Publications

Abstract Context High density lipoprotein (HDL) in humans is composed of a heterogeneous group of particles varying in protein composition as well as biological effects. Objective We investigated the prospective associations between HDL subspecies containing and lacking apolipoprotein (apo) C-III at baseline and insulin sensitivity at year 3. Design, Setting, and Participants A prospective cohort study of 864 healthy volunteers drawn from the relationship between insulin sensitivity and cardiovascular disease (RISC) study, a multicenter European clinical investigation, whose recruitment initiated in 2002, with a follow-up of 3 years. Main Measures Insulin sensitivity was estimated from an oral glucose tolerance test at baseline and year 3, and by euglycemic-hyperinsulinemic clamp at baseline only. The apolipoprotein concentrations were measured at baseline by a sandwich enzyme-linked immunosorbent assay (ELISA)-based method. Results The 2 HDL subspecies demonstrated significantly opposite associations with insulin sensitivity at year 3 (P-heterogeneity = 0.004). The highest quintile of HDL containing apoC-III was associated with a 1.2% reduction in insulin sensitivity (P-trend = 0.02), while the highest quintile of HDL lacking apoC-III was associated with a 1.3% increase (P-trend = 0.01), compared to the lowest quintile. No significant association was observed for total HDL, and very low density lipoprotein (VLDL) and low density lipoprotein (LDL) containing apoC-III. ApoC-III contained in HDL was associated with a decrease in insulin sensitivity even more strongly than plasma total apoC-III. Conclusion Both HDL containing apoC-III and apoC-III in HDL adversely affect the beneficial properties of HDL on insulin response to glucose. Our results support the potential of HDL-associated apoC-III as a promising target for diabetes prevention and treatment.

This paper describes three-dimensional microfluidic paper-based analytical devices (3-D microPADs) that can be programmed (postfabrication) by the user to generate multiple patterns of flow through them. These devices are programmed by pressing single-use 'on' buttons, using a stylus or a ballpoint pen. Pressing a button closes a small space (gap) between two vertically aligned microfluidic channels, and allows fluids to wick from one channel to the other. These devices are simple to fabricate, and are made entirely out of paper and double-sided adhesive tape. Programmable devices expand the capabilities of microPADs and provide a simple method for controlling the movement of fluids in paper-based channels. They are the conceptual equivalent of field-programmable gate arrays (FPGAs) widely used in electronics.

We show that time-oscillating electric fields applied to plasmas present in flames create steady flows of gas. Ions generated within the flame move in the field and migrate a distance $\ensuremath{\delta}$ before recombining; the net flow of ions away from the flame creates a time-averaged force that drives the steady flows observed experimentally. A quantitative model describes the response of the flame and reveals how $\ensuremath{\delta}$ decreases as the frequency of the applied field increases. Interestingly, above a critical frequency, ac fields can be used to manipulate flames at a distance without the need for proximal electrodes.

Abstract For Abstract see ChemInform Abstract in Full Text.

This paper describes a prototype of an integrated fluorescence detection system that uses a microavalanche photodiode (microAPD) as the photodetector for microfluidic devices fabricated in poly(dimethylsiloxane) (PDMS). The prototype device consisted of a reusable detection system and a disposable microfluidic system that was fabricated using rapid prototyping. The first step of the procedure was the fabrication of microfluidic channels in PDMS and the encapsulation of a multimode optical fiber (100-microm core diameter) in the PDMS; the tip of the fiber was placed next to the side wall of one of the channels. The optical fiber was used to couple light into the microchannel for the excitation of fluorescent analytes. The photodetector, a prototype solid-state microAPD array, was embedded in a thick slab (1 cm) of PDMS. A thin (80 microm) colored polycarbonate filter was placed on the top of the embedded microAPD to absorb scattered excitation light before it reached the detector. The microAPD was placed below the microchannel and orthogonal to the axis of the optical fiber. The close proximity (approximately 200 microm) of the microAPD to the microchannel made it unnecessary to incorporate transfer optics; the pixel size of the microAPD (30 microm) matched the dimensions of the channels (50 microm). A blue light-emitting diode was used for fluorescence excitation. The microAPD was operated in Geiger mode to detect the fluorescence. The detection limit of the prototype (approximately 25 nM) was determined by finding the minimum detectable concentration of a solution of fluorescein. The device was used to detect the separation of a mixture of proteins and small molecules by capillary electrophoresis; the separation illustrated the suitability of this integrated fluorescence detection system for bioanalytical applications.

Introduction: The strength and dose-response relationship between fruit and vegetable intake and mortality are still subjects of debate. Hypothesis: We hypothesized that higher fruit and vegetable intake was associated with lower total and cause-specific mortality in a nonlinear dose-response manner. Methods: We followed 66,719 women from the Nurses’ Health Study (1984-2012) and 42,016 men from the Health Professionals Follow-up Study (1986-2012) who were free from cardiovascular disease (CVD), cancer and diabetes at baseline. Diet was assessed using food frequency questionnaires at baseline and updated every 2 to 4 years. Results: Our study documented 28,333 deaths during follow-up. The 3rd quintile of fruit and vegetable intake was associated with the lowest hazard ratio (HR) of total mortality (HR, 0.87, 95% CI, 0.83-0.90, P nonlinear <0.001) compared to the 1st quintile. The nonlinear dose-response relationship plateaued at about 5 servings/day (svg/d), but above that level, higher intake was not associated with additional risk reduction. We found similar nonlinear associations for CVD, cancer and respiratory disease mortality. Compared to fruit and vegetable intake <1.5 svg/d, the intake level ≥5 svg/d was associated with HRs (95% CI) of 0.84 (0.75-0.93), 0.82 (0.72-0.93) and 0.55 (0.44-0.67) for cancer, CVD and respiratory disease mortality, respectively. Among individual fruits and vegetables, the associations of intakes with mortality were heterogeneous. Higher intakes of most fruit and vegetable subgroups were associated with lower total mortality, whereas higher intake of starchy vegetable such as peas and corn was not associated with total mortality. Conclusions: Higher fruit and vegetable intake was associated with lower mortality; the lowest mortality was observed among those who consumed 5 servings of fruit and vegetables per day (2 servings of fruit and 3 servings of vegetables daily). Our findings also suggest the presence of heterogeneity in the health benefits of individual fruits and vegetables.

Pulmonary arterial hypertension (PAH) is characterised by pulmonary vascular remodelling causing premature death from right heart failure. Established DNA variants influence PAH risk, but susceptibility from epigenetic changes is unknown. We addressed this through epigenome-wide association study (EWAS), testing 865,848 CpG sites for association with PAH in 429 individuals with PAH and 1226 controls. Three loci, at Cathepsin Z (CTSZ, cg04917472), Conserved oligomeric Golgi complex 6 (COG6, cg27396197), and Zinc Finger Protein 678 (ZNF678, cg03144189), reached epigenome-wide significance (p < 10-7) and are hypermethylated in PAH, including in individuals with PAH at 1-year follow-up. Of 16 established PAH genes, only cg10976975 in BMP10 shows hypermethylation in PAH. Hypermethylation at CTSZ is associated with decreased blood cathepsin Z mRNA levels. Knockdown of CTSZ expression in human pulmonary artery endothelial cells increases caspase-3/7 activity (p < 10-4). DNA methylation profiles are altered in PAH, exemplified by the pulmonary endothelial function modifier CTSZ, encoding protease cathepsin Z.

Field effect transistors (FETs) based on individual GaN nanowires (NWs) have been fabricated. Gate-dependent electrical transport measurements show that the GaN NWs are n-type and that the conductance of NW−FETs can be modulated by more than 3 orders of magnitude. Electron mobilities determined for the GaN NW FETs, which were estimated from the transconductance, were as high as 650 cm2/V·s. These mobilities are comparable to or larger than thin film materials with similar carrier concentration and thus demonstrate the high quality of these NW building blocks and their potential for nanoscale electronics. In addition, p−n junctions have been assembled in high yield from p-type Si, and these n-type GaN NWs and their potential applications are discussed.

OBJECTIVE Magnesium intake is inversely associated with risk of type 2 diabetes in many observational studies, but few have assessed this association in the context of the carbohydrate quality of the diet. We hypothesized that higher magnesium intake is associated with lower risk of type 2 diabetes, especially in the context of a poor carbohydrate–quality diet characterized by low cereal fiber or high glycemic index (GI) or glycemic load (GL). RESEARCH DESIGN AND METHODS In the Nurses’ Health Study (NHS; 1984–2012, n = 69,176), NHS2 (1991–2013, n = 91,471), and the Health Professionals’ Follow-Up Study (1986–2012, n = 42,096), dietary intake was assessed from food frequency questionnaires every 4 years. Type 2 diabetes was ascertained by biennial and supplementary questionnaires. We calculated multivariate hazard ratios (HRs) of magnesium intake and incident diabetes, adjusted for age, BMI, family history of diabetes, physical activity, smoking, hypertension, hypercholesterolemia, GL, energy intake, alcohol, cereal fiber, polyunsaturated fats, trans fatty acids, and processed meat, and we considered the joint associations of magnesium and carbohydrate quality on diabetes risk. RESULTS We documented 17,130 incident cases of type 2 diabetes over 28 years of follow-up. In pooled analyses across the three cohorts, those with the highest magnesium intake had 15% lower risk of type 2 diabetes compared with those with the lowest intake (pooled multivariate HR in quintile 5 vs. 1: 0.85 [95% CI 0.80–0.91], P &amp;lt; 0.0001). Higher magnesium intake was more strongly associated with lower risk of type 2 diabetes among participants with high GI or low cereal fiber than among those with low GI or high cereal fiber (both P interaction &amp;lt;0.001). CONCLUSIONS Higher magnesium intake is associated with lower risk of type 2 diabetes, especially in the context of lower carbohydrate–quality diets.

To test the hypothesis that an abiotic Earth and its inert atmosphere could form chemically reactive carbon- and nitrogen-containing compounds, we designed a plasma electrochemical setup to mimic lightning-induced electrochemistry under steady-state conditions of the early Earth. Air-gap electrochemical reactions at air-water-ground interfaces lead to remarkable yields, with up to 40 moles of carbon dioxide being reduced into carbon monoxide and formic acid, and 3 moles of gaseous nitrogen being fixed into nitrate, nitrite, and ammonium ions, per mole of transmitted electrons. Interfaces enable reactants (e.g., minerals) that may have been on land, in lakes, and in oceans to participate in radical and redox reactions, leading to higher yields compared to gas-phase-only reactions. Cloud-to-ground lightning strikes could have generated high concentrations of reactive molecules locally, establishing diverse feedstocks for early life to emerge and survive globally.

Introduction: Elevated body mass index (BMI) due to common genetic variants has been linked with the risk for future ischemic heart disease, yet it remains unclear how this association is mediated....

Abstract The role of metabolic syndrome (MetS) as a preceding metabolic state for type 2 diabetes and cardiovascular disease is widely recognised. To accumulate knowledge of the pathological mechanisms behind the condition at the methylation level, we conducted an epigenome-wide association study (EWAS) of MetS and its components, testing 1187 individuals of European ancestry for approximately 470 000 methylation sites throughout the genome. Methylation site cg19693031 in gene TXNIP —previously associated with type 2 diabetes, glucose and lipid metabolism, associated with fasting glucose level ( P = 1.80 × 10 −8 ). Cg06500161 in gene ABCG1 associated both with serum triglycerides ( P = 5.36 × 10 −9 ) and waist circumference ( P = 5.21 × 10 −9 ). The previously identified type 2 diabetes–associated locus cg08309687 in chromosome 21 associated with waist circumference for the first time ( P = 2.24 × 10 −7 ). Furthermore, a novel HDL association with cg17901584 in chromosome 1 was identified ( P = 7.81 × 10 −8 ). Our study supports previous genetic studies of MetS, finding that lipid metabolism plays a key role in pathology of the syndrome. We provide evidence regarding a close interplay with glucose metabolism. Finally, we suggest that in attempts to identify methylation loci linking separate MetS components, cg19693031 appears to represent a strong candidate.

Abstract Type 2 diabetes (T2D) is a global health burden that will benefit from personalised risk prediction and targeted prevention programmes. Omics data have enabled more detailed risk prediction; however, most studies have focussed on directly on the ability of DNA variants predicting T2D onset with less attention given to epigenetic regulation and glycaemic trait variability. By applying machine learning to the longitudinal Northern Finland Birth Cohort 1966 (NFBC 1966) at 31 (T1) and 46 (T2) years old, we predicted fasting glucose (FG) and insulin (FI), glycated haemoglobin (HbA1c) and 2-hour glucose and insulin from oral glucose tolerance test (2hGlu, 2hIns) at T2 in 513 individuals from 1,001 variables at T1 and T2, including anthropometric, metabolic, metabolomic and epigenetic variables. We further tested whether the information obtained by the machine learning models in NFBC could be used to predict glycaemic traits in the independent French study with 48 matching predictors (DESIR, N=769, age range 30-65 years at recruitment, interval between data collections: 9 years). In this study, FG and FI were best predicted, with average R 2 values of 0.38 and 0.53. Sex, branched-chain and aromatic amino acids, HDL-cholesterol, glycerol, ketone bodies, blood pressure at T2 and measurements of adiposity at T1, as well as multiple methylation marks at both time points were amongst the top predictors. In the validation analysis, we reached R 2 values of 0.41/0.55 for FG/FI when trained and tested in NFBC1966 and 0.17/0.30 when trained in NFBC1966 and tested in DESIR. We identified clinically relevant sets of predictors from a large multi-omics dataset and highlighted the potential of methylation markers and longitudinal changes in prediction.