Publications

Liver dysfunction and type 2 diabetes (T2D) are consistently associated. However, it is currently unknown whether liver dysfunction contributes to, results from, or is merely correlated with T2D due to confounding. We used Mendelian randomization to investigate the presence and direction of any causal relation between liver function and T2D risk including up to 64,094 T2D case and 607,012 control subjects. Several biomarkers were used as proxies of liver function (i.e., alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase [ALP], and γ-glutamyl transferase [GGT]). Genetic variants strongly associated with each liver function marker were used to investigate the effect of liver function on T2D risk. In addition, genetic variants strongly associated with T2D risk and with fasting insulin were used to investigate the effect of predisposition to T2D and insulin resistance, respectively, on liver function. Genetically predicted higher circulating ALT and AST were related to increased risk of T2D. There was a modest negative association of genetically predicted ALP with T2D risk and no evidence of association between GGT and T2D risk. Genetic predisposition to higher fasting insulin, but not to T2D, was related to increased circulating ALT. Since circulating ALT and AST are markers of nonalcoholic fatty liver disease (NAFLD), these findings provide some support for insulin resistance resulting in NAFLD, which in turn increases T2D risk.

This article describes the fabrication of a microfluidic device for the liquid culture of many individual nematode worms (Caenorhabditis elegans) in separate chambers. Each chamber houses a single worm from the fourth larval stage until death, and enables examination of a population of individual worms for their entire adult lifespans. Adjacent to the chambers, the device includes microfluidic worm clamps, which enable periodic, temporary immobilization of each worm. The device made it possible to track changes in body size and locomotion in individual worms throughout their lifespans. This ability to perform longitudinal measurements within the device enabled the identification of age-related phenotypic changes that correlate with lifespan in C. elegans.

Background— The comparative importance of physical inactivity and obesity as predictors of coronary heart disease (CHD) risk remains unsettled. Methods and Results— We followed 88 393 women, 34 to 59 years of age, in the Nurses’ Health Study from 1980 to 2000. These participants did not have cardiovascular disease and cancer at baseline. We documented 2358 incident major CHD events (including nonfatal myocardial infarction and fatal CHD) during 20 years of follow-up, including 889 cases of fatal CHD and 1469 cases of nonfatal myocardial infarction. In a multivariate model adjusting for cardiovascular risk factors, overweight and obesity were significantly associated with increased risk of CHD, whereas increasing levels of physical activity were associated with a graded reduction in CHD risk ( P <0.001). In joint analyses of body mass index (BMI) and physical activity in women who had a healthy weight (BMI, 18.5 to 24.9 kg/m 2 ) and were physically active (exercise ≥3.5 h/wk) as the reference group, the relative risks of CHD were 3.44 (95% confidence interval [CI], 2.81 to 4.21) for women who were obese (BMI ≥30 kg/m 2 ) and sedentary (exercise <1 h/wk), 2.48 (95% CI, 1.84 to 3.34) for women who were active but obese, and 1.48 (95% CI, 1.24 to 1.77) for women who had a healthy weight but were sedentary. In combined analyses of waist-hip ratio and physical activity, both waist-hip ratio and physical activity were significant predictors of CHD, and the highest risk was among women in the lowest category of physical activity and the highest tertile of waist-hip ratio (relative risk=3.03; 95% CI, 1.96 to 4.18). Even a modest weight gain (4 to 10 kg) during adulthood was associated with 27% (95% CI, 12% to 45%) increased risk of CHD compared with women with a stable weight after adjusting for physical activity and other cardiovascular risk factors. Conclusions— Obesity and physical inactivity independently contribute to the development of CHD in women. These data underscore the importance of both maintaining a healthy weight and regular physical activity in preventing CHD.

The development of three-dimensional (3D) synthetic biomaterials as structural and bioactive scaffolds is central to fields ranging from cellular biophysics to regenerative medicine. As of yet, these scaffolds cannot electrically probe the physicochemical and biological microenvironments throughout their 3D and macroporous interior, although this capability could have a marked impact in both electronics and biomaterials. Here, we address this challenge using macroporous, flexible and free-standing nanowire nanoelectronic scaffolds (nanoES), and their hybrids with synthetic or natural biomaterials. 3D macroporous nanoES mimic the structure of natural tissue scaffolds, and they were formed by self-organization of coplanar reticular networks with built-in strain and by manipulation of 2D mesh matrices. NanoES exhibited robust electronic properties and have been used alone or combined with other biomaterials as biocompatible extracellular scaffolds for 3D culture of neurons, cardiomyocytes and smooth muscle cells. Furthermore, we show the integrated sensory capability of the nanoES by real-time monitoring of the local electrical activity within 3D nanoES/cardiomyocyte constructs, the response of 3D-nanoES-based neural and cardiac tissue models to drugs, and distinct pH changes inside and outside tubular vascular smooth muscle constructs.

The doses of neutral metastable argon atoms (Ar*) and highly charged xenon ions (HCIs) required to damage self-assembled monolayers (SAMs) of alkanethiolates on gold are compared in a set of experiments carried out concurrently. The extent of damage to the SAM is determined by developing the samples in a gold etching solution, then measuring the decrease in reflectivity of the gold; ≈105 Ar* are required to cause the same amount of damage as 1 HCI, as measured by this assay. We have also demonstrated HCI micropatterning of a surface using a physical mask, suggesting the application of this system in lithography.

No abstract is provided for this article.

Abstract Despite the extensive literature on methods for assessing interactions between genetic and environmental factors, approaches for the joint analysis of multiple G-E interactions are surprisingly lacking. Kim et al. compare the power and robustness.... With growing human genetic and epidemiologic data, there has been increased interest for the study of gene-by-environment (G-E) interaction effects. Still, major questions remain on how to test jointly a large number of interactions between multiple SNPs and multiple exposures. In this study, we first compared the relative performance of four fixed-effect joint analysis approaches using simulated data, considering up to 10 exposures and 300 SNPs: (1) omnibus test, (2) multi-exposure and genetic risk score (GRS) test, (3) multi-SNP and environmental risk score (ERS) test, and (4) GRS-ERS test. Our simulations explored both linear and logistic regression while considering three statistics: the Wald test, the Score test, and the likelihood ratio test (LRT). We further applied the approaches to three large sets of human cohort data (n = 37,664), focusing on type 2 diabetes (T2D), obesity, hypertension, and coronary heart disease with smoking, physical activity, diets, and total energy intake. Overall, GRS-based approaches were the most robust, and had the highest power, especially when the G-E interaction effects were correlated with the marginal genetic and environmental effects. We also observed severe miscalibration of joint statistics in logistic models when the number of events per variable was too low when using either the Wald test or LRT test. Finally, our real data application detected nominally significant interaction effects for three outcomes (T2D, obesity, and hypertension), mainly from the GRS-ERS approach. In conclusion, this study provides guidelines for testing multiple interaction parameters in modern human cohorts including extensive genetic and environmental data.

Higher iron stores (reflected by an elevated ferritin concentration and a lower ratio of transferrin receptors to ferritin) are associated with an increased risk of type 2 diabetes in healthy women independent of known diabetes risk factors.

Commercial hydrogenation results in the formation of trans fatty acids. An unintended consequence of the hydrogenation process is conversion of phylloquinone (vitamin K 1 ) to dihydrophylloquinone. Plasma dihydrophylloquinone concentrations have yet to be characterized in population-based studies. Dietary determinants of plasma dihydrophylloquinone were estimated using a semi-quantitative food frequency questionnaire in 803 men and 913 women in the Framingham Offspring Study. Geometric mean dihydrophylloquinone intake was 21·3 (95 % CI 20·4, 22·3) μg/d in men and 19·4 (95 % CI 18·5, 20·2) μg/d in women. Detectable (>0·05 nmol/l) plasma dihydrophylloquinone concentrations were measured in 41 % and 30 % of men and women, respectively. The multivariate odds ratio (OR) of detectable plasma dihydrophylloquinone from the lowest to the highest quartile category of dihydrophylloquinone intake were 1 (referent), 1·13 (95 % CI 0·83, 1·53), 1·66 (95 % CI 1·21, 2·26) and 1·84 (95 % CI 1·31, 2·58), P for trend <0·001, adjusted for sex, age, body mass index, triacylglycerols, season and energy intake. Higher trans fatty acid intake was associated with higher multivariate OR for detectable plasma dihydrophylloquinone (OR comparing extreme quartiles 2·41 (95 % CI 1·59, 3·64), P for trend <0·001). There were limitations in the use of plasma dihydrophylloquinone, evident in the high proportion of the population that had non-detectable dihydrophylloquinone concentrations. Despite this caveat, higher plasma dihydrophylloquinone was associated with higher dihydrophylloquinone intake and higher trans fatty acid intake.

The use of low-dose aspirin was beneficial for primary prevention of CVD and the decision regarding an aspirin regimen should be made on an individual patient basis. The effects of aspirin therapy varied by sex and diabetes status. A clear benefit of aspirin in the primary prevention of CVD in people with diabetes needs more trials.

<title>Abstract</title> <bold>Background: </bold>Whether weight change around type 2 diabetes (T2D) diagnosis is associated with long-term survival is unclear. We aimed to examine the association between weight change and mortality among participants with incident T2D and evaluate impacts of lifestyle on this association. <bold>Methods: </bold>This prospective analysis included 11,262 incident T2D patients from the Nurses’ Health Study and Health Professionals Follow-up Study. We assessed weight change bracketing T2D diagnosis in relation to mortality. We also examined potential effect modification by a healthy lifestyle consisting of high-quality diet, regular physical activity, non-smoking status and moderate alcohol consumption.<bold>Results:</bold> On average, T2D patients lost 2.3 kg during a two-year time-window spanning the T2D diagnosis, and body weight increased afterwards. Compared with patients with a stable weight, T2D patients who lost ≥10% body weight had a 26% (95% CI: 4%, 52%) increased mortality due to cardiovascular disease (CVD). Lifestyle significantly modified these associations: the hazard ratios (95% CIs) of CVD mortality comparing ≥10% weight loss with stable weight were 1.41 (0.87, 2.30) among participants with a deteriorated lifestyle, 1.46 (1.15, 1.86) for a stable lifestyle, and 0.82 (0.53, 1.27) for an improved lifestyle (<italic>P</italic>_interaction &lt;0.001). Major weight loss was also associated with an increased all-cause mortality, and similar effect modifications by lifestyle were observed.<bold>Conclusions</bold>: Significant weight loss upon T2D incidence was associated with an increased CVD mortality, although improved lifestyle quality abolished these associations. These results highlight the role of adopting a healthy lifestyle for newly diagnosed T2D patients in improving long-term survival.