the mechanics and dislocation kinetics parts, respectively, on a mesh generated on an FCC superlattice. The spatial resolution of the mesh was determined based on the annihilation distance between opposite dislocations. Cross slip rates from discrete dislocation simulation have been incorporated into the continuum model by time coarse graining involving time series analysis. The overall model provides a full solution of the crystal deformation problem, including the space and time evolution of the dislocation density and all internal elastic and plastic fields. Under periodic boundary conditions, the model has been applied to predict the stress-strain behaviour of FCC crystal as well as the dislocation patterns for both monotonic and cyclic loading conditions. For monotonic loading, the cell structure is predicted and the wavelength is detected and shown to satisfy the empirical similitude law. The dislocation patterns are found to depend on the loading mode, monotonic versus cyclic, as well as the crystal orientation. For cyclic loading, the famous vein structure was also predicted by the model and the composition of dislocation veins are analysed. All results are compared with experiments and other discrete dislocation dynamics simulations, yielding a good agreement. An important finding of this investigation is that cross slip was found to be critical in triggering cell structure formation under monotonic loading and that the average cell size evolution was found to strongly depend on the cross slip rate

Computational modeling of dislocation evolution and strain hardening in deformed metals

We develop a continuum model of dislocation dynamics that predicts the main features of the crystal plasticity at the mesoscale. The model is based on a set of kinetic equations of the curl type that govern the space and time evolution of the dislocation density in all slip systems. These equations can take cross-slip and short range reactions into account. The kinetic equations are coupled with crystal mechanics, stress equilibrium, through a staggered finite element scheme customized to capture the crystallographic nature. The results for the evolution of dislocation density, dislocation patterns, lattice rotation field, and stress–strain relationships are going to be presented. These features are compared with X-ray measurements and that obtained by discrete dislocation dynamics. This study was supported by the U.S. DOE Office of Basic Energy Sciences, Division of Materials Science & Engineering via contract # DEFG02-08ER46494 at Florida State University and by funding from the School of Nuclear Engineering at Purdue University

Mendelian Randomisation Study of Childhood BMI and Early Menarche

To infer the causal association between childhood BMI and age at menarche, we performed a mendelian randomisation analysis using twelve established “BMI-increasing” genetic variants as an instrumental variable (IV) for higher BMI. In 8,156 women of European descent from the EPIC-Norfolk cohort, height was measured at age 39–77 years; age at menarche was self-recalled, as was body weight at age 20 years, and BMI at 20 was calculated as a proxy for childhood BMI. DNA was genotyped for twelve BMI-associated common variants (in/near FTO, MC4R, TMEM18, GNPDA2, KCTD15, NEGR1, BDNF, ETV5, MTCH2, SEC16B, FAIM2 and SH2B1), and for each individual a “BMI-increasing-allele-score” was calculated by summing the number of BMI-increasing alleles across all 12 loci. Using this BMI-increasing-allele-score as an instrumental variable for BMI, each 1 kg/m2 increase in childhood BMI was predicted to result in a 6.5% (95% CI: 4.6–8.5%) higher absolute risk of early menarche (before age 12 years). While mendelian randomisation analysis is dependent on a number of assumptions, our findings support a causal effect of BMI on early menarche and suggests that increasing prevalence of childhood obesity will lead to similar trends in the prevalence of early menarche

Association of DNA Methylation at \u3cem\u3eCPT1A\u3c/em\u3e Locus with Metabolic Syndrome in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) Study

In this study, we conducted an epigenome-wide association study of metabolic syndrome (MetS) among 846 participants of European descent in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN). DNA was isolated from CD4+ T cells and methylation at ~470,000 cytosine-phosphate-guanine dinucleotide (CpG) pairs was assayed using the Illumina Infinium HumanMethylation450 BeadChip. We modeled the percentage methylation at individual CpGs as a function of MetS using linear mixed models. A Bonferroni-corrected P-value of 1.1 x 10−7 was considered significant. Methylation at two CpG sites in CPT1A on chromosome 11 was significantly associated with MetS (P for cg00574958 = 2.6x10-14 and P for cg17058475 = 1.2x10-9). Significant associations were replicated in both European and African ancestry participants of the Bogalusa Heart Study. Our findings suggest that methylation in CPT1A is a promising epigenetic marker for MetS risk which could become useful as a treatment target in the future

Genetic variants in nicotinic acetylcholine receptor genes jointly contribute to kidney function in American Indians: the Strong Heart Family Study

Cigarette smoking negatively affects kidney function. Genetic variants in the nicotinic acetylcholine receptors genes (nAChRs) have been associated with nicotine dependence, and are likely to influence renal function and related traits. While each single variant may only exert a small effect, the joint contribution of multiple variants to the risk of disease could be substantial

Mendelian Randomisation Study of Childhood BMI and Early Menarche.

To infer the causal association between childhood BMI and age at menarche, we performed a mendelian randomisation analysis using twelve established "BMI-increasing" genetic variants as an instrumental variable (IV) for higher BMI. In 8,156 women of European descent from the EPIC-Norfolk cohort, height was measured at age 39-77 years; age at menarche was self-recalled, as was body weight at age 20 years, and BMI at 20 was calculated as a proxy for childhood BMI. DNA was genotyped for twelve BMI-associated common variants (in/near FTO, MC4R, TMEM18, GNPDA2, KCTD15, NEGR1, BDNF, ETV5, MTCH2, SEC16B, FAIM2 and SH2B1), and for each individual a "BMI-increasing-allele-score" was calculated by summing the number of BMI-increasing alleles across all 12 loci. Using this BMI-increasing-allele-score as an instrumental variable for BMI, each 1 kg/m(2) increase in childhood BMI was predicted to result in a 6.5% (95% CI: 4.6-8.5%) higher absolute risk of early menarche (before age 12 years). While mendelian randomisation analysis is dependent on a number of assumptions, our findings support a causal effect of BMI on early menarche and suggests that increasing prevalence of childhood obesity will lead to similar trends in the prevalence of early menarche.Peer Reviewe

DNA methylation-based estimator of telomere length

Telomere length (TL) is associated with several aging-related diseases. Here, we present a DNA methylation estimator of TL (DNAmTL) based on 140 CpGs. Leukocyte DNAmTL is applicable across the entire age spectrum and is more strongly associated with age than measured leukocyte TL (LTL) (r ~-0.75 for DNAmTL versus r ~ -0.35 for LTL). Leukocyte DNAmTL outperforms LTL in predicting: i) time-to-death (p=2.5E-20), ii) time-to-coronary heart disease (p=6.6E-5), iii) time-to-congestive heart failure (p=3.5E-6), and iv) association with smoking history (p=1.21E-17). These associations are further validated in large scale methylation data (n=10k samples) from the Framingham Heart Study, Women's Health Initiative, Jackson Heart Study, InChianti, Lothian Birth Cohorts, Twins UK, and Bogalusa Heart Study. Leukocyte DNAmTL is also associated with measures of physical fitness/functioning (p=0.029), age-at-menopause (p=0.039), dietary variables (omega 3, fish, vegetable intake), educational attainment (p=3.3E-8) and income (p=3.1E-5). Experiments in cultured somatic cells show that DNAmTL dynamics reflect in part cell replication rather than TL per se. DNAmTL is not only an epigenetic biomarker of replicative history of cells, but a useful marker of age-related pathologies that are associated with it

Atherosclerosis in young Brazilians suffering violent deaths: a pathological study

<p>Abstract</p> <p>Background</p> <p>Atherosclerosis is the leading cause of coronary heart disease and ischemic stroke, which can cause sudden death in adulthood. In general, the clinical manifestations of cardiovascular diseases are caused by atherosclerosis, which is a process that starts during middle age. More recent studies indicate that the atherosclerotic process begins during childhood.</p> <p>Methods</p> <p>To evaluate the extent of atherosclerotic disease in young Brazilians, we conducted a study of the pathological alterations in the major arteries of victims of violent death. Samples of the right carotid artery, left coronary artery, and thoracic aorta of young victims of violent death were analyzed and graded in accordance with the histological atherosclerotic lesion types proposed by the American Heart Association. Samples were collected from 100 individuals who had died from external causes, aged from 12 to 33 years.</p> <p>Results</p> <p>The majority of cases (83%) were male, and 66% of deaths were homicides caused by firearms. The median age was 20.0 years and mean body mass index was 20.9 kg/m². Of the right carotid artery specimens, 3% were normal, 55% had type I, 40% had type II, 1% had type III, and 1% had type IV atherosclerotic lesions. Of the left coronary artery specimens, 5% were normal, 48% had type I, 41% had type II, 3% had type III, and 3% had type IV lesions. Of the thoracic aorta specimens, none were normal, 13% had type I, 64% had type II, 22% had type III, and 1% had type IV lesions. Overall, 97.34% of arteries examined had some degree of atherosclerosis. The most common histological type was type II (foam cells). No thoracic aorta specimens were normal, and the coronary artery specimens had the most atherosclerosis.</p> <p>Conclusions</p> <p>Our results show a high prevalence of atherosclerotic lesions among young people in Brazil. Intervention should be undertaken to decrease the rate of sudden cardiac death in the adult population.</p

Outbreak of COVID-19 and SARS in mainland China: a comparative study based on national surveillance data

Objective To compare the epidemiological characteristics and transmission dynamics in relation to interventions against the COVID-19 and severe acute respiratory syndrome (SARS) outbreak in mainland China. Design Comparative study based on a unique data set of COVID-19 and SARS. Setting Outbreak in mainland China. Participants The final database included 82 858 confirmed cases of COVID-19 and 5327 cases of SARS. Methods We brought together all existing data sources and integrated them into a comprehensive data set. Individual information on age, sex, occupation, residence location, date of illness onset, date of diagnosis and clinical outcome was extracted. Control measures deployed in mainland China were collected. We compared the epidemiological and spatial characteristics of COVID-19 and SARS. We estimated the effective reproduction number to explore differences in transmission dynamics and intervention effects. Results Compared with SARS, COVID-19 affected more extensive areas (1668 vs 230 counties) within a shorter time (101 vs 193 days) and had higher attack rate (61.8 vs 4.0 per million persons). The COVID-19 outbreak had only one epidemic peak and one epicentre (Hubei Province), while the SARS outbreak resulted in two peaks and two epicentres (Guangdong Province and Beijing). SARSCoV-2 was more likely to infect older people (median age of 52 years), while SARS-CoV tended to infect young adults (median age of 34 years). The case fatality rate (CFR) of either disease increased with age, but the CFR of COVID-19 was significantly lower than that of SARS (5.6% vs 6.4%). The trajectory of effective reproduction number dynamically changed in relation to interventions, which fell below 1 within 2 months for COVID-19 and within 5.5 months for SARS. Conclusions China has taken more prompt and effective responses to combat COVID-19 by learning lessons from SARS, providing us with some epidemiological clues to control the ongoing COVID-19 pandemic worldwid