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Exposure to the pesticide dichlorodiphenyltrichloroethane (DDT) has been associated with increased risk of Alzheimer's disease (AD), a disease also associated with hyperphosphorylated tau (p-tau) protein aggregation. We investigated whether exposure to DDT can exacerbate tau protein toxicity in Caenorhabditiselegans using a transgenic strain that expresses human tau protein prone to aggregation by measuring changes in size, swim behavior, respiration, lifespan, learning, and metabolism. In addition, we examined the association between cerebrospinal fluid (CSF) p-tau protein-as a marker of postmortem tau burden-and global metabolism in both a human population study and in C. elegans , using the same p-tau transgenic strain. From the human population study, plasma and CSF-derived metabolic features associated with p-tau levels were related to drug, amino acid, fatty acid, and mitochondrial metabolism pathways. A total of five metabolites overlapped between plasma and C. elegans , and four between CSF and C. elegans . DDT exacerbated the inhibitory effect of p-tau protein on growth and basal respiration. In the presence of p-tau protein, DDT induced more curling and was associated with reduced levels of amino acids but increased levels of uric acid and adenosylselenohomocysteine. Our findings in C. elegans indicate that DDT exposure and p-tau aggregation both inhibit mitochondrial function and DDT exposure can exacerbate the mitochondrial inhibitory effects of p-tau aggregation. Further, biological pathways associated with exposure to DDT and p-tau protein appear to be conserved between species., (© The Author(s) 2022. Published by Oxford University Press on behalf of the National Academy of Sciences.)

The proper storage and release of monoamines contributes to a wide range of neuronal activity. Here, we examine the effects of altered vesicular monoamine transport in the nematode Caenorhabditis elegans. The gene cat-1 is responsible for the encoding of the vesicular monoamine transporter (VMAT) in C. elegans and is analogous to the mammalian vesicular monoamine transporter 2 (VMAT2). Our laboratory has previously shown that reduced VMAT2 activity confers vulnerability on catecholamine neurons in mice. The purpose of this article was to determine whether this function is conserved and to determine the impact of reduced VMAT activity in C. elegans. Here we show that deletion of cat-1/VMAT increases sensitivity to the neurotoxicant 1-methyl-4-phenylpyridinium (MPP+) as measured by enhanced degeneration of dopamine neurons. Reduced cat-1/VMAT also induces changes in dopamine-mediated behaviors. High-resolution mass spectrometry-based metabolomics in the whole organism reveals changes in amino acid metabolism, including tyrosine metabolism in the cat-1/VMAT mutants. Treatment with MPP+ disrupted tryptophan metabolism. Both conditions altered glycerophospholipid metabolism, suggesting a convergent pathway of neuronal dysfunction. Our results demonstrate the evolutionarily conserved nature of monoamine function in C. elegans and further suggest that high-resolution mass spectrometry-based metabolomics can be used in this model to study environmental and genetic contributors to complex human disease., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The epidemiological and programmatic implications of inclusivity of HIV-positive males in voluntary medical male circumcision (VMMC) programs are uncertain. We modeled these implications using Zambia as an illustrative example., Methods and Findings: We used the Age-Structured Mathematical (ASM) model to evaluate, over an intermediate horizon (2010-2025), the effectiveness (number of VMMCs needed to avert one HIV infection) of VMMC scale-up scenarios with varying proportions of HIV-positive males. The model was calibrated by fitting to HIV prevalence time trend data from 1990 to 2014. We assumed that inclusivity of HIV positive males may benefit VMMC programs by increasing VMMC uptake among higher risk males, or by circumcision reducing HIV male-to-female transmission risk. All analyses were generated assuming no further antiretroviral therapy (ART) scale-up. The number of VMMCs needed to avert one HIV infection was projected to increase from 12.2 VMMCs per HIV infection averted, in a program that circumcises only HIV-negative males, to 14.0, in a program that includes HIV-positive males. The proportion of HIV-positive males was based on their representation in the population (e.g. 12.6% of those circumcised in 2010 would be HIV-positive based on HIV prevalence among males of 12.6% in 2010). However, if a program that only reaches out to HIV-negative males is associated with 20% lower uptake among higher-risk males, the effectiveness would be 13.2 VMMCs per infection averted. If improved inclusivity of HIV-positive males is associated with 20% higher uptake among higher-risk males, the effectiveness would be 12.4. As the assumed VMMC efficacy against male-to-female HIV transmission was increased from 0% to 20% and 46%, the effectiveness of circumcising regardless of HIV status improved from 14.0 to 11.5 and 9.1, respectively. The reduction in the HIV incidence rate among females increased accordingly, from 24.7% to 34.8% and 50.4%, respectively., Conclusion: Improving inclusivity of males in VMMC programs regardless of HIV status increases VMMC effectiveness, if there is moderate increase in VMMC uptake among higher-risk males and/or if there is moderate efficacy for VMMC against male-to-female transmission. In these circumstances, VMMC programs can reduce the HIV incidence rate in males by nearly as much as expected by some ART programs, and additionally, females can benefit from the intervention nearly as much as males., Competing Interests: The authors have declared that no competing interests exist.

Background: Countries in sub-Saharan Africa are scaling-up voluntary male medical circumcision (VMMC) as an HIV intervention. Emerging challenges in these programs call for increased focus on program efficiency (optimizing program impact while minimizing cost). A novel analytic approach was developed to determine how subpopulation prioritization can increase program efficiency using an illustrative application for Zambia., Methods and Findings: A population-level mathematical model was constructed describing the heterosexual HIV epidemic and impact of VMMC programs (age-structured mathematical (ASM) model). The model stratified the population according to sex, circumcision status, age group, sexual-risk behavior, HIV status, and stage of infection. A three-level conceptual framework was also developed to determine maximum epidemic impact and program efficiency through subpopulation prioritization, based on age, geography, and risk profile. In the baseline scenario, achieving 80% VMMC coverage by 2017 among males 15-49 year old, 12 VMMCs were needed per HIV infection averted (effectiveness). The cost per infection averted (cost-effectiveness) was USD $1,089 and 306,000 infections were averted. Through age-group prioritization, effectiveness ranged from 11 (20-24 age-group) to 36 (45-49 age-group); cost-effectiveness ranged from $888 (20-24 age-group) to $3,300 (45-49 age-group). Circumcising 10-14, 15-19, or 20-24 year old achieved the largest incidence rate reduction; prioritizing 15-24, 15-29, or 15-34 year old achieved the greatest program efficiency. Through geographic prioritization, effectiveness ranged from 9-12. Prioritizing Lusaka achieved the highest effectiveness. Through risk-group prioritization, prioritizing the highest risk group achieved the highest effectiveness, with only one VMMC needed per infection averted; the lowest risk group required 80 times more VMMCs., Conclusion: Epidemic impact and efficiency of VMMC programs can be improved by prioritizing young males (sexually active or just before sexual debut), geographic areas with higher HIV prevalence than the national, and high sexual-risk groups.

Background: The voluntary medical male circumcision (VMMC) program in Zimbabwe aims to circumcise 80% of males aged 13-29 by 2017. We assessed the impact of actual VMMC scale-up to date and evaluated the impact of potential alterations to the program to enhance program efficiency, through prioritization of subpopulations., Methods and Findings: We implemented a recently developed analytical approach: the age-structured mathematical (ASM) model and accompanying three-level conceptual framework to assess the impact of VMMC as an intervention. By September 2014, 364,185 males were circumcised, an initiative that is estimated to avert 40,301 HIV infections by 2025. Through age-group prioritization, the number of VMMCs needed to avert one infection (effectiveness) ranged between ten (20-24 age-group) and 53 (45-49 age-group). The cost per infection averted ranged between $811 (20-24 age-group) and $5,518 (45-49 age-group). By 2025, the largest reductions in HIV incidence rate (up to 27%) were achieved by prioritizing 10-14, 15-19, or 20-24 year old. The greatest program efficiency was achieved by prioritizing 15-24, 15-29, or 15-34 year old. Prioritizing males 13-29 year old was programmatically efficient, but slightly inferior to the 15-24, 15-29, or 15-34 age groups. Through geographic prioritization, effectiveness varied from 9-12 VMMCs per infection averted across provinces. Through risk-group prioritization, effectiveness ranged from one (highest sexual risk-group) to 60 (lowest sexual risk-group) VMMCs per infection averted., Conclusion: The current VMMC program plan in Zimbabwe is targeting an efficient and impactful age bracket (13-29 year old), but program efficiency can be improved by prioritizing a subset of males for demand creation and service availability. The greatest program efficiency can be attained by prioritizing young sexually active males and males whose sexual behavior puts them at higher risk for acquiring HIV.

Background: Male circumcision (MC) has been demonstrated to be effective and cost-effective for HIV/AIDS prevention. Global guidance to adopt this intervention was announced in 2007 for countries with high HIV/AIDS prevalence and low MC prevalence. However, scale up of voluntary medical male circumcision (VMMC) programs in MC priority countries have been slow. Many of these countries have particular cultural barriers that impede uptake of this effective intervention. This analysis explored correlates of MC status among men and their socio-economic, health and sexual behaviour factors using DHS data (2006-2011) from 11 MC priority countries., Methods: Our analysis included univariate unadjusted analyses for individual countries and the region (by combining all countries into one dataset) and a multiple logistic regression model., Results: Individual country results vary widely but alignment was mostly found between unadjusted analyses and multiple logistic regression model. The model found that men who are of the Muslim faith, reside in urban areas, have higher or secondary education attainment, hold professional occupations, and be in the richest wealth quintile are more likely to be circumcised. Circumcision is also positively correlated with lower reports of STIs, safe sexual behaviour, and HIV/AIDS prevention knowledge., Conclusions: Since the data collected predate VMMC program launch in these countries, results can only indicate baseline associations. However, characteristics of these existing circumcision practices may be utilized for better population targeting and program management to achieve higher impact with this effective prevention strategy.

Perchlorate (ClO(4)(-)) is ubiquitous in the environment and inhibits the thyroid's uptake of iodide. Food and tap water are likely sources of environmental exposure to perchlorate. The aim of this study was to identify significant dietary sources of perchlorate using perchlorate measured in urine as an exposure indicator. Sample-weighted, age-stratified linear regression models of National Health and Nutrition Examination Survey (NHANES) 2001-2008 data (n=16,955 participants) characterized the association between urinary perchlorate and the mass consumed in USDA food groups, controlling for urinary creatinine and other potential confounders. Separate models of NHANES 2005-2006 data (n=2841) evaluated the association between urinary perchlorate and perchlorate consumed via residential tap water. Consumption of milk products was associated with statistically significant contributions to urinary perchlorate across all age strata: 2.93 ng ClO(4)(-)/ml per kg consumed for children (6-11 years-old (YO)); 1.54 ng ClO(4)(-)/ml per kg for adolescents (12-19 YO); and 0.69 ng ClO(4)(-)/ml per kg for adults (20-84 YO). Vegetables were a significant contributor for adolescents and adults, whereas fruits and eggs contributed significantly only for adults. Dark-green leafy vegetables contributed the most among all age strata: 30.83 ng ClO(4)(-)/ml per kg for adults. Fats, oils, and salad dressings were significant contributors only for children. Three food groups were negatively associated with urinary perchlorate: grain products for children; sugars, sweets, and beverages for adolescents; and home tap water for adults. In a separate model, however, perchlorate consumed via home tap water contributed significantly to adult urinary perchlorate: 2.11E-4 ng ClO(4)(-)/ml per ng perchlorate in tap water consumed. In a nationally representative sample of the United States 6-84 YO, diet and tap water contributed significantly to urinary perchlorate, with diet contributing substantially more than tap water.

Lipopolysaccharide (LPS) is an essential component of the outer membrane (OM) in most gram-negative bacteria, and its structure and biosynthetic pathway are well known. Nevertheless, the mechanisms of transport and assembly of this molecule at the cell surface are poorly understood. The inner membrane (IM) transport protein MsbA is responsible for flipping LPS across the IM. Additional components of the LPS transport machinery downstream of MsbA have been identified, including the OM protein complex LptD/LptE (formerly Imp/RlpB), the periplasmic LptA protein, the IM-associated cytoplasmic ATP binding cassette protein LptB, and LptC (formerly YrbK), an essential IM component of the LPS transport machinery characterized in this work. Here we show that depletion of any of the proteins mentioned above leads to common phenotypes, including (i) the presence of abnormal membrane structures in the periplasm, (ii) accumulation of de novo-synthesized LPS in two membrane fractions with lower density than the OM, and (iii) accumulation of a modified LPS, which is ligated to repeating units of colanic acid in the outer leaflet of the IM. Our results suggest that LptA, LptB, LptC, LptD, and LptE operate in the LPS assembly pathway and, together with other as-yet-unidentified components, could be part of a complex devoted to the transport of LPS from the periplasmic surface of the IM to the OM. Moreover, the location of at least one of these five proteins in every cellular compartment suggests a model for how the LPS assembly pathway is organized and ordered in space.

In 2001, a sampling campaign was conducted in six North American cities--Reno, NV; Griffin, GA; Cleves, OH; Winnipeg, MB; Long Point, ON; and Toronto, ON--to investigate the tropospheric distribution of a suite of polyfluorinated alcohols and amides. Analysis via gas chromatography-chemical ionization-mass spectrometry indicated that both polyfluorinated sulfonamides and fluorinated telomer alcohols (FTOHs) are widely distributed throughout the North American troposphere with mean concentrations ranging from 22 to 403 pg/m3 and from 11 to 165 pg/m3 respectively. The dominant polyfluorinated contaminant was dependent on sampling location. Large mean concentrations of N-methyl perfluorooctane sulfonamidoethanol (359 pg/m3) and N-ethyl perfluorooctane sulfonamidoethanol (199 pg/m3) identified in Griffin and Reno, respectively, may indicate the release of polyfluorinated sulfonamides to the environment through paper and carpet treatment processes. The nonuniform nature of the spatial distribution of both polyfluorinated sulfonamides and FTOHs is indicative of the importance of point sources for the dissemination of these contaminants in the North American troposphere.

A brief review of the history of development of Chinese pharmacognosy and its application to gynecology and obstetrics is presented. An evaluation system is introduced for short-listing some potentially useful and anti-fertility plants. Twenty such plants are listed in order of priority according to our evaluation system. Brief descriptions of the botany, phytochemistry and reputed biological effects are provided. It is hoped that this article may provide an impetus for the development of new antifertility agents.

Electronic pacing is now the accepted therapy for patients with symptomatic slow ventricular heart rates. Pacing may be temporary or permanent, epicardial or endocardial, fixed, synchronous or demand. The choice of pacing mode is dictated by the clinical status of the patient, his progress during temporary pacing, and the presence or absence of competitive rhythm.