Publications

Genome-wide association studies have identified numerous common genetic variants associated with spirometric measures of pulmonary function, including forced expiratory volume in one second (FEV1), forced vital capacity, and their ratio. However, variants with lower minor allele frequencies are less explored. We conducted a large-scale gene-smoking interaction meta-analysis on exonic rare and low-frequency variants involving 44,429 individuals of European ancestry in the discovery stage and sought replication in the UK BiLEVE study with 45,133 European ancestry samples and UK Biobank study with 59,478 samples. We leveraged data on cigarette smoking, the major environmental risk factor for reduced lung function, by testing gene-by-smoking interaction effects only and simultaneously testing the genetic main effects and interaction effects. The most statistically significant signal that replicated was a previously reported low-frequency signal in GPR126, distinct from common variant associations in this gene. Although only nominal replication was obtained for a top rare variant signal rs142935352 in one of the two studies, interaction and joint tests for current smoking and PDE3B were significantly associated with FEV1. This study investigates the utility of assessing gene-by-smoking interactions and underscores their effects on potential pulmonary function.

Obesity is a serious international health problem that increases the risk of several common diseases. The genetic factors predisposing to obesity are poorly understood. A genome-wide search for type 2 diabetes–susceptibility genes identified a common variant in the FTO (fat mass and obesity associated) gene that predisposes to diabetes through an effect on body mass index (BMI). An additive association of the variant with BMI was replicated in 13 cohorts with 38,759 participants. The 16% of adults who are homozygous for the risk allele weighed about 3 kilograms more and had 1.67-fold increased odds of obesity when compared with those not inheriting a risk allele. This association was observed from age 7 years upward and reflects a specific increase in fat mass.

This paper describes the generation of gradients having complex shapes in solution using microfluidic networks. Flowing multiple streams of fluid each carrying different concentrations of substances laminarly and side-by-side generated step concentration gradients perpendicular to the direction of the flow. Appropriately designed networks of microchannels for controlled diffusive mixing of substances generated a range of shapes for the gradients, including linear, parabolic, and periodic. The lateral dimensions of the gradients ranged from 900 to 2200 μm. This paper also demonstrates the generation of overlapping gradients composed of different species. Since solutions in the microfluidic network exist as steady states and are continuously renewed, the gradients established in the capillaries are spatially and temporally constant and can be maintained easily for periods of hours. Using laminar flow to generate gradients should be useful in both biological and nonbiological research.

Elevated circulating levels of soluble adhesion molecules as markers of endothelial dysfunction have been related to insulin resistance and its associated metabolic abnormalities. However, their associations with type 2 diabetes remain inconclusive. We conducted a prospective nested case-control study to examine the associations between plasma levels of E-selectin, intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) and diabetes risk among 82,069 initially healthy women aged 50–79 years from the Women's Health Initiative Observational Study. During a median follow-up of 5.9 years, 1,584 incident diabetes case subjects were matched with 2,198 control subjects by age, ethnicity, clinical center, time of blood draw, and follow-up time. Baseline median levels of the biomarkers were each significantly higher among case subjects than among control subjects (E-selectin, 49 vs. 37 ng/ml; ICAM-1, 324 vs. 280 ng/ml; and VCAM-1, 765 vs. 696 ng/ml [all P values <0.001]). After adjustment for risk factors, the relative risks of diabetes among women in the highest quartile versus those in the lowest quartile were 3.46 for E-selectin (95% CI 2.56–4.68; P for trend <0.0001), 2.34 for ICAM-1 (1.75–3.13; P for trend <0.0001), and 1.48 for VCAM-1 (1.07–2.04; P for trend = 0.009). E-selectin and ICAM-1 remain significant in each ethnic group. In conclusion, higher levels of E-selectin and ICAM-1 were consistently associated with increased diabetes risk in a multiethnic cohort of U.S. postmenopausal women, implicating an etiological role of endothelial dysfunction in the pathogenesis of type 2 diabetes.

BACKGROUND The role of weight training in the primary prevention of type 2 diabetes mellitus (T2DM) is largely unknown. METHODS To examine the association of weight training with risk of T2DM in US men and to assess the influence of combining weight training and aerobic exercise, we performed a prospective cohort study of 32 002 men from the Health Professionals Follow-up Study observed from 1990 to 2008. Weekly time spent on weight training and aerobic exercise (including brisk walking, jogging, running, bicycling, swimming, tennis, squash, and calisthenics/rowing) was obtained from questionnaires at baseline and biennially during follow-up. RESULTS During 508 332 person-years of follow-up (18 years), we documented 2278 new cases of T2DM. In multivariable-adjusted models, we observed a dose-response relationship between an increasing amount of time spent on weight training or aerobic exercise and lower risk of T2DM (P < .001 for trend). Engaging in weight training or aerobic exercise for at least 150 minutes per week was independently associated with a lower risk of T2DM of 34% (95% CI, 7%-54%) and 52% (95% CI, 45%-58%), respectively. Men who engaged in aerobic exercise and weight training for at least 150 minutes per week had the greatest reduction in T2DM risk (59%; 95% CI, 39%-73%). CONCLUSIONS Weight training was associated with a significantly lower risk of T2DM, independent of aerobic exercise. Combined weight training and aerobic exercise conferred a greater benefit.

No abstract is provided for this article.

'Pulsed Focused Ultrasound' published in 'Encyclopedia of Nanotechnology'

This paper describes electrically‐activated fluidic valves that operate based on electrowetting through textiles. The valves are fabricated from electrically conductive, insulated, hydrophobic textiles, but the concept can be extended to other porous materials. When the valve is closed, the liquid cannot pass through the hydrophobic textile. Upon application of a potential (in the range of 100–1000 V) between the textile and the liquid, the valve opens and the liquid penetrates the textile. These valves actuate in less than 1 s, require low energy (≈27 µJ per actuation), and work with a variety of aqueous solutions, including those with low surface tension and those containing bioanalytes. They are bistable in function, and are, in a sense, the electrofluidic analog of thyristors. They can be integrated into paper microfluidic devices to make circuits that are capable of controlling liquid, including autonomous fluidic timers and fluidic logic.

This paper reports the development of Metal-amplified Density Assays, or MADAs - a method of conducting quantitative or multiplexed assays, including immunoassays, by using Magnetic Levitation (MagLev) to measure metal-amplified changes in the density of beads labeled with biomolecules. The binding of target analytes (i.e. proteins, antibodies, antigens) to complementary ligands immobilized on the surface of the beads, followed by a chemical amplification of the binding in a form that results in a change in the density of the beads (achieved by using gold nanoparticle-labeled biomolecules, and electroless deposition of gold or silver), translates analyte binding events into changes in density measureable using MagLev. A minimal model based on diffusion-limited growth of hemispherical nuclei on a surface reproduces the dynamics of the assay. A MADA - when performed with antigens and antibodies - is called a Density-Linked Immunosorbent Assay, or DeLISA. Two immunoassays provided a proof of principle: a competitive quantification of the concentration of neomycin in whole milk, and a multiplexed detection of antibodies against Hepatitis C virus NS3 protein and syphilis T. pallidum p47 protein in serum. MADAs, including DeLISAs, require, besides the requisite biomolecules and amplification reagents, minimal specialized equipment (two permanent magnets, a ruler or a capillary with calibrated length markings) and no electrical power to obtain a quantitative readout of analyte concentration. With further development, the method may be useful in resource-limited or point-of-care settings.