Human Papillomavirus Type 11 Recombinant L1 Capsomeres Induce Virus-Neutralizing Antibodies

The human papillomavirus type 11 (HPV-11) L1 major capsid protein can be trypsinized to generate recombinant capsomeres that retain HPV genotype-restricted capsid antigenicity (M. Li, T. P. Cripe, P. A. Estes, M. K. Lyon, R. C. Rose, and R. L. Garcea, J. Virol. 71:2988–2995, 1997). In the present study, HPV-11 virion-neutralizing monoclonal antibodies H11.F1 and H11.H3, previously characterized as recognizing two distinct HPV-11 capsid-neutralizing antigenic domains (S. W. Ludmerer, D. Benincasa, and G. E. Mark III, J. Virol. 70:4791–4794, 1996), were each found to be highly immunoreactive with trypsin-generated capsomeres in an enzyme-linked immunosorbent assay (ELISA). Capsomeres were used to generate high-titer polyclonal immune sera that demonstrated HPV genotype-restricted reactivity by ELISA. The capsomere antisera were then tested in an in vitro infectivity assay and found to neutralize HPV-11 virions. In this assay, HPV-11 capsomere polyclonal antisera exhibited neutralization titers (10⁻⁵ to 10⁻⁶) comparable to those obtained with a virion-neutralizing antiserum raised previously against intact HPV-11 VLPs (R. C. Rose, R. C. Reichman, and W. Bonnez, J. Gen. Virol. 75:2075–2079, 1994). These results indicate that highly immunogenic, genotype-restricted HPV capsid-neutralizing antigenic domains are contained entirely within capsomeres. Thus, capsomeres may be viable vaccine candidates for the prevention of HPV disease.     

Epidemiological evidence for the role of physical activity in reducing risk of type 2 diabetes and cardiovascular disease.

Epidemiological studies suggest that physically active individuals have a 30-50% lower risk of developing type 2 diabetes than do sedentary persons and that physical activity confers a similar risk reduction for coronary heart disease. Risk reductions are observed with as little as 30 min of moderate-intensity activity per day. Protective mechanisms of physical activity include the regulation of body weight; the reduction of insulin resistance, hypertension, atherogenic dyslipidemia, and inflammation; and the enhancement of insulin sensitivity, glycemic control, and fibrinolytic and endothelial function. Public health initiatives promoting moderate increases in physical activity may offer the best balance between efficacy and feasibility to improve metabolic and cardiovascular health in largely sedentary populations.     

Transmission of different strains of Plasmodium cynomolgi to Aotus nancymaae monkeys and relapse

Forty-four splenectomized Aotus nancymaae monkeys were infected with 6 different strains of Plasmodium cynomolgi, 11 via trophozoites and 33 via sporozoites. Sporozoites from Anopheles dirus, Anopheles freeborni, Anopheles gambiae, Anopheles maculatus, and Anopheles stephensi resulted in prepatent periods ranging from 9 to 39 days (median of 15 days). Importantly, relapse was demonstrated in 5 of 5 sporozoite-induced infections with the Rossan strain following treatment with chloroquine.     

Observations on the exoerythrocytic stages of different isolates of Plasmodium cynomolgi in hepatocytes of New World aotus and Saimiri monkeys

Sporozoites of 3 isolates of Plasmodium cynomolgi dissected from the salivary glands of Anopheles dirus and Anopheles quadrimaculatus were injected intravenously into 9 New World monkeys. Liver stage parasites were demonstrated in all 9 animals; 7 of these animals also produced blood stages after prepatent periods of 9 to 23 days.     

Muscle-Strengthening and Conditioning Activities and Risk of Type 2 Diabetes: A Prospective Study in Two Cohorts of US Women

Background

It is well established that aerobic physical activity can lower the risk of type 2 diabetes (T2D), but whether muscle-strengthening activities are beneficial for the prevention of T2D is unclear. This study examined the association of muscle-strengthening activities with the risk of T2D in women.

Methods and Findings

We prospectively followed up 99,316 middle-aged and older women for 8 years from the Nurses'' Health Study ([NHS] aged 53–81 years, 2000–2008) and Nurses'' Health Study II ([NHSII] aged 36–55 years, 2001–2009), who were free of diabetes, cancer, and cardiovascular diseases at baseline. Participants reported weekly time spent on resistance exercise, lower intensity muscular conditioning exercises (yoga, stretching, toning), and aerobic moderate and vigorous physical activity (MVPA) at baseline and in 2004/2005. Cox regression with adjustment for major determinants for T2D was carried out to examine the influence of these types of activities on T2D risk. During 705,869 person years of follow-up, 3,491 incident T2D cases were documented. In multivariable adjusted models including aerobic MVPA, the pooled relative risk (RR) for T2D for women performing 1–29, 30–59, 60–150, and >150 min/week of total muscle-strengthening and conditioning activities was 0.83, 0.93, 0.75, and 0.60 compared to women reporting no muscle-strengthening and conditioning activities (p<0.001 for trend). Furthermore, resistance exercise and lower intensity muscular conditioning exercises were each independently associated with lower risk of T2D in pooled analyses. Women who engaged in at least 150 min/week of aerobic MVPA and at least 60 min/week of muscle-strengthening activities had substantial risk reduction compared with inactive women (pooled RR = 0.33 [95% CI 0.29–0.38]). Limitations to the study include that muscle-strengthening and conditioning activity and other types of physical activity were assessed by a self-administered questionnaire and that the study population consisted of registered nurses with mostly European ancestry.

Conclusions

Our study suggests that engagement in muscle-strengthening and conditioning activities (resistance exercise, yoga, stretching, toning) is associated with a lower risk of T2D. Engagement in both aerobic MVPA and muscle-strengthening type activity is associated with a substantial reduction in the risk of T2D in middle-aged and older women. Please see later in the article for the Editors'' Summary     

Phosphoproteomic analysis of thrombin- and p38 MAPK-regulated signaling networks in endothelial cells

Endothelial dysfunction is a hallmark of inflammation and is mediated by inflammatory factors that signal through G protein–coupled receptors including protease-activated receptor-1 (PAR1). PAR1, a receptor for thrombin, signals via the small GTPase RhoA and myosin light chain intermediates to facilitate endothelial barrier permeability. PAR1 also induces endothelial barrier disruption through a p38 mitogen-activated protein kinase–dependent pathway, which does not integrate into the RhoA/MLC pathway; however, the PAR1-p38 signaling pathways that promote endothelial dysfunction remain poorly defined. To identify effectors of this pathway, we performed a global phosphoproteome analysis of thrombin signaling regulated by p38 in human cultured endothelial cells using multiplexed quantitative mass spectrometry. We identified 5491 unique phosphopeptides and 2317 phosphoproteins, four distinct dynamic phosphoproteome profiles of thrombin-p38 signaling, and an enrichment of biological functions associated with endothelial dysfunction, including modulators of endothelial barrier disruption and a subset of kinases predicted to regulate p38-dependent thrombin signaling. Using available antibodies to detect identified phosphosites of key p38-regulated proteins, we discovered that inhibition of p38 activity and siRNA-targeted depletion of the p38α isoform increased basal phosphorylation of extracellular signal–regulated protein kinase 1/2, resulting in amplified thrombin-stimulated extracellular signal–regulated protein kinase 1/2 phosphorylation that was dependent on PAR1. We also discovered a role for p38 in the phosphorylation of α-catenin, a component of adherens junctions, suggesting that this phosphorylation may function as an important regulatory process. Taken together, these studies define a rich array of thrombin- and p38-regulated candidate proteins that may serve important roles in endothelial dysfunction.     

Seasonal dynamics of macrophyte communities from a stream flowing over granite flatrock in North Carolina,USA

The seasonal distribution and abundance of benthic macrophytes were characterized from second- and third-order segments of a stream flowing over granite flatrock in the southeastern United States. Eighteen genera were identified over two annual cycles including macroalgae (60% of the total), angiosperms (30%), and bryophytes (10%). Light availability as affected by riparian shading was a major factor influencing community structure. Based on strong agreement among two-way indicator species analysis, detrended correspondence analysis and cluster analysis, we identified four communities characteristic of distinct light regimes and seasons. In shaded sites the red alga Lemanea australis was dominant during cool seasons, and the aquatic moss Fontinalis sp. was dominant during warm seasons. By contrast, in open sites L. australis and the angiosperm Podostemum ceratophyllum were co-dominant during cool seasons, and P. ceratophyllum was also dominant in warm seasons. The prolific macrophyte communities followed a pattern of broad seasonal maxima for dominant species along with rapid fluctuations in ephemerals. The community dynamics suggest that competitive interactions control space partitioning among macrophytes on the granite flatrock.     

Estimating multiple time‐fixed treatment effects using a semi‐Bayes semiparametric marginal structural Cox proportional hazards regression model

Marginal structural models for time‐fixed treatments fit using inverse‐probability weighted estimating equations are increasingly popular. Nonetheless, the resulting effect estimates are subject to finite‐sample bias when data are sparse, as is typical for large‐sample procedures. Here we propose a semi‐Bayes estimation approach which penalizes or shrinks the estimated model parameters to improve finite‐sample performance. This approach uses simple symmetric data‐augmentation priors. Limited simulation experiments indicate that the proposed approach reduces finite‐sample bias and improves confidence‐interval coverage when the true values lie within the central “hill” of the prior distribution. We illustrate the approach with data from a nonexperimental study of HIV treatments.