Cross-sectional detection of acute HIV infection: timing of transmission, inflammation and antiretroviral therapy

Background

Acute HIV infection (AHI) is a critical phase of infection when irreparable damage to the immune system occurs and subjects are very infectious. We studied subjects with AHI prospectively to develop better treatment and public health interventions.

Methods

Cross-sectional screening was employed to detect HIV RNA positive, antibody negative subjects. Date of HIV acquisition was estimated from clinical history and correlated with sequence diversity assessed by single genome amplification (SGA). Twenty-two cytokines/chemokines were measured from enrollment through week 24.

Results

Thirty-seven AHI subjects were studied. In 7 participants with limited exposure windows, the median exposure to HIV occurred 14 days before symptom onset. Lack of viral sequence diversification confirmed the short duration of infection. Transmission dates estimated by SGA/sequencing using molecular clock models correlated with transmission dates estimated by symptom onset in individuals infected with single HIV variants (mean of 28 versus 33 days). Only 10 of 22 cytokines/chemokines were significantly elevated among AHI participants at enrollment compared to uninfected controls, and only 4 participants remained seronegative at enrollment.

Discussion

The results emphasize the difficulty in recruiting subjects early in AHI. Viral sequence diversity proved accurate in estimating time of infection. Regardless of aggressive screening, peak viremia and inflammation occurred before enrollment and potential intervention. Given the personal and public health importance, improved AHI detection is urgently needed.     

Genetic determinants for body iron store and type 2 diabetes risk in US men and women

Background

High body iron store has been associated with an increased risk of type 2 diabetes (T2D); it remains unknown whether the genetic variants related to body iron status affect T2D risk. We aimed at comprehensively investigating the associations between the genetic variants related to body iron status and the T2D risk.

Methodology/Principal Findings

Six common SNPs related to body iron status from recent genome-wide association (GWA) studies were determined in the Nurses’ Health Study (NHS; 1,467 diabetic cases and 1,754 controls) and the Health Professionals Follow-up Study (HPFS; 1,124, diabetic cases and 1,298 controls). Plasma levels of ferritin, soluble transferrin receptor (sTfR), and transferrin were measured in NHS. Significant associations were observed for loci in TPMRSS6 with sTfR (P = 3.47×10⁻⁶), TF with transferrin (P = 0.0002 to 1.72×10⁻¹⁰); and HFE with ferritin (P = 0.017 to 1.6×10⁻⁸), sTfR (P = 0.007 to 7.9×10⁻⁶), and transferrin (P = 0.006 to 0.0007). The six SNPs together explained 5.7%, 2.7%, and 13.3% of the variation in plasma levels of ferritin, sTfR, and transferrin. After adjustment for the conventional risk factors, the T allele of SNP rs855791 in the TPMRSS6 gene was significantly associated with a 19% decreased risk of T2D (OR = 0.81; 95% CI = 0.66–0.98; P = 0.03) in men. Multiple tests attenuated this significant association to null. No associations were observed in women. SNPs at HFE and TF were not associated with diabetes risk in either sex. Dietary iron intake did not modify the associations of the newly identified loci with diabetes risk.

Conclusions/Significance

The newly identified iron-related SNP rs855791 in TPMRSS6 was nominally associated with a decreased risk of T2D in men but not in women. The apparent differences by gender warrant further study.     

DIFFERENCES IN GROWTH AND PHYSIOLOGY OF MARINE SYNECHOCOCCUS (CYANOBACTERIA) ON NITRATE VERSUS AMMONIUM ARE NOT DETERMINED SOLELY BY NITROGEN SOURCE REDOX STATE1

The preference of phytoplankton for ammonium over nitrate has traditionally been explained by the greater metabolic cost of reducing oxidized forms of nitrogen. This “metabolic cost hypothesis” implies that there should be a growth disadvantage on nitrate compared to ammonium or other forms of reduced nitrogen such as urea, especially when light limits growth, but in a variety of phytoplankton taxa, this predicted difference has not been observed. Our experiments with three strains of marine Synechococcus (WH7803, WH7805, and WH8112) did not reveal consistently faster growth (cell division) on ammonium or urea as compared to nitrate. Urease and glutamine synthetase (GS) activities varied with nitrogen source in a manner consistent with regulation by cellular nitrogen status via NtcA (rather than by external availability of nitrogen) in all three strains and indicated that each strain experienced some degree of nitrogen insufficiency during growth on nitrate. At light intensities that strongly limited growth, the composition (carbon, nitrogen, and pigment quotas) of WH7805 cells using nitrate was indistinguishable from that of cells using ammonium, but at saturating light intensities, cellular carbon, nitrogen, and pigment quotas were significantly lower in cells using nitrate than ammonium. These and similar results from other phytoplankton taxa suggest that a limitation in some step of nitrate uptake or assimilation, rather than the extra cost of reducing nitrate per se, may be the cause of differences in growth and physiology between cells using nitrate and ammonium.     

Regulation of Protease-activated Receptor 1 Signaling by the Adaptor Protein Complex 2 and R4 Subfamily of Regulator of G Protein Signaling Proteins

The G protein-coupled protease-activated receptor 1 (PAR1) is irreversibly proteolytically activated by thrombin. Hence, the precise regulation of PAR1 signaling is important for proper cellular responses. In addition to desensitization, internalization and lysosomal sorting of activated PAR1 are critical for the termination of signaling. Unlike most G protein-coupled receptors, PAR1 internalization is mediated by the clathrin adaptor protein complex 2 (AP-2) and epsin-1, rather than β-arrestins. However, the function of AP-2 and epsin-1 in the regulation of PAR1 signaling is not known. Here, we report that AP-2, and not epsin-1, regulates activated PAR1-stimulated phosphoinositide hydrolysis via two different mechanisms that involve, in part, a subset of R4 subfamily of “regulator of G protein signaling” (RGS) proteins. A significantly greater increase in activated PAR1 signaling was observed in cells depleted of AP-2 using siRNA or in cells expressing a PAR1 ⁴²⁰AKKAA⁴²⁴ mutant with defective AP-2 binding. This effect was attributed to AP-2 modulation of PAR1 surface expression and efficiency of G protein coupling. We further found that ectopic expression of R4 subfamily members RGS2, RGS3, RGS4, and RGS5 reduced activated PAR1 wild-type signaling, whereas signaling by the PAR1 AKKAA mutant was minimally affected. Intriguingly, siRNA-mediated depletion analysis revealed a function for RGS5 in the regulation of signaling by the PAR1 wild type but not the AKKAA mutant. Moreover, activation of the PAR1 wild type, and not the AKKAA mutant, induced Gα_q association with RGS3 via an AP-2-dependent mechanism. Thus, AP-2 regulates activated PAR1 signaling by altering receptor surface expression and through recruitment of RGS proteins.     

Mediating Effects of Inflammatory Biomarkers on Insulin Resistance Associated with Obesity

Objective: Obesity is associated with elevated levels of biomarkers of inflammation and endothelial dysfunction [including C‐reactive protein (CRP), E‐selectin, and intercellular adhesion molecule‐1], as well as insulin resistance (IR) and type 2 diabetes. We tested the hypothesis that these biomarkers mediate associations among obesity, IR, and risk of diabetes. Research Methods and Procedures: We stratified 510 initially non‐diabetic women in the Nurses’ Health Study cohort into four phenotypes above/below median BMI (27 kg/m²) and waist circumference (81 cm): low BMI‐low waist (LBLW; N = 190), low BMI‐high waist (LBHW; N = 74), high BMI‐low waist (HBLW; N = 27), and high BMI‐high waist (HBHW; N = 219). Results: In models assessing associations of weight phenotype with IR [fasting insulin (FI)], adjusted for age and diabetes risk factors, mean FI was higher comparing HBHW women (13.6 μU/mL, p < 0.0001) and LBHW (11.5 μU/mL, p = 0.02) with LBLW women (8.6 μU/mL); HBLW and LBLW women were not significantly different. Differences in FI levels were most strongly attenuated after adjustment for E‐selectin comparing LBHW with LBLW women (11.7 vs. 9.7 μU/mL, p = 0.2). Discussion: In logistic regression models, LBHW predicted diabetes (risk factor‐adjusted relative risk 2.06, 1.05 to 6.40), compared with LBLW, but was no longer significant after adjustment for E‐selectin or CRP. After adjusting for CRP and E‐selectin, only HBHW and E‐selectin were significantly associated with risk of diabetes. In women with central adiposity and low BMI, endothelial dysfunction and inflammation may mediate the relationship among central fat, IR, and incident diabetes.     

Real-time remote monitoring of water quality: a review of current applications, and advancements in sensor, telemetry, and computing technologies

Recent advances in communication and sensor technology have catalyzed progress in remote monitoring capabilities for water quality. As a result, the ability to characterize dynamic hydrologic properties at adequate temporal and spatial scales has greatly improved. These advances have led to improved statistical and mechanistic modeling in monitoring of water quality trends at local, watershed and regional scales for freshwater, estuarine and marine ecosystems. In addition, they have greatly enhanced rapid (e.g., real-time) detection of hydrologic variability, recognized as a critical need for early warning systems and rapid response to harmful algal bloom events. Here, we present some of the landmark developments and technological achievements that led to the advent of real-time remote monitors for hydrologic properties. We conclude that increased use and continuing advancements of real-time remote monitoring (RTRM) and sensing technologies will become a progressively more important tool for evaluating water quality. Recent engineering and deployment of RTRM technologies by federal and state regulatory agencies, industries, and academic laboratories is now permitting rapid detection of, and responses to, environmental threats imposed by increased nutrient loadings, development of hypoxic and anoxic areas, toxicants, and harmful algal bloom outbreaks leading to fish kill events and potential human health impacts.     

Crystal structure of rat short chain acyl-CoA dehydrogenase complexed with acetoacetyl-CoA: comparison with other acyl-CoA dehydrogenases.

The acyl-CoA dehydrogenases are a family of flavin adenine dinucleotide-containing enzymes that catalyze the first step in the beta-oxidation of fatty acids and catabolism of some amino acids. They exhibit high sequence identity and yet are quite specific in their substrate binding. Short chain acyl-CoA dehydrogenase has maximal activity toward butyryl-CoA and negligible activity toward substrates longer than octanoyl-CoA. The crystal structure of rat short chain acyl-CoA dehydrogenase complexed with the inhibitor acetoacetyl-CoA has been determined at 2.25 A resolution. Short chain acyl-CoA dehydrogenase is a homotetramer with a subunit mass of 43 kDa and crystallizes in the space group P321 with a = 143.61 A and c = 77.46 A. There are two monomers in the asymmetric unit. The overall structure of short chain acyl-CoA dehydrogenase is very similar to those of medium chain acyl-CoA dehydrogenase, isovaleryl-CoA dehydrogenase, and bacterial short chain acyl-CoA dehydrogenase with a three-domain structure composed of N- and C-terminal alpha-helical domains separated by a beta-sheet domain. Comparison to other acyl-CoA dehydrogenases has provided additional insight into the basis of substrate specificity and the nature of the oxidase activity in this enzyme family. Ten reported pathogenic human mutations and two polymorphisms have been mapped onto the structure of short chain acyl-CoA dehydrogenase. None of the mutations directly affect the binding cavity or intersubunit interactions.     

Dietary Intake of Whole and Refined Grain Breakfast Cereals and Weight Gain in Men

Objective: Prospective studies have suggested that substituting whole grain for refined grain products may lower the risk of overweight and obesity. Breakfast cereal intake is a major source of whole and refined grains and has also been associated with having a lower BMI. The aim of this study was to prospectively assess the association between whole and refined grain breakfast cereal intakes and risk of overweight (BMI ≥ 25 kg/m²) and weight gain. Research Methods and Procedures: We examined 17, 881 U.S. male physicians 40 to 84 years of age in 1982 who were free of cardiovascular disease, diabetes mellitus, and cancer at baseline and reported measures of breakfast cereal intake, weight, and height. Results: Over 8 and 13 years of follow‐up, respectively, men who consumed breakfast cereal, regardless of type, consistently weighed less than those who consumed breakfast cereals less often (p value for trend = 0.01). Whole and refined grain breakfast cereal intake was inversely associated with body weight gain over 8 years, after adjustment for age, smoking, baseline BMI, alcohol intake, physical activity, hypertension, high cholesterol, and use of multivitamins. Compared with men who rarely or never consumed breakfast cereals, those who consumed ≥1 serving/d of breakfast cereals were 22% and 12% less likely to become overweight during follow‐up periods of 8 and 13 years (relative risk, 0.78 and 0.88; 95% confidence interval, 0.67 to 0.91 and 0.76 to 1.00, respectively). Discussion: BMI and weight gain were inversely associated with intake of breakfast cereals, independently of other risk factors.