[National and regional market penetration rates of generic's high dosage buprenorphine: its evolution from 2006 to 2008, using reimbursed drug database].

PubMed

Boczek, Christelle; Frauger, Elisabeth; Micallef, Joëlle; Allaria-Lapierre, Véronique; Reggio, Patrick; Sciortino, Vincent

2012-01-01

To assess the national market penetration rate (PR) of generic high-dosage buprenorphine (HDB) in 2008 and its evolution since their marketing (2006), and making a point for each dosage and at regional level. Retrospective study over data using national and regional health reimbursement database over three years (2006-2008). In 2008, the generic HDB's national MPR was 31%. The PR for each dosage were 45% for 0.4 mg, 36% for 2 mg and 19% for 8 mg. The (PR) based on Defined Daily Dose (DDD) was 23% in 2008, 15% in 2007 and 4% in 2006. In 2008, at the regional level, disparities were observed in the adjusted penetration rate from 15% in Île de France to 39% in Champagne Ardennes Lorraine. The national PR of generic HDB has increased. There are differences in MPR in terms of dosage and area. However, this PR is still low (in 2008, 82% of the delivered drugs are generics). © 2012 Société Française de Pharmacologie et de Thérapeutique.

Seasonal PrEP for partners of migrant miners in southern Mozambique: a highly focused PrEP intervention

PubMed Central

Cremin, Ide; Morales, Fernando; Jewell, Britta L; O'Reilly, Kevin R; Hallett, Timothy B

2015-01-01

Introduction To be used most effectively, pre-exposure prophylaxis (PrEP) should be prioritized to those at high risk of acquisition and would ideally be aligned with time periods of increased exposure. Identifying such time periods is not always straightforward, however. Gaza Province in southern Mozambique is characterized by high levels of HIV transmission and circular labour migration to mines in South Africa. A strong seasonal pattern in births is observable, reflecting an increase in conception in December. Given the potential for increased HIV transmission between miners returning in December and their partners in Gaza Province, PrEP use by the latter would be a useful means of HIV prevention, especially for couples who wish to conceive. Methods A mathematical model was used to represent population-level adult heterosexual HIV transmission in Gaza Province. Increased HIV acquisition among partners of miners in December, coinciding with the miners’ return from South Africa, is represented. In addition to a PrEP intervention, the scale-up of treatment and recent scale-up of male circumcision that have occurred in Gaza are represented. Results Providing time-limited PrEP to the partners of migrant miners, as opposed to providing PrEP all year, would improve the cost per infection averted by 7.5-fold. For the cost per infection averted to be below US$3000, at least 85% of PrEP users would need to be good adherers and PrEP would need to be cheaper than US$115 per person per year. Uncertainty regarding incidence of HIV transmission among partners of miners each year in December has a strong influence on estimates of cost per infection averted. Conclusions Providing time-limited PrEP to partners of migrant miners in Gaza Province during periods of increased exposure would be a novel strategy for providing PrEP. This strategy would allow for a better prioritized intervention, with the potential to improve the efficiency of a PrEP intervention considerably, as well as providing important reproductive health benefits. PMID:26198340

The prevalence of physical activity and its associated effects among students in the São Paulo public school network, Brazil.

PubMed

Silva, Leonardo José; Matsudo, Victor Keihan Rodrigues; Andrade, Douglas Roque; Azevedo, Mário; Ferrari, Gerson Luis de Moraes; Oliveira, Luis Carlos; Araújo, Timóteo Leandro; Matsudo, Sandra Marcela Mahecha

2016-04-01

The current study evaluated physical activity (PA) level and its associated effects among students in the public network of São Paulo, Brazil. A cross-sectional study was taken using a representative sample of students in São Paulo public school system. International Physical Activity Questionnaire determined PA level. Students who reported at least 300 minutes/week of PA were considered active. The independente variables were: gender, age, body mass index, education, region, recognition of the Agita São Paulo program. The prevalence of regular PA was 71.7%. Males (PR = 1.09, 95% CIs = 1.04 -1.15) at least 17 years old (PR = 1.16, 95% CIs 1.09-1.24) in their 3rd year of high school (PR = 1.20, 95% CIs = 1.12-1.29) who resided in the Midwest region (PR = 1.27, 95% CIs 1.16-1.38) were most likely to be active. Males at least 17 years old in their 3rd year of high school who lived in the Midwest and recognized the Agita São Paulo/Agita Galera program had higher levels of PA. São Paulo students presented a high level of PA. Moreover, males older than 17 years, attending their 3rd year of high school, who lived in the Midwest region, and recognized the Agita São Paulo/Agita Galera program were the most likely to be more active.

Hepatitis A outbreak in HIV-infected MSM and in PrEP-using MSM despite a high level of immunity, Lyon, France, January to June 2017.

PubMed

Charre, Caroline; Ramière, Christophe; Roque-Afonso, Anne-Marie; Chidiac, Christian; Zoulim, Fabien; Godinot, Matthieu; Koffi, Joseph; Scholtès, Caroline; Livrozet, Jean-Michel; Hav Lyon Study Group; Cotte, Laurent

2017-11-01

Since 2016, an increase in the number of hepatitis A cases affecting mainly men who have sex with men (MSM) has been reported in low endemic countries in Europe. We calculated the attack rate in Lyon, France, in populations considered at high-risk: HIV-infected MSM and HIV-negative MSM receiving HIV pre-exposure prophylaxis (PrEP). In these populations, high level of immunity did not prevent the outbreak, indicating that vaccination should be reinforced, particularly in younger individuals.

Hepatitis A outbreak in HIV-infected MSM and in PrEP-using MSM despite a high level of immunity, Lyon, France, January to June 2017

PubMed Central

Charre, Caroline; Ramière, Christophe; Roque-Afonso, Anne-Marie; Chidiac, Christian; Zoulim, Fabien; Godinot, Matthieu; Koffi, Joseph; Scholtès, Caroline; Livrozet, Jean-Michel; Cotte, Laurent

2017-01-01

Since 2016, an increase in the number of hepatitis A cases affecting mainly men who have sex with men (MSM) has been reported in low endemic countries in Europe. We calculated the attack rate in Lyon, France, in populations considered at high-risk: HIV-infected MSM and HIV-negative MSM receiving HIV pre-exposure prophylaxis (PrEP). In these populations, high level of immunity did not prevent the outbreak, indicating that vaccination should be reinforced, particularly in younger individuals. PMID:29208161

Assessment of Genetic Diversity of Sweet Potato in Puerto Rico

PubMed Central

Rodriguez-Bonilla, Lorraine; Cuevas, Hugo E.; Montero-Rojas, Milly; Bird-Pico, Fernando; Luciano-Rosario, Dianiris; Siritunga, Dimuth

2014-01-01

Sweet potato (Ipomoea batatas L.) is the seventh most important food crop due to its distinct advantages, such as adaptability to different environmental conditions and high nutritional value. Assessing the genetic diversity of this important crop is necessary due to the constant increase of demand for food and the need for conservation of agricultural and genetic resources. In Puerto Rico (PR), the genetic diversity of sweet potato has been poorly understood, although it has been part of the diet since Pre-Columbus time. Thus, 137 landraces from different localities around PR were collected and subjected to a genetic diversity analysis using 23 SSR-markers. In addition, 8 accessions from a collection grown in Gurabo, PR at the Agricultural Experimental Station (GAES), 10 US commercial cultivars and 12 Puerto Rican accessions from the USDA repository collection were included in this assessment. The results of the analysis of the 23 loci showed 255 alleles in the 167 samples. Observed heterozygosity was high across populations (0.71) while measurements of total heterozygosity revealed a large genetic diversity throughout the population and within populations. UPGMA clustering method revealed two main clusters. Cluster 1 contained 12 PR accessions from the USDA repository collection, while cluster 2 consisted of PR landraces, US commercial cultivars and the PR accessions from GAES. Population structure analysis grouped PR landraces in five groups including four US commercial cultivars. Our study shows the presence of a high level of genetic diversity of sweet potato across PR which can be related to the genetic makeup of sweet potato, human intervention and out-crossing nature of the plant. The history of domestication and dispersal of sweet potato in the Caribbean and the high levels of genetic diversity found through this study makes sweet potato an invaluable resource that needs to be protected and further studied. PMID:25551388

TRMM Precipitation Radar Reflectivity Profiles Compared to High-Resolution Airborne and Ground-Based Radar Measurements

NASA Technical Reports Server (NTRS)

Heymsfield, G. M.; Geerts, B.; Tian, L.

1999-01-01

In this paper, TRMM (Tropical Rainfall Measuring Mission Satellite) Precipitation Radar (PR) products are evaluated by means of simultaneous comparisons with data from the high-altitude ER-2 Doppler Radar (EDOP), as well as ground-based radars. The comparison is aimed primarily at the vertical reflectivity structure, which is of key importance in TRMM rain type classification and latent heating estimation. The radars used in this study have considerably different viewing geometries and resolutions, demanding non-trivial mapping procedures in common earth-relative coordinates. Mapped vertical cross sections and mean profiles of reflectivity from the PR, EDOP, and ground-based radars are compared for six cases. These cases cover a stratiform frontal rainband, convective cells of various sizes and stages, and a hurricane. For precipitating systems that are large relative to the PR footprint size, PR reflectivity profiles compare very well to high-resolution measurements thresholded to the PR minimum reflectivity, and derived variables such as bright band height and rain types are accurate, even at high PR incidence angles. It was found that for, the PR reflectivity of convective cells small relative to the PR footprint is weaker than in reality. Some of these differences can be explained by non-uniform beam filling. For other cases where strong reflectivity gradients occur within a PR footprint, the reflectivity distribution is spread out due to filtering by the PR antenna illumination pattern. In these cases, rain type classification may err and be biased towards the stratiform type, and the average reflectivity tends to be underestimated. The limited sensitivity of the PR implies that the upper regions of precipitation systems remain undetected and that the PR storm top height estimate is unreliable, usually underestimating the actual storm top height. This applies to all cases but the discrepancy is larger for smaller cells where limited sensitivity is compounded by incomplete beam filling. Users of level three TRMM PR products should be aware of this scale dependency.

Preexposure prophylaxis-related stigma: strategies to improve uptake and adherence - a narrative review.

PubMed

Haire, Bridget G

2015-01-01

Despite high levels of efficacy, the implementation of preexposure prophylaxis (PrEP) as a strategy to prevent new HIV infection has been slow. Studies show that PrEP works so long as it is taken, making adherence one of the great challenges of effective PrEP implementation alongside issues of access and uptake. Given that effective PrEP use requires ongoing self-administration of pills by people at high risk of HIV acquisition, it is a strategy best understood not as simply biomedical, but as biobehavioral or biopsychosocial, meaning that that social, psychological, cultural, and structural factors all contribute to the success or failure of the intervention. The willingness of people at risk of HIV to take up and adhere to PrEP depends greatly upon social understandings - whether it is seen as effective, as a healthy option, and a socially acceptable strategy for preventing HIV. Stigma - unfavorable associations - can negatively influence the implementation of PrEP. Because it is associated with high-risk sexual activity, PrEP risks multiple stigmas that can differ according to specific cultural conditions. This includes the stigma of being related to HIV (which may also relate to other stigmas, such as homosexuality, sex work, and/or drug use) and the stigma of PrEP being an alternative to condoms (as condom use is associated with responsible sexual activity). PrEP-related stigma has emerged as a significant social harm that can arise from PrEP research participation, reported by trial participants from a range of different trial sites, different trial populations, and spanning different continents. Social marketing needs to redress PrEP-related stigmas through health promotion campaigns aimed at clinicians, HIV-affected communities, and people at high risk of HIV who might benefit from PrEP access. PrEP access needs to be reframed as a positive and responsible option to help people remain HIV-negative.

Oral Pre-Exposure Prophylaxis (PrEP) for Prevention of HIV in Serodiscordant Heterosexual Couples in the United States: Opportunities and Challenges

PubMed Central

Myers, Julie E.; Kurth, Ann E.; Cohen, Stephanie E.; Mannheimer, Sharon B.; Simmons, Janie; Pouget, Enrique R.; Trabold, Nicole; Haberer, Jessica E.

2014-01-01

Abstract Oral HIV pre-exposure prophylaxis (PrEP) is a promising new biomedical prevention approach in which HIV-negative individuals are provided with daily oral antiretroviral medication for the primary prevention of HIV-1. Several clinical trials have demonstrated efficacy of oral PrEP for HIV prevention among groups at high risk for HIV, with adherence closely associated with level of risk reduction. In the United States (US), three groups have been prioritized for initial implementation of PrEP—injection drug users, men who have sex with men at substantial risk for HIV, and HIV-negative partners within serodiscordant heterosexual couples. Numerous demonstration projects involving PrEP implementation among MSM are underway, but relatively little research has been devoted to study PrEP implementation in HIV-serodiscordant heterosexual couples in the US. Such couples face a unique set of challenges to PrEP implementation at the individual, couple, and provider level with regard to PrEP uptake and maintenance, adherence, safety and toxicity, clinical monitoring, and sexual risk behavior. Oral PrEP also provides new opportunities for serodiscordant couples and healthcare providers for primary prevention and reproductive health. This article provides a review of the critical issues, challenges, and opportunities involved in the implementation of oral PrEP among HIV-serodiscordant heterosexual couples in the US. PMID:25045996

Feasibility, Acceptability, and Adherence with Short-Term HIV Preexposure Prophylaxis in Female Sexual Partners of Migrant Miners in Mozambique.

PubMed

Lahuerta, Maria; Zerbe, Allison; Baggaley, Rachel; Falcao, Joana; Ahoua, Laurence; DiMattei, Pietro; Morales, Fernando; Ramiro, Isaias; El-Sadr, Wafaa M

2017-12-01

Preexposure prophylaxis (PrEP) offers protection from HIV acquisition if taken as prescribed. We evaluated the feasibility, acceptability, and adherence with short-term PrEP among female sexual partners of migrant miners in Mozambique. HIV-negative female sexual partners of migrant miners were offered daily tenofovir/emtricitabine (TDF/FTC) for 6 weeks concurrent with miners' return home. Study visits occurred at baseline, week 4, 6, and 8. Dried blood spots (DBSs) were collected at week 4 and 6. Seventy-four women (median age: 42 years) were enrolled, 95% reported having 1 sexual partner and 80% reported never or rarely using condoms. At baseline, 41% had never tested for HIV; 65% were unaware of partners' HIV status. Of all women, 72 (97%) initiated PrEP, 7 (9%) discontinued PrEP before week 6; only 1 due to adverse events. Missed doses in the last week were self-reported by 8% and 3% of women at week 4 and 6, respectively. Of 66 (89%) women with DBS at week 4, 79% had detectable tenofovir diphosphate (TFV-DP) and 44% had levels consistent with ≥4 pills/wk (≥700 fmol/punch). Of 63 (88%) women with DBS at week 6, 76% had detectable TFV-DP and 42% had levels consistent with ≥4 pills/wk. In this first study assessing the use of short-term PrEP, a high percent of female partners of migrant workers initiated PrEP and had detectable DP levels during follow-up. Further efforts are needed to enhance adherence to ensure protection from HIV acquisition. Short-term PrEP offers promise for populations who are at high risk of HIV during specific periods of time.

Association between the level of education and knowledge, attitudes and practices regarding dengue in the Caribbean region of Colombia.

PubMed

Diaz-Quijano, Fredi Alexander; Martínez-Vega, Ruth Aralí; Rodriguez-Morales, Alfonso J; Rojas-Calero, Ronald Alexander; Luna-González, María Lucrecia; Díaz-Quijano, Ronald Giovanny

2018-01-16

Community integration in dengue control requires assessments of knowledge, attitudes and practices (KAPs), which can vary widely according to demographic and educational factors. We aimed to describe and compare the KAPs according to level of education in municipalities in the Caribbean region of Colombia. A survey was administered from October to December 2015, including families selected through probabilistic sampling in eleven municipalities. The analysis focused on the comparative description of the responses according to level of education. The KAP prevalence ratios (PR) according to education were estimated using Poisson regression (robust), including age and sex as adjustment variables. Out of 1057 participants, 1054 (99.7%) surveys were available for analysis, including 614 (58.3%) who had a high school level of education or higher and 440 (41.7%) who had a lower level of education (not high school graduates). The high school graduates showed a higher frequency of correct answers in relation to knowledge about dengue symptoms and transmission. On the other hand, graduates showed a higher probability of practices and attitudes that favor dengue control, including not storing water in containers (PR: 2.2; 95% Confidence Interval [CI]: 1.42-3.43), attend community meetings (PR: 1.33; 95% CI: 1.07-1.65), educate family members and neighbors in prevention measures (PR: 1.35; 95% CI: 1.15-1.59). Level of education could be a key determinant of knowledge of the disease and its transmission, as well as attitudes and practices, especially those that involve the integration of community efforts for dengue control.

Comparing the novel method of assessing PrEP adherence/exposure using hair samples to other pharmacologic and traditional measures.

PubMed

Baxi, Sanjiv M; Liu, Albert; Bacchetti, Peter; Mutua, Gaudensia; Sanders, Eduard J; Kibengo, Freddie M; Haberer, Jessica E; Rooney, James; Hendrix, Craig W; Anderson, Peter L; Huang, Yong; Priddy, Frances; Gandhi, Monica

2015-01-01

The efficacy of pre-exposure prophylaxis (PrEP) in HIV will diminish with poor adherence; pharmacologic measures of drug exposure have proven critical to PrEP trial interpretation. We assessed drug exposure in hair against other pharmacologic and more routinely used measures to assess pill-taking. Participants were randomized to placebo, daily PrEP, or intermittent PrEP to evaluate safety and tolerability of daily versus intermittent tenofovir/emtricitabine (TFV/FTC) in 2 phase II PrEP clinical trials conducted in Africa. Different measures of drug exposure, including self-report, medication event monitoring system (MEMS)-caps openings, and TFV/FTC levels in hair and other biomatrices were compared. At weeks 8 and 16, self-reported pill-taking, MEMS-caps openings, and TFV/FTC levels in hair, plasma, and peripheral blood mononuclear cells (PBMCs) were measured. Regression models evaluated predictors of TFV/FTC concentrations in the 3 biomatrices; correlation coefficients between pharmacologic and nonpharmacologic measures were calculated. Both trials were registered on ClinicalTrials.gov (NCT00931346/NCT00971230). Hair collection was highly feasible and acceptable (100% in week 8; 96% in week 16). In multivariate analysis, strong associations were seen between pharmacologic measures and MEMS-caps openings (all P < 0.001); self-report was only weakly associated with pharmacologic measures. TFV/FTC hair concentrations were significantly correlated with levels in plasma and PBMCs (correlation coefficients, 0.41-0.86, all P < 0.001). Measuring TFV/FTC exposure in small hair samples in African PrEP trials was feasible and acceptable. Hair levels correlated strongly with PBMC, plasma concentrations, and MEMS-caps openings. As in other PrEP trials, self-report was the weakest measure of exposure. Further study of hair TFV/FTC levels in PrEP trials and demonstration projects to assess adherence/exposure is warranted.

Comparing the Novel Method of Assessing PrEP Adherence/Exposure Using Hair Samples to Other Pharmacologic and Traditional Measures

PubMed Central

Baxi, Sanjiv M.; Liu, Albert; Bacchetti, Peter; Mutua, Gaudensia; Sanders, Eduard J.; Kibengo, Freddie M.; Haberer, Jessica E.; Rooney, James; Hendrix, Craig W.; Anderson, Peter L.; Huang, Yong; Priddy, Frances

2015-01-01

Objective: The efficacy of pre-exposure prophylaxis (PrEP) in HIV will diminish with poor adherence; pharmacologic measures of drug exposure have proven critical to PrEP trial interpretation. We assessed drug exposure in hair against other pharmacologic and more routinely used measures to assess pill-taking. Design: Participants were randomized to placebo, daily PrEP, or intermittent PrEP to evaluate safety and tolerability of daily versus intermittent tenofovir/emtricitabine (TFV/FTC) in 2 phase II PrEP clinical trials conducted in Africa. Different measures of drug exposure, including self-report, medication event monitoring system (MEMS)-caps openings, and TFV/FTC levels in hair and other biomatrices were compared. Methods: At weeks 8 and 16, self-reported pill-taking, MEMS-caps openings, and TFV/FTC levels in hair, plasma, and peripheral blood mononuclear cells (PBMCs) were measured. Regression models evaluated predictors of TFV/FTC concentrations in the 3 biomatrices; correlation coefficients between pharmacologic and nonpharmacologic measures were calculated. Both trials were registered on ClinicalTrials.gov (NCT00931346/NCT00971230). Results: Hair collection was highly feasible and acceptable (100% in week 8; 96% in week 16). In multivariate analysis, strong associations were seen between pharmacologic measures and MEMS-caps openings (all P < 0.001); self-report was only weakly associated with pharmacologic measures. TFV/FTC hair concentrations were significantly correlated with levels in plasma and PBMCs (correlation coefficients, 0.41–0.86, all P < 0.001). Conclusions: Measuring TFV/FTC exposure in small hair samples in African PrEP trials was feasible and acceptable. Hair levels correlated strongly with PBMC, plasma concentrations, and MEMS-caps openings. As in other PrEP trials, self-report was the weakest measure of exposure. Further study of hair TFV/FTC levels in PrEP trials and demonstration projects to assess adherence/exposure is warranted. PMID:25296098

Delivery of TDF/FTC for Pre-Exposure Prophylaxis to Prevent HIV-1 Acquisition in Young Adult Men Who Have Sex with Men and Transgender Women of Color using a Urine Adherence Assay.

PubMed

Lalley-Chareczko, Linden; Clark, Devon; Conyngham, S Caitlin; Zuppa, Athena; Moorthy, Ganesh; Mounzer, Karam; Koenig, Helen

2018-06-12

Pre-exposure prophylaxis(PrEP) for HIV prevention with daily TDF/FTC is effective when taken consistently. Currently, there is no objective way to monitor PrEP adherence. Urine has been shown to be highly correlated with plasma tenofovir levels, with urine tenofovir levels >1000ng/mL demonstrating recent(1-2 days) adherence to PrEP. The present study was conducted at an urban community health center in Philadelphia, Pennsylvania. PrEP was administered to 50 young men who have sex with men and transgender women of color using weekly, biweekly, and/or monthly dispensation schedules. Primary objectives were retention at 48 weeks(in care at week 48 and completing ≥50% of medication pick-ups) and adherence assessed by urine tenofovir levels. Risk behaviors and sexually transmitted infections(STIs) diagnoses were also collected. 70% of participants were retained in care at 48 weeks. The proportion of subjects with urine tenofovir consistent with recent adherence was 80%, 74.4%, 82.4%, 82.4% and 69.7% at weeks 4, 12, 24, 36, and 48 respectively. 61 STIs were diagnosed over 231 screenings throughout 48 weeks, with no significant change between the first and second 24-week periods (p=0.43; 0 seroconversions). At week 48, more than half of subjects reported an increase or no change in condom use, an increase in their ability to discuss HIV with partners, and no change in number of sexual partners from baseline. These data demonstrate PrEP can be successfully delivered to a high-risk population with high program retention and medication adherence measured by urine tenofovir levels.

ck2-dependent phosphorylation of progesterone receptors (PR) on Ser81 regulates PR-B isoform-specific target gene expression in breast cancer cells.

PubMed

Hagan, Christy R; Regan, Tarah M; Dressing, Gwen E; Lange, Carol A

2011-06-01

Progesterone receptors (PR) are critical mediators of mammary gland development and contribute to breast cancer progression. Progestin-induced rapid activation of cytoplasmic protein kinases leads to selective regulation of growth-promoting genes by phospho-PR species. Herein, we show that phosphorylation of PR Ser81 is ck2 dependent and progestin regulated in intact cells but also occurs in the absence of PR ligands when cells enter the G(1)/S phase of the cell cycle. T47D breast cancer cells stably expressing a PR-B mutant receptor that cannot be phosphorylated at Ser79/81 (S79/81A) formed fewer soft agar colonies. Regulation of selected genes by PR-B, but not PR-A, also required Ser79/81 phosphorylation for basal and/or progestin-regulated (BIRC3, HSD11β2, and HbEGF) expression. Additionally, wild-type (wt) PR-B, but not S79/81A mutant PR, was robustly recruited to a progesterone response element (PRE)-containing transcriptional enhancer region of BIRC3; abundant ck2 also associated with this region in cells expressing wt but not S79/81A PR. We conclude that phospho-Ser81 PR provides a platform for ck2 recruitment and regulation of selected PR-B target genes. Understanding how ligand-independent PRs function in the context of high levels of kinase activities characteristic of breast cancer is critical to understanding the basis of tumor-specific changes in gene expression and will speed the development of highly selective treatments.

ck2-Dependent Phosphorylation of Progesterone Receptors (PR) on Ser81 Regulates PR-B Isoform-Specific Target Gene Expression in Breast Cancer Cells ▿

PubMed Central

Hagan, Christy R.; Regan, Tarah M.; Dressing, Gwen E.; Lange, Carol A.

2011-01-01

Progesterone receptors (PR) are critical mediators of mammary gland development and contribute to breast cancer progression. Progestin-induced rapid activation of cytoplasmic protein kinases leads to selective regulation of growth-promoting genes by phospho-PR species. Herein, we show that phosphorylation of PR Ser81 is ck2 dependent and progestin regulated in intact cells but also occurs in the absence of PR ligands when cells enter the G1/S phase of the cell cycle. T47D breast cancer cells stably expressing a PR-B mutant receptor that cannot be phosphorylated at Ser79/81 (S79/81A) formed fewer soft agar colonies. Regulation of selected genes by PR-B, but not PR-A, also required Ser79/81 phosphorylation for basal and/or progestin-regulated (BIRC3, HSD11β2, and HbEGF) expression. Additionally, wild-type (wt) PR-B, but not S79/81A mutant PR, was robustly recruited to a progesterone response element (PRE)-containing transcriptional enhancer region of BIRC3; abundant ck2 also associated with this region in cells expressing wt but not S79/81A PR. We conclude that phospho-Ser81 PR provides a platform for ck2 recruitment and regulation of selected PR-B target genes. Understanding how ligand-independent PRs function in the context of high levels of kinase activities characteristic of breast cancer is critical to understanding the basis of tumor-specific changes in gene expression and will speed the development of highly selective treatments. PMID:21518957

Diagnostic value and clinical laboratory associations of antibodies against recombinant ribosomal P0, P1 and P2 proteins and their native heterocomplex in a Caucasian cohort with systemic lupus erythematosus.

PubMed

Barkhudarova, Fidan; Dähnrich, Cornelia; Rosemann, Anke; Schneider, Udo; Stöcker, Winfried; Burmester, Gerd-Rüdiger; Egerer, Karl; Schlumberger, Wolfgang; Hiepe, Falk; Biesen, Robert

2011-02-10

In this study, we sought to determine the diagnostic value and clinical laboratory associations of autoantibodies against recombinant ribosomal P0, P1 and P2 proteins and their native heterocomplex in systemic lupus erythematosus (SLE). Autoantibodies against recombinant ribosomal P proteins (aRibPR0, aRibPR1 and aRibPR2) and antibodies against native ribosomal P heterocomplex (aRibPNH) were determined in sera from patients with SLE (n = 163), systemic sclerosis (n = 66), Sjögren's syndrome (n = 54), rheumatoid arthritis (n = 90) and healthy donors (n = 100) using enzyme-linked immunosorbent assay. Test results were correlated to medical records, including the American College of Rheumatology criteria, the Systemic Lupus Erythematosus Disease Activity Index 2000, laboratory data and medications of all SLE patients. Sensitivities of 22.0% for aRibPR0, 14.9% for aRibPR2, 14.3% for aRibPNH and 10.7% for aRibPR1 were obtained at a specificity of 99%. The assay for aRibPR0 detection demonstrated the best performance in receiver-operating characteristics analysis, with aRibPR0 detectable in 10% of anti-Smith antibody and anti-double-stranded DNA-negative sera at a specificity of 100%. ARibPR0 positivity was associated with lymphocytopenia. ARibPR1+ patients had significantly higher γ-glutamyl transpeptidase (GGT) levels than their aRibPR1- counterparts. No specific damage occurred in aRibP+ lupus patients compared with a group of age-, sex- and nephritis-matched aRibP- lupus patients within 3 years. The determination of antibodies against ribosomal P proteins improves the diagnosis of SLE and should therefore be implemented in upcoming criteria for the diagnosis or classification of SLE. High titers of aRibPR0 can be associated with lymphocytopenia, and high titers of aRibPR1 can be associated with elevated GGT levels. So far, there is no evidence for a prognostic value of aRibPs for damage.

Growth, spectroscopy, and laser performance of a 2.79 μm Cr,Er,Pr:GYSGG radiation-resistant crystal.

PubMed

Luo, Jianqiao; Sun, Dunlu; Zhang, Huili; Guo, Qiang; Fang, Zhongqing; Zhao, Xuyao; Cheng, Maojie; Zhang, Qingli; Yin, Shaotang

2015-09-15

We demonstrate the growth, spectroscopy, and laser performance of a 2.79 μm Cr,Er,Pr:GYSGG radiation-resistant crystal. The lifetimes for the upper laser level (4)I(11/2) and lower laser level (4)I(13/2) are 0.59 and 0.84 ms, respectively, which are due to the doping of the Pr(3+) ions. A maximum pulse energy of 278 mJ operated at 10 Hz and 2.79 μm is obtained when pumped with a flash lamp, which corresponds to the electrical-to-optical efficiency of 0.6% and a slope efficiency of 0.7%. A maximum average power of 2.9 W at 60 Hz is achieved, which corresponds to the electrical-to-optical efficiency of 0.4% and slope efficiency of 0.8%. Compared with a Cr,Er:YSGG crystal, the Cr,Er,Pr:GYSGG crystal can be operated at a higher pulse repetition rate. These results suggest that doping deactivator Pr(3+) ions can effectively decrease the lower laser level lifetime and improve the laser repetition rate. Therefore, the application fields and range of the Cr,Er,Pr:GYSGG laser can be extended greatly due to its properties of radiation resistance and high repetition frequency.

Towards preparedness for PrEP: PrEP awareness and acceptability among MSM at high risk of HIV transmission who use sociosexual media in four Celtic nations: Scotland, Wales, Northern Ireland and The Republic of Ireland: an online survey.

PubMed

Frankis, Jamie S; Young, Ingrid; Lorimer, Karen; Davis, Mark; Flowers, Paul

2016-06-01

To assess the awareness and acceptability of pre-exposure prophylaxis (PrEP) among men who have sex with men (MSM) and use sociosexual media at high risk of HIV infection in four Celtic nations. Cross-sectional study. Online self-complete survey of 386 HIV-negative/status unknown MSM who reported condomless anal intercourse (CAI) with ≥2 men in the last year, recruited from gay sociosexual media. One-third (34.5%, 132/386) of the participants were aware of PrEP but over half (58.5%, 226/356) reported that they would be willing to use PrEP if it were available to them. Only men who regularly tested for HIV every 6 months (adjusted OR 2.89, 95% CI 1.54 to 5.42) were more likely to be aware of PrEP. PrEP acceptability was only associated with reporting ≥5 CAI partners (OR 2.04, 95% CI 1.2 to 3.46) in the last year. Low levels of PrEP awareness were reported across these Celtic nations. Only one-third of high-risk MSM had heard of PrEP but over one-half would be willing to take a daily pill to prevent HIV infection. Sociodemographic factors, commercial gay scene proximity and social network use were unrelated to considering PrEP use. However, those reporting most CAI partners were more likely to consider PrEP use. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

PrPC expression and prion seeding activity in the alimentary tract and lymphoid tissue of deer

PubMed Central

Davenport, Kristen A.; Hoover, Clare E.; Bian, Jifeng; Telling, Glenn C.; Mathiason, Candace K.; Hoover, Edward A.

2017-01-01

The agent responsible for prion diseases is a misfolded form of a normal protein (PrPC). The prion hypothesis stipulates that PrPC must be present for the disease to manifest. Cervid populations across the world are infected with chronic wasting disease, a horizontally-transmissible prion disease that is likely spread via oral exposure to infectious prions (PrPCWD). Though PrPCWD has been identified in many tissues, there has been little effort to characterize the overall PrPC expression in cervids and its relationship to PrPCWD accumulation. We used immunohistochemistry (IHC), western blot and enzyme-linked immunosorbent assay to describe PrPC expression in naïve white-tailed deer. We used real-time, quaking-induced conversion (RT-QuIC) to detect prion seeding activity in CWD-infected deer. We assessed tissues comprising the alimentary tract, alimentary-associated lymphoid tissue and systemic lymphoid tissue from 5 naïve deer. PrPC was expressed in all tissues, though expression was often very low compared to the level in the CNS. IHC identified specific cell types wherein PrPC expression is very high. To compare the distribution of PrPC to PrPCWD, we examined 5 deer with advanced CWD infection. Using RT-QuIC, we detected prion seeding activity in all 21 tissues. In 3 subclinical deer sacrificed 4 months post-inoculation, we detected PrPCWD consistently in alimentary-associated lymphoid tissue, irregularly in alimentary tract tissues, and not at all in the brain. Contrary to our hypothesis that PrPC levels dictate prion accumulation, PrPC expression was higher in the lower gastrointestinal tissues than in the alimentary-associated lymphoid system and was higher in salivary glands than in the oropharyngeal lymphoid tissue. These data suggest that PrPC expression is not the sole driver of prion accumulation and that alimentary tract tissues accumulate prions before centrifugal spread from the brain occurs. PMID:28880938

PrEP implementation in the Asia-Pacific region: opportunities, implementation and barriers

PubMed Central

Zablotska, Iryna; Grulich, Andrew E; Phanuphak, Nittaya; Anand, Tarandeep; Janyam, Surang; Poonkasetwattana, Midnight; Baggaley, Rachel; van Griensven, Frits; Lo, Ying-Ru

2016-01-01

Introduction HIV epidemics in the Asia-Pacific region are concentrated among men who have sex with men (MSM) and other key populations. Pre-exposure prophylaxis (PrEP) is an effective HIV prevention intervention and could be a potential game changer in the region. We discuss the progress towards PrEP implementation in the Asia-Pacific region, including opportunities and barriers. Discussion Awareness about PrEP in the Asia-Pacific is still low and so are its levels of use. A high proportion of MSM who are aware of PrEP are willing to use it. Key PrEP implementation barriers include poor knowledge about PrEP, limited access to PrEP, weak or non-existent HIV prevention programmes for MSM and other key populations, high cost of PrEP, stigma and discrimination against key populations and restrictive laws in some countries. Only several clinical trials, demonstration projects and a few larger-scale implementation studies have been implemented so far in Thailand and Australia. However, novel approaches to PrEP implementation have emerged: researcher-, facility- and community-led models of care, with PrEP services for fee and for free. The WHO consolidated guidelines on HIV testing, treatment and prevention call for an expanded access to PrEP worldwide and have provided guidance on PrEP implementation in the region. Some countries like Australia have released national PrEP guidelines. There are growing community leadership and consultation processes to initiate PrEP implementation in Asia and the Pacific. Conclusions Countries of the Asia-Pacific region will benefit from adding PrEP to their HIV prevention packages, but for many this is a critical step that requires resourcing. Having an impact on the HIV epidemic requires investment. The next years should see the region transitioning from limited PrEP implementation projects to growing access to PrEP and expansion of HIV prevention programmes. PMID:27760688

PrEP implementation in the Asia-Pacific region: opportunities, implementation and barriers.

PubMed

Zablotska, Iryna; Grulich, Andrew E; Phanuphak, Nittaya; Anand, Tarandeep; Janyam, Surang; Poonkasetwattana, Midnight; Baggaley, Rachel; van Griensven, Frits; Lo, Ying-Ru

2016-01-01

HIV epidemics in the Asia-Pacific region are concentrated among men who have sex with men (MSM) and other key populations. Pre-exposure prophylaxis (PrEP) is an effective HIV prevention intervention and could be a potential game changer in the region. We discuss the progress towards PrEP implementation in the Asia-Pacific region, including opportunities and barriers. Awareness about PrEP in the Asia-Pacific is still low and so are its levels of use. A high proportion of MSM who are aware of PrEP are willing to use it. Key PrEP implementation barriers include poor knowledge about PrEP, limited access to PrEP, weak or non-existent HIV prevention programmes for MSM and other key populations, high cost of PrEP, stigma and discrimination against key populations and restrictive laws in some countries. Only several clinical trials, demonstration projects and a few larger-scale implementation studies have been implemented so far in Thailand and Australia. However, novel approaches to PrEP implementation have emerged: researcher-, facility- and community-led models of care, with PrEP services for fee and for free. The WHO consolidated guidelines on HIV testing, treatment and prevention call for an expanded access to PrEP worldwide and have provided guidance on PrEP implementation in the region. Some countries like Australia have released national PrEP guidelines. There are growing community leadership and consultation processes to initiate PrEP implementation in Asia and the Pacific. Countries of the Asia-Pacific region will benefit from adding PrEP to their HIV prevention packages, but for many this is a critical step that requires resourcing. Having an impact on the HIV epidemic requires investment. The next years should see the region transitioning from limited PrEP implementation projects to growing access to PrEP and expansion of HIV prevention programmes.

Prion disease tempo determined by host-dependent substrate reduction

PubMed Central

Mays, Charles E.; Kim, Chae; Haldiman, Tracy; van der Merwe, Jacques; Lau, Agnes; Yang, Jing; Grams, Jennifer; Di Bari, Michele A.; Nonno, Romolo; Telling, Glenn C.; Kong, Qingzhong; Langeveld, Jan; McKenzie, Debbie; Westaway, David; Safar, Jiri G.

2014-01-01

The symptoms of prion infection can take years or decades to manifest following the initial exposure. Molecular markers of prion disease include accumulation of the misfolded prion protein (PrPSc), which is derived from its cellular precursor (PrPC), as well as downregulation of the PrP-like Shadoo (Sho) glycoprotein. Given the overlapping cellular environments for PrPC and Sho, we inferred that PrPC levels might also be altered as part of a host response during prion infection. Using rodent models, we found that, in addition to changes in PrPC glycosylation and proteolytic processing, net reductions in PrPC occur in a wide range of prion diseases, including sheep scrapie, human Creutzfeldt-Jakob disease, and cervid chronic wasting disease. The reduction in PrPC results in decreased prion replication, as measured by the protein misfolding cyclic amplification technique for generating PrPSc in vitro. While PrPC downregulation is not discernible in animals with unusually short incubation periods and high PrPC expression, slowly evolving prion infections exhibit downregulation of the PrPC substrate required for new PrPSc synthesis and as a receptor for pathogenic signaling. Our data reveal PrPC downregulation as a previously unappreciated element of disease pathogenesis that defines the extensive, presymptomatic period for many prion strains. PMID:24430187

High Willingness to Use HIV Pre-Exposure Prophylaxis Among Transgender Women in Argentina.

PubMed

Zalazar, Virginia; Arístegui, Inés; Kerr, Thomas; Marshall, Brandon D L; Romero, Marcela; Sued, Omar; Socías, M Eugenia

2016-01-01

Purpose: In Argentina, transgender women face a disproportionately high prevalence of HIV infection (34%). Although not currently approved in Argentina, pre-exposure prophylaxis (PrEP) may offer a potential effective HIV prevention tool for this population. In this study, we assessed the willingness to use PrEP among transgender women in Argentina. Methods: Data were drawn from a nationwide cross-sectional survey conducted among transgender women in 2013. Using multivariable logistic regression, we assessed the prevalence of and factors associated with willingness to use PrEP among transgender women with negative or unknown HIV status. Results: This study included 337 transgender women (278 HIV negative and 59 with unknown HIV status), most of whom had a history of sex work involvement (81.8%). Overall, 301 (89.3%) expressed willingness to use PrEP. In a multivariable analysis, having casual sexual partners was positively associated with willingness to use PrEP (adjusted odds ratio [AOR]=4.26, 95% confidence interval [CI] 1.73-10.51), while discrimination by healthcare workers was negatively associated (AOR=0.33, 95% CI 0.12-0.88). Conclusion: We found high levels of willingness to use PrEP among transgender women in Argentina, suggesting that there is high perception of HIV risk in this population. However, discrimination by healthcare workers was a strong negative correlate of willingness to use PrEP, suggesting that multilevel interventions that address gender-based stigma in healthcare settings will be critical for the success of PrEP as an HIV prevention strategy in this population.

High Willingness to Use HIV Pre-Exposure Prophylaxis Among Transgender Women in Argentina

PubMed Central

Zalazar, Virginia; Arístegui, Inés; Kerr, Thomas; Marshall, Brandon D.L.; Romero, Marcela; Sued, Omar; Socías, M. Eugenia

2016-01-01

Abstract Purpose: In Argentina, transgender women face a disproportionately high prevalence of HIV infection (34%). Although not currently approved in Argentina, pre-exposure prophylaxis (PrEP) may offer a potential effective HIV prevention tool for this population. In this study, we assessed the willingness to use PrEP among transgender women in Argentina. Methods: Data were drawn from a nationwide cross-sectional survey conducted among transgender women in 2013. Using multivariable logistic regression, we assessed the prevalence of and factors associated with willingness to use PrEP among transgender women with negative or unknown HIV status. Results: This study included 337 transgender women (278 HIV negative and 59 with unknown HIV status), most of whom had a history of sex work involvement (81.8%). Overall, 301 (89.3%) expressed willingness to use PrEP. In a multivariable analysis, having casual sexual partners was positively associated with willingness to use PrEP (adjusted odds ratio [AOR]=4.26, 95% confidence interval [CI] 1.73–10.51), while discrimination by healthcare workers was negatively associated (AOR=0.33, 95% CI 0.12–0.88). Conclusion: We found high levels of willingness to use PrEP among transgender women in Argentina, suggesting that there is high perception of HIV risk in this population. However, discrimination by healthcare workers was a strong negative correlate of willingness to use PrEP, suggesting that multilevel interventions that address gender-based stigma in healthcare settings will be critical for the success of PrEP as an HIV prevention strategy in this population. PMID:28861540

High Rate of Discontinuation May Diminish PrEP Coverage Among Young Men Who Have Sex with Men.

PubMed

Morgan, Ethan; Ryan, Daniel T; Newcomb, Michael E; Mustanski, Brian

2018-05-04

Understanding pre-exposure prophylaxis (PrEP) discontinuation is key to maximizing its effectiveness at the individual and population levels. Data came from the RADAR cohort study of MSM aged 16-29 years, 2015-2017. Participants included those who reported past 6-month PrEP use and discontinued its use by the interview date. Of the 197 participants who had used PrEP in the past 6 months, 65 discontinued use. Primary reasons for PrEP discontinuation included trouble getting to doctor's appointments (14, 21.5%) and issues related to insurance coverage or loss (13, 20.0%). Few (21%) who discontinued spoke to their doctor first, which has important implications for future long acting formulations.

Alzheimer's amyloid-β oligomers rescue cellular prion protein induced tau reduction via the Fyn pathway.

PubMed

Chen, Rong-Jie; Chang, Wei-Wei; Lin, Yu-Chun; Cheng, Pei-Lin; Chen, Yun-Ru

2013-09-18

Amyloid-β (Aβ) and tau are the pathogenic hallmarks in Alzheimer's disease (AD). Aβ oligomers are considered the actual toxic entities, and the toxicity relies on the presence of tau. Recently, Aβ oligomers have been shown to specifically interact with cellular prion protein (PrP(C)) where the role of PrP(C) in AD is still not fully understood. To investigate the downstream mechanism of PrP(C) and Aβ oligomer interaction and their possible relationships to tau, we examined tau expression in human neuroblastoma BE(2)-C cells transfected with murine PrP(C) and studied the effect under Aβ oligomer treatment. By Western blotting, we found that PrP(C) overexpression down-regulated tau protein and Aβ oligomer binding alleviated the tau reduction induced by wild type but not M128V PrP(C), the high AD risk polymorphic allele in human prion gene. PrP(C) lacking the Aβ oligomer binding site was incapable of rescuing the level of tau reduction. Quantitative RT-PCR showed the PrP(C) effect was attributed to tau reduction at the transcription level. Treatment with Fyn pathway inhibitors, Fyn kinase inhibitor PP2 and MEK inhibitor U0126, reversed the PrP(C)-induced tau reduction and Aβ oligomer treatment modulated Fyn kinase activity. The results suggested Fyn pathway regulated Aβ-PrP(C)-tau signaling. Overall, our results demonstrated that PrP(C) down-regulated tau via the Fyn pathway and the effect can be regulated by Aβ oligomers. Our study facilitated the understanding of molecular mechanisms among PrP(C), tau, and Aβ oligomers.

Prion-Protein-interacting Amyloid-β Oligomers of High Molecular Weight Are Tightly Correlated with Memory Impairment in Multiple Alzheimer Mouse Models*

PubMed Central

Kostylev, Mikhail A.; Kaufman, Adam C.; Nygaard, Haakon B.; Patel, Pujan; Haas, Laura T.; Gunther, Erik C.; Vortmeyer, Alexander; Strittmatter, Stephen M.

2015-01-01

Alzheimer disease (AD) is characterized by amyloid-β accumulation, with soluble oligomers (Aβo) being the most synaptotoxic. However, the multivalent and unstable nature of Aβo limits molecular characterization and hinders research reproducibility. Here, we characterized multiple Aβo forms throughout the life span of various AD mice and in post-mortem human brain. Aβo exists in several populations, where prion protein (PrPC)-interacting Aβo is a high molecular weight Aβ assembly present in multiple mice and humans with AD. Levels of PrPC-interacting Aβo match closely with mouse memory and are equal or superior to other Aβ measures in predicting behavioral impairment. However, Aβo metrics vary considerably between mouse strains. Deleting PrPC expression in mice with relatively low PrPC-interacting Aβo (Tg2576) results in partial rescue of cognitive performance as opposed to complete recovery in animals with a high percentage of PrPC-interacting Aβo (APP/PSEN1). These findings highlight the relative contributions and interplay of Aβo forms in AD. PMID:26018073

Daily workload in the embryology laboratory and in vitro fertilization results.

PubMed

Expósito, Antonia; Matorras, Roberto; Mendoza, Rosario; Crisol, Lorena; Martínez-Astorquiza, Txanton; Prieto, Begoña

2010-01-01

To ascertain if the daily activity in the in vitro fertilization (IVF) laboratory is related to pregnancy rates (PR) and fertilization rates (FR) in an IVF program. A retrospective study was performed to compare the PR and the FR obtained in 845 oocyte retrievals (OR) and 713 embryo transfers (ET), according to the daily workload. Different cutoffs were established: < or = 3 OR per day vs. > 3 OR per day; < or = 3 ET per day vs. > 3 ET per day, and also a cutoff considering the global activity in 3 different categories: optimal (level I), overload (level II) and high overload (level III), both the day of OR and of ET. The PR on the days with < or = 3 OR and with > 3 OR were similar, as were the days with < or = 3 ET or > 3 ET. There were no differences in PR when the activity the day of OR was level I, II or III (24.4%, 25.2% and 28.3%, respectively) or when the activity on the day of ET was level I, II or III (29.6%, 37.3% and 23.7%, respectively). We failed to show any adverse results on our IVF program associated with the daily workload.

A systematic investigation of production of synthetic prions from recombinant prion protein.

PubMed

Schmidt, Christian; Fizet, Jeremie; Properzi, Francesca; Batchelor, Mark; Sandberg, Malin K; Edgeworth, Julie A; Afran, Louise; Ho, Sammy; Badhan, Anjna; Klier, Steffi; Linehan, Jacqueline M; Brandner, Sebastian; Hosszu, Laszlo L P; Tattum, M Howard; Jat, Parmjit; Clarke, Anthony R; Klöhn, Peter C; Wadsworth, Jonathan D F; Jackson, Graham S; Collinge, John

2015-12-01

According to the protein-only hypothesis, infectious mammalian prions, which exist as distinct strains with discrete biological properties, consist of multichain assemblies of misfolded cellular prion protein (PrP). A critical test would be to produce prion strains synthetically from defined components. Crucially, high-titre 'synthetic' prions could then be used to determine the structural basis of infectivity and strain diversity at the atomic level. While there have been multiple reports of production of prions from bacterially expressed recombinant PrP using various methods, systematic production of high-titre material in a form suitable for structural analysis remains a key goal. Here, we report a novel high-throughput strategy for exploring a matrix of conditions, additives and potential cofactors that might generate high-titre prions from recombinant mouse PrP, with screening for infectivity using a sensitive automated cell-based bioassay. Overall, approximately 20,000 unique conditions were examined. While some resulted in apparently infected cell cultures, this was transient and not reproducible. We also adapted published methods that reported production of synthetic prions from recombinant hamster PrP, but again did not find evidence of significant infectious titre when using recombinant mouse PrP as substrate. Collectively, our findings are consistent with the formation of prion infectivity from recombinant mouse PrP being a rare stochastic event and we conclude that systematic generation of prions from recombinant PrP may only become possible once the detailed structure of authentic ex vivo prions is solved. © 2015 The Authors.

A systematic investigation of production of synthetic prions from recombinant prion protein

PubMed Central

Schmidt, Christian; Fizet, Jeremie; Properzi, Francesca; Batchelor, Mark; Sandberg, Malin K.; Edgeworth, Julie A.; Afran, Louise; Ho, Sammy; Badhan, Anjna; Klier, Steffi; Linehan, Jacqueline M.; Brandner, Sebastian; Hosszu, Laszlo L. P.; Tattum, M. Howard; Jat, Parmjit; Clarke, Anthony R.; Klöhn, Peter C.; Wadsworth, Jonathan D. F.; Jackson, Graham S.; Collinge, John

2015-01-01

According to the protein-only hypothesis, infectious mammalian prions, which exist as distinct strains with discrete biological properties, consist of multichain assemblies of misfolded cellular prion protein (PrP). A critical test would be to produce prion strains synthetically from defined components. Crucially, high-titre ‘synthetic' prions could then be used to determine the structural basis of infectivity and strain diversity at the atomic level. While there have been multiple reports of production of prions from bacterially expressed recombinant PrP using various methods, systematic production of high-titre material in a form suitable for structural analysis remains a key goal. Here, we report a novel high-throughput strategy for exploring a matrix of conditions, additives and potential cofactors that might generate high-titre prions from recombinant mouse PrP, with screening for infectivity using a sensitive automated cell-based bioassay. Overall, approximately 20 000 unique conditions were examined. While some resulted in apparently infected cell cultures, this was transient and not reproducible. We also adapted published methods that reported production of synthetic prions from recombinant hamster PrP, but again did not find evidence of significant infectious titre when using recombinant mouse PrP as substrate. Collectively, our findings are consistent with the formation of prion infectivity from recombinant mouse PrP being a rare stochastic event and we conclude that systematic generation of prions from recombinant PrP may only become possible once the detailed structure of authentic ex vivo prions is solved. PMID:26631378

Engaging healthcare providers to implement HIV pre-exposure prophylaxis.

PubMed

Krakower, Douglas; Mayer, Kenneth H

2012-11-01

Recent randomized controlled trials have demonstrated that HIV pre-exposure prophylaxis (PrEP) can decrease HIV incidence among several at-risk populations, including men who have sex with men, serodiscordant couples, and heterosexual men and women. As PrEP is a biomedical intervention that requires clinical monitoring and a high level of medication adherence, maximizing the public health effectiveness of PrEP in real-world settings will require the training of a cadre of healthcare providers to prescribe PrEP. Therefore it is critical to understand provider knowledge, practices, and attitudes towards PrEP prescribing, and to develop strategies for engaging and training providers to provide PrEP. Limited numbers of studies have focused on PrEP implementation by healthcare providers. These studies suggest that some providers are knowledgeable about PrEP, but many are not, or express misgivings. Although many clinicians report willingness to provide PrEP, few have prescribed PrEP in clinical practice. Provider comfort and skills in HIV risk assessment are suboptimal, which could limit identification of individuals who are most likely to benefit from PrEP use. Further studies to understand facilitators and barriers to HIV-risk assessment and PrEP prescribing by practicing clinicians are needed. Innovative training strategies and decision-support interventions for providers could optimize PrEP implementation and therefore merit additional research.

Can we afford to offer pre-exposure prophylaxis to MSM in Catalonia? Cost-effectiveness analysis and budget impact assessment.

PubMed

Reyes-Urueña, J; Campbell, C; Diez, E; Ortún, V; Casabona, J

2018-06-01

Pre-exposure prophylaxis (PrEP) effectiveness has been well established. This study aims to assess the cost-effectiveness of providing PrEP, estimate the number of eligible MSM, and its budget impact in Catalonia. Cost-effectiveness analysis compared costs of on daily basis and "on demand" PrEP to prevent one infection with lifetime costs of one HIV infection. We estimated the total cost of providing PrEP by estimating number of eligible MSM, and included in the budget impact assessment antiretroviral and laboratory costs. Costs were lower for the on-demand PrEP group by €64015.1 and the incremental benefit was nearly 15 life-years and 17 quality-adjusted life-years gained. The incremental cost-effectiveness ratio (ICER) was cost-effective at €6281.62 when undiscounted PrEP was given daily. On-demand PrEP can be considered cost-saving in 20 years if the price is reduced by 90%. The number of eligible MSM in Catalonia ranges from 5,989 to 10,972. At current antiretroviral costs, the annual cost would range between €25.3-46.7 million/year (on demand PrEP), and €42.9-78.7 million/year (daily basis PrEP). PrEP is most cost-effective if targeted towards groups with high incidence rates of over 3%/year. Beneficial ICER depends on reducing the current price of Truvada® and ensuring that effectiveness is maintained at high levels.

[Estrogen and progesterone receptors in normal cervix and primary cervical carcinoma].

PubMed

Shen, K; Yueng, W; Ngan, H

1994-05-01

Estrogen and progesterone receptor levels (ER and PR) were measured in 21 specimens of cervical carcinoma and in 17 normal cervix by monoclonal enzyme immunoassay (ER-EIA and PR-EIA). In normal cervix, 88.2% of specimens were ER-positive (more than 15 fmol/mg protein), 74.5% were PR-positive (more than 15 fmol/mg protein) and 74.5% were both ER and PR-positive. In cervical cancer, 66.7% of malignancies were ER-positive, 42.9% were PR-positive and 38.1% were both ER and PR-positive. There was no significant difference in ER status between the normal cervix and cervical cancer (P > 0.05), but PR status and levels in normal cervix were significantly higher than those in cervical carcinoma (P < 0.05). ER levels in squamous cell carcinoma was not correlated to the tumor stage, histologic grade and menopausal status. PR levels in premenopausal patients with squamous cell carcinoma were significantly higher than those in postmenopausal patients (P < 0.01). Adenocarcinoma of the cervix contained significantly more ER and PR than squamous cell carcinoma (P < 0.01, P < 0.05). In addition, serum E2 level was also assayed in 21 patients with cervical cancer. There was significant difference in E2 levels between the premenopausal and postmenopausal patients (P < 0.01). Patients were stratified according to E2 levels, a significant difference in PR level and in ratio of PR/ER was noted (P < 0.05, P < 0.01).

Potential impact of pre-exposure prophylaxis for female sex workers and men who have sex with men in Bangalore, India: a mathematical modelling study.

PubMed

Mitchell, Kate M; Prudden, Holly J; Washington, Reynold; Isac, Shajy; Rajaram, Subramanian P; Foss, Anna M; Terris-Prestholt, Fern; Boily, Marie-Claude; Vickerman, Peter

2016-01-01

In Bangalore, new HIV infections of female sex workers and men who have sex with men continue to occur, despite high condom use. Pre-exposure prophylaxis (PrEP) has high anti-HIV efficacy for men who have sex with men. PrEP demonstration projects are underway amongst Indian female sex workers. We estimated the impact and efficiency of prioritizing PrEP to female sex workers and/or men who have sex with men in Bangalore. A mathematical model of HIV transmission and treatment for female sex workers, clients, men who have sex with men and low-risk groups was parameterized and fitted to Bangalore data. The proportion of transmission attributable (population attributable fraction) to commercial sex and sex between men was calculated. PrEP impact (infections averted, life-years gained) and efficiency (life-years gained/infections averted per 100 person-years on PrEP) were estimated for different levels of PrEP adherence, coverage and prioritization strategies (female sex workers, high-risk men who have sex with men, both female sex workers and high-risk men who have sex with men, or female sex workers with lower condom use), under current conditions and in a scenario with lower baseline condom use amongst key populations. Population attributable fractions for commercial sex and sex between men have declined over time, and they are predicted to account for 19% of all new infections between 2016 and 2025. PrEP could prevent a substantial proportion of infections amongst female sex workers and men who have sex with men in this setting (23%/27% over 5/10 years, with 60% coverage and 50% adherence), which could avert 2.9%/4.3% of infections over 5/10 years in the whole Bangalore population. Impact and efficiency in the whole population was greater if female sex workers were prioritized. Efficiency increased, but impact decreased, if only female sex workers with lower condom use were given PrEP. Greater impact and efficiency was predicted for the scenario with lower condom use. PrEP could be beneficial for female sex workers and men who have sex with men in Bangalore, and give some benefits in the general population, especially in similar settings with lower condom use levels.

Deep sequencing of small RNA libraries from human prostate epithelial and stromal cells reveal distinct pattern of microRNAs primarily predicted to target growth factors.

PubMed

Singh, Savita; Zheng, Yun; Jagadeeswaran, Guru; Ebron, Jey Sabith; Sikand, Kavleen; Gupta, Sanjay; Sunker, Ramanjulu; Shukla, Girish C

2016-02-28

Complex epithelial and stromal cell interactions are required during the development and progression of prostate cancer. Regulatory small non-coding microRNAs (miRNAs) participate in the spatiotemporal regulation of messenger RNA (mRNA) and regulation of translation affecting a large number of genes involved in prostate carcinogenesis. In this study, through deep-sequencing of size fractionated small RNA libraries we profiled the miRNAs of prostate epithelial (PrEC) and stromal (PrSC) cells. Over 50 million reads were obtained for PrEC in which 860,468 were unique sequences. Similarly, nearly 76 million reads for PrSC were obtained in which over 1 million were unique reads. Expression of many miRNAs of broadly conserved and poorly conserved miRNA families were identified. Sixteen highly expressed miRNAs with significant change in expression in PrSC than PrEC were further analyzed in silico. ConsensusPathDB showed the target genes of these miRNAs were significantly involved in adherence junction, cell adhesion, EGRF, TGF-β and androgen signaling. Let-7 family of tumor-suppressor miRNAs expression was highly pervasive in both, PrEC and PrSC cells. In addition, we have also identified several miRNAs that are unique to PrEC or PrSC cells and their predicted putative targets are a group of transcription factors. This study provides perspective on the miRNA expression in PrEC and PrSC, and reveals a global trend in miRNA interactome. We conclude that the most abundant miRNAs are potential regulators of development and differentiation of the prostate gland by targeting a set of growth factors. Additionally, high level expression of the most members of let-7 family miRNAs suggests their role in the fine tuning of the growth and proliferation of prostate epithelial and stromal cells. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Exploring strategies for PrEP adherence and dosing preferences in the context of sexualized recreational drug use among MSM: a qualitative study.

PubMed

Closson, Elizabeth F; Mitty, Jennifer A; Malone, Jowanna; Mayer, Kenneth H; Mimiaga, Matthew J

2018-02-01

The use of recreational drugs while having sex is associated with increased HIV incidence among men who have sex with men (MSM). Taking a daily antiretroviral pill, or pre-exposure prophylaxis (PrEP) is a biomedical intervention to prevent HIV. However, the efficacy of PrEP is closely tied with high levels of adherence. While PrEP has the potential to reduce HIV acquisition, the use of recreational drugs may impede adherence. We explored perceptions of PrEP utilization and regimen preferences among 40 HIV-negative, MSM who reported concurrent recreational drug use and condomless anal sex with a man. Semi-structured qualitative interviews were conducted and the data were analyzed using a qualitative descriptive approach. Participants perceived that it would be challenging to take PrEP while high on crystal meth, crack, powder cocaine, ecstasy and/or GHB. However, men identified strategies for using PrEP when they were not high on these drugs, including taking the pill when they started their day and integrating PrEP into an established routine, such as when taking other medications or preparing for sex. PrEP regimen preferences seemed to be shaped by the frequency in which participants used drugs and their ability to plan for sex. Taking PrEP everyday was appealing for those who regularly engaged in sexualized recreational drug use. Accounts depict these sexual interactions as frequent but unpredictable. A daily regimen would allow them to be prepared for sex without having to plan. An event-driven regimen was acceptable to men who occasionally used recreational drugs in the context of sex. For this group, sex usually occurred was generally prearranged. Patterns of sex and recreational drug use figured largely into participants' framings of how they would use PrEP. These behaviors will likely play a role in the uptake of and adherence to PrEP among this population.

Evaluation of factors associated with severe and frequent back pain in high school athletes.

PubMed

Noll, Matias; Silveira, Erika Aparecida; Avelar, Ivan Silveira de

2017-01-01

Several studies have shown that half of all young athletes experience back pain (BP). However, high intensity and frequency of BP may be harmful, and the factors associated with BP severity have not been investigated in detail. Here, we investigated the factors associated with a high intensity and high frequency of BP in high school athletes. We included 251 athletes (173 boys and 78 girls [14-20 years old]) in this cross-sectional study. The dependent variables were a high frequency and high intensity of BP, and the independent variables were demographic, socioeconomic, psychosocial, hereditary, anthropometric, behavioural, and postural factors and the level of exercise. The effect measure is presented as prevalence ratio (PR) with 95% confidence interval (CI). Of 251 athletes, 104 reported BP; thus, only these athletes were included in the present analysis. Results of multivariable analysis showed an association between high BP intensity and time spent using a computer (PR: 1.15, CI: 1.01-1.33), posture while writing (PR: 1.41, CI: 1.27-1.58), and posture while using a computer (PR: 1.39, CI: 1.26-1.54). Multivariable analysis also revealed an association of high BP frequency with studying in bed (PR: 1.19, CI: 1.01-1.40) and the method of carrying a backpack (PR: 1.19, CI: 1.01-1.40). In conclusion, we found that behavioural and postural factors are associated with a high intensity and frequency of BP. To the best of our knowledge, this study is the first to compare different intensities and frequencies of BP, and our results may help physicians and coaches to better understand BP in high school athletes.

Evaluation of factors associated with severe and frequent back pain in high school athletes

PubMed Central

Noll, Matias; Silveira, Erika Aparecida; de Avelar, Ivan Silveira

2017-01-01

Several studies have shown that half of all young athletes experience back pain (BP). However, high intensity and frequency of BP may be harmful, and the factors associated with BP severity have not been investigated in detail. Here, we investigated the factors associated with a high intensity and high frequency of BP in high school athletes. We included 251 athletes (173 boys and 78 girls [14–20 years old]) in this cross-sectional study. The dependent variables were a high frequency and high intensity of BP, and the independent variables were demographic, socioeconomic, psychosocial, hereditary, anthropometric, behavioural, and postural factors and the level of exercise. The effect measure is presented as prevalence ratio (PR) with 95% confidence interval (CI). Of 251 athletes, 104 reported BP; thus, only these athletes were included in the present analysis. Results of multivariable analysis showed an association between high BP intensity and time spent using a computer (PR: 1.15, CI: 1.01–1.33), posture while writing (PR: 1.41, CI: 1.27–1.58), and posture while using a computer (PR: 1.39, CI: 1.26–1.54). Multivariable analysis also revealed an association of high BP frequency with studying in bed (PR: 1.19, CI: 1.01–1.40) and the method of carrying a backpack (PR: 1.19, CI: 1.01–1.40). In conclusion, we found that behavioural and postural factors are associated with a high intensity and frequency of BP. To the best of our knowledge, this study is the first to compare different intensities and frequencies of BP, and our results may help physicians and coaches to better understand BP in high school athletes. PMID:28222141

Sanitation and water supply coverage thresholds associated with active trachoma: Modeling cross-sectional data from 13 countries

PubMed Central

Boisson, Sophie; Willis, Rebecca; Bakhtiari, Ana; al-Khatib, Tawfik; Amer, Khaled; Batcho, Wilfrid; Courtright, Paul; Dejene, Michael; Goepogui, Andre; Kalua, Khumbo; Kebede, Biruck; Macleod, Colin K.; Madeleine, Kouakou IIunga Marie; Mbofana, Mariamo Saide Abdala; Mpyet, Caleb; Ndjemba, Jean; Olobio, Nicholas; Pavluck, Alexandre L.; Sokana, Oliver; Southisombath, Khamphoua; Taleo, Fasihah

2018-01-01

Background Facial cleanliness and sanitation are postulated to reduce trachoma transmission, but there are no previous data on community-level herd protection thresholds. We characterize associations between active trachoma, access to improved sanitation facilities, and access to improved water sources for the purpose of face washing, with the aim of estimating community-level or herd protection thresholds. Methods and findings We used cluster-sampled Global Trachoma Mapping Project data on 884,850 children aged 1–9 years from 354,990 households in 13 countries. We employed multivariable mixed-effects modified Poisson regression models to assess the relationships between water and sanitation coverage and trachomatous inflammation—follicular (TF). We observed lower TF prevalence among those with household-level access to improved sanitation (prevalence ratio, PR = 0.87; 95%CI: 0.83–0.91), and household-level access to an improved washing water source in the residence/yard (PR = 0.81; 95%CI: 0.75–0.88). Controlling for household-level water and latrine access, we found evidence of community-level protection against TF for children living in communities with high sanitation coverage (PR80–90% = 0.87; 95%CI: 0.73–1.02; PR90–100% = 0.76; 95%CI: 0.67–0.85). Community sanitation coverage levels greater than 80% were associated with herd protection against TF (PR = 0.77; 95%CI: 0.62–0.97)—that is, lower TF in individuals whose households lacked individual sanitation but who lived in communities with high sanitation coverage. For community-level water coverage, there was no apparent threshold, although we observed lower TF among several of the higher deciles of community-level water coverage. Conclusions Our study provides insights into the community water and sanitation coverage levels that might be required to best control trachoma. Our results suggest access to adequate water and sanitation can be important components in working towards the 2020 target of eliminating trachoma as a public health problem. PMID:29357365

Validation of TRMM precipitation radar monthly rainfall estimates over Brazil

NASA Astrophysics Data System (ADS)

Franchito, Sergio H.; Rao, V. Brahmananda; Vasques, Ana C.; Santo, Clovis M. E.; Conforte, Jorge C.

2009-01-01

In an attempt to validate the Tropical Rainfall Measuring Mission (TRMM) precipitation radar (PR) over Brazil, TRMM PR estimates are compared with rain gauge station data from Agência Nacional de Energia Elétrica (ANEEL). The analysis is conducted on a seasonal basis and considers five geographic regions with different precipitation regimes. The results showed that TRMM PR seasonal rainfall is well correlated with ANEEL rainfall (correlation coefficients are significant at the 99% confidence level) over most of Brazil. The random and systematic errors of TRMM PR are sensitive to seasonal and regional differences. During December to February and March to May, TRMM PR rainfall is reliable over Brazil. In June to August (September to November) TRMM PR estimates are only reliable in the Amazonian and southern (Amazonian and southeastern) regions. In the other regions the relative RMS errors are larger than 50%, indicating that the random errors are high.

Tenofovir Disoproxil Fumarate Fails to Prevent HIV Acquisition or the Establishment of a Viral Reservoir: Two Case Reports.

PubMed

Fox, Julie; Brady, Michael; Alexander, Hannah; Davies, Olubanke; Robinson, Nicola; Pace, Mathew; Else, Laura; Cason, John; Khoo, Saye; Back, David; Fidler, Sarah; Frater, John

2016-03-01

The use of antiretrovirals as pre-exposure prophylaxis (PrEP) is highly efficacious in HIV prevention. The World Health Organization recently recommended Truvada(®) (Gilead Sciences, Inc.) or tenofovir disoproxil fumarate (TDF) for high-risk individuals, with limited data for single-agent TDF PrEP in men who have sex with men (MSM). We report two cases of TDF PrEP failure in MSM who had received long-term TDF for hepatitis B infection and had therapeutic levels of drug immediately after HIV acquisition. Rapid antiretroviral intensification at diagnosis of acute HIV infection failed to limit immune dysfunction or prevent the establishment of a viral reservoir.

Effect of Nanoscale Fillers on the Local Mechanical Behavior of Polymer Nanocomposites

DTIC Science & Technology

2009-12-01

the interparticle spacing can be related to the particle volume fraction, vp, and the particle diameter, d, by [2] r = d 6v„ d) I I (b) Figure...VGCNFs), namely as- fabricated (PR-24-XT PS), high temperature hear treated (PR-24-XT-HHT-LD), and high temperature hear treated and oxidatively...Therefore, hear treatment had a severe effect on the fracture toughness of composites with embedded VGCNFs. This agrees with composite level

Divergent prion strain evolution driven by PrPC expression level in transgenic mice

PubMed Central

Le Dur, Annick; Laï, Thanh Lan; Stinnakre, Marie-George; Laisné, Aude; Chenais, Nathalie; Rakotobe, Sabine; Passet, Bruno; Reine, Fabienne; Soulier, Solange; Herzog, Laetitia; Tilly, Gaëlle; Rézaei, Human; Béringue, Vincent; Vilotte, Jean-Luc; Laude, Hubert

2017-01-01

Prions induce a fatal neurodegenerative disease in infected host brain based on the refolding and aggregation of the host-encoded prion protein PrPC into PrPSc. Structurally distinct PrPSc conformers can give rise to multiple prion strains. Constrained interactions between PrPC and different PrPSc strains can in turn lead to certain PrPSc (sub)populations being selected for cross-species transmission, or even produce mutation-like events. By contrast, prion strains are generally conserved when transmitted within the same species, or to transgenic mice expressing homologous PrPC. Here, we compare the strain properties of a representative sheep scrapie isolate transmitted to a panel of transgenic mouse lines expressing varying levels of homologous PrPC. While breeding true in mice expressing PrPC at near physiological levels, scrapie prions evolve consistently towards different strain components in mice beyond a certain threshold of PrPC overexpression. Our results support the view that PrPC gene dosage can influence prion evolution on homotypic transmission. PMID:28112164

Estrogen and progesterone receptors in normal cervix and primary cervical carcinoma.

PubMed

Shen, K; Yueng, W; Ngan, H

1994-09-01

Estrogen and progesterone receptors (ER, PR) were measured in 21 specimens of cervical cancer and in 17 specimens of normal cervix by monoclonal enzyme immunoassay (EIA). In normal cervix, 88.2% of specimens were ER-positive ( > 15 fmol/mg protein), 74.5% were PR-positive ( > 15 fmol/mg protein) and 74.5% were both ER- and PR-positive. In cervical cancer, 66.7% were ER-positive, 42.9% were PR-positive and 38.1% were both ER- and PR- positive. There was no significant difference in ER status between the normal cervix and cervical cancer (P > 0.05), but PR status and levels in normal cervix were significantly higher than those in cervical carcinoma (P < 0.05). ER levels in squamous cell carcinoma was not correlated to the tumor stage, histologic grade and menopausal status. PR levels in premenopausal patients with squamous cell carcinoma were significantly higher than those in postmenopausal patients (P < 0.01). Adenocarcinoma of the cervix contained significantly more ER and PR than squamous cell carcinoma (P < 0.01, P < 0.05). In addition, serum E2 level was also assayed in 21 patients with cervical cancer. There was significant difference in E2 levels between the premenopausal and postmenopausal patients (P < 0.01). Patients were stratified according to E2 levels, a significant difference in PR levels and in the ratio of PR/ER was noted (P < 0.05, P < 0.01).

Discovery of Novel Anti-prion Compounds Using In Silico and In Vitro Approaches

PubMed Central

Hyeon, Jae Wook; Choi, Jiwon; Kim, Su Yeon; Govindaraj, Rajiv Gandhi; Jam Hwang, Kyu; Lee, Yeong Seon; An, Seong Soo A.; Lee, Myung Koo; Joung, Jong Young; No, Kyoung Tai; Lee, Jeongmin

2015-01-01

Prion diseases are associated with the conformational conversion of the physiological form of cellular prion protein (PrPC) to the pathogenic form, PrPSc. Compounds that inhibit this process by blocking conversion to the PrPSc could provide useful anti-prion therapies. However, no suitable drugs have been identified to date. To identify novel anti-prion compounds, we developed a combined structure- and ligand-based virtual screening system in silico. Virtual screening of a 700,000-compound database, followed by cluster analysis, identified 37 compounds with strong interactions with essential hotspot PrP residues identified in a previous study of PrPC interaction with a known anti-prion compound (GN8). These compounds were tested in vitro using a multimer detection system, cell-based assays, and surface plasmon resonance. Some compounds effectively reduced PrPSc levels and one of these compounds also showed a high binding affinity for PrPC. These results provide a promising starting point for the development of anti-prion compounds. PMID:26449325

Disruption of prion protein-HOP engagement impairs glioblastoma growth and cognitive decline and improves overall survival.

PubMed

Lopes, M H; Santos, T G; Rodrigues, B R; Queiroz-Hazarbassanov, N; Cunha, I W; Wasilewska-Sampaio, A P; Costa-Silva, B; Marchi, F A; Bleggi-Torres, L F; Sanematsu, P I; Suzuki, S H; Oba-Shinjo, S M; Marie, S K N; Toulmin, E; Hill, A F; Martins, V R

2015-06-01

Glioblastomas (GBMs) are resistant to current therapy protocols and identification of molecules that target these tumors is crucial. Interaction of secreted heat-shock protein 70 (Hsp70)-Hsp90-organizing protein (HOP) with cellular prion protein (PrP(C)) triggers a large number of trophic effects in the nervous system. We found that both PrP(C) and HOP are highly expressed in human GBM samples relative to non-tumoral tissue or astrocytoma grades I-III. High levels of PrP(C) and HOP were associated with greater GBM proliferation and lower patient survival. HOP-PrP(C) binding increased GBM proliferation in vitro via phosphatidylinositide 3-kinase and extracellular-signal-regulated kinase pathways, and a HOP peptide mimicking the PrP(C) binding site (HOP230-245) abrogates this effect. PrP(C) knockdown impaired tumor growth and increased survival of mice with tumors. In mice, intratumor delivery of HOP230-245 peptide impaired proliferation and promoted apoptosis of GBM cells. In addition, treatment with HOP230-245 peptide inhibited tumor growth, maintained cognitive performance and improved survival. Thus, together, the present results indicate that interfering with PrP(C)-HOP engagement is a promising approach for GBM therapy.

In situ light responses of the proteorhodopsin-bearing Antarctic sea-ice bacterium, Psychroflexus torques.

PubMed

Burr, David J; Martin, Andrew; Maas, Elizabeth W; Ryan, Ken G

2017-09-01

Proteorhodopsin (PR) is a wide-spread protein found in many marine prokaryotes. PR allows for the potential conversion of solar energy to ATP, possibly assisting in cellular growth and survival during periods of high environmental stress. PR utilises either blue or green light through a single amino acid substitution. We incubated the PR-bearing bacterium Psychroflexus torquis 50 cm deep within Antarctic sea ice for 13 days, exposing cultures to diurnal fluctuations in light and temperature. Enhanced growth occurred most prominently in cultures incubated under irradiance levels of ∼50 μmol photons m -2  s -1 , suggesting PR provides a strong selective advantage. In addition, cultures grown under blue light yielded over 5.5 times more live cells per photon compared to green-light incubations. Because P. torquis expresses an apparently 'green-shifted' PR gene variant, this finding infers that the spectral tuning of PR is more complex than previously thought. This study supports the theory that PR provides additional energy to bacteria under sub-optimal conditions, and raises several points of interest to be addressed by future research.

S1PR3 Signaling Drives Bacterial Killing and Is Required for Survival in Bacterial Sepsis.

PubMed

Hou, JinChao; Chen, QiXing; Wu, XiaoLiang; Zhao, DongYan; Reuveni, Hadas; Licht, Tamar; Xu, MengLong; Hu, Hu; Hoeft, Andreas; Ben-Sasson, Shmuel A; Shu, Qiang; Fang, XiangMing

2017-12-15

Efficient elimination of pathogenic bacteria is a critical determinant in the outcome of sepsis. Sphingosine-1-phosphate receptor 3 (S1PR3) mediates multiple aspects of the inflammatory response during sepsis, but whether S1PR3 signaling is necessary for eliminating the invading pathogens remains unknown. To investigate the role of S1PR3 in antibacterial immunity during sepsis. Loss- and gain-of-function experiments were performed using cell and murine models. S1PR3 levels were determined in patients with sepsis and healthy volunteers. S1PR3 protein levels were up-regulated in macrophages upon bacterial stimulation. S1pr3 -/- mice showed increased mortality and increased bacterial burden in multiple models of sepsis. The transfer of wild-type bone marrow-derived macrophages rescued S1pr3 -/- mice from lethal sepsis. S1PR3-overexpressing macrophages further ameliorated the mortality rate of sepsis. Loss of S1PR3 led to markedly decreased bacterial killing in macrophages. Enhancing endogenous S1PR3 activity using a peptide agonist potentiated the macrophage bactericidal function and improved survival rates in multiple models of sepsis. Mechanically, the reactive oxygen species levels were decreased and phagosome maturation was delayed in S1pr3 -/- macrophages due to impaired recruitment of vacuolar protein-sorting 34 to the phagosomes. In addition, S1RP3 expression levels were elevated in monocytes from patients with sepsis. Higher levels of monocytic S1PR3 were associated with efficient intracellular bactericidal activity, better immune status, and preferable outcomes. S1PR3 signaling drives bacterial killing and is essential for survival in bacterial sepsis. Interventions targeting S1PR3 signaling could have translational implications for manipulating the innate immune response to combat pathogens.

Towards a fair consideration of PrEP as part of combination HIV prevention in Latin America

PubMed Central

Ravasi, Giovanni; Grinsztejn, Beatriz; Baruch, Ricardo; Guanira, Juan Vicente; Luque, Ricardo; Cáceres, Carlos F; Ghidinelli, Massimo

2016-01-01

Introduction Despite progress in scaling up antiretroviral treatment, HIV prevention strategies have not been successful in significantly curbing HIV incidence in Latin America. HIV prevention interventions need to be expanded to target the most affected key populations with a combination approach, including new high impact technologies. Oral pre-exposure prophylaxis (PrEP) is recommended as additional prevention choice for individuals at higher risk of infection and could become a cost-effective prevention tool. We discuss the barriers and solutions for a fair consideration of PrEP as part of combination HIV prevention strategies in Latin America. Discussion Although demonstration projects are ongoing or being planned in a number of countries, to date no Latin American country has implemented a public PrEP programme. The knowledge of policymakers about PrEP implementation needs to be strengthened, and programmatic guidance and cost estimate tools need to be developed to support adequate planning. Despite high levels of awareness among health providers, especially if engaged in HIV or key population care, willingness to prescribe PrEP is still low due to the lack of national policies and guidelines. Key populations, especially men who have sex with men, transgender women and sex workers, have been engaged in demonstration projects, and qualitative research shows high awareness and willingness to use PrEP, especially if accessible in the public sector for free or at affordable price. Concerns of safety, adherence, effectiveness and risk compensation need to be addressed through targeted social communication strategies to improve PrEP knowledge and stimulate demand. Alliance among policymakers, civil society and representatives from key populations, healthcare providers and researchers will be critical for the design and successful implementation of PrEP demonstration projects of locally adapted delivery models. The use of mechanisms of joint negotiation and procurement of antiretrovirals could reduce costs and significantly increase the cost-effectiveness of PrEP. Conclusions PrEP is an additional prevention tool and should be implemented in combination and synergy with other prevention interventions. PrEP programmes should target high-risk individuals from key populations for higher cost-effectiveness. Demonstration projects may generate strategic information for and lead to the implementation of full-scale PrEP programmes. PMID:27760687

Towards a fair consideration of PrEP as part of combination HIV prevention in Latin America.

PubMed

Ravasi, Giovanni; Grinsztejn, Beatriz; Baruch, Ricardo; Guanira, Juan Vicente; Luque, Ricardo; Cáceres, Carlos F; Ghidinelli, Massimo

2016-01-01

Despite progress in scaling up antiretroviral treatment, HIV prevention strategies have not been successful in significantly curbing HIV incidence in Latin America. HIV prevention interventions need to be expanded to target the most affected key populations with a combination approach, including new high impact technologies. Oral pre-exposure prophylaxis (PrEP) is recommended as additional prevention choice for individuals at higher risk of infection and could become a cost-effective prevention tool. We discuss the barriers and solutions for a fair consideration of PrEP as part of combination HIV prevention strategies in Latin America. Although demonstration projects are ongoing or being planned in a number of countries, to date no Latin American country has implemented a public PrEP programme. The knowledge of policymakers about PrEP implementation needs to be strengthened, and programmatic guidance and cost estimate tools need to be developed to support adequate planning. Despite high levels of awareness among health providers, especially if engaged in HIV or key population care, willingness to prescribe PrEP is still low due to the lack of national policies and guidelines. Key populations, especially men who have sex with men, transgender women and sex workers, have been engaged in demonstration projects, and qualitative research shows high awareness and willingness to use PrEP, especially if accessible in the public sector for free or at affordable price. Concerns of safety, adherence, effectiveness and risk compensation need to be addressed through targeted social communication strategies to improve PrEP knowledge and stimulate demand. Alliance among policymakers, civil society and representatives from key populations, healthcare providers and researchers will be critical for the design and successful implementation of PrEP demonstration projects of locally adapted delivery models. The use of mechanisms of joint negotiation and procurement of antiretrovirals could reduce costs and significantly increase the cost-effectiveness of PrEP. PrEP is an additional prevention tool and should be implemented in combination and synergy with other prevention interventions. PrEP programmes should target high-risk individuals from key populations for higher cost-effectiveness. Demonstration projects may generate strategic information for and lead to the implementation of full-scale PrEP programmes.

Sources of social support associated with health and quality of life: a cross-sectional study among Canadian and Latin American older adults

PubMed Central

Bélanger, Emmanuelle; Ahmed, Tamer; Vafaei, Afshin; Curcio, Carmen Lucia; Phillips, Susan P; Zunzunegui, Maria Victoria

2016-01-01

Objectives To examine whether the association between emotional support and indicators of health and quality of life differs between Canadian and Latin American older adults. Design Cross-sectional analysis of the International Mobility in Aging Study (IMIAS). Social support from friends, family members, children and partner was measured with a previously validated social network and support scale (IMIAS-SNSS). Low social support was defined as ranking in the lowest site-specific quartile. Prevalence ratios (PR) of good health, depression and good quality of life were estimated with Poisson regression models, adjusting for age, gender, education, income and disability in activities of daily living. Setting Kingston and Saint-Hyacinthe in Canada, Manizales in Colombia and Natal in Brazil. Participants 1600 community-dwelling adults aged 65–74 years, n=400 at each site. Outcome measures Likert scale question on self-rated health, Center for Epidemiological Studies Depression Scale and 10-point analogical quality-of-life (QoL) scale. Results Relationships between social support and study outcomes differed between Canadian and Latin American older adults. Among Canadians, those without a partner had a lower prevalence of good health (PR=0.90; 95% CI 0.82 to 0.98), and those with high support from friends had a higher prevalence of good health (PR=1.09; 95% CI 1.01 to 1.18). Among Latin Americans, depression was lower among those with high levels of support from family (PR=0.63; 95% CI 0.48 to 0.83), children (PR=0.60; 95% CI 0.45 to 0.80) and partner (PR=0.57; 95% CI 0.31 to 0.77); good QoL was associated with high levels of support from children (PR=1.54; 95% CI 1.20 to 1.99) and partner (PR=1.31; 95% CI 1.03 to 1.67). Conclusions Among older adults, different sources of support were relevant to health across societies. Support from friends and having a partner were related to good health in Canada, whereas in Latin America, support from family, children and partner were associated with less depression and better QoL. PMID:27354077

Functional Knowledge of Pre-Exposure Prophylaxis for HIV Prevention Among Participants in a Web-Based Survey of Sexually Active Gay, Bisexual, and Other Men Who Have Sex With Men: Cross-Sectional Study

PubMed Central

2018-01-01

Background Awareness of pre-exposure prophylaxis (PrEP) for HIV prevention is increasing, but little is known about the functional knowledge of PrEP and its impact on willingness to use PrEP. Objective The objective of this study was to assess the functional knowledge of PrEP among a sample of gay, bisexual, and other men who have sex with men (MSM) participating in a Web-based survey of sexually active MSM. Methods Men at least 18 years old, residing in the United States, and reporting sex with a man in the previous 6 months were recruited through social networking websites. PrEP functional knowledge included the following 4 questions (1) efficacy of consistent PrEP use, (2) inconsistent PrEP use and effectiveness, (3) PrEP and condom use, and (4) effectiveness at reducing sexually transmitted infections (STIs). Ordinal logistic regression was used to identify respondent characteristics associated with PrEP functional knowledge. In a subsample of participants responding to HIV prevention questions, we compared willingness to use PrEP by response to PrEP functional knowledge using logistic regression analysis adjusted for age, race and ethnicity, and education level. Results Among 573 respondents, PrEP knowledge was high regarding adherence (488/573, 85.2%), condom use (532/573, 92.8%), and STIs (480/573, 83.8%), but only 252/573 (44.0%) identified the correct efficacy. Lower functional PrEP knowledge was associated with minority race/ethnicity (P=.005), lower education (P=.01), and not having an HIV test in the past year (P=.02). Higher PrEP knowledge was associated with willingness to use PrEP (P=.009). Younger age was not associated with higher PrEP functional knowledge or willingness to use PrEP. Conclusions PrEP knowledge was generally high in our study, including condom use and consistent use but may be lacking in higher risk MSM. The majority of respondents did not correctly identify PrEP efficacy with consistent use, which could impact motivation to seek out PrEP for HIV prevention. Targeted messaging to increase PrEP knowledge may increase PrEP use. PMID:29362213

Protease resistance of infectious prions is suppressed by removal of a single atom in the cellular prion protein.

PubMed

Leske, Henning; Hornemann, Simone; Herrmann, Uli Simon; Zhu, Caihong; Dametto, Paolo; Li, Bei; Laferriere, Florent; Polymenidou, Magdalini; Pelczar, Pawel; Reimann, Regina Rose; Schwarz, Petra; Rushing, Elisabeth Jane; Wüthrich, Kurt; Aguzzi, Adriano

2017-01-01

Resistance to proteolytic digestion has long been considered a defining trait of prions in tissues of organisms suffering from transmissible spongiform encephalopathies. Detection of proteinase K-resistant prion protein (PrPSc) still represents the diagnostic gold standard for prion diseases in humans, sheep and cattle. However, it has become increasingly apparent that the accumulation of PrPSc does not always accompany prion infections: high titers of prion infectivity can be reached also in the absence of protease resistant PrPSc. Here, we describe a structural basis for the phenomenon of protease-sensitive prion infectivity. We studied the effect on proteinase K (PK) resistance of the amino acid substitution Y169F, which removes a single oxygen atom from the β2-α2 loop of the cellular prion protein (PrPC). When infected with RML or the 263K strain of prions, transgenic mice lacking wild-type (wt) PrPC but expressing MoPrP169F generated prion infectivity at levels comparable to wt mice. The newly generated MoPrP169F prions were biologically indistinguishable from those recovered from prion-infected wt mice, and elicited similar pathologies in vivo. Surprisingly, MoPrP169F prions showed greatly reduced PK resistance and density gradient analyses showed a significant reduction in high-density aggregates. Passage of MoPrP169F prions into mice expressing wt MoPrP led to full recovery of protease resistance, indicating that no strain shift had taken place. We conclude that a subtle structural variation in the β2-α2 loop of PrPC affects the sensitivity of PrPSc to protease but does not impact prion replication and infectivity. With these findings a specific structural feature of PrPC can be linked to a physicochemical property of the corresponding PrPSc.

Molecular cloning and characterisation of a pathogenesis-related protein CsPR10 from Crocus sativus.

PubMed

Gómez-Gómez, L; Rubio-Moraga, A; Ahrazem, O

2011-03-01

Plants have developed many mechanisms to protect themselves against most potential microbial pathogens and diseases. Among these mechanisms, pathogenesis-related proteins are produced as part of the active defence to prevent attack. In this study, a full-length cDNA encoding the CsPR10 protein was identified in fresh saffron stigmas (Crocus sativus). The deduced amino acid sequence from the nucleotide sequence of the coding region showed homology with PR10 proteins. The clone expressed as a protein in fusion with a GST tag produced a 47-kDa protein in E. coli. CsPR10 had ribonuclease activity, with features common to class II-type ribonucleases; its specific activity was quantified as 68.8 U·mg(-1) protein, thus falling within the range of most PR10 proteins exhibiting RNase activity. Antifungal activity of CsPR10 was assayed against Verticillium dahliae, Penicillium sp. and Fusarium oxysporum. CsPR10 inhibited only F. oxysporum growth, and antifungal potency was reflected in a IC(50) of 8.3 μm. Expression analysis showed the presence of high transcript levels in anther and tepal tissues, low levels in stigmas and roots, and no signal detected in leaves. This protein seems to be involved in the active defence response through activation of the jasmonic acid pathway. © 2010 German Botanical Society and The Royal Botanical Society of the Netherlands.

Who Will Use Pre-Exposure Prophylaxis (PrEP) and Why?: Understanding PrEP Awareness and Acceptability amongst Men Who Have Sex with Men in the UK--A Mixed Methods Study.

PubMed

Frankis, Jamie; Young, Ingrid; Flowers, Paul; McDaid, Lisa

2016-01-01

Recent clinical trials suggest that pre-exposure prophylaxis (PrEP) may reduce HIV transmission by up to 86% for men who have sex with men (MSM), whilst relatively high levels of PrEP acceptability have been reported to date. This study examines PrEP awareness amongst sub-groups of MSM communities and acceptability amongst MSM in a low prevalence region (Scotland, UK), using a mixed methods design. Quantitative surveys of n = 690 MSM recruited online via social and sociosexual media were analysed using descriptive statistics and multivariate logistic regression. In addition, n = 10 in-depth qualitative interviews with MSM were analysed thematically. Under one third (29.7%) of MSM had heard of PrEP, with awareness related to living in large cities, degree level education, commercial gay scene use and reporting an HIV test in the last year. Just under half of participants (47.8%) were likely to use PrEP if it were available but there was no relationship between PrEP acceptability and previous PrEP awareness. Younger men (18-25 years) and those who report higher risk UAI were significantly more likely to say they would use PrEP. Qualitative data described specific PrEP scenarios, illustrating how risk, patterns of sexual practice and social relationships could affect motivation for and nature of PrEP use. These findings suggest substantial interest PrEP amongst MSM reporting HIV risk behaviours in Scotland. Given the Proud results, there is a strong case to investigate PrEP implementation within the UK. However, it appears that disparities in awareness have already emerged along traditional indicators of inequality. Our research identifies the need for comprehensive support when PrEP is introduced, including a key online component, to ensure equity of awareness across diverse MSM communities (e.g. by geography, education, gay scene use and HIV proximity), as well as to responding to the diverse informational and sexual health needs of all MSM communities.

Who Will Use Pre-Exposure Prophylaxis (PrEP) and Why?: Understanding PrEP Awareness and Acceptability amongst Men Who Have Sex with Men in the UK – A Mixed Methods Study

PubMed Central

Frankis, Jamie; Young, Ingrid; Flowers, Paul; McDaid, Lisa

2016-01-01

Background Recent clinical trials suggest that pre-exposure prophylaxis (PrEP) may reduce HIV transmission by up to 86% for men who have sex with men (MSM), whilst relatively high levels of PrEP acceptability have been reported to date. This study examines PrEP awareness amongst sub-groups of MSM communities and acceptability amongst MSM in a low prevalence region (Scotland, UK), using a mixed methods design. Methods Quantitative surveys of n = 690 MSM recruited online via social and sociosexual media were analysed using descriptive statistics and multivariate logistic regression. In addition, n = 10 in-depth qualitative interviews with MSM were analysed thematically. Results Under one third (29.7%) of MSM had heard of PrEP, with awareness related to living in large cities, degree level education, commercial gay scene use and reporting an HIV test in the last year. Just under half of participants (47.8%) were likely to use PrEP if it were available but there was no relationship between PrEP acceptability and previous PrEP awareness. Younger men (18–25 years) and those who report higher risk UAI were significantly more likely to say they would use PrEP. Qualitative data described specific PrEP scenarios, illustrating how risk, patterns of sexual practice and social relationships could affect motivation for and nature of PrEP use. Conclusion These findings suggest substantial interest PrEP amongst MSM reporting HIV risk behaviours in Scotland. Given the Proud results, there is a strong case to investigate PrEP implementation within the UK. However, it appears that disparities in awareness have already emerged along traditional indicators of inequality. Our research identifies the need for comprehensive support when PrEP is introduced, including a key online component, to ensure equity of awareness across diverse MSM communities (e.g. by geography, education, gay scene use and HIV proximity), as well as to responding to the diverse informational and sexual health needs of all MSM communities. PMID:27093430

Enhanced 2.7- and 2.9-μm emissions in Er{sup 3+}/Ho{sup 3+} doped fluoride glasses sensitized by Pr{sup 3+} ions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tian, Ying, E-mail: tianyingcjlu@163.com; Wei, Tao; Jing, Xufeng

2016-04-15

Highlights: • Enhanced 2.7 and 2.9 μm emissions were observed in fluoride glass. • Energy transfer mechanism among Er{sup 3+}, Ho{sup 3+} and Pr{sup 3+} was investigated. • High emission cross sections at 2.7- and 2.9-μm were obtained. - Abstract: In this report, Er{sup 3+}/Ho{sup 3+}/Pr{sup 3+} tri-doped fluoride glass was prepared. The enhancement of 2.7 and 2.9 μm emissions from Er{sup 3+}/Ho{sup 3+}doped system were achieved successfully after the addition of Pr{sup 3+}. The combination of low OH{sup −} concentration, low maximum phonon energy and high mid-infrared transmittance is beneficial to the realization of mid-infrared emissions. The energy transfermore » mechanism among Er{sup 3+}, Ho{sup 3+} and Pr{sup 3+} was investigated. The decay profiles of several levels were measured to further examine the enhanced mid-infrared emissions. Moreover, high stimulated emission cross sections at 2.7- and 2.9 μm (1.08 × 10{sup −20} cm{sup 2} and 2.0 × 10{sup −20} cm{sup 2}, respectively) were determined. Er{sup 3+}/Ho{sup 3+}/Pr{sup 3+} tri-doped fluoride glass might provide a new choice for mid-infrared laser.« less

A Highly Toxic Cellular Prion Protein Induces a Novel, Nonapoptotic Form of Neuronal Death

PubMed Central

Christensen, Heather M.; Dikranian, Krikor; Li, Aimin; Baysac, Kathleen C.; Walls, Ken C.; Olney, John W.; Roth, Kevin A.; Harris, David A.

2010-01-01

Several different deletions within the N-terminal tail of the prion protein (PrP) induce massive neuronal death when expressed in transgenic mice. This toxicity is dose-dependently suppressed by coexpression of full-length PrP, suggesting that it results from subversion of a normal physiological activity of cellular PrP. We performed a combined biochemical and morphological analysis of Tg(ΔCR) mice, which express PrP carrying a 21-aa deletion (residues 105-125) within a highly conserved region of the protein. Death of cerebellar granule neurons in Tg(ΔCR) mice is not accompanied by activation of either caspase-3 or caspase-8 or by increased levels of the autophagy marker, LC3-II. In electron micrographs, degenerating granule neurons displayed a unique morphology characterized by heterogeneous condensation of the nuclear matrix without formation of discrete chromatin masses typical of neuronal apoptosis. Our data demonstrate that perturbations in PrP functional activity induce a novel, nonapoptotic, nonautophagic form of neuronal death whose morphological features are reminiscent of those associated with excitotoxic stress. PMID:20472884

Optimal costs of HIV pre-exposure prophylaxis for men who have sex with men

PubMed Central

Chen, Anders; Hoover, Karen W.; Kelly, Jane; Dowdy, David; Sharifi, Parastu; Sullivan, Patrick S.; Rosenberg, Eli S.

2017-01-01

Introduction Men who have sex with men (MSM) are disproportionately affected by HIV due to their increased risk of infection. Oral pre-exposure prophylaxis (PrEP) is a highly effictive HIV-prevention strategy for MSM. Despite evidence of its effectiveness, PrEP uptake in the United States has been slow, in part due to its cost. As jurisdictions and health organizations begin to think about PrEP scale-up, the high cost to society needs to be understood. Methods We modified a previously-described decision-analysis model to estimate the cost per quality-adjusted life-year (QALY) gained, over a 1-year duration of PrEP intervention and lifetime time horizon. Using updated parameter estimates, we calculated: 1) the cost per QALY gained, stratified over 4 strata of PrEP cost (a function of both drug cost and provider costs); and 2) PrEP drug cost per year required to fall at or under 4 cost per QALY gained thresholds. Results When PrEP drug costs were reduced by 60% (with no sexual disinhibition) to 80% (assuming 25% sexual disinhibition), PrEP was cost-effective (at <$100,000 per QALY averted) in all scenarios of base-case or better adherence, as long as the background HIV prevalence was greater than 10%. For PrEP to be cost saving at base-case adherence/efficacy levels and at a background prevalence of 20%, drug cost would need to be reduced to $8,021 per year with no disinhibition, and to $2,548 with disinhibition. Conclusion Results from our analysis suggest that PrEP drug costs need to be reduced in order to be cost-effective across a range of background HIV prevalence. Moreover, our results provide guidance on the pricing of generic emtricitabine/tenofovir disoproxil fumarate, in order to provide those at high risk for HIV an affordable prevention option without financial burden on individuals or jurisdictions scaling-up coverage. PMID:28570572

Baseline Preferences for Daily, Event-Driven, or Periodic HIV Pre-Exposure Prophylaxis among Gay and Bisexual Men in the PRELUDE Demonstration Project.

PubMed

Vaccher, Stefanie J; Gianacas, Christopher; Templeton, David J; Poynten, Isobel M; Haire, Bridget G; Ooi, Catriona; Foster, Rosalind; McNulty, Anna; Grulich, Andrew E; Zablotska, Iryna B

2017-01-01

The effectiveness of daily pre-exposure prophylaxis (PrEP) is well established. However, there has been increasing interest in non-daily dosing schedules among gay and bisexual men (GBM). This paper explores preferences for PrEP dosing schedules among GBM at baseline in the PRELUDE demonstration project. Individuals at high-risk of HIV were enrolled in a free PrEP demonstration project in New South Wales, Australia, between November 2014 and April 2016. At baseline, they completed an online survey containing detailed behavioural, demographic, and attitudinal questions, including their ideal way to take PrEP: daily (one pill taken every day), event-driven (pills taken only around specific risk events), or periodic (daily dosing during periods of increased risk). Overall, 315 GBM (98% of study sample) provided a preferred PrEP dosing schedule at baseline. One-third of GBM expressed a preference for non-daily PrEP dosing: 20% for event-driven PrEP, and 14% for periodic PrEP. Individuals with a trade/vocational qualification were more likely to prefer periodic to daily PrEP [adjusted odds ratio (aOR) = 4.58, 95% confidence intervals (95% CI): (1.68, 12.49)], compared to individuals whose highest level of education was high school. Having an HIV-positive main regular partner was associated with strong preference for daily, compared to event-driven PrEP [aOR = 0.20, 95% CI: (0.04, 0.87)]. Participants who rated themselves better at taking medications were more likely to prefer daily over periodic PrEP [aOR = 0.39, 95% CI: (0.20, 0.76)]. Individuals' preferences for PrEP schedules are associated with demographic and behavioural factors that may impact on their ability to access health services and information about PrEP and patterns of HIV risk. At the time of data collection, there were limited data available about the efficacy of non-daily PrEP schedules, and clinicians only recommended daily PrEP to study participants. Further research investigating how behaviours and PrEP preferences change correspondingly over time is needed. ClinicalTrials.gov NCT02206555. Registered 28 July 2014.

Physical activity and associated factors in high-school adolescents in Southern Brazil.

PubMed

Fermino, Rogério César; Rech, Cassiano Ricardo; Hino, Adriano Akira Ferreira; Rodriguez Añez, Ciro Romelio; Reis, Rodrigo Siqueira

2010-12-01

To estimate the prevalence of physical activity in adolescents and to identify associated factors. A cross-sectional study was conducted with a representative sample (n=1,518, 59.2% females) of students aged between 14 and 18 years, enrolled in the public school network of the city of Curitiba, Southern Brazil, in 2006. Physical activity practice was self-reported, according to the number of days per week when they perform moderate to vigorous physical activity lasting > 60 minutes. This practice was analyzed in two distinct models. In the first model, the variable was dichotomized into "0 day" and "> 1 day"; in the second, into "< 4 days" and "> 5 days". Independent variables were as follows: biological-demographic (sex, age, body mass index); socioeconomic (parents' level of education, number of cars); behavioral (number of hours spent watching television, number of hours spent using a computer); and sociocultural (social support from family and friends and the perception of barriers to the practice of activities), tested with Poisson regression. In the first model of analysis, the prevalence of physical activity was 58.2% (75.1% in males; 46.5% in females; p<0.001), while, in the second, it was 14.5% (22.3% and 9.1%, respectively; p<0.001). In the first model, the variables associated with physical activity were: male sex (PR=1.63, 95% CI: 1.48;1.78), social support from family (PR=1.14, 95% CI: 1.05;1.23), social support from friends (PR=1.52, 95% CI: 1.31;1.78) and high perception of barriers (PR=0.54, 95% CI: 0.46;0.62). In the second model, only male sex (PR=2.45, 95% CI: 1.73;3.46) and high perception of barriers (PR=0.24, 95% CI: 0.15;0.38) were associated with physical activity. More than half of adolescents practice physical activity at least one day of the week, although 14.5% achieved the current recommendations. The recommended levels are associated with a lower number of factors. Gender and perception of barriers were consistently associated with physical activity levels.

Translating PrEP effectiveness into public health impact: key considerations for decision-makers on cost-effectiveness, price, regulatory issues, distributive justice and advocacy for access.

PubMed

Hankins, Catherine; Macklin, Ruth; Warren, Mitchell

2015-01-01

The extraordinary feat of proving the effectiveness of oral pre-exposure prophylaxis (PrEP) in clinical trials in different populations in a variety of settings may prove to have been easier than ensuring it is used well. Decision-makers must make difficult choices to realize the promise of antiretroviral prophylaxis for their countries. This paper outlines key economic, regulatory and distributive justice issues that must be addressed for effective and acceptable PrEP implementation. In considering the role that PrEP can play in combination prevention programmes, decision-makers must determine who can benefit most from PrEP, how PrEP can be provided safely and efficiently, and what kind of health system support will ensure successful implementation. To do this, they need contextualized information on disease burden by population, analyses of how PrEP services might best be delivered, and projections of the human resource and infrastructure requirements for each potential delivery model. There are cost considerations, varying cost-effectiveness results and regulatory challenges. The principles of ethics can inform thorny discussions about who should be prioritized for oral PrEP and how best to introduce it fairly. We describe the cost-effectiveness of PrEP in different populations at higher risk of HIV exposure, its price in low- and middle-income countries, and the current regulatory situation. We explore the principles of ethics that can inform resource allocation decision-making about PrEP anchored in distributive justice, at a time when universal access to antiretroviral treatment remains to be assured. We then highlight the role of advocacy in moving the PrEP agenda forward. The time is ripe now for decisions about whether, how and for whom PrEP should be introduced into a country's HIV response. It has the potential to contribute significantly to high impact HIV prevention if it is tailored to those who can most benefit from it and if current regulatory and pricing barriers can be overcome. Advocacy at all levels can help inform decision-making and push the access agenda to avert HIV infections among those at highest risk of HIV exposure. The benefits will accrue beyond the individual level to slow HIV transmission at the population level.

Pathogenic prions deviate PrPC signaling in neuronal cells and impair A-beta clearance

PubMed Central

Pradines, E; Hernandez-Rapp, J; Villa-Diaz, A; Dakowski, C; Ardila-Osorio, H; Haik, S; Schneider, B; Launay, J-M; Kellermann, O; Torres, J-M; Mouillet-Richard, S

2013-01-01

The subversion of the normal function exerted by the cellular prion protein (PrPC) in neurons by pathogenic prions is assumed to have a central role in the pathogenesis of transmissible spongiform encephalopathies. Using two murine models of prion infection, the 1C11 neuronal cell line and neurospheres, we document that prion infection is associated with the constitutive activation of signaling targets normally coupled with PrPC, including the Fyn kinase, the mitogen-associated protein kinases ERK1/2 and the CREB transcription factor. PrPC-dependent signaling overactivation in infected cells is associated with the recruitment of p38 and JNK stress-associated kinases. Downstream from CREB, prion-infected cells exhibit reduced activity of the matrix metalloprotease (MMP)-9. As MMP-9 catalyzes the degradation of the amyloid A-beta peptide, the decrease in MMP-9 activity in prion-infected cells causes a significant impairment of the clearance of A-beta, leading to its accumulation. By exploiting two 1C11-infected clones accumulating high or moderate levels of prions, we show that the prion-induced changes are correlated with the level of infectivity. Of note, a dose-dependent increase in A-beta levels was also found in the cerebrospinal fluid of mice inoculated with these infected clones. By demonstrating that pathogenic prions trigger increases in A-beta levels through the deviation of PrPC signaling, our data argue that A-beta may exacerbate prion-induced toxicity. PMID:23303130

Progesterone receptor expression during prostate cancer progression suggests a role of this receptor in stromal cell differentiation.

PubMed

Yu, Yue; Yang, Ou; Fazli, Ladan; Rennie, Paul S; Gleave, Martin E; Dong, Xuesen

2015-07-01

The progesterone receptor, like the androgen receptor, belongs to the steroid receptor superfamily. Our previous studies have reported that the PR is expressed specifically in prostate stroma. PR inhibits proliferation of, and regulates cytokine secretion by stromal cells. However, PR protein expression in cancer-associated stroma during prostate cancer progression has not been profiled. Since the phenotypes of prostate stromal cells change dynamically as tumors progress, whether the PR plays a role in regulating stromal cell differentiation needs to be investigated. Immunohistochemistry assays measured PR protein levels on human prostate tissue microarrays containing 367 tissue cores from benign prostate, prostate tumors with different Gleason scores, tumors under various durations of castration therapy, and tumors at the castration-resistant stage. Immunoblotting assays determined whether PR regulated the expression of alpha smooth muscle actin (α-SMA), vimentin, and fibroblast specific protein (FSP) in human prostate stromal cells. PR protein levels decreased in cancer-associated stroma when compared with that in benign prostate stroma. This reduction in PR expression was not correlated with Gleason scores. PR protein levels were elevated by castration therapy, but reduced to pre-castration levels when tumors progressed to the castration-resistant stage. Enhanced PR expression in human prostate stromal cells increased α-SMA, but decreased vimentin and FSP protein levels ligand-independently. These results suggest that PR plays an active role in regulating stromal cell phenotypes during prostate cancer progression. © 2015 Wiley Periodicals, Inc.

Low- and high-spin excited states in 139Pr

NASA Astrophysics Data System (ADS)

Aryaeinejad, R.; McHarris, Wm. C.

1988-05-01

The level structure of the N=80 nucleus 139Pr has been studied in-beam by the 140Ce(p,2nγ)139Pr reaction using a 25-MeV p beam and by the 139La(α,4nγ)139Pr reaction using a 47-MeV α beam. γ-ray singles, γ-γ coincidence (prompt and delayed), and γ-ray angular distribution experiments were performed. We have assigned 41 γ rays deexciting 24 states in 139Pr from the (p,2nγ) reaction and 43 γ rays deexciting 31 (generally higher-spin) states from the (α,4nγ) reaction, for a total of 43 different states. These in-beam experiments, taken together with results from 139Ndm+g decay and the 141Pr(p,t)139Pr reaction, allowed Jπ assignments to be made for most of the states and allowed us to deduce the intrinsic configurations for many of them. These are discussed in terms of single-quasiparticle shell-model states and triaxial weak-coupled collective states and are compared with systematics for this nuclear region.

Melanin or a Melanin-Like Substance Interacts with the N-Terminal Portion of Prion Protein and Inhibits Abnormal Prion Protein Formation in Prion-Infected Cells.

PubMed

Hamanaka, Taichi; Nishizawa, Keiko; Sakasegawa, Yuji; Oguma, Ayumi; Teruya, Kenta; Kurahashi, Hiroshi; Hara, Hideyuki; Sakaguchi, Suehiro; Doh-Ura, Katsumi

2017-03-15

Prion diseases are progressive fatal neurodegenerative illnesses caused by the accumulation of transmissible abnormal prion protein (PrP). To find treatments for prion diseases, we searched for substances from natural resources that inhibit abnormal PrP formation in prion-infected cells. We found that high-molecular-weight components from insect cuticle extracts reduced abnormal PrP levels. The chemical nature of these components was consistent with that of melanin. In fact, synthetic melanin produced from tyrosine or 3-hydroxy-l-tyrosine inhibited abnormal PrP formation. Melanin did not modify cellular or cell surface PrP levels, nor did it modify lipid raft or cellular cholesterol levels. Neither did it enhance autophagy or lysosomal function. Melanin was capable of interacting with PrP at two N-terminal domains. Specifically, it strongly interacted with the PrP region of amino acids 23 to 50 including a positively charged amino acid cluster and weakly interacted with the PrP octarepeat peptide region of residues 51 to 90. However, the in vitro and in vivo data were inconsistent with those of prion-infected cells. Abnormal PrP formation in protein misfolding cyclic amplification was not inhibited by melanin. Survival after prion infection was not significantly altered in albino mice or exogenously melanin-injected mice compared with that of control mice. These data suggest that melanin, a main determinant of skin color, is not likely to modify prion disease pathogenesis, even though racial differences in the incidence of human prion diseases have been reported. Thus, the findings identify an interaction between melanin and the N terminus of PrP, but the pathophysiological roles of the PrP-melanin interaction remain unclear. IMPORTANCE The N-terminal region of PrP is reportedly important for neuroprotection, neurotoxicity, and abnormal PrP formation, as this region is bound by many factors, such as metal ions, lipids, nucleic acids, antiprion compounds, and several proteins, including abnormal PrP in prion disease and the Aβ oligomer in Alzheimer's disease. In the present study, melanin, a main determinant of skin color, was newly found to interact with this N-terminal region and inhibits abnormal PrP formation in prion-infected cells. However, the data for prion infection in mice lacking melanin production suggest that melanin is not associated with the prion disease mechanism, although the incidence of prion disease is reportedly much higher in white people than in black people. Thus, the roles of the PrP-melanin interaction remain to be further elucidated, but melanin might be a useful competitive tool for evaluating the functions of other ligands at the N-terminal region. Copyright © 2017 American Society for Microbiology.

Melanin or a Melanin-Like Substance Interacts with the N-Terminal Portion of Prion Protein and Inhibits Abnormal Prion Protein Formation in Prion-Infected Cells

PubMed Central

Hamanaka, Taichi; Nishizawa, Keiko; Sakasegawa, Yuji; Oguma, Ayumi; Teruya, Kenta; Kurahashi, Hiroshi; Hara, Hideyuki; Sakaguchi, Suehiro

2017-01-01

ABSTRACT Prion diseases are progressive fatal neurodegenerative illnesses caused by the accumulation of transmissible abnormal prion protein (PrP). To find treatments for prion diseases, we searched for substances from natural resources that inhibit abnormal PrP formation in prion-infected cells. We found that high-molecular-weight components from insect cuticle extracts reduced abnormal PrP levels. The chemical nature of these components was consistent with that of melanin. In fact, synthetic melanin produced from tyrosine or 3-hydroxy-l-tyrosine inhibited abnormal PrP formation. Melanin did not modify cellular or cell surface PrP levels, nor did it modify lipid raft or cellular cholesterol levels. Neither did it enhance autophagy or lysosomal function. Melanin was capable of interacting with PrP at two N-terminal domains. Specifically, it strongly interacted with the PrP region of amino acids 23 to 50 including a positively charged amino acid cluster and weakly interacted with the PrP octarepeat peptide region of residues 51 to 90. However, the in vitro and in vivo data were inconsistent with those of prion-infected cells. Abnormal PrP formation in protein misfolding cyclic amplification was not inhibited by melanin. Survival after prion infection was not significantly altered in albino mice or exogenously melanin-injected mice compared with that of control mice. These data suggest that melanin, a main determinant of skin color, is not likely to modify prion disease pathogenesis, even though racial differences in the incidence of human prion diseases have been reported. Thus, the findings identify an interaction between melanin and the N terminus of PrP, but the pathophysiological roles of the PrP-melanin interaction remain unclear. IMPORTANCE The N-terminal region of PrP is reportedly important for neuroprotection, neurotoxicity, and abnormal PrP formation, as this region is bound by many factors, such as metal ions, lipids, nucleic acids, antiprion compounds, and several proteins, including abnormal PrP in prion disease and the Aβ oligomer in Alzheimer's disease. In the present study, melanin, a main determinant of skin color, was newly found to interact with this N-terminal region and inhibits abnormal PrP formation in prion-infected cells. However, the data for prion infection in mice lacking melanin production suggest that melanin is not associated with the prion disease mechanism, although the incidence of prion disease is reportedly much higher in white people than in black people. Thus, the roles of the PrP-melanin interaction remain to be further elucidated, but melanin might be a useful competitive tool for evaluating the functions of other ligands at the N-terminal region. PMID:28077650

High-power and highly efficient diode-cladding-pumped holmium-doped fluoride fiber laser operating at 2.94 microm.

PubMed

Jackson, Stuart D

2009-08-01

A high-power diode-cladding-pumped Ho(3+), Pr(3+)-doped fluoride glass fiber laser is demonstrated. The laser produced a maximum output power of 2.5 W at a slope efficiency of 32% using diode lasers emitting at 1,150 nm. The long-emission wavelength of 2.94 microm measured at maximum pump power, which is particularly suited to medical applications, indicates that tailoring of the proportion of Pr(3+) ions can provide specific emission wavelengths while providing sufficient de-excitation of the lower laser level.

An Ethylene-Induced Regulatory Module Delays Flower Senescence by Regulating Cytokinin Content.

PubMed

Wu, Lin; Ma, Nan; Jia, Yangchao; Zhang, Yi; Feng, Ming; Jiang, Cai-Zhong; Ma, Chao; Gao, Junping

2017-01-01

In many plant species, including rose (Rosa hybrida), flower senescence is promoted by the gaseous hormone ethylene and inhibited by the cytokinin (CTK) class of hormones. However, the molecular mechanisms underlying these antagonistic effects are not well understood. In this study, we characterized the association between a pathogenesis-related PR-10 family gene from rose (RhPR10.1) and the hormonal regulation of flower senescence. Quantitative reverse transcription PCR analysis showed that RhPR10.1 was expressed at high levels during senescence in different floral organs, including petal, sepal, receptacle, stamen, and pistil, and that expression was induced by ethylene treatment. Silencing of RhPR10.1 expression in rose plants by virus-induced gene silencing accelerated flower senescence, which was accompanied by a higher ion leakage rate in the petals, as well as increased expression of the senescence marker gene RhSAG12 CTK content and the expression of three CTK signaling pathway genes were reduced in RhPR10.1-silenced plants, and the accelerated rate of petal senescence that was apparent in the RhPR10.1-silenced plants was restored to normal levels by CTK treatment. Finally, RhHB6, a homeodomain-Leu zipper I transcription factor, was observed to bind to the RhPR10.1 promoter, and silencing of its expression also promoted flower senescence. Our results reveal an ethylene-induced RhHB6-RhPR10.1 regulatory module that functions as a brake of ethylene-promoted senescence through increasing the CTK content. © 2017 American Society of Plant Biologists. All Rights Reserved.

Prevalence and factors associated with neck pain: a population-based study.

PubMed

Genebra, Caio Vitor Dos Santos; Maciel, Nicoly Machado; Bento, Thiago Paulo Frascareli; Simeão, Sandra Fiorelli Almeida Penteado; Vitta, Alberto De

Neck pain is a musculoskeletal condition with high prevalence that may affect the physical, social, and psychological aspects of the individual, contributing to the increase in costs in society and business. To determine the prevalence of neck pain and associated factors in a population-based sample of adults aged 20 and more. Cross-sectional study based on a population survey. A total number of 600 individuals were interviewed in their homes, and the following data were collected: (1) participant characteristics (demographic, socioeconomic, and work-related aspects) using a pre-coded questionnaire; (2) physical activity level using the IPAQ; and (3) musculoskeletal symptoms using the Nordic questionnaire. Descriptive, bivariate, and Poisson regression analyses were performed. The prevalence of neck pain was 20.3% (95% CI 17.3-23.7). The adjusted analyses showed that individuals who were widowers or separated (PR=2.26; 1.42-5.88), had a low income (PR=1.32; 1.22-6.27) or low educational level (PR=1.83; 1.02-5.26), worked while sitting and leaning (PR=1.55; 1.08-2.40), and who reported having two or more diseases (PR=1.71; 1.55-6.31) remained associated with neck pain. This study reveals the high prevalence of neck pain and remarkable association with widowed/separated people who have low income and low educational level, who perform their occupational activities in sitting and leaning positions, and who reported having two or more diseases. Knowledge of these risk factors will contribute to the development of forms of assistance in which neck pain can be prevented and better managed. Copyright © 2017 Associação Brasileira de Pesquisa e Pós-Graduação em Fisioterapia. Publicado por Elsevier Editora Ltda. All rights reserved.

Electronic structure of layered ferroelectric high-k titanate Pr2Ti2O7

NASA Astrophysics Data System (ADS)

Atuchin, V. V.; Gavrilova, T. A.; Grivel, J.-C.; Kesler, V. G.; Troitskaia, I. B.

2012-11-01

The spectroscopic parameters and electronic structure of binary titanate Pr2Ti2O7 have been studied by IR-, Raman and X-ray photoelectron spectroscopy (XPS) for the powder sample prepared by solid state synthesis. The spectral features of valence band and all constituent element core levels have been considered. The Auger parameters of titanium and oxygen in Pr2Ti2O7 have been determined as αTi=872.8 and αO=1042.3 eV. Variations of cation-anion bond ionicity have been discussed using binding energy differences ΔTi=(BE O 1s-BE Ti 2p3/2)=71.6 eV and ΔPr=BE(Pr 3d5/2)-BE(O 1s)=403.8 eV as key parameters in comparison with those of other titanium- and praseodymium-bearing oxides.

Serial transmission in rodents of neurodegeneration from transgenic mice expressing mutant prion protein.

PubMed Central

Hsiao, K K; Groth, D; Scott, M; Yang, S L; Serban, H; Rapp, D; Foster, D; Torchia, M; Dearmond, S J; Prusiner, S B

1994-01-01

Two lines of transgenic (Tg) mice expressing high (H) levels of the mutant P101L prion protein (PrP) developed a neurologic illness and central nervous system pathology indistinguishable from experimental murine scrapie; these mice were designated Tg(MoPrP-P101L)H. Brain homogenates from Tg(MoPrP-P101L)H mice were inoculated intracerebrally into CD-1 Swiss mice, Syrian hamsters, and Tg196 mice, Tg mice expressing the MoPrP-P101L transgene at low levels. None of the CD-1 mice developed central nervous system dysfunction, whereas approximately 10% of hamsters and approximately 40% of the Tg196 mice manifested neurologic signs between 117 and 639 days after inoculation. Serial transmission of neurodegeneration in Tg196 mice and Syrian hamsters was initiated with brain extracts, producing incubation times of approximately 400 and approximately 75 days, respectively. Although the Tg(MoPrP-P101L)H mice appear to accumulate only low levels of infections prions in their brains, the serial transmission of disease to inoculated recipients argues that prion formation occurs de novo in the brains of these uninoculated animals. These Tg mouse studies, taken together with similar findings in humans dying of inherited prion diseases, provide additional evidence that prions lack a foreign nucleic acid. Images PMID:7916462

Prion Disease Induces Alzheimer Disease-Like Neuropathologic Changes

PubMed Central

Tousseyn, Thomas; Bajsarowicz, Krystyna; Sánchez, Henry; Gheyara, Ania; Oehler, Abby; Geschwind, Michael; DeArmond, Bernadette; DeArmond, Stephen J.

2016-01-01

We examined the brains of 266 patients with prion diseases (PrionD) and found that 46 (17%) had Alzheimer disease (AD)-like changes. To explore potential mechanistic links between PrionD and AD, we exposed human brain aggregates (Hu BrnAggs) to brain homogenate from a patient with sporadic Creutzfeldt-Jakob disease (CJD) and found that the neurons in the Hu BrnAggs produced many β-amyloid (β42) inclusions, whereas uninfected, control-exposed Hu BrnAggs did not. Western blots of 20-pooled CJD-infected BrnAggs verified higher Aβ42 levels than controls. We next examined the CA1 region of the hippocampus from 14 patients with PrionD and found that 5 patients had low levels of scrapie-associated prion protein (PrPSc), many Aβ42 intraneuronal inclusions, low APOE-4, and no significant nerve cell loss. Seven patients had high levels of PrPSc, low Aβ42, high APOE-4 and 40% nerve cell loss, suggesting that APOE-4 and PrPSc together cause neuron loss in PrionD. There were also increased levels of hyperphosphorylated tau protein (Hτ) and Hτ-positive neuropil threads and neuron bodies in both PrionD and AD groups. The brains of 6 age-matched control patients without dementia did not contain Aβ42 deposits; however, there were rare Hτ-positive threads in 5 controls and 2 controls had a few Hτ-positive nerve cell bodies. We conclude that PrionD may trigger biochemical changes similar to AD and suggest that PrionD are diseases of PrPSc, Aβ42, APOE-4 and abnormal tau. PMID:26226132

A deletion mutation in the 5' part of the pol gene of Moloney murine leukemia virus blocks proteolytic processing of the gag and pol polyproteins.

PubMed Central

Crawford, S; Goff, S P

1985-01-01

Deletion mutations in the 5' part of the pol gene of Moloney murine leukemia virus were generated by restriction enzyme site-directed mutagenesis of cloned proviral DNA. DNA sequence analysis indicated that one such deletion was localized entirely within the 5' part of the pol gene, did not affect the region encoding reverse transcriptase, and preserved the translational reading frame downstream of the mutation. The major viral precursor polyproteins (Pr65gag, Pr200gag-pol, and gPr80env) were synthesized at wild-type levels in cell lines carrying the mutant genome. These cell lines assembled and released wild-type levels of virion particles into the medium. Cleavage of both Pr65gag and Pr200gag-pol precursors to the mature proteins was completely blocked in the mutant virions. Surprisingly, these virions contained high levels of active reverse transcriptase; examination of the endogenous reverse transcription products synthesized by the mutant virions revealed normal amounts of minus-strand strong-stop DNA, indicating that the RNA genome was packaged and that reverse transcription in detergent-permeabilized virions was not significantly impaired. Processing of gPr80env to gP70env and P15E was not affected by the mutation, but cleavage of P15E to P12E was not observed. The mutant particles were poorly infectious; analysis indicated that infection was blocked at an early stage. The data are consistent with the idea that the 5' part of the pol gene encodes a protease directly responsible for processing Pr65gag, and possibly Pr200gag-pol, to the structural virion proteins. It appears that cleavage of the gag gene product is not required for budding and release of virions and that complete processing of the pol gene product to the mature form of reverse transcriptase is not required for its functional activation. Images PMID:3882995

The Promise of Pre-Exposure Prophylaxis for Black Men Who Have Sex with Men: An Ecological Approach to Attitudes, Beliefs, and Barriers.

PubMed

Philbin, Morgan M; Parker, Caroline M; Parker, Richard G; Wilson, Patrick A; Garcia, Jonathan; Hirsch, Jennifer S

2016-06-01

Research has demonstrated the clinical effectiveness of pre-exposure prophylaxis (PrEP) for HIV prevention, but little is known about how factors at the individual-, interpersonal-, community-, and structural levels impact PrEP use for black men who have sex with men (BMSM). We advance existing work by examining how all levels of the ecological framework must be addressed for PrEP to be successfully implemented as an effective HIV prevention approach. We interviewed 31 BMSM three times each and 17 community stakeholders once each; interviews were taped, transcribed, and analyzed using the constant comparative method. Factors that influence how BMSM experienced PrEP emerged across all levels of the ecological framework: At the individual level, respondents were wary of giving medication to healthy people and of the potential side-effects. At the interpersonal level, BMSM believed that PrEP use would discourage condom use and that PrEP should only be one option for HIV prevention, not the main option. At the community level, men described not trusting the pharmaceutical industry and described PrEP as an option for others, not for themselves. At the structural level, BMSM talked about HIV and sexuality-related stigmas and how they must overcome those before PrEP engagement. BMSM are a key population in the US National HIV/AIDS Strategy, yet few individuals believe that PrEP would be personally helpful. Our research indicates the urgent need to raise awareness and address structural stigma and policies that could be substantial barriers to the scale-up and implementation of PrEP-related services.

The Promise of Pre-Exposure Prophylaxis for Black Men Who Have Sex with Men: An Ecological Approach to Attitudes, Beliefs, and Barriers

PubMed Central

Parker, Caroline M.; Parker, Richard G.; Wilson, Patrick A.; Garcia, Jonathan; Hirsch, Jennifer S.

2016-01-01

Abstract Research has demonstrated the clinical effectiveness of pre-exposure prophylaxis (PrEP) for HIV prevention, but little is known about how factors at the individual-, interpersonal-, community-, and structural levels impact PrEP use for black men who have sex with men (BMSM). We advance existing work by examining how all levels of the ecological framework must be addressed for PrEP to be successfully implemented as an effective HIV prevention approach. We interviewed 31 BMSM three times each and 17 community stakeholders once each; interviews were taped, transcribed, and analyzed using the constant comparative method. Factors that influence how BMSM experienced PrEP emerged across all levels of the ecological framework: At the individual level, respondents were wary of giving medication to healthy people and of the potential side-effects. At the interpersonal level, BMSM believed that PrEP use would discourage condom use and that PrEP should only be one option for HIV prevention, not the main option. At the community level, men described not trusting the pharmaceutical industry and described PrEP as an option for others, not for themselves. At the structural level, BMSM talked about HIV and sexuality-related stigmas and how they must overcome those before PrEP engagement. BMSM are a key population in the US National HIV/AIDS Strategy, yet few individuals believe that PrEP would be personally helpful. Our research indicates the urgent need to raise awareness and address structural stigma and policies that could be substantial barriers to the scale-up and implementation of PrEP-related services. PMID:27220036

Investigation of the interaction between bta-miR-222 and the estrogen receptor alpha gene in the bovine ovarium.

PubMed

Özdemir, Selçuk; Çomaklı, Selim

2018-06-28

The aim of the present study was to investigate the posttranscriptional regulation of bta-miR-222 and the estrogen receptor (ER)-alpha gene in cows. The preovulatory follicles (POFs) were detected and ER-alpha levels in the corpus luteum (CL) were measured via immunofluorescent method. Afterwards, an ELISA test was performed to detect estradiol- and progesterone-active follicles, and the expression levels of ER-alpha, progesterone receptor (PR), and bta-miR-222 were measured via qRT-PCR. Finally, a western blot analysis was performed to determine ER-alpha protein levels. Immunofluorescence staining was highly positive in the follicular phase, showing ER-alpha and PR immunopositivity. In the luteal phase, ER-alpha immunopositivity decreased in lutein cells, whereas the PRs were observed to be similar in intensity to those in follicular phase. While the estradiol levels were higher in the POFs, the progesterone level was higher in the CL. In the CL, the transcription levels of ER-alpha and PR mRNA were observed to be the same as in the POFs; however, the expression of bta-miR-222 was lower. In the CL, the transcription level of ER-alpha mRNA was lower than that of PR mRNA, and the expression level of bta-miR-222 was higher than that of PR mRNA. The results of the western blot analysis show that the ER-alpha protein level in the CL was lower than that in the POFs. Taken together, our results here suggest that there is a negative correlation between bta-miR-222 and ER-alpha expression during follicular development in cow ovaries. Copyright © 2018 Society for Biology of Reproduction & the Institute of Animal Reproduction and Food Research of Polish Academy of Sciences in Olsztyn. Published by Elsevier B.V. All rights reserved.

Influence of agricultural, industrial, and anthropogenic stresses on the distribution and diversity of macroinvertebrates in Juru River Basin, Penang, Malaysia.

PubMed

Al-Shami, Salman A; Md Rawi, Che Salmah; Ahmad, Abu Hassan; Abdul Hamid, Suhaila; Mohd Nor, Siti Azizah

2011-07-01

Abundance and diversity of benthic macroinvertebrates as well as physico-chemical parameters were investigated in five rivers of the Juru River Basin in northern Peninsula Malaysia: Ceruk Tok Kun River (CTKR), Pasir River (PR), Permatang Rawa River (PRR), Kilang Ubi River (KUR), and Juru River (JR). The physico-chemical parameters and calculated water quality index (WQI) were significantly different among the investigated rivers (ANOVA, P<0.05). The WQI classified CTKR, PR, and JR into class III (slightly polluted). However, PRR and KUR fell into class IV (polluted). High diversity and abundance of macroinvertebrates, especially the intolerant taxa, Ephemeroptera, Plecoptera, and Trichoptera, were observed in the least polluted river, CTKR. Decreasing abundance of macroinvertebrates followed the deterioration of river water quality with the least number of the most tolerant taxa collected from PR. On the basis of composition and sensitivity of macroinvertebrates to pollutants in each river, the highest Biological Monitoring Working Party (BMWP) index score of 93 was reported in CTKR (good water quality). BMWP scores in PRR and JR were 38.7 and 20.1, respectively, classifying both of them into "moderate water quality" category. Poor water quality was reported in PR and KUR. The outcome of the multivariate analysis (CCA) was highly satisfactory, explaining 43.32% of the variance for the assemblages of macroinvertebrates as influenced by 19 physical and chemical variables. According to the CCA model, we assert that there were three levels of stresses on macroinvertebrate communities in the investigated rivers: Level 1, characterized of undisturbed or slightly polluted as in the case of CTKR; Level 2, characterized by a lower habitat quality (the JR) compared to the CTKR; and Level 3 showed severe environmental stresses (PRR, PR, and KUR) primarily contributed by agricultural, industrial, and municipal discharges. Copyright © 2011 Elsevier Inc. All rights reserved.

Analysis of protein levels of 24 cytokines in scrapie agent-infected brain and glial cell cultures from mice differing in prion protein expression levels.

PubMed

Tribouillard-Tanvier, Déborah; Striebel, James F; Peterson, Karin E; Chesebro, Bruce

2009-11-01

Activation of microglia and astroglia is seen in many neurodegenerative diseases including prion diseases. Activated glial cells produce cytokines as a protective response against certain pathogens and as part of the host inflammatory response to brain damage. In addition, cytokines might also exacerbate tissue damage initiated by other processes. In the present work using multiplex assays to analyze protein levels of 24 cytokines in scrapie agent-infected C57BL/10 mouse brains, we observed elevation of CCL2, CCL5, CXCL1, CXCL10, granulocyte-macrophage colony-stimulating factor (GM-CSF), gamma interferon (IFN-gamma), interleukin 1alpha (IL-1alpha), IL-1beta, IL-6, and IL-12p40. Scrapie agent-infected wild-type mice and transgenic mice expressing anchorless prion protein (PrP) had similar cytokine responses in spite of extensive differences in neuropathology. Therefore, these responses may be primarily a reaction to brain damage induced by prion infection rather than specific inducers of a particular type of pathology. To study the roles of astroglia and microglia in these cytokine responses, primary glial cultures were exposed to scrapie agent-infected brain homogenates. Microglia produced only IL-12p40 and CXCL10, whereas astroglia produced these cytokines plus CCL2, CCL3, CCL5, CXCL1, G-CSF, IL-1beta, IL-6, IL-12p70, and IL-13. Glial cytokine responses from wild-type mice and transgenic mice expressing anchorless PrP differed only slightly, but glia from PrP-null mice produced only IL-12p40, indicating that PrP expression was required for scrapie agent induction of other cytokines detected. The difference in cytokine response between microglia and astroglia correlated with 20-fold-higher levels of PrP expression in astroglia versus microglia, suggesting that high-level PrP expression on astroglia might be important for induction of certain cytokines.

Pinoresinol reductase 1 impacts lignin distribution during secondary cell wall biosynthesis in Arabidopsis

DOE PAGES

Zhao, Qiao; Zeng, Yining; Yin, Yanbin; ...

2014-08-05

In this paper, pinoresinol reductase (PrR) catalyzes the conversion of the lignan (-)-pinoresinol to (-)-lariciresinol in Arabidopsis thaliana, where it is encoded by two genes, PrR1 and PrR2, that appear to act redundantly. PrR1 is highly expressed in lignified inflorescence stem tissue, whereas PrR2 expression is barely detectable in stems. Co-expression analysis has indicated that PrR1 is co-expressed with many characterized genes involved in secondary cell wall biosynthesis, whereas PrR2 expression clusters with a different set of genes. The promoter of the PrR1 gene is regulated by the secondary cell wall related transcription factors SND1 and MYB46. The loss-of-function mutantmore » of PrR1 shows, in addition to elevated levels of pinoresinol, significantly decreased lignin content and a slightly altered lignin structure with lower abundance of cinnamyl alcohol end groups. Stimulated Raman scattering (SRS) microscopy analysis indicated that the lignin content of the prr1-1 loss-of-function mutant is similar to that of wild-type plants in xylem cells, which exhibit a normal phenotype, but is reduced in the fiber cells. Finally, together, these data suggest an association of the lignan biosynthetic enzyme encoded by PrR1 with secondary cell wall biosynthesis in fiber cells.« less

Linear Dichroism in Angle-Resolved Core-Level Photoemission Spectra Reflecting 4f Ground-State Symmetry of Strongly Correlated Cubic Pr Compounds

NASA Astrophysics Data System (ADS)

Hamamoto, Satoru; Fujioka, Shuhei; Kanai, Yuina; Yamagami, Kohei; Nakatani, Yasuhiro; Nakagawa, Koya; Fujiwara, Hidenori; Kiss, Takayuki; Higashiya, Atsushi; Yamasaki, Atsushi; Kadono, Toshiharu; Imada, Shin; Tanaka, Arata; Tamasaku, Kenji; Yabashi, Makina; Ishikawa, Tetsuya; Matsumoto, Keisuke T.; Onimaru, Takahiro; Takabatake, Toshiro; Sekiyama, Akira

2017-12-01

We report experimentally observed linear dichroism in angle-resolved core-level photoemission spectra of PrIr2Zn20 and PrB6 with cubic symmetry. The different anisotropic 4f charge distributions between the compounds due to the crystalline-electric-field splitting are responsible for the difference in the linear dichroism, which has been verified by spectral simulations with the full multiplet theory for a single-site Pr3+ ion with cubic symmetry. The observed linear dichroism and polarization-dependent spectra in two different photoelectron directions for PrIr2Zn20 are reproduced by theoretical analysis for the Γ3 ground state, whereas those of the Pr 3d and 4d core levels indicate the Γ5 ground state for PrB6.

Isolation of Novel Synthetic Prion Strains by Amplification in Transgenic Mice Coexpressing Wild-Type and Anchorless Prion Proteins

PubMed Central

Raymond, Gregory J.; Race, Brent; Hollister, Jason R.; Offerdahl, Danielle K.; Moore, Roger A.; Kodali, Ravindra; Raymond, Lynne D.; Hughson, Andrew G.; Rosenke, Rebecca; Long, Dan; Dorward, David W.

2012-01-01

Mammalian prions are thought to consist of misfolded aggregates (protease-resistant isoform of the prion protein [PrPres]) of the cellular prion protein (PrPC). Transmissible spongiform encephalopathy (TSE) can be induced in animals inoculated with recombinant PrP (rPrP) amyloid fibrils lacking mammalian posttranslational modifications, but this induction is inefficient in hamsters or transgenic mice overexpressing glycosylphosphatidylinositol (GPI)-anchored PrPC. Here we show that TSE can be initiated by inoculation of misfolded rPrP into mice that express wild-type (wt) levels of PrPC and that synthetic prion strain propagation and selection can be affected by GPI anchoring of the host's PrPC. To create prions de novo, we fibrillized mouse rPrP in the absence of molecular cofactors, generating fibrils with a PrPres-like protease-resistant banding profile. These fibrils induced the formation of PrPres deposits in transgenic mice coexpressing wt and GPI-anchorless PrPC (wt/GPI−) at a combined level comparable to that of PrPC expression in wt mice. Secondary passage into mice expressing wt, GPI−, or wt plus GPI− PrPC induced TSE disease with novel clinical, histopathological, and biochemical phenotypes. Contrary to laboratory-adapted mouse scrapie strains, the synthetic prion agents exhibited a preference for conversion of GPI− PrPC and, in one case, caused disease only in GPI− mice. Our data show that novel TSE agents can be generated de novo solely from purified mouse rPrP after amplification in mice coexpressing normal levels of wt and anchorless PrPC. These observations provide insight into the minimal elements required to create prions in vitro and suggest that the PrPC GPI anchor can modulate the propagation of synthetic TSE strains. PMID:22915801

Metabolic risk in schoolchildren is associated with low levels of cardiorespiratory fitness, obesity, and parents' nutritional profile.

PubMed

Todendi, Pâmela Ferreira; Valim, Andréia Rosane de Moura; Reuter, Cézane Priscila; Mello, Elza Daniel de; Gaya, Anelise Reis; Burgos, Miria Suzana

2016-01-01

Verify the association between metabolic risk profile in students with different levels of cardiorespiratory fitness and body mass index, as well as the nutritional status of their parents. A cross-sectional study comprising 1.254 schoolchildren aged between seven and 17 years. The metabolic risk profile was calculated by summing the standardized values of high density lipoproteins and low density lipoproteins, triglycerides, glucose and systolic blood pressure. The parents' nutritional status was evaluated by self-reported weight and height data, for body mass index calculating. The body mass index of schoolchildren was classified as underweight/normal weight and overweight/obesity. The cardiorespiratory fitness was assessed by 9-minute running/walk test, being categorized as fit (good levels) and unfit (low levels). Data were analyzed using prevalence ratio values (PR). The data indicates a higher occurrence of developing metabolic risk in schoolchildren whose mother is obese (PR: 1.50; 95% CI: 1.01, 2.23), and even higher for those whose father and mother are obese (PR: 2, 79, 95% CI: 1.41; 5.51). Students who have low levels of cardiorespiratory fitness and overweight/obesity have higher occurrence of presenting metabolic risk profile (PR: 5.25; 95% CI: 3.31; 8.16). the occurrence of developing metabolic risk in schoolchildren increase when they have low levels of cardiorespiratory fitness and overweight/obesity, and the presence of parental obesity. Copyright © 2016 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.

Inflammatory Stimuli Increase Progesterone Receptor-A Stability and Transrepressive Activity in Myometrial Cells

PubMed Central

Peters, Gregory A.; Yi, Lijuan; Skomorovska-Prokvolit, Yelenna; Patel, Bansari; Amini, Peyvand; Tan, Huiqing

2017-01-01

The steroid hormone progesterone acting via the nuclear progesterone receptor (PR) isoforms, progesterone receptor A (PR-A) and progesterone receptor B (PR-B), is essential for the maintenance of uterine quiescence during pregnancy. Inhibition of PR signaling augments uterine contractility and induces labor. Human parturition is thought to be triggered by modulation of PR signaling in myometrial cells to induce a functional progesterone withdrawal. One mechanism for functional progesterone withdrawal is increased abundance of PR-A, which decreases progesterone responsiveness by inhibiting the transcriptional activity of PR-B. Human parturition also involves tissue-level inflammation within the myometrium. This study examined the control of PR-A abundance and transrepressive activity in myometrial cells and the role of the inflammatory stimuli in the form of interleukin-1β (IL-1β) and lipopolysaccharide (LPS) in these processes. We found that abundance of PR-A was markedly increased by progesterone and by exposure to IL-1β and LPS via posttranslational mechanisms involving increased PR-A protein stability. In contrast, progesterone decreased abundance of PR-B by increasing its rate of degradation. Together, progesterone and proinflammatory stimuli induced a PR-A–dominant state in myometrial cells similar to that observed in term laboring myometrium. IL-1β and LPS also increased the capacity for PR-A to inhibit the transcriptional activity of PR-B. Taken together, our data suggest that proinflammatory stimuli increase the steady-state levels of PR-A and its transrepressive activity in myometrial cells and support the hypothesis that tissue-level inflammation triggers parturition by inducing PR-A–mediated functional progesterone withdrawal. PMID:27886516

Preventing HIV among adolescents with oral PrEP: observations and challenges in the United States and South Africa

PubMed Central

Hosek, Sybil; Celum, Connie; Wilson, Craig M; Kapogiannis, Bill; Delany-Moretlwe, Sinead; Bekker, Linda-Gail

2016-01-01

Introduction Adolescents and young adults aged <25 are a key population in the HIV epidemic, with very high HIV incidence rates in many geographic settings and a large number who have limited access to prevention services. Thus, any biomedical HIV prevention approach should prepare licensure and implementation strategies for young populations. Oral pre-exposure prophylaxis (PrEP) is the first antiretroviral-based prevention intervention with proven efficacy across many settings and populations, and regulatory and policy approvals at global and national levels are occurring rapidly. We discuss available data from studies in the United States and South Africa on the use of oral PrEP for HIV prevention in adolescent minors, along with some of the implementation challenges. Discussion Ongoing studies in the United States and South Africa among youth under the age of 18 should provide the safety data needed by the end of 2016 to contribute to licensure of Truvada as daily PrEP in adolescents. The challenges of completing these studies as well as foreseeable broader challenges highlighted by this work are presented. Adherence to daily PrEP is a greater challenge for younger populations, and poor adherence was associated with decreased efficacy in all PrEP trials. Individual-level barriers include limited familiarity with antiretroviral-based prevention, stigma, product storage, and social support. Structural challenges include healthcare financing for PrEP, clinician acceptability and comfort with PrEP delivery, and the limited youth-friendly health services available. These challenges are discussed in the context of the work done to date in the United States and South Africa, but will likely be magnified in the setting of limited resources in many other countries that are heavily impacted by HIV. Conclusions Adolescent populations are particularly vulnerable to HIV, and oral PrEP in these populations is likely to have an impact on population-level HIV incidence. The challenges of disseminating an HIV biomedical prevention tool requiring daily usage in adolescents are formidable, but addressing these issues and starting dialogues will lay the groundwork for the many other HIV prevention tools now being developed and tested. PMID:27760684

Targeting pre-exposure prophylaxis among men who have sex with men in the United States and Peru: partnership types, contact rates, and sexual role

PubMed Central

Carnegie, Nicole Bohme; Goodreau, Steven M.; Liu, Albert; Vittinghoff, Eric; Sanchez, Jorge; Lama, Javier R.; Buchbinder, Susan

2015-01-01

Background We aim to identify optimal strategies for deploying pre-exposure prophylaxis among men who have sex with men in the US and Peru to maximize population-level effectiveness in an efficient manner. We use epidemic models to simulate the impact of targeting strategies. Most studies have focused on targeting either the general population or high-risk MSM. Alternative strategies, including serodiscordant couples, may better balance effectiveness and efficiency. Methods We use dynamic, stochastic sexual network models based in exponential-family random graph modeling, parameterized from behavioral surveys of MSM in the US and Peru. These models represent main partnerships and casual contacts separately, permitting modeling of interventions targeting men whose risk derives from combinations of relational types. We also model varying rates of uptake and adherence to PrEP. We assess sensitivity of results to risk compensation via increases in condomless casual contacts and condomless sex in main partnerships. Results Targeting all men who are not exclusively insertive has the largest impact on HIV incidence, but targeting only those with high levels of casual activity yields comparable results using fewer person-years on PrEP. The effect is robust to risk compensation in the US, but less so in Peru. Targeting serodiscordant main partnerships does not significantly impact incidence, but requires fewer person-years on PrEP per infection averted than other strategies. Conclusions PrEP could be effective in reducing new infections at the population level in both settings. Serodiscordant partnerships are an attractive component of a targeting program, but targeting should include other high-risk men. PMID:25942463

Targeting pre-exposure prophylaxis among men who have sex with men in the United States and Peru: partnership types, contact rates, and sexual role.

PubMed

Carnegie, Nicole B; Goodreau, Steven M; Liu, Albert; Vittinghoff, Eric; Sanchez, Jorge; Lama, Javier R; Buchbinder, Susan

2015-05-01

We aim to identify optimal strategies for deploying pre-exposure prophylaxis among men who have sex with men (MSM) in the United States and Peru to maximize population-level effectiveness in an efficient manner. We use epidemic models to simulate the impact of targeting strategies. Most studies have focused on targeting either the general population or high-risk MSM. Alternative strategies, including serodiscordant couples, may better balance effectiveness and efficiency. We use dynamic stochastic sexual network models based on exponential-family random graph modeling, parameterized from behavioral surveys of MSM in the United States and Peru. These models represent main partnerships and casual contacts separately, permitting modeling of interventions targeting men whose risk derives from combinations of relational types. We also model varying rates of uptake and adherence to pre-exposure prophylaxis (PrEP). We assess sensitivity of results to risk compensation through increases in condomless casual contacts and condomless sex in main partnerships. Targeting all men who are not exclusively insertive has the largest impact on HIV incidence, but targeting only those with high levels of casual activity yields comparable results using fewer person-years on PrEP. The effect is robust to risk compensation in the United States, but less so in Peru. Targeting serodiscordant main partnerships does not significantly impact incidence, but requires fewer person-years on PrEP per infection averted than other strategies. PrEP could be effective in reducing new infections at the population level in both settings. Serodiscordant partnerships are an attractive component of a targeting program, but targeting should include other high-risk men.

Increased progesterone receptor expression in uterine leiomyoma: correlation with age, number of leiomyomas, and clinical symptoms.

PubMed

Tsigkou, Anastasia; Reis, Fernando M; Lee, Meng H; Jiang, Bingjie; Tosti, Claudia; Centini, Gabriele; Shen, Fang-Rong; Chen, You-Guo; Petraglia, Felice

2015-07-01

To investigate the possible correlation between progesterone receptor (PR) expression in uterine leiomyoma or adjacent myometrium and patient's age, size/number of leiomyomas, or clinical symptoms such as dysmenorrhea, acyclic pelvic pain, or menstrual and intermenstrual uterine bleeding. Cross-sectional study. Referral center. Sixty-two Chinese women undergoing elective hysterectomy for uterine leiomyomata. None. Evaluation of PR-total and PR-B mRNA with real-time polymerase chain reaction; PR-A and PR-B proteins quantified by Western blot in leiomyoma tissue and myometrium; symptoms rated by the patients using visual analog scores. The PR-B mRNA and PR-A and PR-B proteins were more concentrated in leiomyomas than in matched myometrium. A direct correlation between PR-B mRNA levels in leiomyoma and age (r = 0.347) and number of tumors (r = 0.295) was found. Conversely, there was an inverse correlation between PR-B mRNA levels in leiomyoma and dysmenorrhea (r = -0.260) and intermenstrual bleeding (r = -0.266). Multiple regression analysis indicated that age (β = 0.363) and the number of myomas (β = 0.296) were independently associated with PR-B mRNA levels in leiomyoma tissue. The levels of PR-B mRNA in leiomyoma tissue are directly associated with the number of tumors and inversely correlated with the intensity of intermenstrual bleeding and dysmenorrhea, suggesting that PR signaling may favor leiomyoma growth while attenuating clinical symptoms. This duality should be taken into account in the clinical management of patients with symptomatic uterine leiomyoma. Copyright © 2015 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Genes with mutation significance were highly associated with the clinical pattern of patients with breast cancer.

PubMed

Ding, Wan-Jun; Zeng, Tao; Wang, Li-Jun; Lei, Hong-Bo; Ge, Wei; Wang, Zhi

2017-11-17

In the United States, breast cancer is the second leading cause of cancer death in women. Over the past 20 years, breast cancer incidence and mortality rates increased rapidly in developing regions. We aimed to identify the gene mutation patterns that associated with the clinical patterns, including survival status, histo-pathological classes and so forth, of breast cancer. We retrieved 1098 cases of the clinical information, and level-3 legacy data of mRNA expression level, protein expression data and mutation files from GDC data portal. The genes with mutation significance were obtained. We studied the impacts of mutation types on the expression levels of mRNA and protein. Different statistics methods were used to calculate the correlation between the mutation types and the expression data or histo-clinical measures. There were 24 genes with mutation significance identified. The most mutated genes were selected to study the role of specific mutations played on the patients with breast cancer. One interesting finding was the missense mutations on TP53 were related with high expression levels of mRNA and protein. The missense mutations on TP53 were highly related with the morphology, race, ER status, PR status and HER2 Status, while the truncated mutations were only related with the morphology, ER status and PR status. The missense mutation on PIK3CA was highly associated with the morphology, race, ER status and PR status. The mutants with different mutants and the wild type of the most mutated genes had different impacts on the histo-clinical measures that might help personalized therapy.

Fibrinogen: cardiometabolic risk marker in obese or overweight children and adolescents.

PubMed

Azevedo, Waldeneide F; Cantalice, Anajás S C; Gonzaga, Nathalia C; Simões, Mônica O da S; Guimarães, Anna Larissa V; Carvalho, Danielle F de; Medeiros, Carla Campos Muniz

2015-01-01

To determine the prevalence of increased serum fibrinogen levels and its association with cardiometabolic risk factors in overweight or obese children and adolescents. Cross-sectional study with 138 children and adolescents (overweight or obese) followed at a reference outpatient clinic of the public health care network. Fibrinogen concentration was divided into quartiles, and values above or equal to the third quartile were considered high. The association between high fibrinogen values and cardiometabolic risk factors was assessed using Pearson's chi-squared test or Fisher's exact test, as necessary. Logistic regression was used to adjust variables predictive of fibrinogen levels. Analyses were performed using SPSS version 22.0 and SAS software, considering a confidence interval of 95%. Serum fibrinogen levels were elevated in 28.3% of individuals, showing association with the presence of high CRP (p=0.003, PR: 2.41, 95% CI: 1.30-4.46) and the presence of four or more risk factors (p=0.042; PR: 1.78, 95% CI: 1.00-3.17). After a logistic regression, only elevated CRP remained associated with altered fibrinogen levels (p=0.024; PR: 1.32; 95% CI: 1.09-5.25). Increased fibrinogen was prevalent in the study population and was associated with ultrasensitive C-reactive protein and the presence of four or more cardiovascular risk factors; it should be included in the assessment of individuals at risk. Copyright © 2015 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.

Perceived stress and high fat intake: A study in a sample of undergraduate students

PubMed Central

Vidal, E. Jair; Alvarez, Daily; Martinez-Velarde, Dalia; Vidal-Damas, Lorena; Yuncar-Rojas, Kelly A.; Julca-Malca, Alesia

2018-01-01

Objectives Different studies have reported the association between perceived stress and unhealthy diet choices. We aimed to determine whether there is a relationship between perceived stress and fat intake among undergraduate medical students. Methods/Principal findings A cross-sectional study was performed including first-year medical students. The outcome of interest was the self-report of fat intake assessed using the Block Screening Questionnaire for Fat Intake (high vs. low intake), whereas the exposure was perceived stress (low/normal vs. high levels). The prevalence of high fat intake was estimated and the association of interest was determined using prevalence ratios (PR) and 95% confidence intervals (95%CI). Models were created utilizing Poisson regression with robust standard errors. Data from 523 students were analyzed, 52.0% female, mean age 19.0 (SD 1.7) years. The prevalence of high fat intake was 42.4% (CI: 38.2%–46.7%). In multivariate model and compared with those with lowest levels of stress, those in the middle (PR = 1.59; 95%CI: 1.20–2.12) and highest (PR = 1.92; 95%CI: 1.46–2.53) categories of perceived stress had greater prevalence of fat intake. Gender was an effect modifier of this association (p = 0.008). Conclusions Greater levels of perceived stress were associated with higher fat intake, and this association was stronger among males. More than 40% of students reported having high fat consumption. Our results suggest the need to implement strategies that promote decreased fat intake. PMID:29522535

Enhancing HIV Pre-exposure, Prophylaxis Practices via an Educational Intervention.

PubMed

Newman, Rebecca; Katchi, Tasleem; Karass, Michael; Gennarelli, Melissa; Goutis, Jason; Kifayat, Alina; Solanki, Shantanu; Yandrapalli, Srikanth; Forman, Leanne; Nabors, Christopher

2018-04-20

Pre-exposure prophylaxis (PrEP) for HIV involves using antiretroviral drugs to prevent individuals at high risk from acquiring HIV infection. Most practicing primary care providers believe PrEP to be safe and effective, but less than half have prescribed or referred for PrEP. Attitudes and prescribing patterns among house officers have not been well described previously. Can an educational intervention enhance HIV PrEP practices among internal medicine house officers? This study relied on a pretest/posttest design. All categorical trainees at a medium-sized internal medicine program were offered a baseline survey to assess their knowledge on PrEP. This was followed by a PrEP-focused educational intervention and a postintervention survey. Likert scales captured perceptions regarding safety, effectiveness, barriers, factors that would promote PrEP use, potential side effects, impact on risk-taking behavior, and provider comfort level in assessing behavioral risks and in PrEP prescribing. Data were analyzed using descriptive statistics, Wilcoxon signed rank test, and the Kruskal-Wallis test. Significance was accepted for P < 0.05. Forty-eight (100%) trainees participated in the educational session, 45 (94%) in a preintervention survey, and 36 (75%) in a postintervention survey. Before PrEP training, 22% of respondents were unaware of PrEP, 78% believed PrEP was effective, 66% believed PrEP was safe, 62% had fair or poor awareness of side effects; 18% of residents had referred for or prescribed PrEP, and 31% believed they were likely to prescribe PrEP in the next 6 months. After the intervention, 94% of trainees believed PrEP was effective (P < 0.001), 92% believed PrEP was safe (P < 0.001), and two-thirds believed they were likely to prescribe PrEP in the next 6 months. Brief, focused training on HIV prevention promotes awareness, acceptance, and likelihood of prescribing PrEP by internal medicine trainees.

Progesterone inhibits proliferation and modulates expression of proliferation-Related genes in classical progesterone receptor-negative human BxPC3 pancreatic adenocarcinoma cells.

PubMed

Goncharov, Alexey I; Maslakova, Aitsana A; Polikarpova, Anna V; Bulanova, Elena A; Guseva, Alexandra A; Morozov, Ivan A; Rubtsov, Petr M; Smirnova, Olga V; Shchelkunova, Tatiana A

2017-01-01

Recent studies suggest that progesterone may possess anti-tumorigenic properties. However, a growth-modulatory role of progestins in human cancer cells remains obscure. With the discovery of a new class of membrane progesterone receptors (mPRs) belonging to the progestin and adipoQ receptor gene family, it becomes important to study the effect of this hormone on proliferation of tumor cells that do not express classical nuclear progesterone receptors (nPRs). To identify a cell line expressing high levels of mPRs and lacking nPRs, we examined mRNA levels of nPRs and three forms of mPRs in sixteen human tumor cell lines of different origin. High expression of mPR mRNA has been found in pancreatic adenocarcinoma BxPC3 cells, while nPR mRNA has not been detected in these cells. Western blot analysis confirmed these findings at the protein level. We revealed specific binding of labeled progesterone in these cells with affinity constant similar to that of human mPR expressed in yeast cells. Progesterone at high concentration of 20 μM significantly reduced the mRNA levels of proliferation markers Ki67 and PCNA, as well as of cyclin D1, and increased the mRNA levels of cyclin dependent kinase inhibitors p21 and p27. Progesterone (1 μM and 20 μM) significantly inhibited proliferative activity of BxPC3 cells. These results point to anti-proliferative effects of the progesterone high concentrations on BxPC3 cells and suggest that activation of mPRs may mediate this action. Our data are a starting point for further investigations regarding the application of progesterone in pancreatic cancer. Copyright © 2016 Elsevier Ltd. All rights reserved.

Urine assay for tenofovir to monitor adherence in real time to tenofovir disoproxil fumarate/emtricitabine as pre-exposure prophylaxis.

PubMed

Koenig, H C; Mounzer, K; Daughtridge, G W; Sloan, C E; Lalley-Chareczko, L; Moorthy, G S; Conyngham, S C; Zuppa, A F; Montaner, L J; Tebas, P

2017-07-01

Tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) is approved for pre-exposure prophylaxis (PrEP) against HIV infection. Adherence is critical for the success of PrEP, but current adherence measurements are inadequate for real-time adherence monitoring. We developed and validated a urine assay to measure tenofovir (TFV) to objectively monitor adherence to PrEP. We developed a urine assay using high-performance liquid chromatography coupled to tandem mass spectrometry with high sensitivity/specificity for TFV that allowed us to determine TFV concentrations in log 10 categories between 0 and 10 000 ng/mL. We validated the assay in three cohorts: (1) HIV-positive subjects with undetectable viral loads on a TDF/FTC-based regimen, (2) healthy HIV-negative subjects who received a single dose of TDF/FTC, and (3) HIV-negative subjects receiving daily TDF/FTC as PrEP for 24 weeks. The urine assay detected TFV with greater sensitivity than plasma-based measures and with a window of measurements within 7 days of the last TDF/FTC dose. Based on the urine log-linear clearance after the last dose and its concordance with all detectable plasma levels, a urine TFV concentration > 1000 ng/mL was identified as highly predictive of the presence of TFV in plasma at > 10 ng/mL. The urine assay was able to distinguish high and low adherence patterns within the last 48 h (> 1000 ng/mL versus 10-1000 ng/mL), as well as nonadherence (< 10 ng/mL) extended over at least 1 week prior to measurement. We provide proof of concept that a semiquantitative urine assay measuring levels of TFV could be further developed into a point-of-care test and be a useful tool to monitor adherence to PrEP. © 2017 British HIV Association.

Pre-exposure prophylaxis and antiretroviral resistance: HIV prevention at a cost?

PubMed

Hurt, Christopher B; Eron, Joseph J; Cohen, Myron S

2011-12-01

Pre-exposure prophylaxis (PrEP), the use of antiretrovirals (ARVs) by human immunodeficiency virus (HIV)-uninfected individuals to prevent acquisition of the virus during high-risk sexual encounters, enjoyed its first 2 major successes with the Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004 and the Pre-Exposure Prophylaxis Initiative (iPrEx). These successes were buoyed by additional positive results from the TDF2 and Partners PrEP trials. Although no seroconverters in either arm of CAPRISA developed resistance to tenofovir, 2 participants in iPrEx with undetected, seronegative acute HIV infection were randomized to receive daily oral tenofovir-emtricitabine and resistance to emtricitabine was later discovered in both men. A similar case in the TDF2 study resulted in resistance to both ARVs. These cases prompted us to examine existing literature on the nature of resistance mutations elicited by ARVs used for PrEP. Here, we discuss the impact of signature mutations selected by PrEP, how rapidly these emerge with daily ARV exposure, and the individual-level and public health consequences of ARV resistance.

Factors associated with burnout syndrome in medical residents of a university hospital.

PubMed

Gouveia, Pedro Alves da Cruz; Ribeiro, Maria Hosana Chaves; Aschoff, Carlos Alberto de Moura; Gomes, Doris Pires; Silva, Nadine Anita Fonseca da; Cavalcanti, Helton Alexsandro Firmino

2017-06-01

To determine the prevalence of burnout syndrome among resident physicians of various specialties and to evaluate associated factors. The Maslach Burnout Inventory questionnaire and a sociodemographic questionnaire were used to evaluate factors associated with the syndrome. Burnout was defined as the association of high emotional exhaustion, depersonalization and low professional achievement. Multivariate analysis was performed after adjustment of the Poisson model with the identification of risk factors and calculation of prevalence ratios (PR). Of the 250 resident physicians registered with Hospital das Clínicas of Pernambuco, 129 participated in the study. In the three domains that characterize burnout syndrome, we found a low level of professional achievement in 94.6% of resident physicians interviewed, a high level of depersonalization in 31.8%, and 59.7% with a high level of emotional exhaustion. The prevalence of burnout was 27.9%. Having suffered a stressful event in the last six months (PR: 8.10; 95CI 1.2-57.2) and being a student of surgical specialty (PR: 1.99; 95CI 1.2-3.3) were independently associated with burnout. The prevalence of burnout found in resident physicians is in accordance with previous Brazilian studies. Residents of surgical specialties and those who suffered some stressful event were identified as susceptible in this study. The early identification of risk factors is fundamental for the implementation of preventive measures against burnout syndrome.

Molecular characterization of clinical isolates of human immunodeficiency virus resistant to the protease inhibitor darunavir.

PubMed

Sasková, Klára Grantz; Kozísek, Milan; Rezácová, Pavlína; Brynda, Jirí; Yashina, Tatyana; Kagan, Ron M; Konvalinka, Jan

2009-09-01

Darunavir is the most recently approved human immunodeficiency virus (HIV) protease (PR) inhibitor (PI) and is active against many HIV type 1 PR variants resistant to earlier-generation PIs. Darunavir shows a high genetic barrier to resistance development, and virus strains with lower sensitivity to darunavir have a higher number of PI resistance-associated mutations than viruses resistant to other PIs. In this work, we have enzymologically and structurally characterized a number of highly mutated clinically derived PRs with high levels of phenotypic resistance to darunavir. With 18 to 21 amino acid residue changes, the PR variants studied in this work are the most highly mutated HIV PR species ever studied by means of enzyme kinetics and X-ray crystallography. The recombinant proteins showed major defects in substrate binding, while the substrate turnover was less affected. Remarkably, the overall catalytic efficiency of the recombinant PRs (5% that of the wild-type enzyme) is still sufficient to support polyprotein processing and particle maturation in the corresponding viruses. The X-ray structures of drug-resistant PRs complexed with darunavir suggest that the impaired inhibitor binding could be explained by change in the PR-inhibitor hydrogen bond pattern in the P2' binding pocket due to a substantial shift of the aminophenyl moiety of the inhibitor. Recombinant virus phenotypic characterization, enzyme kinetics, and X-ray structural analysis thus help to explain darunavir resistance development in HIV-positive patients.

Radioimmunotherapy of MCF7 breast cancer cell line with 131I-PR81 monoclonal antibody against MUC1: comparison of direct and indirect radioiodination methods.

PubMed

Mohammadnejad, Javad; Rasaee, Mohammad Javad; Babaei, Mohammad Hosein; Paknejad, Malihe; Hasan, Zahir Mohammad; Salouti, Mojtaba; Gandomkar, Mostafa; Sadri, Keyvan

2010-01-01

PR81 is a monoclonal antibody that binds with high affinity to MUC1, which is over expressed on breast and other tumors. The objective of this study was to compare the two labeling methods (direct and indirect radioiodination) for application of this antibody against MUC1 as a radioimmunotherapeutical agent.Monoclonal antibody (PR81) against the tandem repeat of the core protein (MUC1) was prepared, characterized, purified, and labeled with 131I using the direct (chloramin-T) and indirect (Fmoc-D-Tyr (tBu)-D-Tyr (tBu)-D-Lys (Boc)-OH (YYK) attached to N-hydroxysuccinimide as a linker between PR81 and 131I) methods. The immunoreactivity of 131I-PR81 and 131I-TP-PR81 complexes with MUC1 (the native protein), BSA-P20 (a 20 amino acid corresponding the tandem repeat of MUC1) and MCF7 cell line were performed by RIA. In vitro stability of 131I-PR81 and 131I-YYK-peptide-PR81 complexes in human serum was determined by thin layer chromatography (TLC). Cell toxicity and in vitro internalization studies were performed with the MCF7 cell line, and the tissue biodistribution of the 131I-PR81 and 131I- YYK-peptide -PR81 complexes was evaluated in normal BALB/c mice at 4, 24 and 48 hrs. The labeling efficiency was determined by measuring the percentage recovery of radioactivity in the final product relative to the initial activity in the shipment vial, was found to be 59.9% +/- 7.9% for direct and 50% +/- 3.2% for indirect methods. 131I-PR81 and 131I- YYK- peptide -PR81 complexes showed high immunoreactivity towards MUC1 protein, BSA-P20 and MCF7 cell line. In vitro stability of the labeled products in human serum which was measured by thin layer chromatography (TLC) was found to be more than 50% over 24 hr for 131I-PR81 and 70% for 131I- YYK-peptide -PR81 complexes. Cell toxicity and in vitro internalization studies showed that the 131I-PR81 and 131I- YYK-peptide -PR81 complexes inhibited 80% growth of the MCF7 cultured cell lines in vitro in a high concentration and up to 40% of the 131I-PR81 and 60% of the 131I- YYK-peptide -PR81 complexes internalized after 24 h. Biodistribution studies were performed in normal BALB/c mice at 4, 24 and 48 hrs post-injection. Thyroid and stomach levels from PR81 labeled with 131I- YYK-peptide were two- to three- fold less than those with directly labeled 131I-PR81, suggesting low recognition of its D-iodotyrosine residue by endogenous deiodinase. These results show that the indirect labeling was better than the indirect labeling and 131I- YYK-peptide -PR81 may be considered as a promising candidate for therapy of breast cancer.

Defining Survivorship Trajectories Across Patients With Solid Tumors: An Evidence-Based Approach.

PubMed

Dood, Robert L; Zhao, Yang; Armbruster, Shannon D; Coleman, Robert L; Tworoger, Shelley; Sood, Anil K; Baggerly, Keith A

2018-06-02

Survivorship involves a multidisciplinary approach to surveillance and management of comorbidities and secondary cancers, overseen by oncologists, surgeons, and primary care physicians. Optimal timing and coordination of care, however, is unclear and often based on arbitrary 5-year cutoffs. To determine high- and low-risk periods for all tumor types that could define when survivorship care might best be overseen by oncologists and when to transition to primary care physicians. In this pan-cancer, longitudinal, observational study, excess mortality hazard, calculated as an annualized mortality risk above a baseline population, was plotted over time. The time this hazard took to stabilize defined a high-risk period. The percent morality elevation above age- and sex-matched controls in the latter low-risk period was reported as a mortality gap. The US population-based Surveillance, Epidemiology, and End Results database defined the cancer population, and the US Census life tables defined controls. Incident cases of patients with cancer were separated into tumor types based on International Classification of Diseases for Oncology definitions. Population-level data on incident cancer cases was compared with the general US population. Overall mortality and cause of death were reported on observed cancer cases. A total of 2 317 185 patients (median age, 63 years; 49.8% female) with 66 primary tumor types were evaluated. High-risk surveillance period durations ranged from less than 1 year (breast, prostate, lip, ocular, and parathyroid cancers) up to 19 years (unspecified gastrointestinal cancers). The annualized mortality gap, representing the excess mortality in the stable period, ranged from a median 0.26% to 9.33% excess annual mortality (thyroid and hypopharyngeal cancer populations, respectively). Cluster analysis produced 6 risk cluster groups: group 1, with median survival of 16.2 (5th to 95th percentile range [PR], 10.7-40.2) years and median high-risk period of 2.5 (PR, 0-5.0) years; group 2, 8.3 (PR, 5.1-23.3) and 2.5 (PR, 4.0-8.0) years; group 3, 2.8 (PR, 1.4-3.7) and 7.0 (PR, 6.0-11.1) years; group 4, 1.6 (PR, 1.5-1.8) and 6.0 (PR, 5.1-11.4) years; group 5, 0.8 (PR, 0.5-1.2) and 0.8 (PR, 0.5-1.2) years; and group 6, 0.5 (PR, 0.4-0.8) and 12.0 (PR, 9.3-12.9) years, respectively. Subanalyses of selected tumor types in these groups revealed that stratifying on stage and histologic type can change the risk cluster and guidance for care. These findings indicate that a standardized 5-year surveillance period is inadequate for some cancers while excessive for others. High-risk cancers require the most resources with the longest high-risk period, highest persistent baseline mortality risk, and longest period of primary cancer mortality, all arguing for longer follow-up with an oncologist in these cancers.

Signal transduction in neurons: effects of cellular prion protein on fyn kinase and ERK1/2 kinase.

PubMed

Tomasi, Vittorio

2010-12-16

It has been reported that cellular prion protein (PrPc) co-localizes with caveolin-1 and participates to signal transduction events by recruiting Fyn kinase. As PrPc is a secreted protein anchored to the outer surface membrane through a glycosylphosphatidylinositol (GPI) anchor (secPrP) and caveolin-1 is located in the inner leaflet of plasma membrane, there is a problem of how the two proteins can physically interact each other and transduce signals. By using the GST-fusion proteins system we observed that PrPc strongly interacts with caveolin-1 scaffolding domain and with a caveolin-1 hydrophilic C-terminal region, but not with the caveolin-1 N-terminal region. In vitro binding experiments were also performed to define the site(s) of PrPc interacting with cav-1. The results are consistent with a participation of PrPc octapeptide repeats motif in the binding to caveolin-1 scaffolding domain. The caveolar localization of PrPc was ascertained by co-immunoprecipitation, by co-localization after flotation in density gradients and by confocal microscopy analysis of PrPc and caveolin-1 distributions in a neuronal cell line (GN11) expressing caveolin-1 at high levels. We observed that, after antibody-mediated cross-linking or copper treatment, PrPc was internalized probably into caveolae. We propose that following translocation from rafts to caveolae or caveolae-like domains, secPrP could interact with caveolin-1 and induce signal transduction events.

Praseodymium - A Competent Dopant for Luminescent Downshifting and Photocatalysis in ZnO Thin Films

NASA Astrophysics Data System (ADS)

Narayanan, Nripasree; Deepak, N. K.

2018-05-01

Highly transparent and conducting Zinc oxide (ZnO) thin films doped with Praseodymium (Pr) were deposited on glass substrates by using the spray pyrolysis method. The X-ray diffraction (XRD) analysis revealed the polycrystallinity of the deposited films with a hexagonal wurtzite structure, whereas the energy-dispersive X-ray spectroscopy (EDX) analysis confirmed the incorporation of Pr in the films. The optical energy gap decreased by Pr doping due to the merging of the conduction band with the impurity bands formed within the forbidden gap. The room temperature photoluminescence spectra of the Pr-doped film showed enhancement of visible emission, suggesting efficient luminescent downshifting. The photocatalytic activity of the Pr-doped films is higher than that of undoped films due to the effective suppression of the rapid recombination of the photo-generated electron-hole pairs. The impurity levels formed within the forbidden gap act as efficient luminescent centers and electron traps, which lead to luminescent downshifting and enhanced photocatalytic activity.

CD36 Participates in PrP106–126-Induced Activation of Microglia

PubMed Central

Tan, Rongrong; Shi, Fushan; Lu, Yun; Zhang, Siming; Yin, Xiaomin; Zhou, Xiangmei; Zhao, Deming

2012-01-01

Microglial activation is a characteristic feature of the pathogenesis of prion diseases. The molecular mechanisms that underlie prion-induced microglial activation are not very well understood. In the present study, we investigated the role of the class B scavenger receptor CD36 in microglial activation induced by neurotoxic prion protein (PrP) fragment 106–126 (PrP106–126). We first examined the time course of CD36 mRNA expression upon exposure to PrP106–126 in BV2 microglia. We then analyzed different parameters of microglial activation in PrP106–126-treated cells in the presence or not of anti-CD36 monoclonal antibody (mAb). The cells were first incubated for 1 h with CD36 monoclonal antibody to block the CD36 receptor, and were then treated with neurotoxic prion peptides PrP106–126. The results showed that PrP106–126 treatment led to a rapid yet transitory increase in the mRNA expression of CD36, upregulated mRNA and protein levels of proinflammatory cytokines (IL-1β, IL-6 and TNF-α), increased iNOS expression and nitric oxide (NO) production, stimulated the activation of NF-κB and caspase-1, and elevated Fyn activity. The blockade of CD36 had no effect on PrP106–126-stimulated NF-κB activation and TNF-α protein release, abrogated the PrP106–126-induced iNOS stimulation, downregulated IL-1β and IL-6 expression at both mRNA and protein levels as well as TNF-α mRNA expression, decreased NO production and Fyn phosphorylation, reduced caspase-1 cleavage induced by moderate PrP106–126 –treatment, but had no effect on caspase-1 activation after treatment with a high concentration of PrP106–126. Together, these results suggest that CD36 is involved in PrP106–126-induced microglial activation and that the participation of CD36 in the interaction between PrP106–126 and microglia may be mediated by Src tyrosine kinases. Our findings provide new insights into the mechanisms underlying the activation of microglia by neurotoxic prion peptides and open perspectives for new therapeutic strategies for prion diseases by modulation of CD36 signaling. PMID:22292032

Hypertension control in a large multi-ethnic cohort in Amsterdam, The Netherlands: the HELIUS study.

PubMed

Agyemang, Charles; Kieft, Suzanne; Snijder, Marieke B; Beune, Erik J; van den Born, Bert-Jan; Brewster, Lizzy M; Ujcic-Voortman, Joanne J; Bindraban, Navin; van Montfrans, Gert; Peters, Ron J; Stronks, Karien

2015-03-15

Hypertension is a major problem among European ethnic minority groups. We assessed the current situation of hypertension prevalence and its management among a multi-ethnic population in Amsterdam, The Netherlands. Data from the HELIUS study were used including 12,974 participants (1871 Ghanaian, 2184 African Surinamese, 2278 South-Asian Surinamese, 2277 Turkish, 2222 Moroccan and 2142 Dutch origin people), aged 18-70 years. Comparisons among groups were made using proportions and age-adjusted prevalence ratios (PRs). Hypertension prevalence ranged from 24% and 16% in Moroccan men and women to 52% and 62% in Ghanaian men and women. Except for Moroccan women, age-adjusted PR of hypertension was higher in all the ethnic minority groups than in Dutch. Among hypertensives, ethnic minority groups generally had higher levels of hypertension awareness and BP lowering treatment than Dutch. Moreover, prevalence rates for the prescription of more than one BP lowering drug were generally higher in African and South-Asian origin groups compared with Dutch origin people. By contrast, BP control levels were lower in all the ethnic groups than in Dutch, with control rates being significantly lower in Ghanaian men (26%, PR=0.49; 95% CI, 0.37-0.66) and women (45%, PR=0.64; 0.52-0.77), African-Surinamese men (30%, PR=0.61; 0.46-0.81) and women (45%, PR=0.72; 0.51-0.77), and South-Asian Surinamese men (43%, PR=0.77; 0.61-0.97) and women (47%, PR=0.76; 0.63-0.92) compared with Dutch men (53%) and women (61%). Our findings indicate poor BP control in ethnic minority groups despite the high treatment levels. More work is needed to unravel the potential factors contributing to the poor control in order to improve BP control in ethnic minority groups, particularly among African and South-Asian origin groups. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Oestrogen and progesterone receptor assays in breast tumours. The Prince Henry's Hospital experience, 1983-1990.

PubMed

Pearce, P T; Myles, K M; Funder, J W

1993-08-16

To present and analyse the results of eight years of experience (1983-1990) in breast tumour receptor analysis. All female primary breast tumour samples received (4683) were analysed for seasonal variation, patient age, relative risk index, oestrogen receptor (ER) and progesterone receptor (PR) status, ER and PR status as a function of age, ER and PR levels as a function of age, and ER and PR levels as a function of month of analysis. The assays were done at the Medical Research Centre, Prince Henry's Hospital, Melbourne, as a non-profit service to surgeons, oncologists and pathologists. The numbers of samples referred for assay increased progressively each year, from 473 in 1983 to 1097 in 1990, but the receptor status (ER +/-, PR +/-) appeared not to vary from year to year. ER+PR+ tumours were the most common in all age groups, steadily increasing from between 50% and 60% in premenopausal women to 70% or more in those aged over 80. In postmenopausal women, levels of ER in ER+ tumours were three times those in premenopausal women; PR levels in PR+ tumours, however, were bimodal, with higher levels in the age groups 35-49 and 70-89 years than in women aged 50-69 years. No significant seasonal variation was seen, and the overall patterns of receptor status are similar to those seen in Northern hemisphere studies.

Triggering risk factors of the burnout syndrome in OB/GYN physicians from a reference public university of Brazil.

PubMed

Ferreira Bortoletti, Fátima; Teresa Benevides-Pereira, Ana Maria; Vasconcellos, Esdras Guerreiro; Siqueira, José Oliveira; Araujo Júnior, Edward; Nardozza, Luciano Marcondes Machado; Sebastiani, Ricardo Werner; Moron, Antonio Fernandes

2012-01-01

Objective. To identify the risk factors to the development of Burnout Syndrome in Ob/Gyn Brazilian physicians in four dimensions: emotional exhaustion (EE), professional repression (PR), dehumanization (De), and emotional distancing (EmD). Methods. A prospective cross-sectional study was realized with 48 Ob/Gyn physicians (12 lecturers, 12 attending physicians, 12 medical residents, and 12 graduate students) from Department of Obstetrics, São Paulo Federal University (UNIFESP). We used a sociodemographic questionnaire focusing on the activities (administrative, educational, healthcare, and research). We applied a Burnout Syndrome Inventory (BSI) composed of two parts: triggering factors (ISB1) and the Burnout Syndrome (ISB2). The ISB1 is composed of two scales: positive organizational conditions (POC) and negative organizational conditions (NOC). The ISB2 is composed of four scales: EE, PR, De, and EmD. Results. We observed a rate below and above average to POC and NOC, respectively. The dimensions recorded a level above average to EE, an index at the upper limit of the average to De, a median index to EmD, and a median index to PR. Conclusions. The Ob/Gyn physicians are in an area of vulnerability for the development of Burnout Syndrome due to the high level of EE and De, associated with a median index of PR. The high rate of NOC contributes to the triggering of this scenery.

Triggering Risk Factors of the Burnout Syndrome in Ob/Gyn Physicians from a Reference Public University of Brazil

PubMed Central

Ferreira Bortoletti, Fátima; Teresa Benevides-Pereira, Ana Maria; Vasconcellos, Esdras Guerreiro; Siqueira, José Oliveira; Araujo Júnior, Edward; Nardozza, Luciano Marcondes Machado; Sebastiani, Ricardo Werner; Moron, Antonio Fernandes

2012-01-01

Objective. To identify the risk factors to the development of Burnout Syndrome in Ob/Gyn Brazilian physicians in four dimensions: emotional exhaustion (EE), professional repression (PR), dehumanization (De), and emotional distancing (EmD). Methods. A prospective cross-sectional study was realized with 48 Ob/Gyn physicians (12 lecturers, 12 attending physicians, 12 medical residents, and 12 graduate students) from Department of Obstetrics, São Paulo Federal University (UNIFESP). We used a sociodemographic questionnaire focusing on the activities (administrative, educational, healthcare, and research). We applied a Burnout Syndrome Inventory (BSI) composed of two parts: triggering factors (ISB1) and the Burnout Syndrome (ISB2). The ISB1 is composed of two scales: positive organizational conditions (POC) and negative organizational conditions (NOC). The ISB2 is composed of four scales: EE, PR, De, and EmD. Results. We observed a rate below and above average to POC and NOC, respectively. The dimensions recorded a level above average to EE, an index at the upper limit of the average to De, a median index to EmD, and a median index to PR. Conclusions. The Ob/Gyn physicians are in an area of vulnerability for the development of Burnout Syndrome due to the high level of EE and De, associated with a median index of PR. The high rate of NOC contributes to the triggering of this scenery. PMID:23304541

Prostate Cancer Information Available in Health-Care Provider Offices: An Analysis of Content, Readability, and Cultural Sensitivity.

PubMed

Choi, Seul Ki; Seel, Jessica S; Yelton, Brooks; Steck, Susan E; McCormick, Douglas P; Payne, Johnny; Minter, Anthony; Deutchki, Elizabeth K; Hébert, James R; Friedman, Daniela B

2018-07-01

Prostate cancer (PrCA) is the most common cancer affecting men in the United States, and African American men have the highest incidence among men in the United States. Little is known about the PrCA-related educational materials being provided to patients in health-care settings. Content, readability, and cultural sensitivity of materials available in providers' practices in South Carolina were examined. A total of 44 educational materials about PrCA and associated sexual dysfunction was collected from 16 general and specialty practices. The content of the materials was coded, and cultural sensitivity was assessed using the Cultural Sensitivity Assessment Tool. Flesch Reading Ease, Flesch-Kincaid Grade Level, and the Simple Measure of Gobbledygook were used to assess readability. Communication with health-care providers (52.3%), side effects of PrCA treatment (40.9%), sexual dysfunction and its treatment (38.6%), and treatment options (34.1%) were frequently presented. All materials had acceptable cultural sensitivity scores; however, 2.3% and 15.9% of materials demonstrated unacceptable cultural sensitivity regarding format and visual messages, respectively. Readability of the materials varied. More than half of the materials were written above a high-school reading level. PrCA-related materials available in health-care practices may not meet patients' needs regarding content, cultural sensitivity, and readability. A wide range of educational materials that address various aspects of PrCA, including treatment options and side effects, should be presented in plain language and be culturally sensitive.

Brachytherapy with Intratumoral Injections of Radiometal-Labeled Polymers That Thermoresponsively Self-Aggregate in Tumor Tissues.

PubMed

Sano, Kohei; Kanada, Yuko; Kanazaki, Kengo; Ding, Ning; Ono, Masahiro; Saji, Hideo

2017-09-01

Brachytherapy is a type of radiotherapy wherein titanium capsules containing therapeutic radioisotopes are implanted within tumor tissues, enabling high-dose radioirradiation to tumor tissues around the seeds. Although marked therapeutic effects have been demonstrated, brachytherapy needs a complicated implantation technique under general anesthesia and the seeds could migrate to other organs. The aim of this study was to establish a novel brachytherapy using biocompatible, injectable thermoresponsive polymers (polyoxazoline [POZ]) labeled with 90 Y, which can self-aggregate above a specific transition temperature (Tt), resulting in long-term intratumoral retention of radioactivity and therapeutic effect. Therefore, we evaluated the tumor retention of radiolabeled POZ derivatives and their therapeutic effects. Methods: Using oxazoline derivatives with ethyl (Et), isopropyl (Isp), and propyl (Pr) side chains, we synthesized EtPOZ, IspPOZ, Isp-PrPOZ (heteropolymer), and PrPOZ and measured their characteristic Tts. The intratumoral retention of 111 In-labeled POZ was evaluated until 7 d after injection in nude mice bearing PC-3 human prostate cancer. The intratumoral localization of 111 In-labeled POZ derivatives was investigated by an autoradiographic study. Furthermore, a therapeutic study using 90 Y-labeled Isp-PrPOZ was performed, and tumor growth and survival rate were evaluated. Results: The Tts of EtPOZ, IspPOZ, Isp-PrPOZ, and PrPOZ (∼20 kDa) were greater than 70°C, 34°C, 25°C, and 19°C, respectively. In the intratumoral injection study, Isp-PrPOZ and PrPOZ (2,000 μM) with Tts lower than tumor temperature (33.5°C under anesthesia) showed a significantly higher retention of radioactivity at 1 d after injection (73.6% and 73.9%, respectively) than EtPOZ (5.6%) and IspPOZ (15.8%). Even at low injected dose (100 μM), Isp-PrPOZ exhibited high retention (68.3% at 1 d). The high level of radioactivity of Isp-PrPOZ was retained in the tumor 7 d after injection (69.5%). The autoradiographic study demonstrated that the radioactivity of 111 In-labeled Isp-PrPOZ and PrPOZ was localized in a small area. In the therapeutic study using 90 Y-labeled Isp-PrPOZ, significant suppression of tumor growth and prolonged survival rate were achieved in an injection dose-dependent manner compared with that observed for the vehicle-injected group and nonradioactive Isp-PrPOZ-injected group. Conclusion: The injectable 90 Y-labeled Isp-PrPOZ was retained for a prolonged period within tumor tissues via self-aggregation and exhibited marked therapeutic effect, suggesting its usefulness for brachytherapy. © 2017 by the Society of Nuclear Medicine and Molecular Imaging.

Simulation of TRMM Microwave Imager Brightness Temperature using Precipitation Radar Reflectivity for Convective and Stratiform Rain Areas over Land

NASA Technical Reports Server (NTRS)

Prabhakara, C.; Iacovazzi, R., Jr.; Yoo, J.-M.; Lau, William K. M. (Technical Monitor)

2002-01-01

Rain is highly variable in space and time. In order to measure rainfall over global land with satellites, we need observations with very high spatial resolution and frequency in time. On board the Tropical Rainfall Measuring Mission (TRMM) satellite, the Precipitation Radar (PR) and Microwave Imager (TMI) are flown together for the purpose of estimating rain rate. The basic method to estimate rain from PR has been developed over the past several decades. On the other hand, the TMI method of rain estimation is still in the state development, particularly over land. The objective of this technical memorandum is to develop a theoretical framework that helps relate the observations made by these two instruments. The principle result of this study is that in order to match the PR observations with the TMI observations in convective rain areas, a mixed layer of graupel and supercooled water drops above the freezing level is needed. On the other hand, to match these observations in the stratiform region, a layer of snowflakes with appropriate densities above the freezing level, and a melting layer below the freezing level, are needed. This understanding can lead to a robust rainfall estimation technique from the microwave radiometer observations.

Highly Flexible and Conductive Glycerol-Doped PEDOT:PSS Films Prepared Under an Electric Field

NASA Astrophysics Data System (ADS)

Yamaguchi, Hiroyuki; Aizawa, Kengo; Chonan, Yasunori; Komiyama, Takao; Aoyama, Takashi; Sakai, Eiichi; Qiu, Jianhui; Sato, Naoki

2018-06-01

Poly(3,4-ethylenedioxythiophene):poly(4-styrenesulfonate) (PEDOT:PSS) films doped with several sugar alcohols, viz. xylitol (XL), glycerol (GL), and polyglycerol (PG), at various levels have been synthesized and their thermoelectric properties studied. Among these specimens, 2.5 vol.% GL-doped films showed the best performance with electrical conductivity σ, Seebeck coefficient S, and power factor S 2 σ at room temperature reaching 1040 S/cm, 19 μV/K, and 37 μW/m-K2, respectively. Next, we synthesized films under an electric field E pr for the purpose of crystal growth. GL-doped films showed σ enhancement with increase of E pr. The highest σ value of 1300 S/cm was attained at E pr = 4 kV/cm. S and thermal conductivity κ values were almost independent of E pr. The ZT value was calculated to be between 0.017 and 0.101 at room temperature. We also examined film flexibility. High flexibility was achieved on GL doping, and it was not deteriorated when synthesized under an electric field.

Highly Flexible and Conductive Glycerol-Doped PEDOT:PSS Films Prepared Under an Electric Field

NASA Astrophysics Data System (ADS)

Yamaguchi, Hiroyuki; Aizawa, Kengo; Chonan, Yasunori; Komiyama, Takao; Aoyama, Takashi; Sakai, Eiichi; Qiu, Jianhui; Sato, Naoki

2018-04-01

Poly(3,4-ethylenedioxythiophene):poly(4-styrenesulfonate) (PEDOT:PSS) films doped with several sugar alcohols, viz. xylitol (XL), glycerol (GL), and polyglycerol (PG), at various levels have been synthesized and their thermoelectric properties studied. Among these specimens, 2.5 vol.% GL-doped films showed the best performance with electrical conductivity σ, Seebeck coefficient S, and power factor S 2 σ at room temperature reaching 1040 S/cm, 19 μV/K, and 37 μW/m-K2, respectively. Next, we synthesized films under an electric field E pr for the purpose of crystal growth. GL-doped films showed σ enhancement with increase of E pr. The highest σ value of 1300 S/cm was attained at E pr = 4 kV/cm. S and thermal conductivity κ values were almost independent of E pr. The ZT value was calculated to be between 0.017 and 0.101 at room temperature. We also examined film flexibility. High flexibility was achieved on GL doping, and it was not deteriorated when synthesized under an electric field.

Variability Studies of Two Prunus-Infecting Fabaviruses with the Aid of High-Throughput Sequencing

PubMed Central

Sarkisova, Tatiana; Lenz, Ondřej; Přibylová, Jaroslava; Špak, Josef; Lotos, Leonidas; Beta, Christina; Katsiani, Asimina; Candresse, Thierry

2018-01-01

During their lifetime, perennial woody plants are expected to face multiple infection events. Furthermore, multiple genotypes of individual virus species may co-infect the same host. This may eventually lead to a situation where plants harbor complex communities of viral species/strains. Using high-throughput sequencing, we describe co-infection of sweet and sour cherry trees with diverse genomic variants of two closely related viruses, namely prunus virus F (PrVF) and cherry virus F (CVF). Both viruses are most homologous to members of the Fabavirus genus (Secoviridae family). The comparison of CVF and PrVF RNA2 genomic sequences suggests that the two viruses may significantly differ in their expression strategy. Indeed, similar to comoviruses, the smaller genomic segment of PrVF, RNA2, may be translated in two collinear proteins while CVF likely expresses only the shorter of these two proteins. Linked with the observation that identity levels between the coat proteins of these two viruses are significantly below the family species demarcation cut-off, these findings support the idea that CVF and PrVF represent two separate Fabavirus species. PMID:29670059

Increased Adipocyte Size, Macrophage Infiltration, and Adverse Local Adipokine Profile in Perirenal Fat in Cushing's Syndrome.

PubMed

Roerink, Sean H P P; Wagenmakers, Margreet A E M; Langenhuijsen, Johan F; Ballak, Dov B; Rooijackers, Hanne M M; d'Ancona, Frank C; van Dielen, François M; Smit, Jan W A; Plantinga, Theo S; Netea-Maier, Romana T; Hermus, Ad R M M

2017-08-01

To analyze changes in fat cell size, macrophage infiltration, and local adipose tissue adipokine profiles in different fat depots in patients with active Cushing's syndrome. Subcutaneous (SC) and perirenal (PR) adipose tissue of 10 patients with Cushing's syndrome was compared to adipose tissue of 10 gender-, age-, and BMI-matched controls with regard to adipocyte size determined by digital image analysis on hematoxylin and eosin stainings, macrophage infiltration determined by digital image analysis on CD68 stainings, and adipose tissue leptin and adiponectin levels using fluorescent bead immunoassays and ELISA techniques. Compared to the controls, mean adipocyte size was larger in PR adipose tissue in patients. The percentage of macrophage infiltration of the PR adipose tissue and PR adipose tissue lysate leptin levels were higher and adiponectin levels were lower in SC and PR adipose tissue lysates in patients. The adiponectin levels were also lower in the SC adipose tissue supernatants of patients. Associations were found between the severity of hypercortisolism and PR adipocyte size. Cushing's syndrome is associated with hypertrophy of PR adipocytes and a higher percentage of macrophage infiltration in PR adipose tissue. These changes are associated with an adverse local adipokine profile. © 2017 The Obesity Society.

Measuring and understanding the attitudes of Australian gay and bisexual men towards biomedical HIV prevention using cross-sectional data and factor analyses.

PubMed

Wilkinson, Anna L; Draper, Bridget L; Pedrana, Alisa E; Asselin, Jason; Holt, Martin; Hellard, Margaret E; Stoové, Mark

2017-11-21

Contemporary responses to HIV embrace biomedical prevention, particularly treatment as prevention (TasP) and pre-exposure prophylaxis (PrEP). However, large-scale implementation of biomedical prevention should be ideally preceded by assessments of their community acceptability. We aimed to understand contemporary attitudes of gay and bisexual men (GBM) in Australia towards biomedical-based HIV prevention and propose a framework for their measurement and ongoing monitoring. A cross-sectional, online survey of GBM ≥18 years has been conducted annually in Victoria, Australia, since 2008. In 2016, 35 attitudinal items on biomedical HIV prevention were added. Items were scored on five-point Likert scales. We used principal factor analysis to identify key constructs related to GBM's attitudes to biomedical HIV prevention and use these to characterise levels of support for TasP and PrEP. A total of 462 HIV-negative or HIV-status-unknown men, not using PrEP, provided valid responses for all 35 attitudinal items. We extracted four distinct and interpretable factors we named: 'Confidence in PrEP', 'Judicious approach to PrEP', 'Treatment as prevention optimism' and 'Support for early treatment'. High levels of agreement were seen across PrEP-related items; 77.9% of men agreed that PrEP prevented HIV acquisition and 83.6% of men agreed that users were protecting themselves. However, the agreement levels for HIV TasP items were considerably lower, with <20% of men agreeing treatment (undetectable viral load) reduced HIV transmission risk. Better understanding of community attitudes is crucial for shaping policy and informing initiatives that aim to improve knowledge, acceptance and uptake of biomedical prevention. Our analyses suggest confidence in, acceptability of and community support for PrEP among GBM. However, strategies to address scepticism towards HIV treatment when used for prevention may be needed to optimise combination biomedical HIV prevention. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Prevalence of chronic stress in general practitioners and practice assistants: Personal, practice and regional characteristics

PubMed Central

Kersting, Christine; Thielmann, Anika; Weltermann, Birgitta

2017-01-01

Background The majority of studies investigating stress in primary care have focused either on general practitioners (GPs) or practice assistants (PAs), but did not measure stress on a practice level. We analyzed the prevalence of chronic stress for both professional groups and on a practice level and investigated personal, practice, and regional characteristics. Methods Chronic stress was measured in GPs and PAs from 136 German practices using the standardized, self-administered TICS-SSCS questionnaire (12 items). Based on a sum-score, participants per professional group were categorized as having low or high strain due to chronic stress (≤ 25th and ≥ 75th percentile of the study population´s distribution, respectively). For a cluster-level analysis, the mean of all practice means was used to categorize low- and high-stress practices. The intra-class correlation coefficient (ICC) was calculated using ANOVA. Prevalence Ratios (PR) were used to compare low versus high strain due to stress, stratified for personal, practice and regional characteristics. Results The response rate was 74.1% (n = 137/185). Data from 214 GPs (34.1% female), 500 PAs (99.4% female), and 50 PAs in training (98.0% female) were analyzed. Chronic stress was highest in female GPs (median 19, IQR (interquartile range) 11.5), followed by PAs (16, IQR 12.25) and male GPs (15, IQR 10). On a practice level, 26.3% of the practice personnel reported a high stress level. We observed an overall ICC of 0.25, with higher ICCs when stratifying by professional group (PAs: ICC 0.36, GPs in group practices: ICC 0.51). High chronic stress was observed as the number of working hours per week increased (GPs: PR 2.03, 95% CI 1.16–3.56; PAs: PR 2.02, 95% CI 1.22–3.35). There were no differences for practice type (solo/group) and the various regional characteristics. Conclusion Personal and practice characteristics were associated with chronic stress in GPs, PAs, and on a practice level. The high ICCs indicate a need for stress-reduction strategies geared at both professions on a practice level. PMID:28489939

A PR-4 gene identified from Malus domestica is involved in the defense responses against Botryosphaeria dothidea.

PubMed

Bai, Suhua; Dong, Chaohua; Li, Baohua; Dai, Hongyi

2013-01-01

Pathogenesis-related protein-4 (PR-4) family is a group of proteins with a Barwin domain in C-terminus and generally thought to be involved in plant defense responses. However, their detailed roles are poorly understood in defense of apple plant against pathogenic infection. In the present study, a new PR-4 gene (designated as MdPR-4) was identified from Malus domestica, and its roles in defense responses of apple were investigated. The open reading frame of MdPR-4 gene is of 447 bp encoding a protein of 148 amino acids with a Barwin domain in C-terminus and a signal peptide of 26 amino acids in N-terminus. Sequence and structural analysis indicated that MdPR-4 protein belongs to class II of PR-4 family. The high-level expression of MdPR-4 was observed in flowers and leaves as revealed by quantitative real time PCR. The temporal expression analysis demonstrated that MdPR-4 expression could be up-regulated by Botryosphaeria dothidea infection and salicylic acid (SA) or methyl jasmonate (MeJA) treatment, but suppressed by diethyldithiocarbamic acid (DIECA). In vitro assays, recombinant MdPR-4 protein exhibited ribonuclease activity specific for single strand RNA and significant inhibition to hyphal growth of three apple pathogenic fungi B. dothidea, Valsa ceratosperma and Glomerella cingulata. Moreover, the inhibition was reduced by the presence of 5'-ADP. Taken all together, the results indicate that MdPR-4 protein is involved in the defense responses of apple against pathogenic attack by directly inhibiting hyphal growth, and the inhibition is correlated with its ribonuclease activity, where as MdPR-4 expression is regulated by both SA and JA signaling pathway. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

Association between maternal education and malocclusion in Mongolian adolescents: a cross-sectional study

PubMed Central

Tumurkhuu, Tsasan; Fujiwara, Takeo; Komazaki, Yuko; Kawaguchi, Yoko; Inazawa, Johji; Ganburged, Ganjargal; Bazar, Amarsaikhan; Ogawa, Takuya; Moriyama, Keiji

2016-01-01

Objective Malocclusion is a highly prevalent condition, affecting 20–60% of adolescents worldwide. Although its treatment is often expensive and unaffordable for disadvantaged individuals, few studies have examined the relationship between malocclusion and socioeconomic status. We investigated the prevalence of malocclusion among Mongolian adolescents and its association with maternal education in a community-based sample in Mongolia. Design Cross-sectional study. Settings 2 large secondary schools with different backgrounds in Ulaanbaatar, Mongolia. Participants Complete dental casts of 557 randomly recruited Mongolian schoolchildren aged 11–16 years were evaluated using the Dental Health Component of the Index of Orthodontic Treatment Need to dichotomise orthodontic treatment requirements. Exclusion criteria were the presence of orthodontic treatment history and absence of maternal educational status. Questionnaires were administered to caregivers to assess socioeconomic status. Poisson regression analysis was performed to examine the association between malocclusion and maternal educational status. Results The prevalence of malocclusion requiring orthodontic treatment among all adolescents was 35.2% (95% CI 31.2 to 39.2). In the unadjusted analysis, the prevalence ratio (PR) for malocclusion was higher (PR=1.46; 95% CI 0.96 to 2.20) among adolescents of mothers with a high educational background than among those of mothers with a low educational background. After adjusting for covariates, the PR remained significantly higher (PR=1.72; 95% CI 1.06 to 2.82) among adolescents of mothers with a high educational background. Other socioeconomic status variables, including family income and the educational level of the father, showed no association with malocclusion. Conclusions These findings suggest that malocclusion requiring orthodontic treatment in adolescents is more prevalent among children of mothers with high levels of education. Further studies are needed to clarify the behavioural factors and environmental circumstance that contribute to this. PMID:27803108

Optimizing content for pre-exposure prophylaxis (PrEP) counseling for men who have sex with men: Perspectives of PrEP users and high-risk PrEP naïve men.

PubMed

Wade Taylor, S; Mayer, Kenneth H; Elsesser, Steven M; Mimiaga, Matthew J; O'Cleirigh, Conall; Safren, Steven A

2014-05-01

Existing trials of antiretroviral (ARV) medication as chemoprophylaxis against HIV reveal that the degree of protection is primarily dependent on product adherence. However, there is a lack of data on targets for behavioral interventions to improve adherence to ARV as prevention. Information from individuals who have used ARV as pre-exposure prophylaxis (PrEP) can inform behavioral intervention development. Thirty-nine HIV-uninfected MSM at high risk for HIV acquisition participated in one of four semi-structured focus groups. Two of the focus groups consisted of MSM who had been prescribed and used PrEP in the context of a clinical trial; the other two consisted of high-risk MSM who had not previously used PrEP. An in-depth, within-case/across-case content analysis resulted in six descriptive themes potentially salient for a PrEP adherence behavioral intervention: (1) motivations to use PrEP, (2) barriers to PrEP use, (3) facilitators to PrEP use, (4) sexual decision-making in the context of PrEP, (5) prospective PrEP education content, and, (6) perceived effective characteristics of PrEP delivery personnel. Addressing these themes in behavioral interventions in the context of prescribing PrEP may result in the optimal "packaging" public health programs that implement PrEP for high-risk MSM.

Intergenerational education mobility and depressive symptoms in a population of Mexican origin

PubMed Central

Ward, Julia B.; Haan, Mary N.; Garcia, Maria E.; Lee, Anne; To, Tu My

2016-01-01

Purpose Low educational attainment has been associated with depression among Latinos. However, few studies have collected intergenerational data to assess mental health effects of educational mobility across generations. Methods Using data from the Niños Lifestyle and Diabetes Study, we assessed the influence of intergenerational education on depressive symptoms among 603 Mexican-origin individuals. Intergenerational educational mobility was classified: stable-low (low parent/low offspring education), upwardly-mobile (low parent/high offspring education), stable-high (high parent/high offspring education), or downwardly-mobile (high parent/low offspring education). High depressive symptoms were defined as scoring ≥10 on the CESD-10. We examined prevalence ratios (PR) for depressive symptoms with levels of educational mobility. We used general estimating equations with log-binomial models to account for within-family clustering, adjusting for age, sex, and offspring and parent nativity. Results Compared to stable-low participants, the lowest prevalence of CESD-10 score ≥10 occurred in upwardly-mobile (PR=0.55; 95% confidence interval [CI]=0.39–0.78) and stable-high (PR=0.62; 95%CI=0.44–0.87) participants. Downwardly-mobile participants were also less likely to have a CESD-10 score ≥10 compared to stable-low participants (PR=0.65; 95%CI=0.38–1.11), although the estimate was not statistically significant. Conclusions Sustained stress from low intergenerational education may adversely affect depression. Latinos with stable-low or downwardly-mobile intergenerational educational attainment may need closer monitoring for depressive symptoms. PMID:27346705

Prostate stromal cells express the progesterone receptor to control cancer cell mobility.

PubMed

Yu, Yue; Lee, Jennifer Suehyun; Xie, Ning; Li, Estelle; Hurtado-Coll, Antonio; Fazli, Ladan; Cox, Michael; Plymate, Stephen; Gleave, Martin; Dong, Xuesen

2014-01-01

Reciprocal interactions between epithelium and stroma play vital roles for prostate cancer development and progression. Enhanced secretions of cytokines and growth factors by cancer associated fibroblasts in prostate tumors create a favorable microenvironment for cancer cells to grow and metastasize. Our previous work showed that the progesterone receptor (PR) was expressed specifically in prostate stromal fibroblasts and smooth muscle cells. However, the expression levels of PR and its impact to tumor microenvironment in prostate tumors are poorly understood. Immunohistochemistry assays are applied to human prostate tissue biopsies. Cell migration, invasion and proliferation assays are performed using human prostate cells. Real-time PCR and ELISA are applied to measure gene expression at molecular levels. Immunohistochemistry assays showed that PR protein levels were decreased in cancer associated stroma when compared with paired normal prostate stroma. Using in vitro prostate stromal cell models, we showed that conditioned media collected from PR positive stromal cells inhibited prostate cancer cell migration and invasion, but had minor suppressive impacts on cancer cell proliferation. PR suppressed the secretion of stromal derived factor-1 (SDF-1) and interlukin-6 (IL-6) by stromal cells independent to PR ligands. Blocking PR expression by siRNA or supplementation of exogenous SDF-1 or IL-6 to conditioned media from PR positive stromal cells counteracted the inhibitory effects of PR to cancer cell migration and invasion. Decreased expression of the PR in cancer associated stroma may contribute to the elevated SDF-1 and IL-6 levels in prostate tumors and enhance prostate tumor progression.

Prostate cancer incidence and tumor severity in Georgia: descriptive epidemiology, racial disparity, and geographic trends.

PubMed

Wagner, Sara E; Bauer, Sarah E; Bayakly, A Rana; Vena, John E

2013-01-01

Limited research has been conducted to describe the geographical clustering and distribution of prostate cancer (PrCA) incidence in Georgia (GA). This study describes and compares the temporal and geographic trends of PrCA incidence in GA with a specific focus on racial disparities. GA Comprehensive Cancer Registry PrCA incidence data were obtained for 1998-2008. Directly standardized age-adjusted PrCA incidence rates per 100,000 were analyzed by race, stage, grade, and county. County-level hotspots of PrCA incidence were analyzed with the Getis-Ord Gi* statistic in a geographic information system; a census tract-level cluster analysis was performed with a Discrete Poisson model and implemented in SaTScan(®) software. Significant (p < 0.05) hotspots of PrCA incidence were observed in nine southwestern counties and six centrally located counties among men of both races. Six significant (p < 0.1) clusters of PrCA incidence rates were detected for men of both races in north and northwest central Georgia. When stratified by race, clusters among white and black men were similar, although centroids were slightly shifted. Most notably, a large (122 km radius) cluster in northwest central Georgia was detected only in whites, and two smaller clusters (0-32 km radii) were detected in Southwest Georgia only in black men. Clusters of high-grade and late-stage tumors were identified primarily in the northern portion of the state among men of both races. This study revealed a pattern of higher incidence and more advanced disease in northern and northwest central Georgia, highlighting geographic patterns that need more research and investigation of possible environmental determinants.

Physical Therapists as Providers of Care: Exercise Prescriptions and Resultant Outcomes in Cardiac and Pulmonary Rehabilitation Programs in New York State

PubMed Central

Scott, Lisa Benz

2008-01-01

Purpose: Physical therapists have engaged in cardiac rehabilitation (CR) and pulmonary rehabilitation (PR) for decades, but the extent of their current involvement in this practice area is unclear. This study surveyed directors of CR and PR programs on a statewide level to ascertain what type of provider is writing the prescription, which methods of exercise formulation are used, which outcome measures are used and their congruency with established guidelines. Methods: A convenience sample of outpatient CR and PR directors (n=31) representing 38 CR and/or PR programs located in New York completed a survey in spring 2005 (29 CR and 9 PR). Results: Results showed that only 2 physical therapists were responsible for writing exercise prescriptions in CR and PR programs. Most program directors were registered nurses (53%), who also wrote the majority of CR exercise prescriptions. Exercise intensity was most frequently determined using formulae and data that were highly patient-specific. Clinical outcomes most frequently included Quality of Life scales and stress tests. Conclusions: Physical therapists are minimally involved in directing programs and writing exercise prescriptions. Exercise prescriptions are individualized to the patient. Outcome measures most frequently used by participating CR and PR program directors are consistent with nationally-recognized best practice. PMID:20467497

Functional and genetic epidemiological characterisation of the FFAR4 (GPR120) p.R270H variant in the Danish population.

PubMed

Vestmar, Marie A; Andersson, Ehm A; Christensen, Charlotte R; Hauge, Maria; Glümer, Charlotte; Linneberg, Allan; Witte, Daniel R; Jørgensen, Marit E; Christensen, Cramer; Brandslund, Ivan; Lauritzen, Torsten; Pedersen, Oluf; Holst, Birgitte; Grarup, Niels; Schwartz, Thue W; Hansen, Torben

2016-09-01

p.R270H (rs116454156) in the long chain fatty acid 7TM receptor FFAR4 (GPR120) which results in impaired Gαq (Gq) coupled signalling, has been associated with obesity. We aimed to extend the functional in vitro analyses of p.R270H and to investigate the association with obesity and glucose-related traits in the Danish population. Surface expression, Gq and Gi coupled signalling as well as β-arrestin recruitment were examined in vitro. p.R270H was genotyped using the exome chip array in 11 479 Danish adult individuals. Of these 4391 were obese and 4415 were normal weight. Association with quantitative metabolic traits comprised 8720 non-diabetic individuals. p.R270H showed reduced surface expression of FFAR4. Ligand-independent activity was eliminated and strongly impaired through the Gq and Gi signalling pathways, respectively. The ligand-induced maximal signalling efficacy of p.R270H was reduced only through the Gq pathway. The p.R270H variant did not affect β-arrestin recruitment. p.R270H was not associated with increased risk of obesity nor increased fasting plasma glucose levels in the Danish study populations. Nor was it associated with these two traits in the European Network for Genetic and Genomic Epidemiology consortium data (N=34 901-71 175; p>0.70). It was also not associated with waist-hip ratio, glucose metabolism during an oral glucose tolerance test, lipid levels or with markers of adiposity (leptin, adiponectin), inflammation (high-sensitive C reactive protein; hs-CRP) and liver function (alanine aminotransferase) in the Danish population (p>0.05). We demonstrate that p.R270H of FFAR4 impairs Gq and Gi signalling of FFAR4 in vitro; however, this impaired signalling for p.R270H does not translate into associations with human metabolic phenotypes in the investigated populations. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

AirMSPI Level 1B2 V006 New Data for the SPEX-PR Campaign

Atmospheric Science Data Center

2018-05-08

... Imager (AirMSPI) Level 1B2 data products for the SPEX engineering flights + Porter Ranch gas leak overflights (SPEX-PR) flight ... AirMSPI data contains all targets acquired during the SPEX engineering flights + Porter Ranch gas leak overflights (SPEX-PR) flight ...

Getting PrEPared for HIV Prevention Navigation: Young Black Gay Men Talk About HIV Prevention in the Biomedical Era.

PubMed

Mutchler, Matt G; McDavitt, Bryce; Ghani, Mansur A; Nogg, Kelsey; Winder, Terrell J A; Soto, Juliana K

2015-09-01

Biomedical HIV prevention strategies, such as pre-exposure prophylaxis (PrEP) and post-exposure prophylaxis (PEP), represent new opportunities to reduce critically high HIV infection rates among young black men who have sex with men (YBMSM). We report results of 24 dyadic qualitative interviews (N=48), conducted in Los Angeles, CA, exploring how YBMSM and their friends view PrEP and PEP. Interviews were analyzed using a grounded theory approach. Participants had widely divergent levels of knowledge about these prevention methods. Misconceptions and mistrust regarding PrEP were common, and concerns were expressed about PrEP-related stigma and the potential for gossip among peers who might assume a person on PrEP was HIV-positive. Yet participants also framed PrEP and PEP as valuable new options within an expanded "tool kit" of HIV prevention strategies that created possibilities for preventing new HIV infections, dating men with a different HIV status, and decreased anxiety about exposure to HIV. We organized themes around four main areas: (1) information and misinformation about biomedical HIV prevention; (2) expectations about PrEP, sexual behavior, and stigma; (3) gossip, disclosure, and "spreading the word" about PrEP and PEP; and (4) the roles of PrEP and PEP in an expanded HIV prevention tool kit. The findings suggest a need for guidance in navigating the increasingly complex array of HIV-prevention options available to YBMSM. Such "prevention navigation" could counter misconceptions and address barriers, such as stigma and mistrust, while helping YBMSM make informed selections from among expanded HIV prevention options.

Perceived discrimination and depressive symptoms, smoking, and recent alcohol use in pregnancy.

PubMed

Bennett, Ian M; Culhane, Jennifer F; Webb, David A; Coyne, James C; Hogan, Vijaya; Mathew, Leny; Elo, Irma T

2010-06-01

Perceived discrimination is associated with poor mental health and health-compromising behaviors in a range of vulnerable populations, but this link has not been assessed among pregnant women. We aimed to determine whether perceived discrimination was associated with these important targets of maternal health care among low-income pregnant women. Face-to-face interviews were conducted in English or Spanish with 4,454 multiethnic, low-income, inner-city women at their first prenatal visit at public health centers in Philadelphia, Penn, USA, from 1999 to 2004. Perceived chronic everyday discrimination (moderate and high levels) in addition to experiences of major discrimination, depressive symptomatology (CES-D >or= 23), smoking in pregnancy (current), and recent alcohol use (12 months before pregnancy) were assessed by patients' self-report. Moderate everyday discrimination was reported by 873 (20%) women, high everyday discrimination by 238 (5%) women, and an experience of major discrimination by 789 (18%) women. Everyday discrimination was independently associated with depressive symptomatology (moderate = prevalence ratio [PR] of 1.58, 95% CI: 1.38-1.79; high = PR of 1.82, 95% CI: 1.49-2.21); smoking (moderate = PR of 1.19, 95% CI: 1.05-1.36; high = PR of 1.41, 95% CI: 1.15-1.74); and recent alcohol use (moderate = PR of 1.23, 95% CI: 1.12-1.36). However, major discrimination was not independently associated with these outcomes. This study demonstrated that perceived chronic everyday discrimination, but not major discrimination, was associated with depressive symptoms and health-compromising behaviors independent of potential confounders, including race and ethnicity, among pregnant low-income women.

Methamphetamine increases Prion Protein and induces dopamine-dependent expression of protease resistant PrPsc.

PubMed

Ferrucci, M; Ryskalin, L; Biagioni, F; Gambardella, S; Busceti, C L; Falleni, A; Lazzeri, G; Fornai, F

2017-07-01

The cellular prion protein (PrPc) is physiologically expressed within selective brain areas of mammals. Alterations in the secondary structure of this protein lead to scrapie-like prion protein (PrPsc), which precipitates in the cell. PrPsc has been detected in infectious, inherited or sporadic neurodegenerative disorders. Prion protein metabolism is dependent on autophagy and ubiquitin proteasome. Despite not being fully elucidated, the physiological role of prion protein relates to chaperones which rescue cells under stressful conditions.Methamphetamine (METH) is a widely abused drug which produces oxidative stress in various brain areas causing mitochondrial alterations and protein misfolding. These effects produce a compensatory increase of chaperones while clogging cell clearing pathways. In the present study, we explored whether METH administration modifies the amount of PrPc. Since high levels of PrPc when the clearing systems are clogged may lead to its misfolding into PrPsc, we further tested whether METH exposure triggers the appearance of PrPsc. We analysed the effects of METH and dopamine administration in PC12 and striatal cells by using SDS-PAGE Coomassie blue, immune- histochemistry and immune-gold electron microscopy. To analyze whether METH administration produces PrPsc aggregates we used antibodies directed against PrP following exposure to proteinase K or sarkosyl which digest folded PrPc but misfolded PrPsc. We fond that METH triggers PrPsc aggregates in DA-containing cells while METH is not effective in primary striatal neurons which do not produce DA. In the latter cells exogenous DA is needed to trigger PrPsc accumulation similarly to what happens in DA containing cells under the effects of METH. The present findings, while fostering novel molecular mechanisms involving prion proteins, indicate that, cell pathology similar to prion disorders can be mimicked via a DA-dependent mechanism by a drug of abuse.

Progesterone induces progesterone receptor gene (PGR) expression via rapid activation of protein kinase pathways required for cooperative estrogen receptor alpha (ER) and progesterone receptor (PR) genomic action at ER/PR target genes.

PubMed

Diep, Caroline H; Ahrendt, Hannah; Lange, Carol A

2016-10-01

Progesterone Receptors (PRs) are critical effectors of estrogen receptor (ER) signaling required for mammary gland development and reproductive proficiency. In breast and reproductive tract malignancies, PR expression is a clinical prognostic marker of ER action. While estrogens primarily regulate PR expression, other factors likely contribute to a dynamic range of receptor expression across diverse tissues. In this study, we identified estrogen-independent but progestin (R5020)-dependent regulation of ER target genes including PGR in ER+/PR+ cancer cell lines. R5020 (10nM-10μM range) induced dose-dependent PR mRNA and protein expression in the absence of estrogen but required both PR and ERα. Antagonists of either PR (RU486, onapristone) or ERα (ICI 182,780) attenuated R5020 induction of TFF1, CTSD, and PGR. Chromatin immunoprecipitation (ChIP) assays performed on ER+/PR+ cells demonstrated that both ERα and PR were recruited to the same ERE/Sp1 site-containing region of the PGR proximal promoter in response to high dose progestin (10μM). Recruitment of ERα and PR to chromatin and subsequent PR mRNA induction were dependent upon rapid activation of MAPK/ERK and AKT; inhibition of these kinase pathways via U0126 or LY294002 blocked these events. Overall, we have identified a novel mechanism of ERα activation initiated by rapid PR-dependent kinase pathway activation and associated with phosphorylation of ERα Ser118 for estrogen-independent but progestin-dependent ER/PR cross talk. These studies may provide insight into mechanisms of persistent ER-target gene expression during periods of hormone (i.e. estrogen) ablation and suggest caution following prolonged treatment with aromatase or CYP17 inhibitors (i.e. contexts when progesterone levels may be abnormally elevated). Copyright © 2016 Elsevier Inc. All rights reserved.

Expression of progesterone receptor B is associated with G0/G1 arrest of the cell cycle and growth inhibition in NIH3T3 cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Horiuchi, Shinji; Kato, Kiyoko; Suga, Shin

2005-05-01

Previously, we found a significant reduction of progesterone receptor B (PR-B) expression levels in the Ras-mediated NIH3T3 cell transformation, and re-expression of exogenous PR-B eliminated the tumorigenic potential. We hypothesized that this reduction is of biological significance in cell transformation. In the present study, we determined the correlation between PR-B expression and cell cycle progression. In synchronized NIH3T3 cells, we found an increase in PR-B protein and p27 CDK inhibitor levels in the G0/G1 phase and a reduction due to redistribution in the S and G2/M phases. The MEK inhibitor or cAMP stimulation arrested NIH3T3 cells in the G0/G1 phasemore » of the cell cycle. The expression of PR-B and p27 CDK inhibitors was up-regulated by treatment with both the MEK inhibitor and cAMP. Treatment of synchronized cells with a PKA inhibitor in the presence of 1% calf serum resulted in a significant reduction in both PR-B and p27 levels. The decrease in the PR-B levels caused by anti-sense oligomers or siRNA corresponded to the reduction in p27 levels. PR-B overexpression by adenovirus infection induced p27 and suppressed cell growth. Finally, we showed that PR-B modulation involved in the regulation of NIH3T3 cell proliferation was independent of nuclear estrogen receptor (ER) activity but dependent on non-genomic ER activity.« less

Sexual risk behaviors and acceptability of HIV pre-exposure prophylaxis among HIV-negative gay and bisexual men in serodiscordant relationships: a mixed methods study.

PubMed

Brooks, Ronald A; Landovitz, Raphael J; Kaplan, Rachel L; Lieber, Eli; Lee, Sung-Jae; Barkley, Thomas W

2012-02-01

The objective of this mixed methods study was to examine current sexual risk behaviors, acceptability and potential adoption of pre-exposure prophylaxis (PrEP) for HIV prevention, and sexual behavior intentions with PrEP adoption among HIV-negative gay and bisexual men (GBM) in HIV serodiscordant relationships. A multiracial/ethnic sample of 25 HIV-negative GBM in serodiscordant relationships completed a qualitative interview and a brief interviewer-administered survey. A modified grounded theory approach was used to identify key themes relating to acceptability and future adoption of PrEP. Participants reported engaging in sexual risk behaviors that place them at risk for HIV infection. Participants also reported a high level of acceptability for PrEP and willingness to adopt PrEP for HIV prevention. Qualitative themes explaining future PrEP adoption included: (1) the opportunity to engage in sex using a noncondom HIV prevention method, (2) protection from HIV infection, and (3) less anxiety when engaging in sex with an HIV-positive partner. Associated with the future adoption of PrEP, a majority (64%) of participants indicated the likelihood for an increase in sexual risk behaviors and a majority (60%) of participants also indicated the likelihood for a decrease or abandonment of condom use, both of which are in contrast to the findings from the large iPrEx study. These findings suggest that the use of PrEP by HIV-negative GBM in serodiscordant relationships carries with it the potential for risk compensation. The findings suggest that PrEP only be offered as part of a comprehensive HIV prevention strategy that includes ongoing risk reduction counseling in the delivery of PrEP to help moderate risk compensation.

Energy transfer and radiative recombination processes in (Gd, Lu)3Ga3Al2O12:Pr3+ scintillators

NASA Astrophysics Data System (ADS)

Wu, Yuntao; Ren, Guohao

2013-10-01

(GdxLu3-x)Ga3Al2O12:0.3 at.%Pr (x = 0.025, 0.05, 0.1, 0.2, 0.4, 0.6) (GLGAG:Pr) polycrystalline powders are prepared by solid-state reaction method. To better understand the luminescence mechanism, the optical diffuse reflectance, photoluminescence emission and excitation, X-ray excited luminescence spectra and decay kinetics of GLGAG:Pr were investigated in detailed, allowing the determination of energy transfer from 5d state of Pr3+ to 4f state of Gd3+, and the non-radiative relaxation from 5d to 4f state of Pr3+. Besides, the former process plays more negative role in the emission quenching of GLGAG:Pr than later one. Pr3+ ion is regarded as an ineffective activation ion in Gd-based multicomponent aluminate garnets. In addition, the wavelength-resolved thermoluminescence spectra of GLGAG:Pr were studied after UV and X-ray irradiation. It is revealed that the localized recombination processes from electron traps to lower lying 4f levels of Pr3+ occurs without populating the higher 5d levels of Pr3+.

Dental caries and periodontal disease in Brazilian children and adolescents with cerebral palsy.

PubMed

Cardoso, Andreia M R; Gomes, Lays N; Silva, Clara Regina D; Soares, Renata de S C; Abreu, Mauro Henrique N G de; Padilha, Wilton W N; Cavalcanti, Alessandro L

2014-12-29

The aim of the present study was determine the prevalence and factors associated with dental caries and periodontal disease in Brazilian children and adolescents with cerebral palsy (CP). This is a cross-sectional study conducted with 80 patients ranging in age from 2 to 18 years old. Oral exams were conducted by an examiner with records of DMFT, dmft, Gingival Bleeding Index (GBI) and Community Periodontal Index (CPI). The statistical analysis used Poisson Regression with robust variance estimation (α = 0.05). The prevalence of dental caries was 59.3%, with DMFT and mean dmft of 1.71 ± 2.42 and 2.22 ± 3.23, respectively. The mean GBI was 22.44%, and in the CPI, the prevalence of gingival bleeding, calculus, shallow and deep pockets were 94.73%, 79.62%, 12.90% and 3.22%, respectively. The caregiver's educational level of less than eight years were associated with the dental caries experience (PR = 1.439; 95%CI = 1.09-1.89). The periodontal alterations were associated with female sex (PR = 0.82; 95%CI = 0.69-0.97), caregiver's educational level of less than eight years (PR = 1.15; 95%CI = 1.03-1.29), poor oral perception (PR = 0.89; 95%CI = 0.80-0.98), serious communication problem (PR = 0.87; 95%CI = 0.76-0.99) and athetoid type of CP (PR = 0.85; 95%CI = 0.75-0.97). The patients with CP presented high dental caries experience and periodontal alterations, which were associated with their demographic, socioeconomic, oral health perception and systemic information.

Association of serum interleukin-10, interleukin-17A and transforming growth factor-α levels with human benign and malignant breast diseases.

PubMed

Lv, Zhuangwei; Liu, Min; Shen, Jinghui; Xiang, Dong; Ma, Yunfeng; Ji, Yanhong

2018-06-01

Interleukin-10 (IL-10), interleukin-17A (IL-17A) and transforming growth factor α (TGF-α) have been implicated in the progression of breast cancer. However, the diagnostic and prognostic roles of these cytokines in ductal carcinoma remain unclear. The present study therefore aimed to determine the serum levels of IL-10, IL-17 and TGF-α in subjects with benign and malignant breast diseases and to evaluate the clinical significance of these cytokines in ductal carcinoma. Pre-operative serum samples were collected from 378 patients with breast disease and 70 healthy subjects. IL-10, IL-17A and TGF-α levels were measured using ELISA. Serum levels of these cytokine in patients with different breast diseases were evaluated. Furthermore, correlations between levels of these cytokines and the expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) in ductal carcinoma were determined. The results demonstrated that serum levels of IL-10 and IL-17A were significantly increased in subjects with atypical hyperplasia and ductal carcinoma. Furthermore, IL-10 and IL-17A levels were increased in patients with a more serious clinical tumor stage and tumors that were ER - and PR - . Furthermore, high serum levels of TGF-α were associated with HER2 + tumors. A strong positive correlation was identified between TGF-α and IL-17A levels. Therefore, the results of the current study revealed that elevated serum IL-10, IL-17A and TGF-α levels are strongly associated with ductal carcinoma, specifically with tumor stage. High serum levels of IL-10 and IL-17A were also associated with the negative expression of ER and PR in ductal carcinoma, and high serum levels of TGF-α were associated with the positive expression of HER2 in ductal carcinoma. Thus, serum cytokine levels may be measured to identify patients with a poor prognosis who may benefit from more aggressive management and treatment.

Enzymatic Formulation Capable of Degrading Scrapie Prion under Mild Digestion Conditions

PubMed Central

Okoroma, Emeka A.; Purchase, Diane; Garelick, Hemda; Morris, Roger; Neale, Michael H.; Windl, Otto; Abiola, Oduola O.

2013-01-01

The prion agent is notoriously resistant to common proteases and conventional sterilisation procedures. The current methods known to destroy prion infectivity such as incineration, alkaline and thermal hydrolysis are harsh, destructive, environmentally polluting and potentially hazardous, thus limit their applications for decontamination of delicate medical and laboratory devices, remediation of prion contaminated environment and for processing animal by-products including specified risk materials and carcases. Therefore, an environmentally friendly, non-destructive enzymatic degradation approach is highly desirable. A feather-degrading Bacillus licheniformis N22 keratinase has been isolated which degraded scrapie prion to undetectable level of PrPSc signals as determined by Western Blot analysis. Prion infectivity was verified by ex vivo cell-based assay. An enzymatic formulation combining N22 keratinase and biosurfactant derived from Pseudomonas aeruginosa degraded PrPSc at 65°C in 10 min to undetectable level -. A time-course degradation analysis carried out at 50°C over 2 h revealed the progressive attenuation of PrPSc intensity. Test of residual infectivity by standard cell culture assay confirmed that the enzymatic formulation reduced PrPSc infectivity to undetectable levels as compared to cells challenged with untreated standard scrapie sheep prion (SSBP/1) (p-value = 0.008 at 95% confidence interval). This novel enzymatic formulation has significant potential application for prion decontamination in various environmentally friendly systems under mild treatment conditions. PMID:23874511

Significantly greater expression of ER, PR, and ECAD in advanced-stage low-grade ovarian serous carcinoma as revealed by immunohistochemical analysis.

PubMed

Wong, Kwong-Kwok; Lu, Karen H; Malpica, Anais; Bodurka, Diane C; Shvartsman, Hyun S; Schmandt, Rosemarie E; Thornton, Angela D; Deavers, Michael T; Silva, Elvio G; Gershenson, David M

2007-10-01

A 2-tier system that classifies ovarian serous carcinoma (OSC) as low grade or high grade is gaining acceptance. Women with low-grade OSC generally have higher 5-year survival rates than do women with high-grade OSC. We examined the expression of various markers to further understand the molecular differences between low-grade and high-grade OSCs: the potential therapeutic targets or prognostic markers Her-2/neu, estrogen receptor, and progesterone receptor (PR); the metastasis-associated markers cyclin D1 (BCL1), E-cadherin, matrix metalloproteinase (MMP) 2, and MMP-9; and the cell proliferation-associated markers BCL1, Ki-67 antigen (Ki-67), and p53. For this immunohistochemical analysis, we used paraffin-embedded specimens from 47 patients with advanced-stage low-grade OSC and from 49 patients with advanced-stage high-grade OSC. Our results showed that low-grade tumors expressed significantly higher levels of estrogen receptor, PR, and E-cadherin than did high-grade tumors, suggesting the involvement of gonadal steroid hormones, especially in the pathogenesis of low-grade OSC; the PR positivity was also observed in the stromal component of these low-grade tumors. On the other hand, high-grade tumors trended toward increased expression of MMP-9, BCL1, p53, and Ki-67, and robust MMP-9 positivity was observed in the stromal component of these high-grade tumors. These differences may lead to the development of different therapeutic strategies for women with either the low-grade or the high-grade form of OSC.

Systemic distribution, subcellular localization and differential expression of sphingosine-1-phosphate receptors in benign and malignant human tissues.

PubMed

Wang, Chunyi; Mao, Jinghe; Redfield, Samantha; Mo, Yinyuan; Lage, Janice M; Zhou, Xinchun

2014-10-01

Five sphingosine-1-phosphate receptors (S1PR): S1PR1, S1PR2, S1PR3, S1PR4 and S1PR5 (S1PR1-5) have been shown to be involved in the proliferation and progression of various cancers. However, none of the S1PRs have been systemically investigated. In this study, we performed immunohistochemistry (IHC) for S1PR1-S1PR5 on different tissues, in order to simultaneously determine the systemic distribution, subcellular localization and expression level of all five S1PRs. We constructed tissue microarrays (TMAs) from 384 formalin-fixed paraffin-embedded (FFPE) blocks containing 183 benign and 201 malignant tissues from 34 human organs/systems. Then we performed IHC for all five S1PRs simultaneously on these TMA slides. The distribution, subcellular localization and expression of each S1PR were determined for each tissue. The data in benign and malignant tissues from the same organ/tissue were then compared using the Student's t-test. In order to reconfirm the subcellular localization of each S1PR as determined by IHC, immunocytochemistry (ICC) was performed on several malignant cell lines. We found that all five S1PRs are widely distributed in multiple human organs/systems. All S1PRs are expressed in both the cytoplasm and nucleus, except S1PR3, whose IHC signals are only seen in the nucleus. Interestingly, the S1PRs are rarely expressed on cellular membranes. Each S1PR is unique in its organ distribution, subcellular localization and expression level in benign and malignant tissues. Among the five S1PRs, S1PR5 has the highest expression level (in either the nucleus or cytoplasm), with S1PR1, 3, 2 and 4 following in descending order. Strong nuclear expression was seen for S1PR1, S1PR3 and S1PR5, whereas S1PR2 and S1PR4 show only weak staining. Four organs/tissues (adrenal gland, liver, brain and colon) show significant differences in IHC scores for the multiple S1PRs (nuclear and/or cytoplasmic), nine (stomach, lymphoid tissues, lung, ovary, cervix, pancreas, skin, soft tissues and uterus) show differences for only one S1PR (cytoplasmic or nuclear), and twenty three organs/tissues show no significant difference in IHC scores for any S1PR (cytoplasmic or nuclear) between benign and malignant changes. This is the first study to evaluate the expression level of all S1PRs in benign and malignant tissues from multiple human organs. This study provides data regarding the systemic distribution, subcellular localization and differences in expression of all five S1PRs in benign and malignant changes for each organ/tissue. Copyright © 2014 Elsevier Inc. All rights reserved.

Systemic distribution, subcellular localization and differential expression of sphingosine-1-phosphate receptors in benign and malignant human tissues

PubMed Central

Wang, Chunyi; Mao, Jinghe; Redfield, Samantha; Mo, Yinyuan; Lage, Janice M.; Zhou, Xinchun

2014-01-01

Aims Five sphingosine-1-phosphate receptors (S1PR): S1PR1, S1PR2, S1PR3, S1PR4 and S1PR5 (S1PR1-5) have been shown to be involved in the proliferation and progression of various cancers. However, none of the S1PRs have been systemically investigated. In this study, we performed immunohistochemistry (IHC) for S1PR1-S1PR5 on different tissues, in order to simultaneously determine the systemic distribution, subcellular localization and expression level of all five S1PRs. Methods We constructed tissue microarrays (TMAs) from 384 formalin-fixed paraffin-embedded (FFPE) blocks containing 183 benign and 201 malignant tissues from 34 human organs/systems. Then we performed IHC for all five S1PRs simultaneously on these TMA slides. The distribution, subcellular localization and expression of each S1PR were determined for each tissue. The data were then compared in benign and malignant tissues from the same organ/tissue using the student t-test. In order to reconfirm the subcellular localization of each S1PR as determined by IHC, immunocytochemistry (ICC) was performed on several malignant cell lines. Results We found that all five S1PRs are widely distributed in multiple human organs/systems. All S1PRs are expressed in both the cytoplasm and nucleus, except S1PR3, whose IHC signals are only seen in the nucleus. Interestingly, the S1PRs are rarely expressed on cellular membranes. Each S1PR is unique in its organ distribution, subcellular localization and expression level in benign and malignant tissues. Among the five S1PRs, S1PR5 has the highest expression level (either in nucleus or cytoplasm), with S1PR1, 3, 2 and 4 following in descending order. Strong nuclear expression was seen for S1PR1, S1PR3 and S1PR5, whereas S1PR2 and S1PR4 show only weak staining. Four organs/tissues (adrenal gland, liver, brain and colon) show significant differences in IHC scores for the multiple S1PRs (nuclear and/or cytoplasmic), nine (stomach, lymphoid tissues, lung, ovary, cervix, pancreas, skin, soft tissues and uterus) show differences for only one S1PR (cytoplasmic or nuclear), and twenty three organs/tissues show no significant difference in IHC score of any S1PR (cytoplasmic or nuclear) between benign and malignant changes. Conclusion This is the first study to evaluate the expression level of all S1PRs in benign and malignant tissues from multiple human organs. This study provides data regarding the systemic distribution, subcellular localization and differences in expression of all five S1PRs in benign and malignant changes for each organ/tissue. PMID:25084322

Gestational Protein Restriction Increases Angiotensin II Production in Rat Lung1

PubMed Central

Gao, Haijun; Yallampalli, Uma; Yallampalli, Chandra

2013-01-01

ABSTRACT Gestational protein restriction (PR) alters the renin-angiotensin system in uterine arteries and placentas and elevates plasma levels of angiotensin II in pregnant rats. To date, how PR increases maternal plasma levels of angiotensin II remains unknown. In this study, we hypothesize that the expression and/or the activity of angiotensin I converting enzyme (peptidyl-dipeptidase A) 1 (ACE) in lungs, but not kidneys and blood, largely contribute to elevated plasma angiotensin II levels in pregnant rats subject to gestational PR. Time-scheduled pregnant Sprague-Dawley rats were fed a normal or low-protein diet from Day 3 of pregnancy until euthanized at Day 19 or 22. Expressions of Ace and Ace2 (angiotens in I converting enzyme [peptidyl-dipeptidase A] 2) in lungs and kidneys from pregnant rats by quantitative real-time PCR and Western blotting, and the activities of these proteins in lungs, kidneys, and plasma, were measured. The mRNA levels of Ace and Ace2 in lungs were elevated by PR at both Days 19 and 22 of pregnancy. The abundance of ACE protein in lungs was increased, but ACE2 protein was decreased, by PR. The activities of ACE, but not ACE2, in lungs were increased by PR. PR did not change expressions of Ace and Ace2, the activities of both ACE and ACE2 in kidneys, and the abundance and activity of plasma ACE. These findings suggest that maternal lungs contribute to the elevated plasma levels of angiotensin II by increasing both the expression and the activity of ACE in response to gestational PR. PMID:23365412

Principals: Learn P.R. Survival Skills.

ERIC Educational Resources Information Center

Reep, Beverly B.

1988-01-01

School building level public relations depends on the principal or vice principal. Strategies designed to enhance school public relations programs include linking school and community, working with the press, and keeping morale high inside the school. (MLF)

Strong relationship between oral dose and tenofovir hair levels in a randomized trial: hair as a potential adherence measure for pre-exposure prophylaxis (PrEP).

PubMed

Liu, Albert Y; Yang, Qiyun; Huang, Yong; Bacchetti, Peter; Anderson, Peter L; Jin, Chengshi; Goggin, Kathy; Stojanovski, Kristefer; Grant, Robert; Buchbinder, Susan P; Greenblatt, Ruth M; Gandhi, Monica

2014-01-01

Pre-exposure prophylaxis (PrEP) trials using tenofovir-based regimens have demonstrated that high levels of adherence are required to evaluate efficacy; the incorporation of objective biomarkers of adherence in trial design has been essential to interpretation, given the inaccuracy of self-report. Antiretroviral measurements in scalp hair have been useful as a marker of long-term exposure in the HIV treatment setting, and hair samples are relatively easy and inexpensive to collect, transport, and store for analysis. To evaluate the relationship between dose and tenofovir concentrations in hair, we examined the dose proportionality of tenofovir in hair in healthy, HIV-uninfected adults. A phase I, crossover pharmacokinetic study was performed in 24 HIV-negative adults receiving directly-observed oral tenofovir tablets administered 2, 4, and 7 doses/week for 6 weeks, with a ≥3-week break between periods. Small samples of hair were collected after each six-week period and analyzed for tenofovir concentrations. Geometric-mean-ratios compared levels between each pair of dosing conditions. Intensive plasma pharmacokinetic studies were performed during the daily-dosing period to calculate areas-under-the-time-concentration curves (AUCs). Over 90% of doses were observed per protocol. Median tenofovir concentrations in hair increased monotonically with dose. A log-linear relationship was seen between dose and hair levels, with an estimated 76% (95% CI 60-93%) increase in hair level per 2-fold dose increase. Tenofovir plasma AUCs modestly predicted drug concentrations in hair. This study found a strong linear relationship between frequency of dosing and tenofovir levels in scalp hair. The analysis of quantitative drug levels in hair has the potential to improve adherence measurement in the PrEP field and may be helpful in determining exposure thresholds for protection and explaining failures in PrEP trials. Hair measures for adherence monitoring may also facilitate adherence measurement in real-world settings and merit further investigation in upcoming PrEP implementation studies and programs. ClinicalTrials.gov NCT00903084.

Strong Relationship between Oral Dose and Tenofovir Hair Levels in a Randomized Trial: Hair as a Potential Adherence Measure for Pre-Exposure Prophylaxis (PrEP)

PubMed Central

Liu, Albert Y.; Yang, Qiyun; Huang, Yong; Bacchetti, Peter; Anderson, Peter L.; Jin, Chengshi; Goggin, Kathy; Stojanovski, Kristefer; Grant, Robert; Buchbinder, Susan P.; Greenblatt, Ruth M.; Gandhi, Monica

2014-01-01

Background Pre-exposure prophylaxis (PrEP) trials using tenofovir-based regimens have demonstrated that high levels of adherence are required to evaluate efficacy; the incorporation of objective biomarkers of adherence in trial design has been essential to interpretation, given the inaccuracy of self-report. Antiretroviral measurements in scalp hair have been useful as a marker of long-term exposure in the HIV treatment setting, and hair samples are relatively easy and inexpensive to collect, transport, and store for analysis. To evaluate the relationship between dose and tenofovir concentrations in hair, we examined the dose proportionality of tenofovir in hair in healthy, HIV-uninfected adults. Methods A phase I, crossover pharmacokinetic study was performed in 24 HIV-negative adults receiving directly-observed oral tenofovir tablets administered 2, 4, and 7 doses/week for 6 weeks, with a ≥3-week break between periods. Small samples of hair were collected after each six-week period and analyzed for tenofovir concentrations. Geometric-mean-ratios compared levels between each pair of dosing conditions. Intensive plasma pharmacokinetic studies were performed during the daily-dosing period to calculate areas-under-the-time-concentration curves (AUCs). Results Over 90% of doses were observed per protocol. Median tenofovir concentrations in hair increased monotonically with dose. A log-linear relationship was seen between dose and hair levels, with an estimated 76% (95% CI 60–93%) increase in hair level per 2-fold dose increase. Tenofovir plasma AUCs modestly predicted drug concentrations in hair. Conclusions This study found a strong linear relationship between frequency of dosing and tenofovir levels in scalp hair. The analysis of quantitative drug levels in hair has the potential to improve adherence measurement in the PrEP field and may be helpful in determining exposure thresholds for protection and explaining failures in PrEP trials. Hair measures for adherence monitoring may also facilitate adherence measurement in real-world settings and merit further investigation in upcoming PrEP implementation studies and programs. Trial Registration ClinicalTrials.gov +NCT00903084. PMID:24421901

Markedly Increased Susceptibility to Natural Sheep Scrapie of Transgenic Mice Expressing Ovine PrP

PubMed Central

Vilotte, Jean-Luc; Soulier, Solange; Essalmani, Rachid; Stinnakre, Marie-George; Vaiman, Daniel; Lepourry, Laurence; Da Silva, Jose Costa; Besnard, Nathalie; Dawson, Mike; Buschmann, Anne; Groschup, Martin; Petit, Stephanie; Madelaine, Marie-Francoise; Rakatobe, Sabine; Le Dur, Annick; Vilette, Didier; Laude, Hubert

2001-01-01

The susceptibility of sheep to scrapie is known to involve, as a major determinant, the nature of the prion protein (PrP) allele, with the VRQ allele conferring the highest susceptibility to the disease. Transgenic mice expressing in their brains three different ovine PrPVRQ-encoding transgenes under an endogenous PrP-deficient genetic background were established. Nine transgenic (tgOv) lines were selected and challenged with two scrapie field isolates derived from VRQ-homozygous affected sheep. All inoculated mice developed neurological signs associated with a transmissible spongiform encephalopathy (TSE) disease and accumulated a protease-resistant form of PrP (PrPres) in their brains. The incubation duration appeared to be inversely related to the PrP steady-state level in the brain, irrespective of the transgene construct. The survival time for animals from the line expressing the highest level of PrP was reduced by at least 1 year compared to those of two groups of conventional mice. With one isolate, the duration of incubation was as short as 2 months, which is comparable to that observed for the rodent TSE models with the briefest survival times. No survival time reduction was observed upon subpassaging of either isolate, suggesting no need for adaptation of the agent to its new host. Overexpression of the transgene was found not to be required for transmission to be accelerated compared to that observed with wild-type mice. Conversely, transgenic mice overexpressing murine PrP were found to be less susceptible than tgOv lines expressing ovine PrP at physiological levels. These data argue that ovine PrPVRQ provided a better substrate for sheep prion replication than did mouse PrP. Altogether, these tgOv mice could be an improved model for experimental studies on natural sheep scrapie. PMID:11390599

Pre-exposure Prophylaxis With Tenofovir Disoproxil Fumarate/Emtricitabine and Kidney Tubular Dysfunction in HIV-Uninfected Individuals.

PubMed

Jotwani, Vasantha; Scherzer, Rebecca; Glidden, David V; Mehrotra, Megha; Defechereux, Patricia; Liu, Albert; Gandhi, Monica; Bennett, Michael; Coca, Steven G; Parikh, Chirag R; Grant, Robert M; Shlipak, Michael G

2018-06-01

Pre-exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) is becoming increasingly adopted for HIV prevention. Tenofovir can cause proximal tubular damage and chronic kidney disease in HIV-infected persons, but little is known regarding its nephrotoxic potential among HIV-uninfected persons. In this study, we evaluated the effects of PrEP on urine levels of the following: α1-microglobulin (α1m), a marker of impaired tubular reabsorption; albuminuria, a measure of glomerular injury; and total proteinuria. The Iniciativa Profilaxis Pre-Exposicion (iPrEx) study randomized HIV-seronegative men and transgender women who have sex with men to oral TDF/FTC or placebo. The iPrEx open-label extension (iPrEx-OLE) study enrolled former PrEP trial participants to receive open-label TDF/FTC. A cross-sectional analysis compared urine biomarker levels by study arm in iPrEx (N = 100 treatment arm, N = 100 placebo arm). Then, urine biomarker levels were compared before and after PrEP initiation in 109 participants of iPrEx-OLE. In iPrEx, there were no significant differences in urine α1m, albuminuria, or proteinuria by treatment arm. In iPrEx-OLE, after 24 weeks on PrEP, urine α1m and proteinuria increased by 21% [95% confidence interval (CI): 10 to 33] and 18% (95% CI: 8 to 28), respectively. The prevalence of detectable α1m increased from 44% to 65% (P < 0.001) and estimated glomerular filtration rate declined by 4 mL/min/1.73 m (P < 0.001). There was no significant change in albuminuria (6%; 95% CI: -7% to 20%). PrEP with TDF/FTC was associated with a statistically significant rise in urine α1m and proteinuria after 6 months, suggesting that PrEP may result in subclinical tubule dysfunction.

Progesterone Receptor-A and -B Have Opposite Effects on Proinflammatory Gene Expression in Human Myometrial Cells: Implications for Progesterone Actions in Human Pregnancy and Parturition

PubMed Central

Tan, Huiqing; Yi, Lijuan; Rote, Neal S.; Hurd, William W.

2012-01-01

Context: Progesterone promotes uterine relaxation during pregnancy and its withdrawal induces labor. Progesterone withdrawal in human parturition is mediated in part by changes in the relative levels of the nuclear progesterone receptor isoforms, PR-A and PR-B, in myometrial cells. Parturition also involves myometrial inflammation; however, the functional link between nuclear PR-mediated progesterone actions and inflammation in human myometrial cells is unclear. Objective: Our objective was to determine how PR-A and PR-B regulate progesterone action in human myometrial cells and specifically the expression of genes encoding contraction-associated proteins and proinflammatory mediators. Design: Effects of PR-A and PR-B on the capacity for progesterone to modulate gene expression was determined using an immortalized human myometrial cell line stably transfected with inducible PR-A and PR-B expression transgenes and conditioned to express various PR-A and PR-B levels. Gene expression was assessed by genome wide transcriptome analysis, quantitative RT-PCR and immunoblotting. Results: PR-A and PR-B were each transcriptionally active in response to progesterone and affected the expression of distinct gene cohorts. The capacity for progesterone to affect gene expression was dependent on the PR-A to PR-B ratio. This was especially apparent for the expression of proinflammatory genes. Progesterone decreased proinflammatory gene expression when the PR-A to PR-B ratio favored PR-B and increased proinflammatory gene expression when the ratio favored PR-A. Progesterone via PR-B increased expression of inhibitor-κBα, a repressor of the nuclear factor-κB transcription factor, and inhibited basal and lipopolysaccharide-induced proinflammatory gene expression. Both of those PR-B-mediated effects were inhibited by PR-A. Conclusions: Our data suggest that during most of human pregnancy, when myometrial cells are PR-B dominant, progesterone promotes myometrial quiescence through PR-B-mediated antiinflammatory actions. At parturition, the rise in PR-A expression promotes labor by inhibiting the antiinflammatory actions of PR-B and stimulating proinflammatory gene expression in response to progesterone. PMID:22419721

Traditional and pyramidal resistance training systems improve muscle quality and metabolic biomarkers in older women: A randomized crossover study.

PubMed

Ribeiro, Alex S; Schoenfeld, Brad J; Souza, Mariana F; Tomeleri, Crisieli M; Venturini, Danielle; Barbosa, Décio S; Cyrino, Edilson S

2016-06-15

The purpose of this study was to compare the effect of RT performed in a pyramid (PR) and traditional (TD) straight set training system on muscle quality and metabolic biomarkers in older women. Twenty-five physically independent older women (67.6±5.1years, 65.9±11.1kg, 154.7±5.8cm) performed a RT program in TD and PR training systems in a balanced crossover design. Measurements of muscle quality, serum levels of C-reactive protein (CRP), glucose (GLU), total cholesterol, high-density lipoprotein (HDL-C), low-density lipoprotein (LDL-C), and triglycerides (TG) were obtained at different moments. The TD program consisted of 3 sets of 8-12 repetitions maximum (RM) with a constant weight for the 3 sets, whereas the PR training consisted of 3 sets of 12/10/8 RM with incremental weight for each set. The training was performed in 2 phases of 8weeks each, with a 12-week washout period between phases. Significant (P<0.05) improvements were observed in both groups for muscle quality (TD=+8.6% vs. PR=+6.8%), GLU (TD=-4.5% vs. PR=-1.9%), TG (TD=-18.0% vs. PR=-11.7%), HDL-C (TD=+10.6 vs. PR=+7.8%), LDL-C (TD=-23.3% vs. PR=-21.0%), and CRP (TD=-19.4% vs. PR=-14.3%) with no differences between training systems. These results suggest that RT improves muscle quality and metabolic biomarkers of older women independently of the training system. Copyright © 2016 Elsevier Inc. All rights reserved.

Acceptability of an "on-demand" pre-exposure HIV prophylaxis trial among men who have sex with men living in France.

PubMed

Lorente, Nicolas; Fugon, Lionel; Carrieri, Maria Patrizia; Andreo, Christian; Le Gall, Jean-Marie; Cook, Emmanuel; Aboulker, Jean-Pierre; Capitant, Catherine; Molina, Jean-Michel; Spire, Bruno

2012-01-01

Although predictors of willingness to take daily, self-administered pre-exposure HIV prophylaxis (PrEP) for men who have sex with men (MSM) have been studied in the context of several PrEP trials internationally, little is known about MSM interested in participating in a trial on the use of PrEP on an "on -demand" basis, i.e., taking a first dose of combined tenofovir/emtricitabine a few hours before possible HIV sexual exposure and a second dose a few hours afterwards. A double-blind placebo randomized PrEP trial will soon begin in France to evaluate the effectiveness of PrEP in terms of reducing HIV infection rates, among MSM self-administering "on-demand" PrEP. To assess potential participants' characteristics associated with willingness to participate in the trial and identify barriers and facilitators to implementation, MSM completed a self-administered questionnaire, distributed via gay venues and community websites. Among the 443 respondents who reported being HIV-negative, 40% reported being interested in participating. Factors independently associated with interest included: reporting lower educational level, more than 20 male sexual partners in the previous year, reporting unprotected anal sex with casual partners and preferring PrEP follow-up visits in a devoted area within a hospital. There is great interest in participating in a future "on-demand" PrEP trial among HIV-negative MSM and particularly in those at potentially high risk of HIV exposure. Providing confidentiality and tailored counseling during PrEP follow-up are important issues.

Awareness and Willingness to Use HIV Pre-Exposure Prophylaxis amongst Gay and Bisexual Men in Scotland: Implications for Biomedical HIV Prevention

PubMed Central

Young, Ingrid; Li, Jessica; McDaid, Lisa

2013-01-01

Objectives To investigate the awareness of, and willingness to use, HIV Pre-Exposure Prophylaxis (PrEP), and willingness to take part in a PrEP study among gay and bisexual men in Scotland. Methods Cross-sectional survey of 17 gay commercial venues in Glasgow and Edinburgh in May 2011 (N = 1515, 65.2% response rate); 1393 are included in the analyses. Results Just under one-third of participants had heard of PrEP (n = 434; 31.2%), with awareness associated with being aged older than 35 years, talking to UAI partners about HIV, and with having had an HIV or STI test in the previous 12 months. Around half were willing to take part in a PrEP study (n = 695; 49.9%) or to take PrEP on a daily basis (n = 756; 54.3%). In multivariate analysis, willingness to take PrEP was associated with lower levels of education, regular gay scene attendance, ‘high-risk’ unprotected anal intercourse (UAI) and testing for HIV or STI in the previous 12 months. Reasons for not wanting to participate in a PrEP study or take PrEP included perceptions of low personal risk of HIV and concerns with using medication as an HIV prevention method. Conclusions There is a willingness to engage in new forms of HIV prevention and research amongst a significant number of gay and bisexual men in Scotland. Future biomedical HIV interventions need to consider the links between sexual risk behaviour, testing, and potential PrEP use. PMID:23691143

Prandtl-number Effects in High-Rayleigh-number Spherical Convection

NASA Astrophysics Data System (ADS)

Orvedahl, Ryan J.; Calkins, Michael A.; Featherstone, Nicholas A.; Hindman, Bradley W.

2018-03-01

Convection is the predominant mechanism by which energy and angular momentum are transported in the outer portion of the Sun. The resulting overturning motions are also the primary energy source for the solar magnetic field. An accurate solar dynamo model therefore requires a complete description of the convective motions, but these motions remain poorly understood. Studying stellar convection numerically remains challenging; it occurs within a parameter regime that is extreme by computational standards. The fluid properties of the convection zone are characterized in part by the Prandtl number \\Pr = ν/κ, where ν is the kinematic viscosity and κ is the thermal diffusion; in stars, \\Pr is extremely low, \\Pr ≈ 10‑7. The influence of \\Pr on the convective motions at the heart of the dynamo is not well understood since most numerical studies are limited to using \\Pr ≈ 1. We systematically vary \\Pr and the degree of thermal forcing, characterized through a Rayleigh number, to explore its influence on the convective dynamics. For sufficiently large thermal driving, the simulations reach a so-called convective free-fall state where diffusion no longer plays an important role in the interior dynamics. Simulations with a lower \\Pr generate faster convective flows and broader ranges of scales for equivalent levels of thermal forcing. Characteristics of the spectral distribution of the velocity remain largely insensitive to changes in \\Pr . Importantly, we find that \\Pr plays a key role in determining when the free-fall regime is reached by controlling the thickness of the thermal boundary layer.

Expression and Functional Characterization of two Pathogenesis-Related Protein 10 Genes from Zea mays

USDA-ARS?s Scientific Manuscript database

Pathogenesis-related protein 10 (PR10) is one of seventeen PR protein families and plays important roles in plant response to biotic and abiotic stresses. A novel PR10 gene (ZmPR10.1), which shares 89.8% and 85.7% identity to the previous ZmPR10 at the nucleotide and amino acid sequence level, respe...

Pressure ulcer prevention in long-term-care facilities: a pilot study implementing standardized nurse aide documentation and feedback reports.

PubMed

Horn, Susan D; Sharkey, Siobhan S; Hudak, Sandra; Gassaway, Julie; James, Roberta; Spector, William

2010-03-01

To design and facilitate implementation of practice-based evidence changes associated with decreases in pressure ulcer (PrU) development in long-term-care (LTC) facilities and promote these practices as part of routine care. Pre/post observational study. Frail older adult residents in 11 US LTC facilities. Project facilitators assisted frontline multidisciplinary teams (certified nurse aides [CNAs], nurses, and dietitians/dietary aides) to develop streamlined standardized CNA documentation and weekly reports to identify high-risk residents and to integrate clinical reports into day-to-day practice and clinical decision making. The program was called "Real-Time Optimal Care Plans for Nursing Home QI" (Real-Time). Prevalence of PrUs using Centers for Medicare & Medicaid Services (CMS) quality measures (QMs), number of in-house-acquired PrUs, and number and completeness of CNA documentation forms. Seven study LTC facilities that reported data to CMS experienced a combined 33% (SD, 36.1%) reduction in the CMS high-risk PrU QM in 18 months and reduction in newly occurring PrUs (number of ulcers in the fourth quarter of 2003: range, 2-19; and in the third quarter of 2005: range, 1-6). Five of these LTC facilities that fully implemented Real-Time experienced a combined 48.1% (SD, 23.4%) reduction in the CMS high-risk PrU QM. Ten facilities reduced by an average of 2 to 5 their number of CNA documentation forms; CNA weekly documentation completeness reached a consistent level of 90% to 95%, and 8 facilities integrated the use of 2 to 4 weekly project reports in routine clinical decision making. Quality improvement efforts that provide access to focused and timely clinical information, facilitate change, and promote staff working together in multidisciplinary teams impacted clinical outcomes. Prevention of PrUs showed a trend of improvement in facilities that fully integrated tools to identify high-risk residents into day-to-day practice. CNA documentation facilitated better information for clinical decision making. More than 70 additional LTC facilities across the United States are implementing this QI program.

Hematological shift in goat kids naturally devoid of prion protein.

PubMed

Reiten, Malin R; Bakkebø, Maren K; Brun-Hansen, Hege; Lewandowska-Sabat, Anna M; Olsaker, Ingrid; Tranulis, Michael A; Espenes, Arild; Boysen, Preben

2015-01-01

The physiological role of the cellular prion protein (PrP(C)) is incompletely understood. The expression of PrP(C) in hematopoietic stem cells and immune cells suggests a role in the development of these cells, and in PrP(C) knockout animals altered immune cell proliferation and phagocytic function have been observed. Recently, a spontaneous nonsense mutation at codon 32 in the PRNP gene in goats of the Norwegian Dairy breed was discovered, rendering homozygous animals devoid of PrP(C). Here we report hematological and immunological analyses of homozygous goat kids lacking PrP(C) (PRNP(Ter/Ter) ) compared to heterozygous (PRNP (+/Ter)) and normal (PRNP (+/+)) kids. Levels of cell surface PrP(C) and PRNP mRNA in peripheral blood mononuclear cells (PBMCs) correlated well and were very low in PRNP (Ter/Ter), intermediate in PRNP (+/Ter) and high in PRNP (+/+) kids. The PRNP (Ter/Ter) animals had a shift in blood cell composition with an elevated number of red blood cells (RBCs) and a tendency toward a smaller mean RBC volume (P = 0.08) and an increased number of neutrophils (P = 0.068), all values within the reference ranges. Morphological investigations of blood smears and bone marrow imprints did not reveal irregularities. Studies of relative composition of PBMCs, phagocytic ability of monocytes and T-cell proliferation revealed no significant differences between the genotypes. Our data suggest that PrP(C) has a role in bone marrow physiology and warrant further studies of PrP(C) in erythroid and immune cell progenitors as well as differentiated effector cells also under stressful conditions. Altogether, this genetically unmanipulated PrP(C)-free animal model represents a unique opportunity to unveil the enigmatic physiology and function of PrP(C).

A Multi-US City Assessment of Awareness and Uptake of Pre-exposure Prophylaxis (PrEP) for HIV Prevention Among Black Men and Transgender Women Who Have Sex with Men.

PubMed

Eaton, Lisa A; Matthews, Derrick D; Driffin, Daniel D; Bukowski, Leigh; Wilson, Patrick A; Stall, Ron D

2017-07-01

The HIV epidemic among Black men and transgender women who have sex with men (BMTW) demands an urgent public health response. HIV point prevalence among this population ranges from 25 to 43%-a rate far exceeding any other group. Pre-exposure prophylaxis (PrEP) for HIV prevention is a very promising prevention tool; however, its full potential to slow the epidemic has yet to be realized. For the current study, random time-location sampling at Black Gay Pride Events was used to collect data from N = 1274 BMTW, from five US cities, reporting HIV-negative/unknown status. In-field HIV testing was also provided to participants. Participants were assessed on awareness and use of PrEP, health care factors, HIV testing history, psychosocial variables, and sex behaviors. About one third of participants were aware of PrEP (39%), and a small percentage of participants were users of PrEP (4.6%). In multivariable analyses, being in a relationship, testing for HIV in the past 6 months, and others being aware of one's sexuality were positively associated with PrEP awareness. Higher levels of internalized homophobia and greater numbers of female sex partners were positively associated with PrEP use, while education and condom use were negatively associated. Based on study findings, messaging and uptake of PrEP needs greater expansion and requires novel approaches for scale-up. Improving linkage to HIV testing services is likely critical for engaging BMTW with PrEP. The potential for PrEP to slow the HIV epidemic is high; however, we must strengthen efforts to ensure universal availability and uptake.

Nutrients removal and substrate enzyme activities in vertical subsurface flow constructed wetlands for mariculture wastewater treatment: Effects of ammonia nitrogen loading rates and salinity levels.

PubMed

Li, Meng; Liang, Zhenlin; Callier, Myriam D; Roque d'orbcastel, Emmanuelle; Sun, Guoxiang; Ma, Xiaona; Li, Xian; Wang, Shunkui; Liu, Ying; Song, Xiefa

2018-06-01

This study aims to investigate the effects of ammonia nitrogen loading rates and salinity levels on nutrients removal rates and substrate enzyme activities of constructed wetland (CW) microcosms planted with Salicornia bigelovii treating mariculture wastewater. Activities of urease (UA), dehydrogenase (DA), protease (PrA) and phosphatase (PA) were considered. Using principal component analysis (PCA), nutrient removal index (NRI) and enzyme activity index (EAI) were developed to evaluate the effects. The results revealed that increasing ammonia nitrogen loading rates had positive effects on nitrogen removal rates (i.e. NH 4 -N and DIN) and enhanced substrate enzyme activities. Compared with low salinity (i.e. 15 and 22), high salinity levels (i.e. 29 and 36) enhanced nutrients removal rates, DA and UA, but weaken PA and PrA. In conclusion, CW microcosms with Salicornia bigelovii can be used for the removal of nutrients under a range of ammonia nitrogen loadings and high salinity levels. Copyright © 2018 Elsevier Ltd. All rights reserved.

Comparison of Plasma Levels of Renin, Vasopressin and Atrial Natriuretic Peptide in Hypertensive Amlodipine Induced Pedal Oedema, Non-Oedema and Cilnidipine Treated Patients

PubMed Central

Shetty, Kiran; Rao, Pragna; Ballal, Mamatha; Kiran, Amruth; Reddy, Sravan; Pai, Umesh; Samanth, Jyothi

2017-01-01

Introduction Amlodipine is a third generation dihydropyridine group of calcium channel blocker and having an excellent antihypertensive profile. Pedal Oedema (PE) is the major drawback of amlodipine therapy and the incidence of Amlodipine Induced Pedal Oedema (AIPE) has been found significantly high. Several neurohumoral factors influence the incidence of oedema. Aim We aimed to compare the plasma levels of renin, vasopressin and atrial natriuretic peptide in hypertensive AIPE, non-oedema and cilnidipine treated patients. Materials and Methods The present prospective, interventional study was conducted on 104 mild to moderate hypertensive patients (52 patients in each group), after due consideration of eligibility criteria. Plasma Renin (PR), Vasopressin (VAS), and the Atrial Natriuretic Peptide (ANP) was estimated by ELISA test and compared between the AIPE, Amlodipine Treated Non-Oedema (ATNE) in Phase I, and AIPE and Cilnidipine Treated (CT) Groups in Phase II. Results The clinical and demographic parameters were matched. PR was significantly high in AIPE group than the ATNE, and it was significantly reduced after one month follow up with the substitution of cilnidipine. The median (IQR) value of PR was 4.87 (3.58, 6.63), 3.50 (1.44, 5.47) and 2.66 (1.02, 5.66) ng/ml in AIPE, ATNE, CT group respectively. VAS was significantly high in AIPE group than ATNE, and it significantly reduced after one month follow up with CT group. The median (IQR) value of vasopressin was 6.78 (2.55, 9.16), 2.58 (1.61, 5.73) and 2.50 (1.23, 5.00) ng/ml in AIPE, ATNE and CT groups respectively. There was no significant difference seen in plasma ANP levels between the groups. The p-value was <0.05 which is statistically significant. Conclusion The AIPE may not be volume overload or fluid retention; it may be due to persistent raise in adrenergic activity followed chronic amlodipine therapy. Cilnidipine relatively suppresses the sympathetic activity, and completely resolves the AIPE by significantly reducing PR and VAS levels. ANP did not show a difference between groups. Cilnidipine is the suitable alternative antihypertensive drug for AIPE patients. PMID:28764190

The impact of Public Reporting on clinical outcomes: a systematic review and meta-analysis.

PubMed

Campanella, Paolo; Vukovic, Vladimir; Parente, Paolo; Sulejmani, Adela; Ricciardi, Walter; Specchia, Maria Lucia

2016-07-22

To assess both qualitatively and quantitatively the impact of Public Reporting (PR) on clinical outcomes, we carried out a systematic review of published studies on this topic. Pubmed, Web of Science and SCOPUS databases were searched to identify studies published from 1991 to 2014 that investigated the relationship between PR and clinical outcomes. Studies were considered eligible if they investigated the relationship between PR and clinical outcomes and comprehensively described the PR mechanism and the study design adopted. Among the clinical outcomes identified, meta-analysis was performed for overall mortality rate which quantitative data were exhaustively reported in a sufficient number of studies. Two reviewers conducted all data extraction independently and disagreements were resolved through discussion. The same reviewers evaluated also the quality of the studies using a GRADE approach. Twenty-seven studies were included. Mainly, the effect of PR on clinical outcomes was positive. Meta-analysis regarding overall mortality included, in a context of high heterogeneity, 10 studies with a total of 1,840,401 experimental events and 3,670,446 control events and resulted in a RR of 0.85 (95 % CI, 0.79-0.92). The introduction of PR programs at different levels of the healthcare sector is a challenging but rewarding public health strategy. Existing research covering different clinical outcomes supports the idea that PR could, in fact, stimulate providers to improve healthcare quality.

Metabolic syndrome in fixed-shift workers.

PubMed

Canuto, Raquel; Pattussi, Marcos Pascoal; Macagnan, Jamile Block Araldi; Henn, Ruth Liane; Olinto, Maria Teresa Anselmo

2015-01-01

OBJECTIVE To analyze if metabolic syndrome and its altered components are associated with demographic, socioeconomic and behavioral factors in fixed-shift workers. METHODS A cross-sectional study was conducted on a sample of 902 shift workers of both sexes in a poultry processing plant in Southern Brazil in 2010. The diagnosis of metabolic syndrome was determined according to the recommendations from Harmonizing the Metabolic Syndrome. Its frequency was evaluated according to the demographic (sex, skin color, age and marital status), socioeconomic (educational level, income and work shift), and behavioral characteristics (smoking, alcohol intake, leisure time physical activity, number of meals and sleep duration) of the sample. The multivariate analysis followed a theoretical framework for identifying metabolic syndrome in fixed-shift workers. RESULTS The prevalence of metabolic syndrome in the sample was 9.3% (95%CI 7.4;11.2). The most frequently altered component was waist circumference (PR 48.4%; 95%CI 45.5;51.2), followed by high-density lipoprotein. Work shift was not associated with metabolic syndrome and its altered components. After adjustment, the prevalence of metabolic syndrome was positively associated with women (PR 2.16; 95%CI 1.28;3.64), workers aged over 40 years (PR 3.90; 95%CI 1.78;8.93) and those who reported sleeping five hours or less per day (PR 1.70; 95%CI 1.09;2.24). On the other hand, metabolic syndrome was inversely associated with educational level and having more than three meals per day (PR 0.43; 95%CI 0.26;0.73). CONCLUSIONS Being female, older and deprived of sleep are probable risk factors for metabolic syndrome, whereas higher educational level and higher number of meals per day are protective factors for metabolic syndrome in fixed-shift workers.

Transient expression of progesterone receptor and cathepsin-l in human granulosa cells during the periovulatory period.

PubMed

García, Víctor; Kohen, Paulina; Maldonado, Carola; Sierralta, Walter; Muñoz, Alex; Villarroel, Claudio; Strauss, Jerome F; Devoto, Luigi

2012-03-01

To study in vivo the progesterone receptor (PR) expression levels in human granulosa cells (GCs) during the periovulatory period and the affect of the protein kinase A (PKA) pathway on PR expression and cathepsin-L expression-activation. Experimental study. University research unit. Twenty-five women of reproductive age. Follicular fluid and GCs obtained from spontaneous cycles before and during the normal luteinizing hormone surge, and samples obtained 36 hours after human chorionic gonadotropin (hCG) administration in patients undergoing in vitro fertilization. To determine PR, cathepsin-L messenger RNA (mRNA) analysis via real-time polymerase chain reaction, and protein of PR, cathepsin-L, and PKA in human GCs. The Western blot analysis revealed that bands of PR (isoform A) were the most abundant and that mRNA (PR-A and PR-B) have a temporal pattern of expression throughout the periovulatory period. The protein levels of PR and cathepsin-L were up-regulated by hCG. The abundance of PR was diminished in the presence of PKA inhibitor, and cathepsin-L with PR receptor antagonist. The transient expression of PR in human GCs of the preovulatory follicle suggests that PR and its ligand play a role in the activation of cathepsin-L, which is presumably involved in the degradation of the follicular extracellular matrix during human ovulation. Copyright © 2012 American Society for Reproductive Medicine. All rights reserved.

[Regulatory effect and mechanism of RNA binding motif protein 38 on the expression of progesterone receptor in human breast cancer ZR-75-1 cells].

PubMed

Lou, P P; Li, C L; Xia, T S; Shi, L; Wu, J; Zhou, X J; Wang, Y; Ding, Q

2016-06-23

To investigate the regulatory mechanism of RNA binding motif protein 38 (RNPC1) on the expression of progesterone receptor (PR) in breast cancer cell line ZR-75-1. Lentiviral vector was used to induce overexpression of RNPC1 in ZR-75-1 cells. qRT-PCR and Western blot were used to assess the regulatory effect of RNPC1 on PR expression. Actinomycin was used to detect the regulatory mechanism involved. Immunohistochemical (IHC) staining was used to determine the protein expression of RNPC1 and PR in 80 breast cancer tissues. IHC staining showed that the expression of RNPC1 was significantly higher in the PR positive breast cancer tissues than that in the PR negative breast cancer tissues (P<0.05). The qRT-PCR results showed that overexpression of RNPC1 in ZR-75-1 cells significantly upregulated the mRNA level of PR (1.764±0.028 vs. 1.001±0.037, P<0.01), whereas knockdown of RNPC1 did the opposite (0.579± 0.007 vs. 1.000±0.002, P<0.01). The Western blot results also showed that overexpression of RNPC1 up-regulated PR levels, while knockdown of RNPC1 resulted in down-regulation of PR levels in the ZR-75-1 cells.The actinomycin assay showed that overexpression of RNPC1 increased the mRNA stability of PR. The half-life of PR mRNA was increased from 4.0 h to 6.5 h. Knockdown of RNPC1 decreased the mRNA stability of PR and the half-life of PR transcript was decreased from 4.1 h to 3.0 h. RNPC1 plays a crucial role in regulating the expression of PR in breast cancer ZR-75-1 cells.

Feasibility of infectious prion digestion using mild conditions and commercial subtilisin.

PubMed

Pilon, John L; Nash, Paul B; Arver, Terry; Hoglund, Don; Vercauteren, Kurt C

2009-10-01

Two serine protease enzymes, subtilisin 309 and subtilisin 309-v, were used to digest brain homogenates containing high levels of prion infectivity using mildly alkaline conditions to investigate prion decontamination methods. To establish that PrP(res) infectivity was eliminated, we utilized the Rocky Mountain Laboratory (RML) mouse-adapted scrapie model system for bioassay. Only one digestion condition (subtilisin 309 at 138mAU/ml, 55 degrees C and 14h digestion time pH 7.9) was considered to be highly relevant statistically (P<0.001) compared to control, with 52% of challenged mice surviving until the end of the study period. In contrast, treatment of PrP(res) by autoclaving at 134 degrees C or treatment with hypochlorite at a concentration of 20,000 ppm completely protected mice from prionosis. Further, in vitro assays suggest that potential proteolytic based PrP(res) decontamination methods must use high enzyme concentration, pH values >9.0, and elevated temperatures to be a safely efficacious, thereby limiting applicability on delicate surgical instruments and use in the environment.

Internal consistency of the Spanish health literacy test (TOFHLA-SPR) for Puerto Rico.

PubMed

Rivero-Méndez, Marta; Suárez, Erick; Solís-Báez, Solymar S; Hernández, Gloryvee; Cordero, Wanda; Vázquez, Irma; Medina, Zullettevy; Padilla, Raisa; Flores, Aida; Bonilla, José Luis; Holzemer, William L

2010-03-01

Low functional health literacy has been related to poor viral control, and lower levels of ART adherence in people living with HIV/AIDS. Research in functional health literacy among people living with HIV/AIDS in Puerto Rico (PR) is an unexplored area. The purpose of this paper is to describe how the full-length Spanish Version of the Test of Functional Health Literacy in Adults (TOFHLA-S) scale was adapted to PR. Thirty participants (women = 16, men = 14) completed a basic demographic questionnaire, the TOFHLA-S and participated in an interview. Analyses were performed to examine the information provided by participants and the internal consistency of the TOFHLA-S. The mean age was 47.7 years (range 34-77). Thirty-seven percent had less than 12 years of formal schooling and 43% reported having education above high school. Changes suggested by participants included: increasing font size from 14 to 16 points for better readability and changes/simplification of several words in order to make them colloquial and comprehensible for the PR context. The reliability coefficient obtained for this scale was strong (estimated alpha = 0.95) however, differences were observed by subtype: numeracy (estimated alpha(num) = .819 vs. comprehension (estimated alpha =. 953). Based on this process, we have adapted the original version of the TOFHLA-S and the new version of the full-length TOFHLA-S, PR is now valid for further research and testing levels of functional health literacy in a larger sample in PR.

Internal Consistency of the Spanish Health Literacy Test (TOFHLA-SPR) for Puerto Rico

PubMed Central

Rivero-Méndez, Marta; Suárez, Erick; Solís-Báez, Solymar S.; Hernández, Gloryvee; Cordero, Wanda; Vázquez, Irma; Medina, Zullettevy; Padilla, Raisa; Flores, Aida; Bonilla, José Luis; Holzemer, William L.

2010-01-01

Background Low functional health literacy has been related to poor viral control, and lower levels of ART adherence in people living with HIV/AIDS. Research in functional health literacy among people living with HIV/AIDS in Puerto Rico (PR) is an unexplored area. The purpose of this paper is to describe how the full-length Spanish Version of the Test of Functional Health Literacy in Adults (TOFHLA-S) scale was adapted to PR. Methods Thirty participants (women = 16, men = 14) completed a basic demographic questionnaire, the TOFHLA-S and participated in an interview. Analyses were performed to examine the information provided by participants and the internal consistency of the TOFHLA-S. Results The mean age was 47.7 years (range 34-77). Thirty-seven percent had less than 12 years of formal schooling and 43% reported having education above high school. Changes suggested by participants included: increasing font size from 14 to 16 points for better readability and changes/simplification of several words in order to make them colloquial and comprehensible for the PR context. The reliability coefficient obtained for this scale was strong (estimated alpha = 0.95) however, differences were observed by subtype: numeracy (estimated alphanum = .819 vs. comprehension (estimated alpha =. 953). Conclusions Based on this process, we have adapted the original version of the TOFHLA-S and the new version of the full-length TOFHLA-S, PR is now valid for further research and testing levels of functional health literacy in a larger sample in PR. PMID:20222334

Implementation and Operational Research: A Cost-Effective, Clinically Actionable Strategy for Targeting HIV Preexposure Prophylaxis to High-Risk Men Who Have Sex With Men.

PubMed

Ross, Eric L; Cinti, Sandro K; Hutton, David W

2016-07-01

Preexposure prophylaxis (PrEP) is effective at preventing HIV infection among men who have sex with men (MSM), but there is uncertainty about how to identify high-risk MSM who should receive PrEP. We used a mathematical model to assess the cost-effectiveness of using the HIV Incidence Risk Index for MSM (HIRI-MSM) questionnaire to target PrEP to high-risk MSM. We simulated strategies of no PrEP, PrEP available to all MSM, and eligibility thresholds set to HIRI-MSM scores between 5 and 45, in increments of 5 (where a higher score predicts greater HIV risk). Based on the iPrEx, IPERGAY, and PROUD trials, we evaluated PrEP efficacies from 44% to 86% and annual costs from $5900 to 8700. We designate strategies with incremental cost-effectiveness ratio (ICER) ≤$100,000/quality-adjusted life-year (QALY) as "cost-effective." Over 20 years, making PrEP available to all MSM is projected to prevent 33.5% of new HIV infections, with an ICER of $1,474,000/QALY. Increasing the HIRI-MSM score threshold reduces the prevented infections, but improves cost-effectiveness. A threshold score of 25 is projected to be optimal (most QALYs gained while still being cost-effective) over a wide range of realistic PrEP efficacies and costs. At low cost and high efficacy (IPERGAY), thresholds of 15 or 20 are optimal across a range of other input assumptions; at high cost and low efficacy (iPrEx), 25 or 30 are generally optimal. The HIRI-MSM provides a clinically actionable means of guiding PrEP use. Using a score of 25 to determine PrEP eligibility could facilitate cost-effective use of PrEP among high-risk MSM who will benefit from it most.

A 2.5-Kilobase Deletion Containing a Cluster of Nine MicroRNAs in the Latency-Associated-Transcript Locus of the Pseudorabies Virus Affects the Host Response of Porcine Trigeminal Ganglia during Established Latency

PubMed Central

Mahjoub, Nada; Dhorne-Pollet, Sophie; Fuchs, Walter; Endale Ahanda, Marie-Laure; Lange, Elke; Klupp, Barbara; Arya, Anoop; Loveland, Jane E.; Lefevre, François; Mettenleiter, Thomas C.

2014-01-01

ABSTRACT The alphaherpesvirus pseudorabies virus (PrV) establishes latency primarily in neurons of trigeminal ganglia when only the transcription of the latency-associated transcript (LAT) locus is detected. Eleven microRNAs (miRNAs) cluster within the LAT, suggesting a role in establishment and/or maintenance of latency. We generated a mutant (M) PrV deleted of nine miRNA genes which displayed properties that were almost identical to those of the parental PrV wild type (WT) during propagation in vitro. Fifteen pigs were experimentally infected with either WT or M virus or were mock infected. Similar levels of virus excretion and host antibody response were observed in all infected animals. At 62 days postinfection, trigeminal ganglia were excised and profiled by deep sequencing and quantitative RT-PCR. Latency was established in all infected animals without evidence of viral reactivation, demonstrating that miRNAs are not essential for this process. Lower levels of the large latency transcript (LLT) were found in ganglia infected by M PrV than in those infected by WT PrV. All PrV miRNAs were expressed, with highest expression observed for prv-miR-LLT1, prv-miR-LLT2 (in WT ganglia), and prv-miR-LLT10 (in both WT and M ganglia). No evidence of differentially expressed porcine miRNAs was found. Fifty-four porcine genes were differentially expressed between WT, M, and control ganglia. Both viruses triggered a strong host immune response, but in M ganglia gene upregulation was prevalent. Pathway analyses indicated that several biofunctions, including those related to cell-mediated immune response and the migration of dendritic cells, were impaired in M ganglia. These findings are consistent with a function of the LAT locus in the modulation of host response for maintaining a latent state. IMPORTANCE This study provides a thorough reference on the establishment of latency by PrV in its natural host, the pig. Our results corroborate the evidence obtained from the study of several LAT mutants of other alphaherpesviruses encoding miRNAs from their LAT regions. Neither PrV miRNA expression nor high LLT expression levels are essential to achieve latency in trigeminal ganglia. Once latency is established by PrV, the only remarkable differences are found in the pattern of host response. This indicates that, as in herpes simplex virus, LAT functions as an immune evasion locus. PMID:25320324

Experiences with HPTN 067/ADAPT Study-Provided Open-Label PrEP Among Women in Cape Town: Facilitators and Barriers Within a Mutuality Framework.

PubMed

Amico, K Rivet; Wallace, Melissa; Bekker, Linda-Gail; Roux, Surita; Atujuna, Millicent; Sebastian, Elaine; Dye, Bonnie J; Elharrar, Vanessa; Grant, Robert M

2017-05-01

Placebo-controlled trials of pre-exposure prophylaxis (PrEP) have reported challenges with study-product uptake and use, with the greatest challenges reported in studies with young women in sub-Saharan Africa. We conducted a qualitative sub-study to explore experiences with open-label PrEP among young women in Cape Town, South Africa participating in HTPN 067/Alternative Dosing to Augment Pre-Exposure Prophylaxis Pill Taking (ADAPT). HPTN 067/ADAPT provided open label oral FTC/TDF PrEP to young women in Cape Town, South Africa who were randomized to daily and non-daily PrEP regimens. Following completion of study participation, women were invited into a qualitative sub-study including focus groups and in-depth interviews. Interviews and groups followed a semi-structured guide, were recorded, transcribed, and translated to English from isiXhosa, and coded using framework analysis. Sixty of the 179 women enrolled in HPTN 067/ADAPT participated in either a focus group (six groups for a total of 42 participants) or an in-depth interview (n = 18). This sample of mostly young, unmarried women identified facilitators of and barriers to PrEP use, as well as factors influencing study participation. Cross-cutting themes characterizing discourse suggested that women placed high value on contributing to the well-being of one's community (Ubuntu), experienced a degree of skepticism towards PrEP and the study more generally, and reported a wide range of approaches towards PrEP (ranging from active avoidance to high levels of persistence and adherence). A Mutuality Framework is proposed that identifies four dynamics (distrust, uncertainty, alignment, and mutuality) that represent distinct interactions between self, community and study and serve to contextualize women's experiences. Implications for better understanding PrEP use, and non-use, and intervention opportunities are discussed. In this sample of women, PrEP use in the context of an open-label research trial was heavily influenced by underlying beliefs about safety, reciprocity of contributions to community, and trust in transparency and integrity of the research. Greater attention to factors positioning women in the different dynamics of the proposed Mutuality Framework could direct intervention approaches in clinical trials, as well as open-label PrEP scale-up.

Dental Caries and Periodontal Disease in Brazilian Children and Adolescents with Cerebral Palsy

PubMed Central

Cardoso, Andreia M. R.; Gomes, Lays N.; Silva, Clara Regina D.; de S. C. Soares, Renata; de Abreu, Mauro Henrique N. G.; Padilha, Wilton W. N.; Cavalcanti, Alessandro L.

2014-01-01

The aim of the present study was determine the prevalence and factors associated with dental caries and periodontal disease in Brazilian children and adolescents with cerebral palsy (CP). This is a cross-sectional study conducted with 80 patients ranging in age from 2 to 18 years old. Oral exams were conducted by an examiner with records of DMFT, dmft, Gingival Bleeding Index (GBI) and Community Periodontal Index (CPI). The statistical analysis used Poisson Regression with robust variance estimation (α = 0.05). The prevalence of dental caries was 59.3%, with DMFT and mean dmft of 1.71 ± 2.42 and 2.22 ± 3.23, respectively. The mean GBI was 22.44%, and in the CPI, the prevalence of gingival bleeding, calculus, shallow and deep pockets were 94.73%, 79.62%, 12.90% and 3.22%, respectively. The caregiver’s educational level of less than eight years were associated with the dental caries experience (PR = 1.439; 95%CI = 1.09–1.89). The periodontal alterations were associated with female sex (PR = 0.82; 95%CI = 0.69–0.97), caregiver’s educational level of less than eight years (PR = 1.15; 95%CI = 1.03–1.29), poor oral perception (PR = 0.89; 95%CI = 0.80–0.98), serious communication problem (PR = 0.87; 95%CI = 0.76–0.99) and athetoid type of CP (PR = 0.85; 95%CI = 0.75–0.97). The patients with CP presented high dental caries experience and periodontal alterations, which were associated with their demographic, socioeconomic, oral health perception and systemic information. PMID:25551517

Satisfaction, discomfort, obligations, and concerns in population-based breast cancer screening: cross-sectional study in a Danish population.

PubMed

Gabel, Pernille; Larsen, Mette Bach; Nielsen, Pernille Bjørnholt; Svendstrup, Dorte Brandt; Andersen, Berit

2017-07-14

Potential barriers to breast cancer screening adherence include patient satisfaction, as well as pain, feeling obliged to participate, and other concerns that might compromise the level of satisfaction. The present study aimed to assess the overall satisfaction of Danish citizens with their breast cancer screening experiences, as well as their level of discomfort, concerns, and feelings of obligation to participate. Furthermore, we analyzed the associations between overall satisfaction and the remaining outcomes. Questionnaires were mailed to 3000 women in the Central Denmark Region who received screening examination results in the fall of 2013. The questionnaire assessed satisfaction (overall, telephone hot-line, and web-based self-service), discomfort (pain and boundaries of modesty), concerns (at invitation, while waiting for results, and after receiving results), and feelings of obligation to participate. Background information was retrieved from Statistics Denmark. Pearson's chi-square test was used to test differences in outcomes and demographic characteristic distributions between respondents and non-respondents and highly satisfied vs. less satisfied participants. Prevalence ratios (PR) with 95% CI were assessed using Poisson regression with robust variance, to estimate associations between satisfaction and the remaining outcomes. Among the participants, 70.3% and 29.4%, respectively, reported really good and good impressions of the screening program. Lower satisfaction was associated with feeling pain (prevalence ratio (PR), 0.82), feeling that modesty boundaries were transgressed (PR, 0.79), experiencing screening-induced concerns (PR, 0.84), and feeling obliged to participate (PR, 0.96). Of the participants, 36.2% and 12.9%, respectively, felt very much and moderately obliged to participate. A total of 72.6% reported no screening-induced concerns, including 73.3% of those with negative screening results and 38.1% of those with positive screening results. Overall satisfaction with breast cancer screening was very high, but discomfort, feelings of obligation, and concerns were associated with lower satisfaction levels. A continuing focus on high service in breast cancer screening is important for achieving the highest benefit from the program. This includes initiatives to employ the least painful techniques, to respect the patients' modesty as much as possible, and to deliver fast screening results and thus minimize concerns among women awaiting results.

Abundance and Localization of Progesterone Receptor Isoforms in Endometrium in Women With and Without Endometriosis and in Peritoneal and Ovarian Endometriotic Implants

PubMed Central

Bedaiwy, Mohamed A.; Dahoud, Wissam; Skomorovska-Prokvolit, Yelena; Yi, Lijuan; Liu, James H.; Falcone, Tommaso; Hurd, William W.; Mesiano, Sam

2015-01-01

Background: Several studies suggest that resistance to progesterone may contribute to the pathophysiology of endometriosis. Progesterone mediates its biological activity via the 2 progesterone receptor (PR) isoforms (PR-A and PR-B). Effects of progesterone are determined by the PR-A:PR-B ratio such that a PR-B-dominant state promotes progesterone signaling, whereas a PR-A-dominant state decreases progesterone responsiveness. Our objective was to compare the abundance and cellular localization of the PR isoforms in endometrium and endometriotic lesions from women with and without peritoneal and ovarian endometriosis. Methods: This in vitro study was conducted in a tertiary care facility. Reproductive-age women with surgically diagnosed endometriosis (n = 18) and asymptomatic control individuals (n = 20) were prospectively recruited at the late proliferative and the early secretory phases. At laparoscopy, samples of eutopic endometrium, peritoneal and ovarian endometriosis, and disease-free peritoneum were obtained for subsequent immunohistochemical and immunoblot analysis of PR-B and total PR localization and PR-A and PR-B abundance, respectively. Results: The PR-A and PR-B were detected in eutopic endometrium and in peritoneal and ovarian endometriosis but not in disease-free peritoneum from patients with and without endometriosis. In peritoneal endometriosis, PR-A was the predominant isoform detected, whereas both receptors were detected in ovarian endometriosis and eutopic endometrium. In eutopic endometrium, levels of PR-A were significantly elevated in women with endometriosis compared with women without disease, regardless of menstrual phase. The PR-A levels were significantly elevated in ovarian endometriosis compared with peritoneal endometriosis. Conclusions: Endometriotic lesions and eutopic endometrium from women with endometriosis are uniform in a PR-A-dominant state. The data suggest that menstrual efflux of a PR-A-dominant endometrial tissue into the peritoneal cavity may play a role in the pathophysiology of endometriosis. PMID:26037298

Systemic resistance induced in Arabidopsis thaliana by Trichoderma asperellum SKT-1, a microbial pesticide of seedborne diseases of rice.

PubMed

Yoshioka, Yohei; Ichikawa, Haruki; Naznin, Hushna Ara; Kogure, Atsushi; Hyakumachi, Mitsuro

2012-01-01

Trichoderma asperellum SKT-1 is a microbial pesticide of seedborne diseases of rice. To investigate the mechanisms of disease suppression in SKT-1, the ability to induce systemic resistance by SKT-1, or its cell-free culture filtrate (CF), was tested using Arabidopsis thaliana Col-0 plants. Both SKT-1 and its CF elicit an induced systemic resistance against the bacterial leaf speck pathogen Pseudomonas syringae pv. tomato DC3000 in Col-0 plants. Involvement of plant hormones in the induced resistance by SKT-1 and CF was assessed using Arabidopsis genotypes such as the jasmonic acid (JA)-resistant mutant jar1, the ethylene (ET)-resistant mutant etr1, the plant impaired in salicylic acid (SA) signalling transgenic NahG and the mutant npr1 impaired in NPR1 activity. In soil experiments using SKT-1, no significant disease suppression effect was observed in NahG transgenic plants or npr1 mutant plants. Expression levels of SA-inducible genes such as PR-1, PR-2 and PR-5 increased substantially in the leaves of Col-0 plants. Expression levels of JA/ET-induced genes such as PDF1.2a, PR-3, PR-4 and AtVsp1 were also induced, but the levels were not as high as for SA-inducible genes. In a hydroponic experiment using CF from SKT-1, all Arabidopsis genotypes showed an induced systemic resistance by CF and increased expression levels of JA/ET- and SA-inducible genes in leaves of CF-treated plants. The SA signalling pathway is important in inducing systemic resistance to colonisation by SKT-1, and both SA and JA/ET signalling pathways combine in the signalling of induced resistance by CF. These results indicate that the response of A. thaliana is different from that found in root treatments with barley grain inoculum and CF from SKT-1. Copyright © 2011 Society of Chemical Industry.

Octarepeat region flexibility impacts prion function, endoproteolysis and disease manifestation

PubMed Central

Lau, Agnes; McDonald, Alex; Daude, Nathalie; Mays, Charles E; Walter, Eric D; Aglietti, Robin; Mercer, Robert CC; Wohlgemuth, Serene; van der Merwe, Jacques; Yang, Jing; Gapeshina, Hristina; Kim, Chae; Grams, Jennifer; Shi, Beipei; Wille, Holger; Balachandran, Aru; Schmitt-Ulms, Gerold; Safar, Jiri G; Millhauser, Glenn L; Westaway, David

2015-01-01

The cellular prion protein (PrPC) comprises a natively unstructured N-terminal domain, including a metal-binding octarepeat region (OR) and a linker, followed by a C-terminal domain that misfolds to form PrPSc in Creutzfeldt-Jakob disease. PrPC β-endoproteolysis to the C2 fragment allows PrPSc formation, while α-endoproteolysis blocks production. To examine the OR, we used structure-directed design to make novel alleles, ‘S1’ and ‘S3’, locking this region in extended or compact conformations, respectively. S1 and S3 PrP resembled WT PrP in supporting peripheral nerve myelination. Prion-infected S1 and S3 transgenic mice both accumulated similar low levels of PrPSc and infectious prion particles, but differed in their clinical presentation. Unexpectedly, S3 PrP overproduced C2 fragment in the brain by a mechanism distinct from metal-catalysed hydrolysis reported previously. OR flexibility is concluded to impact diverse biological endpoints; it is a salient variable in infectious disease paradigms and modulates how the levels of PrPSc and infectivity can either uncouple or engage to drive the onset of clinical disease. PMID:25661904

Occupational risk for Legionella infection among dental healthcare workers: meta-analysis in occupational epidemiology.

PubMed

Petti, Stefano; Vitali, Matteo

2017-07-13

The occupational risk for Legionella infection among dental healthcare workers (DHCWs) is conjectured because of the risk of routine inhalation of potentially contaminated aerosols produced by the dental instruments. Nevertheless, occupational epidemiology studies are contrasting. This meta-analysis assessed the level of scientific evidence regarding the relative occupational risk for Legionella infection among DHCWs. Literature search was performed without time and language restrictions, using broad data banks (PubMed, Scopus, Web of Science, GOOGLE Scholar) and generic keywords ('legionella' AND 'dent*'). Analytical cross-sectional studies comparing prevalence of high serum Legionella antibody levels in DHCWs and occupationally unexposed individuals were considered. The relative occupational risk was assessed through prevalence ratio (PR) with 95% CI. Between-study heterogeneity was assessed (Cochran's Q test) and was used to choose the meta-analytic method. Study quality (modified Newcastle-Ottawa Scale) and publication bias (Begg and Mazumdar's test, Egger and colleagues' test, trim and fill R 0 method) were assessed formally and considered for the sensitivity analysis. Sensitivity analysis to study inclusion, subgroup analyses (dental staff categories; publication year, before vs after 1998, ie, 5 years after the release by the Centers for Disease Control and Prevention of the infection control guidelines in dental healthcare setting) were performed. Seven studies were included (2232 DHCWs, 1172 occupationally unexposed individuals). No evidence of publication bias was detected. The pooled PR estimate was statistically non-significant at 95% level (1.7; 95% CI 0.8 to 3.2), study-quality adjustment did not change the PR considerably (PR, 1.5; 95% CI 0.5 to 4.1). PR was statistically significant before 1998 and no longer significant after 1998. Subgroup analysis according to DHCW categories was inconclusive. There is no scientific evidence that DHCWs are at high occupational risk. The differences between former and recent studies could be due to different characteristics of municipal water systems and the infection control guideline dissemination. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Submergence Tolerance and Germination Dynamics of Roegneria nutans Seeds in Water-Level Fluctuation Zones with Different Water Rhythms in the Three Gorges Reservoir

PubMed Central

Zeng, Bo; Pan, Xiaojiao; Su, Xiaolei

2016-01-01

The Three Gorges Dam features two water-level fluctuation zones (WLFZs): the preupland drawdown zone (PU-DZ) and the preriparian drawdown zone (PR-DZ). To investigate the vegetation potential of Roegneria nutans in WLFZs, we compared the submergence tolerance and germination dynamics in the natural riparian zone (NRZ), PU-DZ and PR-DZ. We found that the NRZ seeds maintained an 81.3% intactness rate and >91% germination rate. The final seed germination rate and germination dynamics were consistent with those of the controls. Meanwhile, the PU-DZ seeds submerged at 5 m, 10 m, 15 m, and 20 m exhibited intactness rates of 70.5%, 79.95%, 40.75%, and 39.87%, respectively, and >75% germination. Furthermore, the PR-DZ seeds exhibited intactness rates of 22.44%, 61.13%, 81.87%, and 15.36% at 5 m, 10 m, 15 m, and 17 m, respectively, and 80% germination. The germination rates of the intact seeds submerged >10 m were >80%. Finally, the intact seeds germinated quickly in all WLFZs. The high proportion of intact seeds, rapid germination capacity, and high germination rate permit R. nutans seeds to adapt to the complicated water rhythms of the PU-DZ and PR-DZ and indicate the potential for their use in vegetation restoration and recovery. Thus, perennial seeds can be used for vegetation restoration in the WLFZs of large reservoirs and in other regions with water rhythms similar to the Three Gorges Reservoir. PMID:27031104

The Novel Gene VpPR4-1 from Vitis pseudoreticulata Increases Powdery Mildew Resistance in Transgenic Vitis vinifera L.

PubMed Central

Dai, Lingmin; Wang, Dan; Xie, Xiaoqing; Zhang, Chaohong; Wang, Xiping; Xu, Yan; Wang, Yuejin; Zhang, Jianxia

2016-01-01

Pathogenesis-related proteins (PRs) can lead to increased resistance of the whole plant to pathogen attack. Here, we isolate and characterize a PR-4 protein (VpPR4-1) from a wild Chinese grape Vitis pseudoreticulata which shows greatly elevated transcription following powdery mildew infection. Its expression profiles under a number of abiotic stresses were also investigated. Powdery mildew, salicylic acid, and jasmonic acid methyl ester significantly increased the VpPR4-1 induction while NaCl and heat treatments just slightly induced VpPR4-1 expression. Abscisic acid and cold treatment slightly affected the expression level of VpPR4-1. The VpPR4-1 gene was overexpressed in 30 regenerated V. vinifera cv. Red Globe via Agrobacterium tumefaciens-mediated transformation and verified by the Western blot. The 26 transgenic grapevines exhibited higher expression levels of PR-4 protein content than wild-type vines and six of them were inoculated with powdery mildew which showed that the growth of powdery mildew was repressed. The powdery mildew-resistance of Red Globe transformed with VpPR4-1 was enhanced inoculated with powdery mildew. Moreover, other powdery mildew resistant genes were associated with feedback regulation since VpPR4-1 is in abundance. This study demonstrates that PR-4 protein in grapes plays a vital role in defense against powdery mildew invasion. PMID:27303413

The Novel Gene VpPR4-1 from Vitis pseudoreticulata Increases Powdery Mildew Resistance in Transgenic Vitis vinifera L.

PubMed

Dai, Lingmin; Wang, Dan; Xie, Xiaoqing; Zhang, Chaohong; Wang, Xiping; Xu, Yan; Wang, Yuejin; Zhang, Jianxia

2016-01-01

Pathogenesis-related proteins (PRs) can lead to increased resistance of the whole plant to pathogen attack. Here, we isolate and characterize a PR-4 protein (VpPR4-1) from a wild Chinese grape Vitis pseudoreticulata which shows greatly elevated transcription following powdery mildew infection. Its expression profiles under a number of abiotic stresses were also investigated. Powdery mildew, salicylic acid, and jasmonic acid methyl ester significantly increased the VpPR4-1 induction while NaCl and heat treatments just slightly induced VpPR4-1 expression. Abscisic acid and cold treatment slightly affected the expression level of VpPR4-1. The VpPR4-1 gene was overexpressed in 30 regenerated V. vinifera cv. Red Globe via Agrobacterium tumefaciens-mediated transformation and verified by the Western blot. The 26 transgenic grapevines exhibited higher expression levels of PR-4 protein content than wild-type vines and six of them were inoculated with powdery mildew which showed that the growth of powdery mildew was repressed. The powdery mildew-resistance of Red Globe transformed with VpPR4-1 was enhanced inoculated with powdery mildew. Moreover, other powdery mildew resistant genes were associated with feedback regulation since VpPR4-1 is in abundance. This study demonstrates that PR-4 protein in grapes plays a vital role in defense against powdery mildew invasion.

Willingness to Use Pre-Exposure Prophylaxis (PrEP): An Empirical Test of the Information-Motivation-Behavioral Skills (IMB) Model among High-Risk Drug Users in Treatment.

PubMed

Shrestha, Roman; Altice, Frederick L; Huedo-Medina, Tania B; Karki, Pramila; Copenhaver, Michael

2017-05-01

Evidence from recent pre-exposure prophylaxis (PrEP) trials has demonstrated its safety and efficacy in significantly reducing the risk of HIV acquisition for those who are at considerable risk of acquiring HIV infection. With a rapid increase in the amount of research on the efficacy of PrEP for HIV prevention, complementary research on the willingness to use PrEP has grown, especially among MSM, but limited research has been focused among people who use drugs (PWUD). As part of the formative process, we utilized the information-motivation-behavioral skills (IMB) model of health behavior change to characterize and guide intervention development for promoting willingness to use PrEP among high-risk PWUD. The analysis included 400 HIV-negative high-risk PWUD enrolled in a community-based methadone maintenance treatment who reported drug- and/or sex-related HIV risk behaviors in the past 6-months. Analyses revealed support for the IMB model as PrEP-related behavioral skills were found to mediate the influence of PrEP-related information and motivation on willingness to use PrEP. The results provide evidence as to the utility of the IMB model to increase willingness to use PrEP among high-risk PWUD. It therefore makes an important contribution to our understanding of the applicability of theoretically-grounded models of willingness to use PrEP among high-risk PWUD, who are one of the key risk populations who could benefit from the use of PrEP.

Willingness to Use Pre-Exposure Prophylaxis (PrEP): An Empirical Test of the Information-Motivation-Behavioral Skills (IMB) Model among High-Risk Drug Users in Treatment

PubMed Central

Shrestha, Roman; Altice, Frederick L.; Huedo-Medina, Tania B.; Karki, Pramila; Copenhaver, Michael

2016-01-01

Evidence from recent pre-exposure prophylaxis (PrEP) trials has demonstrated its safety and efficacy in significantly reducing the risk of HIV acquisition for those who are at considerable risk of acquiring HIV infection. With a rapid increase in the amount of research on the efficacy of PrEP for HIV prevention, complementary research on the willingness to use PrEP has grown, especially among MSM, but limited research has been focused among people who use drugs (PWUD). As part of the formative process, we utilized the Information-Motivation-Behavioral Skills (IMB) model of health behavior change to characterize and guide intervention development for promoting willingness to use PrEP among high-risk PWUD. The analysis included 400 HIV-negative high-risk PWUD enrolled in a community-based methadone maintenance treatment who reported drug- and/or sex-related HIV risk behaviors in the past 6-months. Analyses revealed support for the IMB model as PrEP-related behavioral skills were found to mediate the influence of PrEP-related information and motivation on willingness to use PrEP. The results provide evidence as to the utility of the IMB model to increase willingness to use PrEP among high-risk PWUD. It therefore makes an important contribution to our understanding of the applicability of theoretically-grounded models of willingness to use PrEP among high-risk PWUD, who are one of the key risk populations who could benefit from the use of PrEP. PMID:27990587

From modeling to morals: imagining the future of HIV PREP in Lesotho.

PubMed

Kenworthy, Nora J; Bulled, Nicola

2013-08-01

Amidst growing global endorsements of new biomedical HIV prevention strategies, ARV-based pre-exposure prophylaxis (ARV PrEP) has garnered considerable attention as a potentially promising prevention strategy. Though it may offer more effective protection for certain at-risk groups than conventional prevention strategies (such as sexual partner reduction, condom use, and prevention of mother-to-child transmission), PrEP is more costly. PrEP requires more ongoing contact between individuals and providers, and a level of surveillance from the health system that is not necessary with other preventive measures. In this sense, it represents a new bio-technology for HIV prevention that poses particular challenges for worldwide implementation, given developing countries' struggling health systems and incomplete HIV treatment programs. Since the emergence of PrEP has stimulated ethical discussions premised on incomplete knowledge of efficacy and implementation, this paper explores the ethical parameters of a likely scenario for PrEP usage in a single, resource-poor country. We first develop a plausible model for PrEP deployment and utilization based on current PrEP research, while carefully considering the reigning institutional values of feasibility and effectiveness in global health approaches. Drawing on ethnographic research of HIV treatment and prevention approaches in Lesotho, we address ethical questions arising from this scenario of PrEP delivery. Lesotho presents a compelling and emblematic case study of PrEP's potential successes and pitfalls in a developing country, given the country's high HIV prevalence, struggles to achieve universal access to HIV treatment regimes, continued existence of stigma around the epidemic, and difficulties in addressing persistent social inequalities that fuel infections. © 2013 John Wiley & Sons Ltd.

Association between maternal education and malocclusion in Mongolian adolescents: a cross-sectional study.

PubMed

Tumurkhuu, Tsasan; Fujiwara, Takeo; Komazaki, Yuko; Kawaguchi, Yoko; Tanaka, Toshihiro; Inazawa, Johji; Ganburged, Ganjargal; Bazar, Amarsaikhan; Ogawa, Takuya; Moriyama, Keiji

2016-11-01

Malocclusion is a highly prevalent condition, affecting 20-60% of adolescents worldwide. Although its treatment is often expensive and unaffordable for disadvantaged individuals, few studies have examined the relationship between malocclusion and socioeconomic status. We investigated the prevalence of malocclusion among Mongolian adolescents and its association with maternal education in a community-based sample in Mongolia. Cross-sectional study. 2 large secondary schools with different backgrounds in Ulaanbaatar, Mongolia. Complete dental casts of 557 randomly recruited Mongolian schoolchildren aged 11-16 years were evaluated using the Dental Health Component of the Index of Orthodontic Treatment Need to dichotomise orthodontic treatment requirements. Exclusion criteria were the presence of orthodontic treatment history and absence of maternal educational status. Questionnaires were administered to caregivers to assess socioeconomic status. Poisson regression analysis was performed to examine the association between malocclusion and maternal educational status. The prevalence of malocclusion requiring orthodontic treatment among all adolescents was 35.2% (95% CI 31.2 to 39.2). In the unadjusted analysis, the prevalence ratio (PR) for malocclusion was higher (PR=1.46; 95% CI 0.96 to 2.20) among adolescents of mothers with a high educational background than among those of mothers with a low educational background. After adjusting for covariates, the PR remained significantly higher (PR=1.72; 95% CI 1.06 to 2.82) among adolescents of mothers with a high educational background. Other socioeconomic status variables, including family income and the educational level of the father, showed no association with malocclusion. These findings suggest that malocclusion requiring orthodontic treatment in adolescents is more prevalent among children of mothers with high levels of education. Further studies are needed to clarify the behavioural factors and environmental circumstance that contribute to this. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

PR Toxin – Biosynthesis, Genetic Regulation, Toxicological Potential, Prevention and Control Measures: Overview and Challenges

PubMed Central

Dubey, Manish K.; Aamir, Mohd; Kaushik, Manish S.; Khare, Saumya; Meena, Mukesh; Singh, Surendra; Upadhyay, Ram S.

2018-01-01

Out of the various mycotoxigenic food and feed contaminant, the fungal species belonging to Penicillium genera, particularly Penicillium roqueforti is of great economic importance, and well known for its crucial role in the manufacturing of Roquefort and Gorgonzola cheese. The mycotoxicosis effect of this mold is due to secretion of several metabolites, of which PR toxin is of considerable importance, with regard to food quality and safety challenges issues. The food products and silages enriched with PR toxin could lead into damage to vital internal organs, gastrointestinal perturbations, carcinogenicity, immunotoxicity, necrosis, and enzyme inhibition. Moreover, it also has the significant mutagenic potential to disrupt/alter the crucial processes like DNA replication, transcription, and translation at the molecular level. The high genetic diversities in between the various strains of P. roqueforti persuaded their nominations with Protected Geographical Indication (PGI), accordingly to the cheese type, they have been employed. Recently, the biosynthetic mechanism and toxicogenetic studies unraveled the role of ari1 and prx gene clusters that cross-talk with the synthesis of other metabolites or involve other cross-regulatory pathways to negatively regulate/inhibit the other biosynthetic route targeted for production of a strain-specific metabolites. Interestingly, the chemical conversion that imparts toxic properties to PR toxin is the substitution/oxidation of functional hydroxyl group (-OH) to aldehyde group (-CHO). The rapid conversion of PR toxin to the other derivatives such as PR imine, PR amide, and PR acid, based on conditions available reflects their unstability and degradative aspects. Since the PR toxin-induced toxicity could not be eliminated safely, the assessment of dose-response and other pharmacological aspects for its safe consumption is indispensable. The present review describes the natural occurrences, diversity, biosynthesis, genetics, toxicological aspects, control and prevention strategies, and other management aspects of PR toxin with paying special attention on economic impacts with intended legislations for avoiding PR toxin contamination with respect to food security and other biosafety purposes. PMID:29651243

PR Toxin - Biosynthesis, Genetic Regulation, Toxicological Potential, Prevention and Control Measures: Overview and Challenges.

PubMed

Dubey, Manish K; Aamir, Mohd; Kaushik, Manish S; Khare, Saumya; Meena, Mukesh; Singh, Surendra; Upadhyay, Ram S

2018-01-01

Out of the various mycotoxigenic food and feed contaminant, the fungal species belonging to Penicillium genera, particularly Penicillium roqueforti is of great economic importance, and well known for its crucial role in the manufacturing of Roquefort and Gorgonzola cheese. The mycotoxicosis effect of this mold is due to secretion of several metabolites, of which PR toxin is of considerable importance, with regard to food quality and safety challenges issues. The food products and silages enriched with PR toxin could lead into damage to vital internal organs, gastrointestinal perturbations, carcinogenicity, immunotoxicity, necrosis, and enzyme inhibition. Moreover, it also has the significant mutagenic potential to disrupt/alter the crucial processes like DNA replication, transcription, and translation at the molecular level. The high genetic diversities in between the various strains of P. roqueforti persuaded their nominations with Protected Geographical Indication (PGI), accordingly to the cheese type, they have been employed. Recently, the biosynthetic mechanism and toxicogenetic studies unraveled the role of ari1 and prx gene clusters that cross-talk with the synthesis of other metabolites or involve other cross-regulatory pathways to negatively regulate/inhibit the other biosynthetic route targeted for production of a strain-specific metabolites. Interestingly, the chemical conversion that imparts toxic properties to PR toxin is the substitution/oxidation of functional hydroxyl group (-OH) to aldehyde group (-CHO). The rapid conversion of PR toxin to the other derivatives such as PR imine, PR amide, and PR acid, based on conditions available reflects their unstability and degradative aspects. Since the PR toxin-induced toxicity could not be eliminated safely, the assessment of dose-response and other pharmacological aspects for its safe consumption is indispensable. The present review describes the natural occurrences, diversity, biosynthesis, genetics, toxicological aspects, control and prevention strategies, and other management aspects of PR toxin with paying special attention on economic impacts with intended legislations for avoiding PR toxin contamination with respect to food security and other biosafety purposes.

The effects of graded levels of calorie restriction: II. Impact of short term calorie and protein restriction on circulating hormone levels, glucose homeostasis and oxidative stress in male C57BL/6 mice

PubMed Central

Mitchell, Sharon E.; Delville, Camille; Konstantopedos, Penelope; Hurst, Jane; Derous, Davina; Green, Cara; Chen, Luonan; Han, Jackie J.D.; Wang, Yingchun; Promislow, Daniel E.L.; Lusseau, David; Douglas, Alex; Speakman, John R.

2015-01-01

Limiting food intake attenuates many of the deleterious effects of aging, impacting upon healthspan and leading to an increased lifespan. Whether it is the overall restriction of calories (calorie restriction: CR) or the incidental reduction in macronutrients such as protein (protein restriction: PR) that mediate these effects is unclear. The impact of 3 month CR or PR, (10 to 40%), on C57BL/6 mice was compared to controls fed ad libitum. Reductions in circulating leptin, tumor necrosis factor-α and insulin-like growth factor-1 (IGF-1) were relative to the level of CR and individually associated with morphological changes but remained unchanged following PR. Glucose tolerance and insulin sensitivity were improved following CR but not affected by PR. There was no indication that CR had an effect on oxidative damage, however CR lowered antioxidant activity. No biomarkers of oxidative stress were altered by PR. CR significantly reduced levels of major urinary proteins suggesting lowered investment in reproduction. Results here support the idea that reduced adipokine levels, improved insulin/IGF-1 signaling and reduced reproductive investment play important roles in the beneficial effects of CR while, in the short-term, attenuation of oxidative damage is not applicable. None of the positive effects were replicated with PR. PMID:26061745

Spatial distribution and ecological risk assessment of phthalic acid esters and phenols in surface sediment from urban rivers in Northeast China.

PubMed

Li, Bin; Liu, Ruixia; Gao, Hongjie; Tan, Ruijie; Zeng, Ping; Song, Yonghui

2016-12-01

Concentration and spatial distribution of six phthalic acid esters (PAEs) and eight phenols in sediments of urban rivers, namely the Xi River (XR) and Pu River (PR) in Shenyang city, Northeast China were investigated and the ecological risk of these target pollutants was assessed based on the risk quotient (RQ) approach. Target PAEs and phenols were detected in most of sediment samples collected from the XR and PR. The concentrations of total PAEs in sediments varied from 22.4 to 369 μg/g dw in the XR and 3.71-46.9 μg/g dw in the PR. The levels of phenols ranged from 2.72 to 106 μg/g dw in the XR and 0.811-25.0 μg/g dw in the PR, respectively. The dominant pollutants in both XR and PR were DEHP, phenol and 4-methylphnol. The sampling locations XR1-3 in the XR suffered severe contamination from PAEs and phenols. The sites PR1 and PR6 were heavily polluted by phenols and PAEs, respectively. Almost all target PAEs and phenolic compounds in sediment of the XR exhibited medium or high ecological risk to organisms and the ecological risk in the PR mainly originated from PEAs, phenol and 4-methylphenol. These results would provide guidance for individual pollutant control and indicate that it is imperative to take some effective measures to reduce the pollution of those contaminants. Copyright © 2016 Elsevier Ltd. All rights reserved.

Conserved Epigenetic Mechanisms Could Play a Key Role in Regulation of Photosynthesis and Development-Related Genes during Needle Development of Pinus radiata.

PubMed

Valledor, Luis; Pascual, Jesús; Meijón, Mónica; Escandón, Mónica; Cañal, María Jesús

2015-01-01

Needle maturation is a complex process that involves cell growth, differentiation and tissue remodelling towards the acquisition of full physiological competence. Leaf induction mechanisms are well known; however, those underlying the acquisition of physiological competence are still poorly understood, especially in conifers. We studied the specific epigenetic regulation of genes defining organ function (PrRBCS and PrRBCA) and competence and stress response (PrCSDP2 and PrSHMT4) during three stages of needle development and one de-differentiated control. Gene-specific changes in DNA methylation and histone were analysed by bisulfite sequencing and chromatin immunoprecipitation (ChIP). The expression of PrRBCA and PrRBCS increased during needle maturation and was associated with the progressive loss of H3K9me3, H3K27me3 and the increase in AcH4. The maturation-related silencing of PrSHMT4 was correlated with increased H3K9me3 levels, and the repression of PrCSDP2, to the interplay between AcH4, H3K27me3, H3K9me3 and specific DNA methylation. The employ of HAT and HDAC inhibitors led to a further determination of the role of histone acetylation in the regulation of our target genes. The integration of these results with high-throughput analyses in Arabidopsis thaliana and Populus trichocarpa suggests that the specific epigenetic mechanisms that regulate photosynthetic genes are conserved between the analysed species.

Conserved Epigenetic Mechanisms Could Play a Key Role in Regulation of Photosynthesis and Development-Related Genes during Needle Development of Pinus radiata

PubMed Central

Meijón, Mónica; Escandón, Mónica; Cañal, María Jesús

2015-01-01

Needle maturation is a complex process that involves cell growth, differentiation and tissue remodelling towards the acquisition of full physiological competence. Leaf induction mechanisms are well known; however, those underlying the acquisition of physiological competence are still poorly understood, especially in conifers. We studied the specific epigenetic regulation of genes defining organ function (PrRBCS and PrRBCA) and competence and stress response (PrCSDP2 and PrSHMT4) during three stages of needle development and one de-differentiated control. Gene-specific changes in DNA methylation and histone were analysed by bisulfite sequencing and chromatin immunoprecipitation (ChIP). The expression of PrRBCA and PrRBCS increased during needle maturation and was associated with the progressive loss of H3K9me3, H3K27me3 and the increase in AcH4. The maturation-related silencing of PrSHMT4 was correlated with increased H3K9me3 levels, and the repression of PrCSDP2, to the interplay between AcH4, H3K27me3, H3K9me3 and specific DNA methylation. The employ of HAT and HDAC inhibitors led to a further determination of the role of histone acetylation in the regulation of our target genes. The integration of these results with high-throughput analyses in Arabidopsis thaliana and Populus trichocarpa suggests that the specific epigenetic mechanisms that regulate photosynthetic genes are conserved between the analysed species. PMID:25965766

Progesterone receptor knockout mice have an improved glucose homeostasis secondary to -cell proliferation

NASA Astrophysics Data System (ADS)

Picard, Frédéric; Wanatabe, Mitsuhiro; Schoonjans, Kristina; Lydon, John; O'Malley, Bert W.; Auwerx, Johan

2002-11-01

Gestational diabetes coincides with elevated circulating progesterone levels. We show that progesterone accelerates the progression of diabetes in female db/db mice. In contrast, RU486, an antagonist of the progesterone receptor (PR), reduces blood glucose levels in both female WT and db/db mice. Furthermore, female, but not male, PR-/- mice had lower fasting glycemia than PR+/+ mice and showed higher insulin levels on glucose injection. Pancreatic islets from female PR-/- mice were larger and secreted more insulin consequent to an increase in -cell mass due to an increase in -cell proliferation. These findings demonstrate an important role of progesterone signaling in insulin release and pancreatic function and suggest that it affects the susceptibility to diabetes.

Estrogen and progesterone receptors have distinct roles in the establishment of the hyperplastic phenotype in PR-A transgenic mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Simian, Marina; Bissell, Mina J.; Barcellos-Hoff, Mary Helen

2009-05-11

Expression of the A and B forms of progesterone receptor (PR) in an appropriate ratio is critical for mammary development. Mammary glands of PR-A transgenic mice, carrying an additional A form of PR as a transgene, exhibit morphological features associated with the development of mammary tumors. Our objective was to determine the roles of estrogen (E) and progesterone (P) in the genesis of mammary hyperplasias/preneoplasias in PR-A transgenics. We subjected PR-A mice to hormonal treatments and analyzed mammary glands for the presence of hyperplasias and used BrdU incorporation to measure proliferation. Quantitative image analysis was carried out to compare levelsmore » of latency-associated peptide and transforming growth factor beta 1 (TGF{beta}1) between PR-A and PR-B transgenics. Basement membrane disruption was examined by immunofluorescence and proteolytic activity by zymography. The hyperplastic phenotype of PR-A transgenics is inhibited by ovariectomy, and is reversed by treatment with E + P. Studies using the antiestrogen ICI 182,780 or antiprogestins RU486 or ZK 98,299 show that the increase in proliferation requires signaling through E/estrogen receptor alpha but is not sufficient to give rise to hyperplasias, whereas signaling through P/PR has little impact on proliferation but is essential for the manifestation of hyperplasias. Increased proliferation is correlated with decreased TGF{beta}1 activation in the PR-A transgenics. Analysis of basement membrane integrity showed loss of laminin-5, collagen III and collagen IV in mammary glands of PR-A mice, which is restored by ovariectomy. Examination of matrix metalloproteases (MMPs) showed that total levels of MMP-2 correlate with the steady-state levels of PR, and that areas of laminin-5 loss coincide with those of activation of MMP-2 in PR-A transgenics. Activation of MMP-2 is dependent on treatment with E and P in ovariectomized wild-type mice, but is achieved only by treatment with P in PR-A mice. These data establish a link between hormonal response, proliferation, modulation of MMP activity and maintenance of basement membrane integrity that depend on a balance in the expression levels of PR-A and PR-B isoforms. Notably, concomitant increased proliferation, due to inhibition of TGF{beta}1 activation, and loss of basement membrane integrity, via increased MMP-2 activity, appear to be prerequisites for the PR-A hyperplastic phenotype.« less

Cost-effectiveness of the highly effective direct-acting antivirals in the treatment of chronic hepatitis C in Hong Kong.

PubMed

Lo, Angeline Oi-Shan; Chan, Henry Lik-Yuen; Wong, Vincent Wai-Sun; Wong, Grace Lai-Hung

2017-05-01

In Asia-Pacific where cost is a major concern, peginterferon plus ribavirin (PR) often remain as the standard of care in chronic hepatitis C (CHC) treatment, while the direct-acting antivirals (DAAs) are commonly recommended as retreatment. Newer DAAs can achieve a sustained virological response (SVR) of nearly 100% with pan-genotypic coverage, that is "Highly Effective DAAs." We aimed to investigate the most desirable cost range for the Highly Effective DAAs using Hong Kong as an example. Markov modeling was performed using PR as the reference strategy. The cost-effectiveness of the Highly Effective DAAs was compared with sofosbuvir-PR (first-line and rescue) and boceprevir-PR therapies. A 50-year-old genotype 1b hepatitis C virus (HCV) infected treatment-naïve patient with METAVIR F3 was used as the base case scenario to reflect the commonest HCV genotype in Hong Kong. The use of PR would incur a lifetime cost of US$35,854 and effectiveness of 14.85 quality-adjusted life-year (QALY). Sofosbuvir-PR as first-line treatment was dominated by other regimes. If Sofosbuvir-PR rescue therapy was used, the drug cost of Highly Effective DAAs should be set below US$43,553, with a cost-effectiveness ratio (CER) of US$3035/QALY compared with PR. In regions where Boceprevir-PR was still used as first-line therapy, the desirable drug cost of Highly Effective DAAs would be below US$56,985 to achieve a CER of US$5427/QALY. The most desirable costs of the Highly Effective DAAs would be below US$43,553 if Sofosbuvir-PR rescue therapy is used and below US$56,985 if Boceprevir-PR therapy is used. © 2016 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

Prediction of tumor mutation burden in breast cancer based on the expression of ER, PR, HER-2, and Ki-67.

PubMed

Xu, Junnan; Guo, Xiangyu; Jing, Mingxi; Sun, Tao

2018-01-01

Cancer immunoediting is the process of eliminating highly immunogenic tumor cells by somatic evolution and protecting the host from tumor development in the host immune system. Frequencies of somatic mutations or tumor mutation burden (TMB) were associated with immunogenicity of breast cancer. This study aimed to predict the level of TMB in patients with breast cancer by the expression of estrogen (ER), progesterone (PR), HER-2, and Ki-67, thereby anticipating the prognosis of patients and the possible response to immunotherapy. In 53 patients with breast cancer, the 453 multigenes panel based on NGS was used to determine the TMB value of breast cancer in the patient's primary tumor tissues. The predicted TMB value was divided into 4 groups: A (0-3.33), B (3.33-5.56), C (5.56-8.89), and D (>8.89), according to the quartile method, with group A as reference level. Logistic regression was used to analyze the risk ratio of each molecule type, and the prediction model was established. Survival probabilities by covariates were assessed using Kaplan-Meier estimator survival analysis and Cox's proportional hazards models. In 53 patients, the TMB value measured by the NGS polygenic panel was between 0 and 14.4/Mb. TMB distribution in 53 cases of breast cancer tissue: 18 cases in A group, 22 cases in B group, 10 cases in C group, and 3 cases in D group. HER-2 expression positivity was significantly associated with TMB (HER-2 positive vs HER-2 negative, odds ratio [OR] =34.81, 95% confidence interval [CI]: 3.711-821.689, P =0.0065). Higher TMB was distributed in the patients who were Ki-67 expression positive (>14%) than those who were Ki-67 expression negative (≤14%) (OR =0.217, 95% CI: 0.054-0.806, P =0.0242). However, no significant differences of TMB were found between ER-positive group and ER-negative group (OR =3.133, 95% CI: 0.124-127.687, P =0.4954) and between PR-positive group and PR-negative group in terms of TMB (OR =1.702, 95% CI: 0.162-20.335, P =0.6492). The predicted model is TMB = -1.14×ER +0.53×PR +3.55×HER-2-1.53×Ki-67+ CONSTANT (INTERCEPT). Patients with low TMB had a better disease-free survival (DFS) than those with high TMB (83 vs 59 m, P =0.002). In a multivariate analysis, high TMB (>5.56) was an independent predictive factor for decreased DFS (adjusted hazard ratio [HR], 5.594; 95% CI: 1.694-18.473; P = 0.005). The preliminary results suggest that the level of TMB value in patients with breast cancer can be predicted based on the expression levels of ER, PR, HER-2, and Ki-67, which may indicate the prognostic and predictive value of immunotherapy in patients with breast cancer.

Stigma and Conspiracy Beliefs Related to Pre-exposure Prophylaxis (PrEP) and Interest in Using PrEP Among Black and White Men and Transgender Women Who Have Sex with Men

PubMed Central

Kalichman, Seth C.; Price, Devon; Finneran, Stephanie; Allen, Aerielle; Maksut, Jessica

2018-01-01

The HIV/AIDS epidemic in the US continues to persist, in particular, among race, sexual orientation, and gender minority populations. Pre-exposure prophylaxis (PrEP), or using antiretroviral medications for HIV prevention, is an effective option, but uptake of PrEP has been slow. Sociocultural barriers to using PrEP have been largely underemphasized, yet have the potential to stall uptake and, therefore, warrant further understanding. In order to assess the relationships between potential barriers to PrEP (i.e., PrEP stigma and conspiracy beliefs), and interest in PrEP, Black men and transgender women who have sex with men (BMTW, N = 85) and White MTW (WMTW, N = 179) were surveyed at a gay pride event in 2015 in a large southeastern US city. Bivariate and multivariate logistic regression analyses were completed to examine factors associated with PrEP interest. Among the full sample, moderate levels of PrEP awareness (63%) and low levels of use (9%) were observed. Believing that PrEP is for people who are promiscuous (stigma belief) was strongly associated with lack of interest in using PrEP, and individuals who endorsed this belief were more likely to report sexual risk taking behavior. Conspiracy beliefs related to PrEP were reported among a large minority of the sample (42%) and were more frequently reported among BMTW than WMTW. Given the strong emphasis on the use of biomedical strategies for HIV prevention, addressing sociocultural barriers to PrEP access is urgently needed and failure to do so will weaken the potential benefits of biomedical prevention. PMID:28108878

Resection of the large bowel suppresses hunger and food intake and modulates gastrointestinal fermentation.

PubMed

Hettiarachchi, Priyadarshika; Wickremasinghe, A Rajitha; Frost, Gary S; Deen, Kemal I; Pathirana, Ajith A; Murphy, Kevin G; Jayaratne, SriLal D

2016-08-01

To assess appetite and gut hormone levels in patients following partial (PR) or total resection (TR) of the large bowel. A comparative cross sectional study was carried out with healthy controls (n = 99) and patients who had undergone PR (n = 64) or TR (n = 12) of the large bowel. Participants consumed a standard (720 kcal) breakfast meal at 0830 (t = 0) h followed by lactulose (15 g) and a buffet lunch (t = 210 min). Participants rated the subjective feelings of hunger at t = -30, 0, 30, 60, 120, and 180 min. Breath hydrogen (BH) concentrations were also evaluated. In a matched subset (11 controls, 11 PR and 9 TR patients) PYY and GLP-1 concentrations were measured following breakfast. The primary outcome measure was appetite, as measured using visual analogue scales and the buffet lunch. The secondary outcome was BH concentrations following a test meal. PR and TR participants had lower hunger and energy intake at the buffet lunch meal compared to controls. PR subjects had higher BH concentrations compared to controls and TR subjects. BH levels correlated with circulating GLP-1 levels at specific time points. PR or TR of the large bowel reduced feelings of hunger and energy intake, and PR increased gastrointestinal fermentation. © 2016 The Obesity Society.

Use of care management practices in small- and medium-sized physician groups: do public reporting of physician quality and financial incentives matter?

PubMed

Alexander, Jeffrey A; Maeng, Daniel; Casalino, Lawrence P; Rittenhouse, Diane

2013-04-01

To examine the effect of public reporting (PR) and financial incentives tied to quality performance on the use of care management practices (CMPs) among small- and medium-sized physician groups. Survey data from The National Study of Small and Medium-sized Physician Practices were used. Primary data collection was also conducted to assess community-level PR activities. The final sample included 643 practices engaged in quality reporting; about half of these practices were subject to PR. We used a treatment effects model. The instrumental variables were the community-level variables that capture the level of PR activity in each community in which the practices operate. (1) PR is associated with increased use of CMPs, but the estimate is not statistically significant; (2) financial incentives are associated with greater use of CMPs; (3) practices' awareness/sensitivity to quality reports is positively related to their use of CMPs; and (4) combined PR and financial incentives jointly affect CMP use to a greater degree than either of these factors alone. Small- to medium-sized practices appear to respond to PR and financial incentives by greater use of CMPs. Future research needs to investigate the appropriate mix and type of incentive arrangements and quality reporting. © Health Research and Educational Trust.

Induction of salicylic acid-mediated defense response in perennial ryegrass against infection by Magnaporthe oryzae.

PubMed

Rahman, Alamgir; Kuldau, Gretchen A; Uddin, Wakar

2014-06-01

Incorporation of plant defense activators is an innovative approach to development of an integrated strategy for the management of turfgrass diseases. The effects of salicylic acid (SA), benzothiadiazole (BTH, chemical analog of SA), jasmonic acid (JA), and ethephon (ET, an ethylene-releasing compound) on development of gray leaf spot in perennial ryegrass (Lolium perenne L.) caused by Magnaporthe oryzae were evaluated. Gray leaf spot disease incidence and severity were significantly decreased when plants were treated prior to inoculation with SA, BTH, and partially by ET but not by JA. Accumulation of endogenous SA and elevated expression of pathogenesis-related (PR)-1, PR-3.1, and PR-5 genes were associated with inoculation of plants by M. oryzae. Treatment of plants with SA enhanced expression levels of PR-3.1 and PR-5 but did not affect the PR-1 level, whereas BTH treatment enhanced relative expression levels of all three PR genes. Microscopic observations of leaves inoculated with M. oryzae revealed higher frequencies of callose deposition at the penetration sites in SA- and BTH-treated plants compared with the control plants (treated with water). These results suggest that early and higher induction of these genes by systemic resistance inducers may provide perennial ryegrass with a substantial advantage to defend against infection by M. oryzae.

The prevalence of actinic cheilitis in farmers in a semi-arid northeastern region of Brazil.

PubMed

Martins-Filho, Paulo Ricardo Saquete; Da Silva, Luiz Carlos Ferreira; Piva, Marta Rabello

2011-09-01

Actinic cheilitis (AC) is a potentially malignant disorder of the lip caused by chronic exposure to solar radiation. Despite being a relatively common lesion in tropical countries, the data related to AC prevalence in Brazil are sparse, particularly in regions with high levels of ultraviolet radiation. To estimate AC prevalence among farmers in a semiarid northeastern Brazil. Cross-sectional study was carried out involving a representative sample (n = 240) of the farm workers. Sociodemographic, clinical, and histopathological variables were analyzed. AC prevalence was 16.7% [95% confidence interval (CI): 12.0% to 21.4%]. The disease was more prevalent in males [prevalence ratio (PR) = 2.72; 95% CI: 1.52-4.90], fair-skinned farmers (PR = 2.07; 95% CI: 1.00-4.30), age over 50 years (PR = 2.91; 95% CI: 1.40-6.04), daily exposure time more than eight hours (PR = 1.84; 95% CI: 1.03-3.27), and among smokers/ex-smokers (PR = 2.17; 95% CI: 1.22-3.87). Mantel-Haenszel test showed a positive relationship between cumulative exposure time and development of AC (P < 0.001). Two cases were diagnosed as microinvasive squamous cell carcinoma. Our results suggest that farmers in this semiarid area have a high risk of lip cancer and indicate the need for health public programs in the early detection of AC and education to teach the population about precautions to be taken during sun exposure. © 2011 The International Society of Dermatology.

The HIV-1 late domain-2 S40A polymorphism in antiretroviral (or ART)-exposed individuals influences protease inhibitor susceptibility.

PubMed

Watanabe, Susan M; Simon, Viviana; Durham, Natasha D; Kemp, Brittney R; Machihara, Satoshi; Kemal, Kimdar Sherefa; Shi, Binshan; Foley, Brian; Li, Hongru; Chen, Benjamin K; Weiser, Barbara; Burger, Harold; Anastos, Kathryn; Chen, Chaoping; Carter, Carol A

2016-09-06

The p6 region of the HIV-1 structural precursor polyprotein, Gag, contains two motifs, P7TAP11 and L35YPLXSL41, designated as late (L) domain-1 and -2, respectively. These motifs bind the ESCRT-I factor Tsg101 and the ESCRT adaptor Alix, respectively, and are critical for efficient budding of virus particles from the plasma membrane. L domain-2 is thought to be functionally redundant to PTAP. To identify possible other functions of L domain-2, we examined this motif in dominant viruses that emerged in a group of 14 women who had detectable levels of HIV-1 in both plasma and genital tract despite a history of current or previous antiretroviral therapy. Remarkably, variants possessing mutations or rare polymorphisms in the highly conserved L domain-2 were identified in seven of these women. A mutation in a conserved residue (S40A) that does not reduce Gag interaction with Alix and therefore did not reduce budding efficiency was further investigated. This mutation causes a simultaneous change in the Pol reading frame but exhibits little deficiency in Gag processing and virion maturation. Whether introduced into the HIV-1 NL4-3 strain genome or a model protease (PR) precursor, S40A reduced production of mature PR. This same mutation also led to high level detection of two extended forms of PR that were fairly stable compared to the WT in the presence of IDV at various concentrations; one of the extended forms was effective in trans processing even at micromolar IDV. Our results indicate that L domain-2, considered redundant in vitro, can undergo mutations in vivo that significantly alter PR function. These may contribute fitness benefits in both the absence and presence of PR inhibitor.

The future of pre-exposure prophylaxis (PrEP) for human immunodeficiency virus (HIV) infection.

PubMed

Özdener, Ayşe Elif; Park, Tae Eun; Kalabalik, Julie; Gupta, Rachna

2017-05-01

People at high risk for HIV acquisition should be offered pre-exposure prophylaxis (PrEP). Tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) is currently the only medication recommended for pre-exposure prophylaxis (PrEP) by the Centers for Disease Control and Prevention (CDC) in people at high risk for HIV acquisition. This article will review medications currently under investigation and the future landscape of PrEP therapy. Areas covered: This article will review clinical trials that have investigated nontraditional regimens of TDF/FTC, antiretroviral agents from different drug classes such as integrase strand transfer inhibitors (INSTI), nucleoside reverse transcriptase inhibitors (NRTI), and non-nucleoside reverse transcriptase inhibitors (NNRTI) as potential PrEP therapies. Expert commentary: Currently, there are several investigational drugs in the pipeline for PrEP against HIV infection. Increased utilization of PrEP therapy depends on provider identification of people at high risk for HIV transmission. Advances in PrEP development will expand options and access for people and reduce the risk of HIV acquisition.

High ambient temperature increases intravenous methamphetamine self-administration on fixed and progressive ratio schedules in rats.

PubMed

Cornish, Jennifer L; Clemens, Kelly J; Thompson, Murray R; Callaghan, Paul D; Dawson, Bronwyn; McGregor, Iain S

2008-01-01

Methamphetamine is a drug that is often consumed at dance parties or nightclubs where the ambient temperature is high. The present study determined whether such high ambient temperatures alter intravenous methamphetamine self-administration in the rat. Male Hooded Wistar rats were trained to self-administer intravenous methamphetamine (0.1 mg/kg/infusion) under a fixed ratio 1 (FR1) or progressive ratio (PR) schedule of reinforcement at an ambient temperature of 23 +/- 1 degrees C. They were then given their daily self-administration session at a raised ambient temperature of 30 +/- 1 degrees C. Methamphetamine self-administration was increased at 30 degrees C under both FR1 and PR reinforcement schedules, with the latter effect indicating that heat enhances the motivation to obtain methamphetamine. High temperatures did not alter self-administration of the D1 receptor agonist SKF 82958 in methamphetamine-experienced rats suggesting some specificity in the methamphetamine effect. When rats were given access to drink isotonic saline solution during methamphetamine self-administration sessions they drank much more solution at 30 degrees C than 23 degrees C. However, availability of isotonic saline to drink did not alter the heat-induced facilitation of methamphetamine self-administration (PR schedule) indicating that the heat effect does not simply reflect increased motivation for intravenous fluids. Hyperthermia was evident in rats self-administering methamphetamine at high ambient temperatures and fluid consumption did not prevent this effect. Heat did not affect blood levels of methamphetamine, or its principal metabolite amphetamine indicating that the facilitatory effect of heat did not reflect altered methamphetamine pharmacokinetics. Overall, these results show that high ambient temperatures increase the reinforcing efficacy of methamphetamine and encourage higher levels of drug intake.

Expression of nuclear progesterone receptor and progesterone receptor membrane components 1 and 2 in the oviduct of cyclic and pregnant cows during the post-ovulation period

PubMed Central

2012-01-01

Background Progesterone (P4) may modulate oviductal functions to promote early embryo development in cattle. In addition to its nuclear receptor (PR), P4 may mediate its actions through P4 receptor membrane component 1 (PGRMC1) and its relative, PGRMC2. Two successive experiments were undertaken to characterise the expression of PR, PGRMC1 and PGRMC2 in the bovine oviduct during the post-ovulation period, and to relate their expression to the presence of an embryo, the proximity of the CL and to the region of the oviduct. Methods In the first experiment (Exp. I), whole oviduct sections were collected from Holstein cows at Day 1.5, Day 4 and Day 5 post-ovulation (n = 2 cows per stage). The expression of PR, PGRMC1 and PGRMC2 was studied in the ampulla and isthmus by RT-PCR, western-blot and immunohistochemistry. In Exp. II, oviduct epithelial cells were collected from cyclic and pregnant Charolais cows (n = 4 cows per status) at Day 3.5 post-ovulation and mRNA expression of PR, PGRMC1 and PGRMC2 was examined in the ampulla and isthmus by real-time quantitative PCR. Results In Exp. I, PR, PGRMC1 and PGRMC2 were expressed in all oviduct samples. PGRMC1 was mainly localised in the luminal epithelium whereas PR and PGRMC2 were localised in the epithelium as well as in the muscle and stroma layers of the oviduct. The expression was primarily nuclear for PR, primarily cytoplasmic for PGRMC1 and both nuclear and cytoplasmic for PGRMC2. In Exp. II, mRNA levels for PR, PGRMC1 and PGRMC2 were not affected by either the pregnancy status or the side relative to the CL. However, the expression of PR and PGRMC2 varied significantly with the region of the oviduct: PR was more highly expressed in the isthmus whereas PGRMC2 was more highly expressed in the ampulla. Conclusions This is the first evidence of PGRMC2 expression in the bovine oviduct. Our findings suggest that P4 regulates the functions of the bovine oviduct in a region-specific manner and through both classical and non classical pathways during the post-ovulation period. PMID:22958265

Acceptability of microbicidal vaginal rings and oral pre-exposure prophylaxis for HIV prevention among female sex workers in a high-prevalence US city.

PubMed

Peitzmeier, Sarah M; Tomko, Catherine; Wingo, Erin; Sawyer, Anne; Sherman, Susan G; Glass, Nancy; Beyrer, Chris; Decker, Michele R

2017-11-01

Biomedical HIV prevention tools including oral pre-exposure prophylaxis (PrEP) and vaginal microbicidal rings hold unique value for high-risk women who may have limited capacity for condom negotiation, including the key populations of sex workers and drug users. Commercial sex is a PrEP indicator in CDC guidelines, yet little is known about female sex workers' (FSWs) knowledge of and attitudes toward PrEP or the recently developed monthly vaginal microbicide rings. We describe knowledge and attitudes toward PrEP and microbicide rings in a sample of 60 mostly drug-using FSWs in Baltimore, Maryland, a high HIV-prevalence US city. Just 33% had heard of PrEP, but 65% were interested in taking daily oral PrEP and 76% were interested in a microbicide vaginal ring; 87% were interested in at least one of the two methods. Results suggest method mix will be important as biomedical tools for HIV prophylaxis are implemented and scaled up in this population, as 12% were interested in PrEP but not vaginal rings, while 19% were interested in vaginal rings but not in PrEP. Self-efficacy for daily oral adherence was high (79%) and 78% were interested in using PrEP even if condoms were still necessary. Women who had experienced recent client-perpetrated violence were significantly more interested in PrEP (86% vs 53%, p = 0.009) and microbicidal rings (91% vs 65%, p = 0.028) than women who had not recently experienced violence. No differences were observed by demographics nor HIV risk behaviors, suggesting broad potential interest in daily PrEP and monthly-use vaginal microbicides in this high-risk population.

Normal Cellular Prion Protein Protects against Manganese-induced Oxidative Stress and Apoptotic Cell Death

PubMed Central

Choi, Christopher J.; Anantharam, Vellareddy; Saetveit, Nathan J.; Houk, Robert. S.; Kanthasamy, Arthi; Kanthasamy, Anumantha G.

2012-01-01

The normal prion protein is abundantly expressed in the CNS, but its biological function remains unclear. The prion protein has octapeptide repeat regions that bind to several divalent metals, suggesting that the prion proteins may alter the toxic effect of environmental neurotoxic metals. In the present study, we systematically examined whether prion protein modifies the neurotoxicity of manganese (Mn) by comparing the effect of Mn on mouse neural cells expressing prion protein (PrPC -cells) and prion-knockout (PrPKO -cells). Exposure to Mn (10 μM-1 mM) for 24 hr produced a dose-dependent cytotoxic response in both PrPC -cells and PrPKO -cells. Interestingly, PrPC -cells (EC50 117.6μM) were more resistant to Mn-induced cytotoxicity, as compared to PrPKO -cells (EC50 59.9μM), suggesting a protective role for PrPC against Mn neurotoxicity. Analysis of intracellular Mn levels showed less Mn accumulation in PrPC -cells as compared to PrPKO -cells. Furthermore, Mn-induced mitochondrial depolarization and ROS generation were significantly attenuated in PrPC -cells as compared to PrPKO -cells. Measurement of antioxidant status revealed similar basal levels of glutathione (GSH) in PrPC -cells and PrPKO -cells; however, Mn treatment caused greater depletion of GSH in PrPKO -cells. Mn-induced mitochondrial depolarization and ROS production were followed by time- and dose-dependent activation of the apoptotic cell death cascade involving caspase-9 and -3. Notably, DNA fragmentation induced by both Mn treatment and oxidative stress-inducer hydrogen peroxide (100μM) was significantly suppressed in PrPC -cells as compared to PrPKO -cells. Together, these results demonstrate that prion protein interferes with divalent metal Mn uptake and protects against Mn-induced oxidative stress and apoptotic cell death. PMID:17483122

91. World War II observation post, Cabarello level looking from ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

91. World War II observation post, Cabarello level looking from Carmen Bastion (similar to HABS PR-48-24) - Castillo de San Felipe del Morro, Northwest end of San Juan, San Juan, San Juan Municipio, PR

The cost-effectiveness of HIV pre-exposure prophylaxis in men who have sex with men and transgender women at high risk of HIV infection in Brazil.

PubMed

Luz, Paula M; Osher, Benjamin; Grinsztejn, Beatriz; Maclean, Rachel L; Losina, Elena; Stern, Madeline E; Struchiner, Claudio J; Parker, Robert A; Freedberg, Kenneth A; Mesquita, Fabio; Walensky, Rochelle P; Veloso, Valdilea G; Paltiel, A David

2018-03-01

Men who have sex with men (MSM) and transgender women (TGW) in Brazil experience high rates of HIV infection. We examined the clinical and economic outcomes of implementing a pre-exposure prophylaxis (PrEP) programme in these populations. We used the Cost-Effectiveness of Preventing AIDS Complications (CEPAC)-International model of HIV prevention and treatment to evaluate two strategies: the current standard of care (SOC) in Brazil, including universal ART access (No PrEP strategy); and the current SOC plus daily tenofovir/emtracitabine PrEP (PrEP strategy) until age 50. Mean age (31 years, SD 8.4 years), age-stratified annual HIV incidence (age ≤ 40 years: 4.3/100 PY; age > 40 years: 1.0/100 PY), PrEP effectiveness (43% HIV incidence reduction) and PrEP drug costs ($23/month) were from Brazil-based sources. The analysis focused on direct medical costs of HIV care. We measured the comparative value of PrEP in 2015 United States dollars (USD) per year of life saved (YLS). Willingness-to-pay threshold was based on Brazil's annual per capita gross domestic product (GDP; 2015: $8540 USD). Lifetime HIV infection risk among high-risk MSM and TGW was 50.5% with No PrEP and decreased to 40.1% with PrEP. PrEP increased per-person undiscounted (discounted) life expectancy from 36.8 (20.7) years to 41.0 (22.4) years and lifetime discounted HIV-related medical costs from $4100 to $8420, which led to an incremental cost-effectiveness ratio (ICER) of $2530/YLS. PrEP remained cost-effective (<1x GDP) under plausible variation in key parameters, including PrEP effectiveness and cost, initial cohort age and HIV testing frequency on/off PrEP. Daily tenofovir/emtracitabine PrEP among MSM and TGW at high risk of HIV infection in Brazil would increase life expectancy and be highly cost-effective. © 2018 The Authors. Journal of the International AIDS Society published by John Wiley & sons Ltd on behalf of the International AIDS Society.

PrP0\\0 mice show behavioral abnormalities that suggest PrPC has a role in maintaining the cytoskeleton.

USDA-ARS?s Scientific Manuscript database

Background/Introduction. PrPC is highly conserved among mammals, but its natural function is unclear. Prnp ablated mice (PrP0/0) appear to develop normally and are able to reproduce. These observations seem to indicate that the gene is not essential for viability, in spite of it being highly conse...

Improved Shoot Regeneration, Salinity Tolerance and Reduced Fungal Susceptibility in Transgenic Tobacco Constitutively Expressing PR-10a Gene.

PubMed

Agarwal, Parinita; Dabi, Mitali; More, Prashant; Patel, Khantika; Jana, Kalyanashis; Agarwal, Pradeep K

2016-01-01

Plants in ecosystems are simultaneously exposed to abiotic and biotic stresses, which restrict plant growth and development. The complex responses to these stresses are largely regulated by plant hormones, which in turn, orchestrate the different biochemical and molecular pathways to maneuver stress tolerance. The PR-10 protein family is reported to be involved in defense regulation, stress response and plant growth and development. The JcPR-10a overexpression resulted in increased number of shoot buds in tobacco (Nicotiana tabacum), which could be due to high cytokinin to auxin ratio in the transgenics. The docking analysis shows the binding of three BAP molecules at the active sites of JcPR-10a protein. JcPR-10a transgenics showed enhanced salt tolerance, as was evident by increased germination rate, shoot and root length, relative water content, proline, soluble sugar and amino acid content under salinity. Interestingly, the transgenics also showed enhanced endogenous cytokinin level as compared to WT, which, further increased with salinity. Exposure of gradual salinity resulted in increased stomatal conductance, water use efficiency, photosynthesis rate and reduced transpiration rate. Furthermore, the transgenics also showed enhanced resistance against Macrophomina fungus. Thus, JcPR-10a might be working in co-ordination with cytokinin signaling in mitigating the stress induced damage by regulating different stress signaling pathways, leading to enhanced stress tolerance.

Evaluating the impact of prioritization of antiretroviral pre-exposure prophylaxis (PrEP) in New York City

PubMed Central

Kessler, Jason; Myers, Julie E.; Nucifora, Kimberly A.; Mensah, Nana; Toohey, Christopher; Khademi, Amin; Cutler, Blayne; Braithwaite, R. Scott

2015-01-01

Objective To compare the value and effectiveness of different prioritization strategies of pre-exposure prophylaxis (PrEP) in New York City (NYC). Design Mathematical modeling utilized as clinical trial is not feasible. Methods Using a model accounting for both sexual and parenteral transmission of HIV we compare different prioritization strategies (PPS) for PrEP to two scenarios—no PrEP and PrEP for all susceptible at-risk individuals. The PPS included PrEP for all MSM, only high-risk MSM, high-risk heterosexuals, and injection drug users, and all combinations of these four strategies. Outcomes included HIV infections averted, and incremental cost effectiveness (per-infection averted) ratios. Initial assumptions regarding PrEP included a 44% reduction in HIV transmission, 50% uptake in the prioritized population and an annual cost per person of $9,762. Sensitivity analyses on key parameters were conducted. Results Prioritization to all MSM results in a 19% reduction in new HIV infections. Compared to PrEP for all persons at-risk this PPS retains 79% of the preventative effect at 15% of the total cost. PrEP prioritized to only high-risk MSM results in a reduction in new HIV infections of 15%. This PPS retains 60% of the preventative effect at 6% of the total cost. There are diminishing returns when PrEP utilization is expanded beyond this group. Conclusions PrEP implementation is relatively cost-inefficient under our initial assumptions. Our results suggest that PrEP should first be promoted among MSM who are at particularly high-risk of HIV acquisition. Further expansion beyond this group may be cost-effective, but is unlikely to be cost-saving. PMID:25493594

A dynamical systems model of progesterone receptor interactions with inflammation in human parturition.

PubMed

Brubaker, Douglas; Barbaro, Alethea; R Chance, Mark; Mesiano, Sam

2016-08-19

Progesterone promotes uterine relaxation and is essential for the maintenance of pregnancy. Withdrawal of progesterone activity and increased inflammation within the uterine tissues are key triggers for parturition. Progesterone actions in myometrial cells are mediated by two progesterone receptor (PR) isoforms, PR-A and PR-B, that function as ligand-activated transcription factors. PR-B mediates relaxatory actions of progesterone, in part, by decreasing myometrial cell responsiveness to pro-inflammatory stimuli. These same pro-inflammatory stimuli promote the expression of PR-A which inhibits the anti-inflammatory activity of PR-B. Competitive interaction between the progesterone receptors then augments myometrial responsiveness to pro-inflammatory stimuli. The interaction between PR-B transcriptional activity and inflammation in the pregnancy myometrium is examined using a dynamical systems model in which quiescence and labor are represented as phase-space equilibrium points. Our model shows that PR-B transcriptional activity and the inflammatory load determine the stability of the quiescent and laboring phenotypes. The model is tested using published transcriptome datasets describing the mRNA abundances in the myometrium before and after the onset of labor at term. Surrogate transcripts were selected to reflect PR-B transcriptional activity and inflammation status. The model coupling PR-B activity and inflammation predicts contractile status (i.e., laboring or quiescent) with high precision and recall and outperforms uncoupled single and two-gene classifiers. Linear stability analysis shows that phase space bifurcations exist in our model that may reflect the phenotypic states of the pregnancy uterus. The model describes a possible tipping point for the transition of the quiescent to the contractile laboring phenotype. Our model describes the functional interaction between the PR-A:PR-B hypothesis and tissue level inflammation in the pregnancy uterus and is a first step in more sophisticated dynamical systems modeling of human partition. The model explains observed biochemical dynamics and as such will be useful for the development of a range of systems-based models using emerging data to predict preterm birth and identify strategies for its prevention.

Beyond "getting drugs into bodies": social science perspectives on pre-exposure prophylaxis for HIV.

PubMed

Auerbach, Judith D; Hoppe, Trevor A

2015-01-01

Social scientists have much to contribute to the analysis of the real and potential contribution of pre-exposure prophylaxis (PrEP) to HIV prevention around the world. Beyond just a matter of clinical efficacy and getting pills into people's mouths, PrEP raises a number of important social-psychological questions that must be attended to in order to translate biomedical and clinical findings into uptake of PrEP among enough people at risk of HIV infection to produce population-level effectiveness. PrEP is a dynamic phenomenon with "dialectical" attributes that invite both optimism and cynicism as a desirable and effective HIV prevention strategy. PrEP disrupts traditional notions of "safe" and "unsafe" sex; it confers on its users a level of agency and control not generally achieved with condoms; and it affects sexual practices and sexual cultures in meaningful ways. As these dynamics play out in different contexts, and as new modes of PrEP administration emerge, it will be important for social scientists to be engaged in assessing their impact on PrEP implementation and effectiveness.

Progesterone receptor isoforms in the mammary gland of cats and dogs.

PubMed

Gracanin, A; de Gier, J; Zegers, K; Bominaar, M; Rutteman, G R; Schaefers-Okkens, A C; Kooistra, H S; Mol, J A

2012-12-01

Progesterone exerts its effect by binding to specific progesterone receptors (PR) within the cell. In dogs and cats, no data are available on PR isoforms as found in other species. We therefore investigated the sequence of the PR gene and encoded protein in dogs and cats, the expression of PR isoforms in mammary tissue using Western blots and the presence of PR in mammary tissue using immunohistochemistry. Comparison of the amino acid sequence of the canine and feline PR with human PR revealed major differences in the PR-B-specific upstream segment (BUS). However, the essential activation function 3 (AF3) domain was intact in the cat but mutated in the dog. The DNA and ligand-binding domains were highly similar among the species. In cats with fibroadenomatous hyperplasia (FAH), high expression of PR mRNA together with growth hormone (GH), GH receptor (GHR) and IGF-I mRNA was found in comparison with feline mammary carcinomas. Immunohistochemical analysis showed strong nuclear as well as cytoplasmic staining for PR in FAH. Western blot analysis revealed expression of the PR-A and PR-B isoforms in the feline mammary gland. In canine mammary tissue, the most abundant PR staining was found in proliferative zones of the mammary gland. Western blot analyses showed mainly staining for PR-A with lower PR-B staining. It is concluded that in dogs and cats both PR isoforms are expressed. The role of mutations found in the canine PR-B is discussed. © 2012 Blackwell Verlag GmbH.

High-affinity copper transport and Snq2 export permease of saccharomyces cerevisiae modulate cytotoxicity of PR-10 from Theobroma cacao.

PubMed

Pungartnik, Cristina; da Silva, Aline Clara; de Melo, Sarah Alves; Gramacho, Karina Peres; de Mattos Cascardo, Júlio Cézar; Brendel, Martin; Micheli, Fabienne; da Silva Gesteira, Abelmon

2009-01-01

A pathogenesis-related (PR) protein from Theobroma cacao (TcPR-10) was identified from a cacao-Moniliophthora perniciosa interaction cDNA library. Nucleotide and amino acid sequences showed homology with other PR-10 proteins having P loop motif and Betv1 domain. Recombinant TcPR-10 showed in vitro and in vivo ribonuclease activity, and antifungal activity against the basidiomycete cacao pathogen M. perniciosa and the yeast Saccharomyces cerevisiae. Fluorescein isothiocyanate-labeled TcPR-10 was internalized by M. perniciosa hyphae and S. cerevisiae cells and inhibited growth of both fungi. Energy and temperature-dependent internalization of the TcPR-10 suggested an active importation into the fungal cells. Chronical exposure to TcPR-10 of 29 yeast mutants with single gene defects in DNA repair, general membrane transport, metal transport, and antioxidant defenses was tested. Two yeast mutants were hyperresistant compared with their respective isogenic wild type: ctr3Delta mutant, lacking the high-affinity plasma membrane copper transporter and mac1Delta, the copper-sensing transcription factor involved in regulation of high-affinity copper transport. Acute exposure of exponentially growing yeast cells revealed that TcPR-10 resistance is also enhanced in the Snq2 export permease-lacking mutant which has reduced intracellular presence of TcPR-10.

HIV providers' likelihood to prescribe pre-exposure prophylaxis (PrEP) for HIV prevention differs by patient type: a short report.

PubMed

Adams, Leah M; Balderson, Benjamin H

2016-09-01

Pre-exposure prophylaxis (PrEP), the antiretroviral treatment regimen for HIV-negative people at high risk of acquiring HIV, has demonstrated efficacy across clinical trials in several patient populations. The Centers for Disease Control (CDC) have released detailed guidelines to aid providers in prescribing PrEP for their high-risk patients, including men who have sex with men (MSM), high-risk heterosexuals, and injection drug users (IDUs). Given that much attention in PrEP has focused on MSM patients, the present study used an online survey to assess factors involved in HIV care providers' (n = 363) decisions about prescribing PrEP, along with their willingness to prescribe PrEP to patients from various risk populations (e.g., MSM, heterosexuals, IDUs). The efficacy of PrEP was an important factor in providers' decisions about prescribing PrEP, as were considerations about patients' adherence to the regimen, regular follow-up for care, and medication costs. This survey's findings also suggest that providers' willingness to prescribe PrEP varies by patient group, with providers most willing to initiate the regimen with MSM who have an HIV-positive partner, and least willing to prescribe to high-risk heterosexuals or IDUs. In the context of the current CDC recommendations for PrEP that include MSM, heterosexuals, and IDUs, examining providers' rationales for and barriers against supporting this HIV prevention strategy across patient groups merits further attention.

Alignment of adherence and risk for HIV acquisition in a demonstration project of pre-exposure prophylaxis among HIV serodiscordant couples in Kenya and Uganda: a prospective analysis of prevention-effective adherence.

PubMed

Haberer, Jessica E; Kidoguchi, Lara; Heffron, Renee; Mugo, Nelly; Bukusi, Elizabeth; Katabira, Elly; Asiimwe, Stephen; Thomas, Katherine K; Celum, Connie; Baeten, Jared M

2017-07-25

Adherence is essential for pre-exposure prophylaxis (PrEP) to protect against HIV acquisition, but PrEP use need not be life-long. PrEP is most efficient when its use is aligned with periods of risk - a concept termed prevention-effective adherence. The objective of this paper is to describe prevention-effective adherence and predictors of adherence within an open-label delivery project of integrated PrEP and antiretroviral therapy (ART) among HIV serodiscordant couples in Kenya and Uganda (the Partners Demonstration Project). We offered PrEP to HIV-uninfected participants until the partner living with HIV had taken ART for ≥6 months (a strategy known as "PrEP as a bridge to ART"). The level of adherence sufficient to protect against HIV was estimated in two ways: ≥4 and ≥6 doses/week (per electronic monitoring). Risk for HIV acquisition was considered high if the couple reported sex with <100% condom use before six months of ART, low if they reported sex but had 100% condom use and/or six months of ART and very low if no sex was reported. We assessed prevention-effective adherence by cross-tabulating PrEP use with HIV risk and used multivariable regression models to assess predictors of ≥4 and ≥6 doses/week. Results A total of 985 HIV-uninfected participants initiated PrEP; 67% were male, median age was twenty-nine years, and 67% reported condomless sex in the month before enrolment. An average of ≥4 doses and ≥6 doses/week were taken in 81% and 67% of participant-visits, respectively. Adherence sufficient to protect against HIV acquisition was achieved in 75-88% of participant-visits with high HIV risk. The strongest predictor of achieving sufficient adherence was reporting sex with the study partner who was living with HIV; other statistically significant predictors included no concerns about daily PrEP, pregnancy or pregnancy intention, females aged >25 years, older male partners and desire for relationship success. Predictors of not achieving sufficient adherence were no longer being a couple, delayed PrEP initiation, >6 months  of follow-up, ART use >6 months  by the partner living with HIV and problem alcohol use. Over three-quarters of participant-visits by HIV-uninfected partners in serodiscordant couples achieved prevention-effective adherence with PrEP. Greater adherence was observed during months with HIV risk and the strongest predictor of achieving sufficient adherence was sexual activity.

The correlation between dental calculus and disturbed mineral metabolism in paediatric patients with chronic kidney disease.

PubMed

Davidovich, Esti; Davidovits, Miriam; Peretz, Benny; Shapira, Joseph; Aframian, Doron J

2009-08-01

Vascular calcifications have been documented in children with end-stage renal disease. However, only a few reports have described abundant dental calculus formation in children suffering from chronic kidney disease (CKD). Moreover, dental calculus scores (DCS) and their correlation with renal disease severity have not been studied. DCS in 74 young CKD patients were evaluated: 25 pre-dialytic (PrD), 18 on dialysis (D) and 31 with transplants (T) compared to 32 healthy participants (C). Saliva and serum analysis included creatinine (Cr), urea (U), calcium (Ca), phosphorous (P), magnesium (Mg) as well as intraoral pH levels. All patient groups presented high DCS. DCS and pH levels were higher in the D group with a positive correlation between pH and lower incisor DCS (r = 0.56, P = 0.017). The highest salivary Ca was found in the PrD group. Salivary P in the PrD group was found to be higher than in the T and C groups. The lowest salivary Mg was found in the D group while the highest salivary Ca x P product was found in the PrD group. In all patient groups, salivary U was higher than in the C group with a 2.5-fold increase in the D group. Salivary Cr resembled the U salivary concentrations. Alterations in salivary Ca, P, Mg, U, Cr and intraoral pH levels were observed in the patient groups. DCS correlated with renal disease severity and therefore may be a reflection of other tissue calcification pathologies found in these patients.

Highly Efficient Protein Misfolding Cyclic Amplification

PubMed Central

Ostapchenko, Valeriy G.; Savtchenk, Regina; Alexeeva, Irina; Rohwer, Robert G.; Baskakov, Ilia V.

2011-01-01

Protein misfolding cyclic amplification (PMCA) provides faithful replication of mammalian prions in vitro and has numerous applications in prion research. However, the low efficiency of conversion of PrPC into PrPSc in PMCA limits the applicability of PMCA for many uses including structural studies of infectious prions. It also implies that only a small sub-fraction of PrPC may be available for conversion. Here we show that the yield, rate, and robustness of prion conversion and the sensitivity of prion detection are significantly improved by a simple modification of the PMCA format. Conducting PMCA reactions in the presence of Teflon beads (PMCAb) increased the conversion of PrPC into PrPSc from ∼10% to up to 100%. In PMCAb, a single 24-hour round consistently amplified PrPSc by 600-700-fold. Furthermore, the sensitivity of prion detection in one round (24 hours) increased by 2-3 orders of magnitude. Using serial PMCAb, a 1012-fold dilution of scrapie brain material could be amplified to the level detectible by Western blotting in 3 rounds (72 hours). The improvements in amplification efficiency were observed for the commonly used hamster 263K strain and for the synthetic strain SSLOW that otherwise amplifies poorly in PMCA. The increase in the amplification efficiency did not come at the expense of prion replication specificity. The current study demonstrates that poor conversion efficiencies observed previously have not been due to the scarcity of a sub-fraction of PrPC susceptible to conversion nor due to limited concentrations of essential cellular cofactors required for conversion. The new PMCAb format offers immediate practical benefits and opens new avenues for developing fast ultrasensitive assays and for producing abundant quantities of PrPSc in vitro. PMID:21347353

Inactivation of the Progesterone Receptor in Mx1+ Cells Potentiates Osteogenesis in Calvaria but Not in Long Bone.

PubMed

Zhong, Zhendong A; Sun, Weihua; Chen, Haiyan; Zhang, Hongliang; Lane, Nancy E; Yao, Wei

2015-01-01

The effect of progesterone on bone remains elusive. We previously reported that global progesterone receptor (PR) knockout mice displayed high bone mass phenotype, suggesting that PR influences bone growth and modeling. Recently, Mx1+ cells were characterized to be mesenchymal stem cell-like pluripotent Cells. The aim of this study was to evaluate whether the PR in Mx1+ cells regulates osteogenesis. Using the Mx1-Cre;mT/mG reporter mouse model, we found that the calvarial cells exhibited minimal background Mx1-Cre activity prior to Cre activation by IFNα treatment as compared to the bone marrow stromal cells. IFNα treatment significantly activated Mx1-Cre in the calvarial cells. When the PR gene was deleted in the Mx1-Cre;PR-flox calvarial cells in vitro, significantly higher levels of expression of osteoblast maturation marker genes (RUNX2, Osteocalcin, and Dmp1) and osteogenic potential were detected. The PR-deficient calvariae exhibited greater bone volume, especially in the males. Although Mx1-Cre activity could be induced on the bone surface in vivo, the Mx1+ cells did not differentiate into osteocytes in long bones. Bone volumes at the distal femurs and the bone turnover marker serum Osteocalcin were similar between the Mx1-Cre;PR-flox mutant mice and the corresponding wild types in both sexes. In conclusion, our data demonstrates that blocking progesterone signaling via PRs in calvarial Mx1+ cells promoted osteoblast differentiation in the calvaria. Mx1+ was expressed by heterogeneous cells in bone marrow and did not differentiate into osteocyte during long bone development in vivo. Selectively inactivating the PR gene in Mx1+ cells affected the membrane bone formation but did not affect peripheral skeletal homeostasis.

Factorial inferential grid grouping and representativeness analysis for a systematic selection of representative grids

NASA Astrophysics Data System (ADS)

Cheng, Guanhui; Huang, Guohe; Dong, Cong; Xu, Ye; Yao, Yao

2017-08-01

A factorial inferential grid grouping and representativeness analysis (FIGGRA) approach is developed to achieve a systematic selection of representative grids in large-scale climate change impact assessment and adaptation (LSCCIAA) studies and other fields of Earth and space sciences. FIGGRA is applied to representative-grid selection for temperature (Tas) and precipitation (Pr) over the Loess Plateau (LP) to verify methodological effectiveness. FIGGRA is effective at and outperforms existing grid-selection approaches (e.g., self-organizing maps) in multiple aspects such as clustering similar grids, differentiating dissimilar grids, and identifying representative grids for both Tas and Pr over LP. In comparison with Pr, the lower spatial heterogeneity and higher spatial discontinuity of Tas over LP lead to higher within-group similarity, lower between-group dissimilarity, lower grid grouping effectiveness, and higher grid representativeness; the lower interannual variability of the spatial distributions of Tas results in lower impacts of the interannual variability on the effectiveness of FIGGRA. For LP, the spatial climatic heterogeneity is the highest in January for Pr and in October for Tas; it decreases from spring, autumn, summer to winter for Tas and from summer, spring, autumn to winter for Pr. Two parameters, i.e., the statistical significance level (α) and the minimum number of grids in every climate zone (Nmin), and their joint effects are significant for the effectiveness of FIGGRA; normalization of a nonnormal climate-variable distribution is helpful for the effectiveness only for Pr. For FIGGRA-based LSCCIAA studies, a low value of Nmin is recommended for both Pr and Tas, and a high and medium value of α for Pr and Tas, respectively.

Adherence to Pre-Exposure Prophylaxis for HIV Prevention in a Clinical Setting.

PubMed

Montgomery, Madeline C; Oldenburg, Catherine E; Nunn, Amy S; Mena, Leandro; Anderson, Peter; Liegler, Teri; Mayer, Kenneth H; Patel, Rupa; Almonte, Alexi; Chan, Philip A

2016-01-01

The HIV epidemic in the United States (US) disproportionately affects gay, bisexual, and other men who have sex with men (MSM). Pre-exposure prophylaxis (PrEP) using co-formulated tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) has demonstrated high efficacy in reducing HIV incidence among MSM. However, low adherence was reported in major efficacy trials and may present a substantial barrier to successful PrEP implementation. Rates of adherence to PrEP in "real-world" clinical settings in the US remain largely unknown. We reviewed demographic and clinical data for the first 50 patients to enroll in a clinical PrEP program in Providence, Rhode Island. We analyzed self-reported drug adherence as well as drug concentrations in dried blood spots (DBS) from patients who attended either a three- or six-month follow-up appointment. We further assessed drug concentrations and the resistance profile of a single patient who seroconverted while taking PrEP. Of the first 50 patients to be prescribed PrEP, 62% attended a follow-up appointment at three months and 38% at six months. Of those who attended an appointment at either time point (70%, n = 35), 92% and 95% reported taking ±4 doses/week at three and six months, respectively. Drug concentrations were performed on a random sample of 20 of the 35 patients who attended a follow-up appointment. TDF levels consistent with ±4 doses/week were found in 90% of these patients. There was a significant correlation between self-reported adherence and drug concentrations (r = 0.49, p = 0.02). One patient who had been prescribed PrEP seroconverted at his three-month follow-up visit. The patient's drug concentrations were consistent with daily dosing. Population sequencing and ultrasensitive allele-specific PCR detected the M184V mutation, but no other TDF- or FTC-associated mutations, including those present as minor variants. In this clinical PrEP program, adherence was high, and self-reported drug adherence accurately reflected drug concentrations as measured by DBS.

Gene and pathway level analyses of germline DNA-repair gene variants and prostate cancer susceptibility using the iCOGS-genotyping array.

PubMed

Saunders, Edward J; Dadaev, Tokhir; Leongamornlert, Daniel A; Al Olama, Ali Amin; Benlloch, Sara; Giles, Graham G; Wiklund, Fredrik; Gronberg, Henrik; Haiman, Christopher A; Schleutker, Johanna; Nordestgaard, Borge G; Travis, Ruth C; Neal, David; Pasayan, Nora; Khaw, Kay-Tee; Stanford, Janet L; Blot, William J; Thibodeau, Stephen N; Maier, Christiane; Kibel, Adam S; Cybulski, Cezary; Cannon-Albright, Lisa; Brenner, Hermann; Park, Jong Y; Kaneva, Radka; Batra, Jyotsna; Teixeira, Manuel R; Pandha, Hardev; Govindasami, Koveela; Muir, Ken; Easton, Douglas F; Eeles, Rosalind A; Kote-Jarai, Zsofia

2016-04-12

Germline mutations within DNA-repair genes are implicated in susceptibility to multiple forms of cancer. For prostate cancer (PrCa), rare mutations in BRCA2 and BRCA1 give rise to moderately elevated risk, whereas two of B100 common, low-penetrance PrCa susceptibility variants identified so far by genome-wide association studies implicate RAD51B and RAD23B. Genotype data from the iCOGS array were imputed to the 1000 genomes phase 3 reference panel for 21 780 PrCa cases and 21 727 controls from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. We subsequently performed single variant, gene and pathway-level analyses using 81 303 SNPs within 20 Kb of a panel of 179 DNA-repair genes. Single SNP analyses identified only the previously reported association with RAD51B. Gene-level analyses using the SKAT-C test from the SNP-set (Sequence) Kernel Association Test (SKAT) identified a significant association with PrCa for MSH5. Pathway-level analyses suggested a possible role for the translesion synthesis pathway in PrCa risk and Homologous recombination/Fanconi Anaemia pathway for PrCa aggressiveness, even though after adjustment for multiple testing these did not remain significant. MSH5 is a novel candidate gene warranting additional follow-up as a prospective PrCa-risk locus. MSH5 has previously been reported as a pleiotropic susceptibility locus for lung, colorectal and serous ovarian cancers.

Police trauma and cardiovascular disease: association between PTSD symptoms and metabolic syndrome.

PubMed

Violanti, John M; Fekedulegn, Desta; Hartley, Tara A; Andrew, Michael E; Charles, Luenda E; Mnatsakanova, Anna; Burchfiel, Cecil M

2006-01-01

Although prior evidence exists concerning the association between posttraumatic stress disorder (PTSD) and cardiovascular disease, few studies have examined associations of PTSD symptomatology and the metabolic syndrome in the high stress occupation of police work. The metabolic syndrome is a clustering of cardiovascular disease risk factors that have also been independently associated with psychological conditions. The aim of this study was to examine associations between the PTSD symptoms and metabolic syndrome in police officers. A stratified sample of 115 police officers was randomly selected from the Buffalo, NY Police Department. PTSD symptoms were measured with the Impact of Event scale (IES), divided into categories of subclinical, mild, moderate and severe symptom levels. The metabolic syndrome was considered present if three or more of its component parameters (obesity, elevated blood pressure, reduced high density lipoprotein (HDL) cholesterol, elevated triglycerides, and abnormal glucose levels) were present in each officer. Results indicated a significantly increased prevalence of the metabolic syndrome among those officers in the severe PTSD symptom category compared with the lowest PTSD severity category (prevalence ratio (PR) = 3.31, 95% C.I. = 1.19 - 9.22). Adjustment for age did not alter the association appreciably (PR = 3.12, 95% C.I. = 1.15 - 8.50). Adjustment for several demographic and lifestyle factors (age, education, smoking, alcohol intake) reduced the magnitude of the prevalence ratio slightly for the severe versus subclinical PTSD category (PR = 2.69, 95% C.I. = 0. 79 - 9.13), with adjustment for age and education accounting for most of the attenuation (PR = 2.71, 95% C.I. = 0.99 - 7.37). Thus, officers with severe PTSD symptoms were approximately three times more likely to have the metabolic syndrome and education may account for some of this association.

Enhanced expression of cro-beta-galactosidase fusion proteins under the control of the PR promoter of bacteriophage lambda.

PubMed Central

Zabeau, M; Stanley, K K

1982-01-01

Hybrid plasmids carrying cro-lacZ gene fusions have been constructed by joining DNA segments carrying the PR promoter and the start of the cro gene of bacteriophage lambda to the lacZ gene fragment carried by plasmid pLG400 . Plasmids in which the translational reading frames of the cro and lacZ genes are joined in-register (type I) direct the synthesis of elevated levels of cro-beta-galactosidase fusion protein amounting to 30% of the total cellular protein, while plasmids in which the genes are fused out-of-register (type II) produce a low level of beta-galactosidase protein. Sequence rearrangements downstream of the cro initiator AUG were found to influence the efficiency of translation, and have been correlated with alterations in the RNA secondary structure of the ribosome-binding site. Plasmids which direct the synthesis of high levels of beta-galactosidase are conditionally lethal and can only be propagated when the PR promoter is repressed. Deletion of sequences downstream of the lacZ gene restored viability, indicating that this region of the plasmid encodes a function which inhibits the growth of the cells. The different applications of these plasmids for expression of cloned genes are discussed. Images Fig. 6. PMID:6327257

Rab27a controls HIV-1 assembly by regulating plasma membrane levels of phosphatidylinositol 4,5-bisphosphate

PubMed Central

Gerber, Pehuén Pereyra; Cabrini, Mercedes; Jancic, Carolina; Paoletti, Luciana; Banchio, Claudia; von Bilderling, Catalina; Sigaut, Lorena; Pietrasanta, Lía I.; Duette, Gabriel; Freed, Eric O.; de Saint Basile, Genevieve; Moita, Catarina Ferreira; Moita, Luis Ferreira; Amigorena, Sebastian; Benaroch, Philippe; Geffner, Jorge

2015-01-01

During the late stages of the HIV-1 replication cycle, the viral polyprotein Pr55Gag is recruited to the plasma membrane (PM), where it binds phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) and directs HIV-1 assembly. We show that Rab27a controls the trafficking of late endosomes carrying phosphatidylinositol 4-kinase type 2 α (PI4KIIα) toward the PM of CD4+ T cells. Hence, Rab27a promotes high levels of PM phosphatidylinositol 4-phosphate and the localized production of PI(4,5)P2, therefore controlling Pr55Gag membrane association. Rab27a also controls PI(4,5)P2 levels at the virus-containing compartments of macrophages. By screening Rab27a effectors, we identified that Slp2a, Slp3, and Slac2b are required for the association of Pr55Gag with the PM and that Slp2a cooperates with Rab27a in the recruitment of PI4KIIα to the PM. We conclude that by directing the trafficking of PI4KIIα-positive endosomes toward the PM, Rab27a controls PI(4,5)P2 production and, consequently, HIV-1 replication. PMID:25940347

Dynamic compressive behavior of Pr-Nd alloy at high strain rates and temperatures

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang Huanran; Cai Canyuan; Chen Danian

2012-07-01

Based on compressive tests, static on 810 material test system and dynamic on the first compressive loading in split Hopkinson pressure bar (SHPB) tests for Pr-Nd alloy cylinder specimens at high strain rates and temperatures, this study determined a J-C type [G. R. Johnson and W. H. Cook, in Proceedings of Seventh International Symposium on Ballistics (The Hague, The Netherlands, 1983), pp. 541-547] compressive constitutive equation of Pr-Nd alloy. It was recorded by a high speed camera that the Pr-Nd alloy cylinder specimens fractured during the first compressive loading in SHPB tests at high strain rates and temperatures. From highmore » speed camera images, the critical strains of the dynamic shearing instability for Pr-Nd alloy in SHPB tests were determined, which were consistent with that estimated by using Batra and Wei's dynamic shearing instability criterion [R. C. Batra and Z. G. Wei, Int. J. Impact Eng. 34, 448 (2007)] and the determined compressive constitutive equation of Pr-Nd alloy. The transmitted and reflected pulses of SHPB tests for Pr-Nd alloy cylinder specimens computed with the determined compressive constitutive equation of Pr-Nd alloy and Batra and Wei's dynamic shearing instability criterion could be consistent with the experimental data. The fractured Pr-Nd alloy cylinder specimens of compressive tests were investigated by using 3D supper depth digital microscope and scanning electron microscope.« less

Plasmatic antioxidant capacity due to ascorbate using TEMPO scavenging and electron spin resonance.

PubMed

Piehl, Lidia L; Facorro, Graciela B; Huarte, Mónica G; Desimone, Martín F; Copello, Guillermo J; Díaz, Luis E; de Celis, Emilio Rubín

2005-09-01

Ascorbate is the most effective water-soluble antioxidant and its plasma concentration is usually measured by different methods including colorimetric assays, HPLC or capillary electrophoresis. Plasma antioxidant capacity is determined by indexes such as total reactive antioxidant potential, total antioxidant reactivity, oxygen radical absorbance capacity, etc. We developed an alternative method for the evaluation of the plasma antioxidant status due to ascorbate. TEMPO kinetics scavenging analyzed by ESR spectroscopy was performed on plasma samples in different antioxidant situations. Plasma ascorbate concentrations were determined by capillary electrophoresis. Ascorbyl radical levels were measured by ESR. Plasma reactivity with TEMPO (PR-T) reflected plasma ascorbate levels. Average PR-T for normal plasmas resulted 85+/-27 micromol/l (n=43). PR-T during ascorbic acid intake (1 g/day) increased to an average value of 130+/-20 micromol/l (p<0.001, n=20). PR-T correlated with the plasmatic ascorbate levels determined by capillary electrophoresis (r=0.92), presenting as an advantage the avoiding of the deproteination step. Plasma ascorbyl radical levels increase from 16+/-2 to 24+/-3 nmol/l (p<0.005, n=14) after ascorbate intake. PR-T could be considered as a measure of the plasmatic antioxidant capacity due to the plasma ascorbate levels and could be useful to investigate different antioxidant situations.

Modulation of Progesterone Receptor Isoform Expression in Pregnant Human Myometrium

PubMed Central

2017-01-01

Background. Regulation of myometrial progesterone receptor (PR) expression is an unresolved issue central to understanding the mechanism of functional progesterone withdrawal and initiation of labor in women. Objectives. To determine whether pregnant human myometrium undergoes culture-induced changes in PR isoform expression ex situ and, further, to determine if conditions approaching the in vivo environment stabilise PR isoform expression in culture. Methods. Term nonlaboring human myometrial tissues were cultured under specific conditions: serum supplementation, steroids, stretch, cAMP, PMA, PGF2α, NF-κB inhibitors, or TSA. Following 48 h culture, PR-T, PR-A, and PR-B mRNA levels were determined using qRT-PCR. PR-A/PR-B ratios were calculated. Results. PR-T and PR-A expression and the PR-A/PR-B ratio significantly increased in culture. Steroids prevented the culture-induced increase in PR-T and PR-A expression. Stretch blocked the effects of steroids on PR-T and PR-A expression. PMA further increased the PR-A/PR-B ratio, while TSA blocked culture-induced increases of PR-A expression and the PR-A/PR-B ratio. Conclusion. Human myometrial tissue in culture undergoes changes in PR gene expression consistent with transition toward a laboring phenotype. TSA maintained the nonlaboring PR isoform expression pattern. This suggests that preserving histone and/or nonhistone protein acetylation is critical for maintaining the progesterone dependent quiescent phenotype of human myometrium in culture. PMID:28540297

Use of an HIV-risk screening tool to identify optimal candidates for PrEP scale-up among men who have sex with men in Toronto, Canada: disconnect between objective and subjective HIV risk.

PubMed

Wilton, James; Kain, Taylor; Fowler, Shawn; Hart, Trevor A; Grennan, Troy; Maxwell, John; Tan, Darrell Hs

2016-01-01

Identifying appropriate pre-exposure prophylaxis (PrEP) candidates is a challenge in planning for the safe and effective roll-out of this strategy. We explored the use of a validated HIV risk screening tool, HIV Incidence Risk Index for Men who have Sex with Men (HIRI-MSM), to identify "optimal" candidates among MSM testing at a busy sexual health clinic's community testing sites in Toronto, Canada. Between November 2014 and April 2015, we surveyed MSM undergoing anonymous HIV testing at community testing sites in Toronto, Canada, to quantify "optimal" candidates for scaling up PrEP roll-out, defined as being at high objective HIV risk (scoring ≥10 on the HIRI-MSM), perceiving oneself at moderate-to-high HIV risk and being willing to use PrEP. Cascades were constructed to identify barriers to broader PrEP uptake. The association between HIRI-MSM score and both willingness to use PrEP and perceived HIV risk were explored in separate multivariable logistic regression analyses. Of 420 respondents, 64.4% were objectively at high risk, 52.5% were willing to use PrEP and 27.2% perceived themselves at moderate-to-high HIV risk. Only 16.4% were "optimal" candidates. Higher HIRI-MSM scores were positively associated with both willingness to use PrEP (aOR=1.7 per 10 score increase, 95%CI=1.3-2.2) and moderate-to-high perceived HIV risk (aOR=1.7 per 10 score increase, 95%CI=1.2-2.3). The proportion of men who were "optimal" candidates increased to 42.9% when the objective HIV risk cut-off was changed to top quartile of HIRI-MSM scores (≥26). In our full cascade, a very low proportion (5.3%) of MSM surveyed could potentially benefit from PrEP under current conditions. The greatest barrier in the cascade was low perception of HIV risk among high-risk men, but considerable numbers were also lost in downstream cascade steps. Of men at high objective HIV risk, 68.3% did not perceive themselves to be at moderate-to-high HIV risk, 23.6% were unaware of PrEP, 40.1% were not willing to use PrEP, 47.6% lacked a family physician with whom they felt comfortable discussing sexual health, and 31.6% had no means to cover the cost of PrEP. A higher HIRI-MSM cut-off may be helpful for identifying candidates for PrEP scale-up. Improving engagement in the PrEP cascade will require interventions to simultaneously address multiple barriers.

Use of an HIV-risk screening tool to identify optimal candidates for PrEP scale-up among men who have sex with men in Toronto, Canada: disconnect between objective and subjective HIV risk

PubMed Central

Wilton, James; Kain, Taylor; Fowler, Shawn; Hart, Trevor A; Grennan, Troy; Maxwell, John; Tan, Darrell HS

2016-01-01

Introduction Identifying appropriate pre-exposure prophylaxis (PrEP) candidates is a challenge in planning for the safe and effective roll-out of this strategy. We explored the use of a validated HIV risk screening tool, HIV Incidence Risk Index for Men who have Sex with Men (HIRI-MSM), to identify “optimal” candidates among MSM testing at a busy sexual health clinic's community testing sites in Toronto, Canada. Methods Between November 2014 and April 2015, we surveyed MSM undergoing anonymous HIV testing at community testing sites in Toronto, Canada, to quantify “optimal” candidates for scaling up PrEP roll-out, defined as being at high objective HIV risk (scoring ≥10 on the HIRI-MSM), perceiving oneself at moderate-to-high HIV risk and being willing to use PrEP. Cascades were constructed to identify barriers to broader PrEP uptake. The association between HIRI-MSM score and both willingness to use PrEP and perceived HIV risk were explored in separate multivariable logistic regression analyses. Results Of 420 respondents, 64.4% were objectively at high risk, 52.5% were willing to use PrEP and 27.2% perceived themselves at moderate-to-high HIV risk. Only 16.4% were “optimal” candidates. Higher HIRI-MSM scores were positively associated with both willingness to use PrEP (aOR=1.7 per 10 score increase, 95%CI=1.3–2.2) and moderate-to-high perceived HIV risk (aOR=1.7 per 10 score increase, 95%CI=1.2–2.3). The proportion of men who were “optimal” candidates increased to 42.9% when the objective HIV risk cut-off was changed to top quartile of HIRI-MSM scores (≥26). In our full cascade, a very low proportion (5.3%) of MSM surveyed could potentially benefit from PrEP under current conditions. The greatest barrier in the cascade was low perception of HIV risk among high-risk men, but considerable numbers were also lost in downstream cascade steps. Of men at high objective HIV risk, 68.3% did not perceive themselves to be at moderate-to-high HIV risk, 23.6% were unaware of PrEP, 40.1% were not willing to use PrEP, 47.6% lacked a family physician with whom they felt comfortable discussing sexual health, and 31.6% had no means to cover the cost of PrEP. Conclusions A higher HIRI-MSM cut-off may be helpful for identifying candidates for PrEP scale-up. Improving engagement in the PrEP cascade will require interventions to simultaneously address multiple barriers. PMID:27265490

The Oxidant and Antioxidant Status in Pityriasis Rosea

PubMed Central

Emre, Selma; Akoglu, Gulsen; Metin, Ahmet; Demirseren, Duriye Deniz; Isikoglu, Semra; Oztekin, Aynure; Erel, Ozcan

2016-01-01

Background: Pityriasis rosea (PR) is usually an asymptomatic and self-limiting papulosquamous skin disease with acute onset. The etiology has not been clarified yet. Recently, increased oxidative stress was found to play a role in etiopathogenesis of multiple cutaneous diseases with T cell-mediated immune response. However, there are no studies demonstrating the oxidative stress status in PR. Aim: The aim of the study is to determine the status of oxidative stress (OS) and paraoxonase (PON) 1/arylesterase enzyme activities in PR. Materials and Methods: Study included 51 patients with active PR lesions, and 45 healthy volunteers. Serum levels of total oxidant status (TOS), total antioxidant status (TAS), and PON1/arylesterase (ARES) activity were determined and oxidative stress index (OSI) was calculated in all patients and controls. Results: TAS levels and ARES activities in the patient group were significantly lower than the control group. On the other hand, TOS and OSI levels were significantly higher in patients compared with controls. There was no significant correlation between the duration of disease and TAS, TOS, OSI levels, and ARES activities. Conclusion: A systemic oxidative stress exists in PR, which suggests that OS may be involved in the etiopathogenesis of disease. PMID:26955119

Salicylic acid-dependent and -independent impact of an RNA-binding protein on plant immunity.

PubMed

Hackmann, Christian; Korneli, Christin; Kutyniok, Magdalene; Köster, Tino; Wiedenlübbert, Matthias; Müller, Caroline; Staiger, Dorothee

2014-03-01

Plants overexpressing the RNA-binding protein AtGRP7 (AtGRP7-ox plants) constitutively express the PR-1 (PATHOGENESIS-RELATED-1), PR-2 and PR-5 transcripts associated with salicylic acid (SA)-mediated immunity and show enhanced resistance against Pseudomonas syringae pv. tomato (Pto) DC3000. Here, we investigated whether the function of AtGRP7 in plant immunity depends on SA. Endogenous SA was elevated fivefold in AtGRP7-ox plants. The elevated PR-1, PR-2 and PR-5 levels were eliminated upon expression of the salicylate hydroxylase nahG in AtGRP7-ox plants and elevated PR-1 levels were suppressed by sid (salicylic acid deficient) 2-1 that is impaired in SA biosynthesis. RNA immunoprecipitation showed that AtGRP7 does not bind the PR-1 transcript in vivo, whereas it binds PDF1.2. Constitutive or inducible AtGRP7 overexpression increases PR-1 promoter activity, indicating that AtGRP7 affects PR-1 transcription. In line with this, the effect of AtGRP7 on PR-1 is suppressed by npr (non-expressor of PR genes) 1. Whereas AtGRP7-ox plants restricted growth of Pto DC3000 compared with wild type (wt), sid2-1 AtGRP7-ox plants allowed more growth than AtGRP7-ox plants. Furthermore, we show an enhanced hypersensitive response triggered by avirulent Pto DC3000 (AvrRpt2) in AtGRP7-ox compared with wt. In sid2-1 AtGRP7-ox, an intermediate phenotype was observed. Thus, AtGRP7 has both SA-dependent and SA-independent effects on plant immunity. © 2013 John Wiley & Sons Ltd.

Correlation between Infectivity and Disease Associated Prion Protein in the Nervous System and Selected Edible Tissues of Naturally Affected Scrapie Sheep

PubMed Central

Chianini, Francesca; Cosseddu, Gian Mario; Steele, Philip; Hamilton, Scott; Hawthorn, Jeremy; Síso, Sílvia; Pang, Yvonne; Finlayson, Jeanie; Eaton, Samantha L.; Reid, Hugh W.; Dagleish, Mark P.; Di Bari, Michele Angelo; D’Agostino, Claudia; Agrimi, Umberto; Terry, Linda; Nonno, Romolo

2015-01-01

The transmissible spongiform encephalopathies (TSEs) or prion diseases are a group of fatal neurodegenerative disorders characterised by the accumulation of a pathological form of a host protein known as prion protein (PrP). The validation of abnormal PrP detection techniques is fundamental to allow the use of high-throughput laboratory based tests, avoiding the limitations of bioassays. We used scrapie, a prototype TSE, to examine the relationship between infectivity and laboratory based diagnostic tools. The data may help to optimise strategies to prevent exposure of humans to small ruminant TSE material via the food chain. Abnormal PrP distribution/accumulation was assessed by immunohistochemistry (IHC), Western blot (WB) and ELISA in samples from four animals. In addition, infectivity was detected using a sensitive bank vole bioassay with selected samples from two of the four sheep and protein misfolding cyclic amplification using bank vole brain as substrate (vPMCA) was also carried out in selected samples from one animal. Lymph nodes, oculomotor muscles, sciatic nerve and kidney were positive by IHC, WB and ELISA, although at levels 100–1000 fold lower than the brain, and contained detectable infectivity by bioassay. Tissues not infectious by bioassay were also negative by all laboratory tests including PMCA. Although discrepancies were observed in tissues with very low levels of abnormal PrP, there was an overall good correlation between IHC, WB, ELISA and bioassay results. Most importantly, there was a good correlation between the detection of abnormal PrP in tissues using laboratory tests and the levels of infectivity even when the titre was low. These findings provide useful information for risk modellers and represent a first step toward the validation of laboratory tests used to quantify prion infectivity, which would greatly aid TSE risk assessment policies. PMID:25807559

Immunization of pigs with an attenuated pseudorabies virus recombinant expressing the haemagglutinin of pandemic swine origin H1N1 influenza A virus.

PubMed

Klingbeil, Katharina; Lange, Elke; Teifke, Jens P; Mettenleiter, Thomas C; Fuchs, Walter

2014-04-01

Pigs can be severely harmed by influenza, and represent important reservoir hosts, in which new human pathogens such as the recent pandemic swine-origin H1N1 influenza A virus can arise by mutation and reassortment of genome segments. To obtain novel, safe influenza vaccines for pigs, and to investigate the antigen-specific immune response, we modified an established live-virus vaccine against Aujeszky's disease of swine, pseudorabies virus (PrV) strain Bartha (PrV-Ba), to serve as vector for the expression of haemagglutinin (HA) of swine-origin H1N1 virus. To facilitate transgene insertion, the genome of PrV-Ba was cloned as a bacterial artificial chromosome. HA expression occurred under control of the human or murine cytomegalovirus immediate early promoters (P-HCMV, P-MCMV), but could be substantially enhanced by synthetic introns and adaptation of the codon usage to that of PrV. However, despite abundant expression, the heterologous glycoprotein was not detectably incorporated into mature PrV particles. Replication of HA-expressing PrV in cell culture was only slightly affected compared to that of the parental virus strain. A single immunization of pigs with the PrV vector expressing the codon-optimized HA gene under control of P-MCMV induced high levels of HA-specific antibodies. The vaccinated animals were protected from clinical signs after challenge with a related swine-origin H1N1 influenza A virus, and challenge virus shedding was significantly reduced.

Chemotherapy and plasma adipokines level in patients with colorectal cancer.

PubMed

Słomian, Grzegorz; Świętochowska, Elżbieta; Nowak, Grzegorz; Pawlas, Krystyna; Żelazko, Aleksandra; Nowak, Przemysław

2017-04-12

Adipokines are molecules produced and secreted by adipose tissue and are linked to multiple malignancies. Adipokines can suppress or promote particular cell behaviors in different types of cancer. The aim of this study was to investigate the impact of chemotherapy on select adipokines in patients with colorectal cancer (CRC). Blood samples were collected from 42 patients with pathologically documented advanced CRC, who required palliative chemotherapy. Leptin, adiponectin, resistin and visfatin levels were measured by ELISA before and 3 months after the administration of chemotherapy. Among the 42 patients evaluated, 18 achieved a partial response (PR), 16 achieved stable disease (SD) and 8 patients experienced disease progression (PD). We found that 5-fluorouracil-based chemotherapy regimens significantly increased plasma levels of leptin and adiponectin and decreased plasma levels of resistin and visfatin in PR and SD patients, whereas the plasma levels of these molecules were not affected in PD patients. Furthermore, the mean plasma levels of leptin were significantly lower, and the mean plasma levels of resistin and visfatin were significantly greater in patients with PD compared with PR and SD both before and after chemotherapy treatment. We conclude that palliative chemotherapy in CRC patients, in addition to providing clinical benefits, positively affects cytokine production and secretion in PR and SD patients. Specifically, we found that palliative chemotherapy increased plasma levels of the anti-inflammatory adipokine adiponectin and decreased the plasma levels of visfatin and resistin, molecules known to promote angiogenesis and cancer cell proliferation in PR and SD patients. Moreover, the baseline values of leptin, visfatin and resistin might serve as prognostic indicators of a poor response to chemotherapy.

Educational health disparities in hypertension and diabetes mellitus among African descent populations in the Caribbean and the USA: a comparative analysis from the Spanish town cohort (Jamaica) and the Jackson heart study (USA).

PubMed

Bidulescu, Aurelian; Ferguson, Trevor S; Hambleton, Ian; Younger-Coleman, Novie; Francis, Damian; Bennett, Nadia; Griswold, Michael; Fox, Ervin; MacLeish, Marlene; Wilks, Rainford; Harris, E Nigel; Sullivan, Louis W

2017-02-14

Studies have suggested that social inequalities in chronic disease outcomes differ between industrialized and developing countries, but few have directly compared these effects. We explored inequalities in hypertension and diabetes prevalence between African-descent populations with different levels of educational attainment in Jamaica and in the United States of America (USA), comparing disparities within each location, and between countries. We analyzed baseline data from the Jackson Heart Study (JHS) in the USA and Spanish Town Cohort (STC) in Jamaica. Participants reported their highest level of educational attainment, which was categorized as 'less than high school' (HS). Educational disparities in the prevalence of hypertension and diabetes were examined using prevalence ratios (PR), controlling for age, sex and body mass index (BMI). Analyses included 7248 participants, 2382 from STC and 4866 from JHS, with mean age of 47 and 54 years, respectively (p < 0.001). Prevalence for both hypertension and diabetes was significantly higher in the JHS compared to STC, 62% vs. 25% (p < 0.001) and 18% vs. 13% (p < 0.001), respectively. In bivariate analyses there were significant disparities by education level for both hypertension and diabetes in both studies; however, after accounting for confounding or interaction by age, sex and BMI these effects were attenuated. For hypertension, after adjusting for age and BMI, a significant education disparity was found only for women in JHS, with PR of 1.10 (95% CI 1.04-1.16) for < HS vs > HS and 1.07 (95% CI 1.01-1.13) for HS vs > HS. For diabetes; when considering age-group and sex specific estimates adjusted for BMI, among men: significant associations were seen only in the 45-59 years age-group in JHS with PR 1.84 (95% CI 1.16-2.91) for < HS vs > HS. Among women, significant PR comparing < HS to > HS was seen for all three age-groups for JHS, but not in STC; PR were 3.95 (95% CI 1.94-8.05), 1.53 (95% CI 1.10-2.11) and 1.32 (95% CI 1.06-1.64) for 25-44, 45-59 and 60-74 age-groups, respectively. In Jamaica, educational disparities were largely explained by age, sex and BMI, while in the USA these disparities were larger and persisted after accounting these variables.

Minihepcidins prevent iron overload in a hepcidin-deficient mouse model of severe hemochromatosis

PubMed Central

Ramos, Emilio; Ruchala, Piotr; Goodnough, Julia B.; Kautz, Léon; Preza, Gloria C.; Nemeth, Elizabeta

2012-01-01

The deficiency of hepcidin, the hormone that controls iron absorption and its tissue distribution, is the cause of iron overload in nearly all forms of hereditary hemochromatosis and in untransfused iron-loading anemias. In a recent study, we reported the development of minihepcidins, small drug-like hepcidin agonists. Here we explore the feasibility of using minihepcidins for the prevention and treatment of iron overload in hepcidin-deficient mice. An optimized minihepcidin (PR65) was developed that had superior potency and duration of action compared with natural hepcidin or other minihepcidins, and favorable cost of synthesis. PR65 was administered by subcutaneous injection daily for 2 weeks to iron-depleted or iron-loaded hepcidin knockout mice. PR65 administration to iron-depleted mice prevented liver iron loading, decreased heart iron levels, and caused the expected iron retention in the spleen and duodenum. At high doses, PR65 treatment also caused anemia because of profound iron restriction. PR65 administration to hepcidin knockout mice with pre-existing iron overload had a more moderate effect and caused partial redistribution of iron from the liver to the spleen. Our study demonstrates that minihepcidins could be beneficial in iron overload disorders either used alone for prevention or possibly as adjunctive therapy with phlebotomy or chelation. PMID:22990014

Determinants of tobacco use by students

PubMed Central

Vargas, Lorena Silva; Lucchese, Roselma; da Silva, Andrécia Cósmem; Guimarães, Rafael Alves; Vera, Ivânia; de Castro, Paulo Alexandre

2017-01-01

ABSTRACT OBJECTIVE Estimate the prevalence and determinants of tobacco use by students. METHODS This cross-sectional study, carried out between 2013 and 2014, evaluates 701 public school students between 10 and 79 years of age living in a city in the countryside of the State of Goias, Midwest of Brazil. A structured questionnaire collected the data and the predictor variables were demographic data, family nucleus, religion, physical activity practice, family functionality and parental smoking. Two multivariable models were implemented, the first for occasional tobacco use and the second for regular use, acquiring the measure of prevalence ratio (PR) and their respective 95%CI. Variables with p < 0.10 were included in Poisson regression models with robust variance to obtain the adjusted PR (adPR) and 95%CI. The Wald Chi-Squared test examined the differences between proportions, and values with p < 0.05 were statistically significant. RESULTS The prevalence of occasional and regular tobacco use were 33.4% (95%CI 29.8–36.9) and 6.7% (95%CI 5.0–8.8), respectively. The factors associated with occasional tobacco consumption were age of 15 to 17 years (adPR = 1.98) and above 18 years (adPR = 3.87), male gender (adPR = 1.23), moderate family dysfunction (adPR = 1.30), high family dysfunction (adPR = 1.97) and parental smoking (adPR = 1.60). In regards to regular consumption of tobacco, age above 18 years (adPR = 4.63), lack of religion (adPR = 2.08), high family dysfunction (adPR = 2.35) and parental smoking (adPR = 2.89) remained associated. CONCLUSIONS Students exhibit a high prevalence of occasional and regular tobacco use. This consumption relates to sociodemographic variables and family dysfunction. PMID:28492760

The down-conversion and up-conversion photoluminescence properties of Na{sub 0.5}Bi{sub 0.5}TiO{sub 3}:Yb{sup 3+}/Pr{sup 3+} ceramics

DOE Office of Scientific and Technical Information (OSTI.GOV)

Huang, Yinpeng; Luo, Laihui, E-mail: luolaihui@nbu.edu.cn; Wang, Jia

2015-07-28

Na{sub 0.5}Bi{sub 0.5−x−y}Yb{sub x}Pr{sub y}TiO{sub 3} (NBT:xYb/yPr) ceramics with different Yb and Pr contents are prepared. Both the down-conversion (DC) and up-conversion (UC) photoluminescence (PL) of the ceramics via 453 and 980 nm excitation, respectively, are investigated. The effect of Yb{sup 3+} and Pr{sup 3+} doping contents on the DC and UC PL is significantly different from each other. Furthermore, the UC PL of the ceramics as a function of temperatures is measured to investigate the UC process in detail. Based on energy level diagram of Pr{sup 3+} and Yb{sup 3+} ions and the DC and UC PL spectra, the DCmore » and UC PL mechanisms of Pr{sup 3+} and Yb{sup 3+} ions are discussed. Especially, the UC PL mechanism is clarified, which is different from the previously reported literature. Also, the temperature sensing properties of the ceramics are studied based on the photoluminescence ratio technique, using the thermal coupling energy levels of Pr{sup 3+}.« less

Different structural stability and toxicity of PrP(ARR) and PrP(ARQ) sheep prion protein variants.

PubMed

Paludi, Domenico; Thellung, Stefano; Chiovitti, Katia; Corsaro, Alessandro; Villa, Valentina; Russo, Claudio; Ianieri, Adriana; Bertsch, Uwe; Kretzschmar, Hans A; Aceto, Antonio; Florio, Tullio

2007-12-01

The polymorphisms at amino acid residues 136, 154, and 171 in ovine prion protein (PrP) have been associated with different susceptibility to scrapie: animals expressing PrP(ARQ) [PrP(Ala136/Arg154/Gln171)] show vulnerability, whereas those that express PrP(ARR) [PrP(Ala136/Arg154/Arg171)] are resistant to scrapie. The aim of this study was to evaluate the in vitro toxic effects of PrP(ARR) and PrP(ARQ) variants in relation with their structural characteristics. We show that both peptides cause cell death inducing apoptosis but, unexpectedly, the scrapie resistant PrP(ARR) form was more toxic than the scrapie susceptible PrP(ARQ) variant. Moreover, the alpha-helical conformation of PrP(ARR) was less stable than that of PrP(ARQ) and the structural determinants responsible of these different conformational stabilities were characterized by spectroscopic analysis. We observed that PrP toxicity was inversely related to protein structural stability, being the unfolded conformation more toxic than the native one. However, the PrP(ARQ) variant displays a higher propensity to form large aggregates than PrP(ARR). Interestingly, in the presence of small amounts of PrP(ARR), PrP(ARQ) aggregability was reduced to levels similar to that of PrP(ARR). Thus, in contrast to PrP(ARR) toxicity, scrapie transmissibility seems to reside in the more stable conformation of PrP(ARQ) that allows the formation of large amyloid fibrils.

Threefold Increase in PrEP Uptake Over Time with High Adherence Among Young Men Who Have Sex With Men in Chicago.

PubMed

Morgan, Ethan; Moran, Kevin; Ryan, Daniel T; Mustanski, Brian; Newcomb, Michael E

2018-05-04

The goal of this work is to better understand utilization and uptake of pre-exposure prophylaxis (PrEP) among young men who have sex with men (YMSM) and transgender women (TGW). We assessed trends and correlates of PrEP use and adherence across three time points of longitudinal data collection among 885 YMSM and TGW (aged 16-29) from the RADAR cohort in Chicago, 2015-2017. Past 6-month PrEP use increased across three visits: from 6.6 to 17.5%. In multivariable models, past 6-month PrEP use was significantly associated with participation in condomless sex, having more sexual partners, and older age. At least three-quarters of current PrEP users reported being ≥ 90% adherent to PrEP medication across all visits. Past 6-month PrEP use increased over time with those who participated in high-risk HIV behaviors also those most likely to have taken PrEP. As PrEP uptake continues to rise, more research will be needed to understand predictors of PrEP usage, as well as patterns of sexual behavior change following uptake.

Factors associated with last dental visit or not to visit the dentist by Brazilian adolescents: A population-based study.

PubMed

Fonseca, Emílio P da; Frias, Antonio C; Mialhe, Fábio L; Pereira, Antonio C; Meneghim, Marcelo de C

2017-01-01

We investigated the factors associated with no dental visit within the last two years by adolescents in the state of São Paulo, Brazil, by using data from the Oral Health Conditions of São Paulo state population Project (SBSP-2015) conducted in 2015. This was a cross-sectional epidemiological study with a representative sample of adolescents aged 15 to higher years residing in São Paulo State. The examiners were calibrated and dental visits were measured categorically as 1- Less than 1 year, 2- One to two years, 3 - Three years or more, 4- I have never visited the dentist. Based on the literature we dichotomized the outcome in two groups: response 1 plus 2 against response 3 plus 4. Then, Multilevel Poisson Regression (MPR) was used to estimate the prevalence ratios of last dental visit three years or had never been to a dentist by adolescents compared with those who had visited the dentist within the past two years, with contextual variables as the distal level; sociodemographic variables, mesial; and individual variables, proximal level. A high percentage of adolescents (84.9%) reported visiting the dentist in the last 2 years. Whereas, 626 (11.6%) had not visited the dentist for over 3 years and 188 (3.4%) had never been. A significantly higher proportion of females than males reported visiting the dentist in the past 2 years (p = 0.003). The oral and dental condition was reported as satisfactory by 4,350 respondents (80.6%), and when they accessed the health service, 2,286 (42.3%) went to the public service. Lower mean family income (1.62PR;95%CI;1.36-1.94); ≥ 1,000 inhabitant/Dental Surgeons (1.25PR;95%IC;1.03-1.56);male (1.26PR;95%CI; 1.11-1.43) non-Caucasian ethnicity (Mulatto:1.30PR;95%CI;1.13-1.50 and Black:1.58PR;95%CI;1.29-1.93); dissatisfaction with the oral health condition (1.20PR;95%CI;1.01-1.45),last visit to the public service versus private service (2.26PR; 95%CI;1.91-2.65) and presenting with periodontal disease in the form of dental calculus as the worst situation (1.38PR; 95%CI; 1.16-1.53) were associated with last visit to the dentist. A high proportion of adolescents had visited the dentist in the last two years. No dental visit within the last two years by adolescents were associated with contextual, health care system, sociodemographic, personal and oral health status, demonstrating that this is a complex phenomenon. Actions to promote regular dental visits by adolescents in Brazil should take these factors into consideration.

Safety and adherence to intermittent pre-exposure prophylaxis (PrEP) for HIV-1 in African men who have sex with men and female sex workers.

PubMed

Mutua, Gaudensia; Sanders, Eduard; Mugo, Peter; Anzala, Omu; Haberer, Jessica E; Bangsberg, David; Barin, Burc; Rooney, James F; Mark, David; Chetty, Paramesh; Fast, Patricia; Priddy, Frances H

2012-01-01

Little is known about safety of and adherence to intermittent HIV PrEP regimens, which may be more feasible than daily dosing in some settings. We present safety and adherence data from the first trial of an intermittent PrEP regimen among Kenyan men who have sex with men (MSM) and female sex workers (FSW). MSM and FSW were randomized to daily oral FTC/TDF or placebo, or intermittent (Monday, Friday and within 2 hours after sex, not to exceed one dose per day) oral FTC/TDF or placebo in a 2:1:2:1 ratio; volunteers were followed monthly for 4 months. Adherence was assessed with the medication event monitoring system (MEMS). Sexual activity data were collected via daily text message (SMS) queries and timeline followback interviews with a one-month recall period. Sixty-seven men and 5 women were randomized into the study. Safety was similar among all groups. Median MEMS adherence rates were 83% [IQR: 63-92] for daily dosing and 55% [IQR:28-78] for fixed intermittent dosing (p = 0.003), while adherence to any post-coital doses was 26% [IQR:14-50]. SMS response rates were low, which may have impaired measurement of post-coital dosing adherence. Acceptability of PrEP was high, regardless of dosing regimen. Adherence to intermittent dosing regimens, fixed doses, and in particular coitally-dependent doses, may be more difficult than adherence to daily dosing. However, intermittent dosing may still be appropriate for PrEP if intracellular drug levels, which correlate with prevention of HIV acquisition, can be attained with less than daily dosing and if barriers to adherence can be addressed. Additional drug level data, qualitative data on adherence barriers, and better methods to measure sexual activity are necessary to determine whether adherence to post-coital PrEP could be comparable to more standard regimens. ClinicalTrials.gov NCT00971230.

A World Malaria Map: Plasmodium falciparum Endemicity in 2007

PubMed Central

Hay, Simon I; Guerra, Carlos A; Gething, Peter W; Patil, Anand P; Tatem, Andrew J; Noor, Abdisalan M; Kabaria, Caroline W; Manh, Bui H; Elyazar, Iqbal R. F; Brooker, Simon; Smith, David L; Moyeed, Rana A; Snow, Robert W

2009-01-01

Background Efficient allocation of resources to intervene against malaria requires a detailed understanding of the contemporary spatial distribution of malaria risk. It is exactly 40 y since the last global map of malaria endemicity was published. This paper describes the generation of a new world map of Plasmodium falciparum malaria endemicity for the year 2007. Methods and Findings A total of 8,938 P. falciparum parasite rate (PfPR) surveys were identified using a variety of exhaustive search strategies. Of these, 7,953 passed strict data fidelity tests for inclusion into a global database of PfPR data, age-standardized to 2–10 y for endemicity mapping. A model-based geostatistical procedure was used to create a continuous surface of malaria endemicity within previously defined stable spatial limits of P. falciparum transmission. These procedures were implemented within a Bayesian statistical framework so that the uncertainty of these predictions could be evaluated robustly. The uncertainty was expressed as the probability of predicting correctly one of three endemicity classes; previously stratified to be an informative guide for malaria control. Population at risk estimates, adjusted for the transmission modifying effects of urbanization in Africa, were then derived with reference to human population surfaces in 2007. Of the 1.38 billion people at risk of stable P. falciparum malaria, 0.69 billion were found in Central and South East Asia (CSE Asia), 0.66 billion in Africa, Yemen, and Saudi Arabia (Africa+), and 0.04 billion in the Americas. All those exposed to stable risk in the Americas were in the lowest endemicity class (PfPR2−10 ≤ 5%). The vast majority (88%) of those living under stable risk in CSE Asia were also in this low endemicity class; a small remainder (11%) were in the intermediate endemicity class (PfPR2−10 > 5 to < 40%); and the remaining fraction (1%) in high endemicity (PfPR2−10 ≥ 40%) areas. High endemicity was widespread in the Africa+ region, where 0.35 billion people are at this level of risk. Most of the rest live at intermediate risk (0.20 billion), with a smaller number (0.11 billion) at low stable risk. Conclusions High levels of P. falciparum malaria endemicity are common in Africa. Uniformly low endemic levels are found in the Americas. Low endemicity is also widespread in CSE Asia, but pockets of intermediate and very rarely high transmission remain. There are therefore significant opportunities for malaria control in Africa and for malaria elimination elsewhere. This 2007 global P. falciparum malaria endemicity map is the first of a series with which it will be possible to monitor and evaluate the progress of this intervention process. PMID:19323591

'I am not a man': Trans-specific barriers and facilitators to PrEP acceptability among transgender women.

PubMed

Sevelius, Jae M; Keatley, JoAnne; Calma, Nikki; Arnold, Emily

2016-01-01

The frequent conflation of transgender ('trans') women with 'men who have sex with men (MSM)' in HIV prevention obscures trans women's unique gender identities, social and behavioural vulnerabilities, and their disproportionately high rates of HIV infection. Pre-exposure prophylaxis (PrEP) is an efficacious biomedical HIV prevention approach. However, trans women are underrepresented in PrEP research, and are often aggregated with MSM without consideration for their unique positions within sociocultural contexts. This study examined PrEP acceptability among trans women via three focus groups and nine individual interviews (total N = 30) in San Francisco. While knowledge of PrEP was low, interest was relatively high once participants were informed. Due to past negative healthcare experiences, ability to obtain PrEP from a trans-competent provider was cited as essential to PrEP uptake and adherence. Participants noted that PrEP could address situations in which trans women experience reduced power to negotiate safer sex, including sex work. Trans-specific barriers included lack of trans-inclusive marketing of PrEP, prioritisation of hormone use, and medical mistrust due to transphobia. Findings underscore the importance of disaggregating trans women from MSM in HIV prevention strategies to mitigate disparate risk among this highly vulnerable population.

Endometrial estrogen and progesterone receptors within 2-14 days of missed menses in the human.

PubMed

Garg, K; Sujata, P; Kumari, G L; Pandey, P K; Padubidri, V; Anand, C

1993-04-01

Serial changes in the endometrial levels of estrogen and progesterone receptors (ER and PR) were measured in 50 women from days 2 to 14 of missed menses and correlated with the plasma concentrations of hCG, progesterone and 17 beta-estradiol. Both ER and PR of nuclei were higher than cytosolic proteins, with a shift in the ratio of nER/nPR to nPR from 4th day after missed menses. On Scatchard analysis of the cytosolic and nuclear binding proteins, two classes of proteins, corresponding to Type I and II, were found. While the increasing levels of hCG maintained luteal secretion of progesterone and 17 beta-estradiol at normal mid-luteal phase levels, a gradual increase in 17 beta estradiol from 9th day of missed menses was noted. This delicate balance between circulating levels of progesterone and 17 beta-estradiol and their nuclear receptors at early stages of pregnancy may be of significance.

Multi-drug resistance profile of PR20 HIV-1 protease is attributed to distorted conformational and drug binding landscape: molecular dynamics insights.

PubMed

Chetty, Sarentha; Bhakat, Soumendranath; Martin, Alberto J M; Soliman, Mahmoud E S

2016-01-01

The PR20 HIV-1 protease, a variant with 20 mutations, exhibits high levels of multi-drug resistance; however, to date, there has been no report detailing the impact of these 20 mutations on the conformational and drug binding landscape at a molecular level. In this report, we demonstrate the first account of a comprehensive study designed to elaborate on the impact of these mutations on the dynamic features as well as drug binding and resistance profile, using extensive molecular dynamics analyses. Comparative MD simulations for the wild-type and PR20 HIV proteases, starting from bound and unbound conformations in each case, were performed. Results showed that the apo conformation of the PR20 variant of the HIV protease displayed a tendency to remain in the open conformation for a longer period of time when compared to the wild type. This led to a phenomena in which the inhibitor seated at the active site of PR20 tends to diffuse away from the binding site leading to a significant change in inhibitor-protein association. Calculating the per-residue fluctuation (RMSF) and radius of gyration, further validated these findings. MM/GBSA showed that the occurrence of 20 mutations led to a drop in the calculated binding free energies (ΔGbind) by ~25.17 kcal/mol and ~5 kcal/mol for p2-NC, a natural peptide substrate, and darunavir, respectively, when compared to wild type. Furthermore, the residue interaction network showed a diminished inter-residue hydrogen bond network and changes in inter-residue connections as a result of these mutations. The increased conformational flexibility in PR20 as a result of loss of intra- and inter-molecular hydrogen bond interactions and other prominent binding forces led to a loss of protease grip on ligand. It is interesting to note that the difference in conformational flexibility between PR20 and WT conformations was much higher in the case of substrate-bound conformation as compared to DRV. Thus, developing analogues of DRV by retaining its key pharmacophore features will be the way forward in the search for novel protease inhibitors against multi-drug resistant strains.

Space Transportation Technology Workshop: Propulsion Research and Technology

NASA Technical Reports Server (NTRS)

2000-01-01

This viewgraph presentation gives an overview of the Space Transportation Technology Workshop topics, including Propulsion Research and Technology (PR&T) project level organization, FY 2001 - 2006 project roadmap, points of contact, foundation technologies, auxiliary propulsion technology, PR&T Low Cost Turbo Rocket, and PR&T advanced reusable technologies RBCC test bed.

Retention, engagement, and adherence to pre-exposure prophylaxis for men who have sex with men and transgender women in PrEP Brasil: 48 week results of a demonstration study.

PubMed

Grinsztejn, Beatriz; Hoagland, Brenda; Moreira, Ronaldo I; Kallas, Esper G; Madruga, Jose V; Goulart, Silvia; Leite, Iuri C; Freitas, Lucilene; Martins, Luana M S; Torres, Thiago S; Vasconcelos, Ricardo; De Boni, Raquel B; Anderson, Peter L; Liu, Albert; Luz, Paula M; Veloso, Valdiléa G

2018-03-01

PrEP Brasil was a demonstration study to assess feasibility of daily oral tenofovir diphosphate disoproxil fumarate plus emtricitabine provided at no cost to men who have sex with men (MSM) and transgender women at high risk for HIV within the Brazilian public health system. We report week 48 pre-exposure prophylaxis (PrEP) retention, engagement, and adherence, trends in sexual behaviour, and incidence of HIV and sexually transmitted infections in this study cohort. PrEP Brasil was a 48 week, open-label, demonstration study that assessed PrEP delivery at three referral centres for HIV prevention and care in Rio de Janeiro, Brazil (Fundação Oswaldo Cruz), and São Paulo, Brazil (Universidade de São Paulo and Centro de Referência e Treinamento em DST e AIDS). Eligible participants were MSM and transgender women who were HIV negative, aged at least 18 years, resident in Rio de Janeiro or São Paulo, and reported one or more sexual risk criteria in the previous 12 months (eg, condomless anal sex with two or more partners, two or more episodes of anal sex with an HIV-infected partner, or history of sexually transmitted infection [STI] diagnosis). Participants were seen at weeks 4, 12, 24, 36, and 48 for PrEP provision, clinical and laboratory evaluation, and HIV testing. Computer-assisted self-interviews were also done at study visits 12, 24, 36, and 48, and assessed sexual behaviour and drug use. PrEP retention was defined by attendance at the week 48 visit, PrEP engagement was an ordinal five-level variable combining presence at the study visit and drug concentrations, and PrEP adherence was evaluated by measuring tenofovir diphosphate concentrations in dried blood spots. Logistic regression models were used to quantify the association of variables with high adherence (≥4 doses per week). The study is registered with ClinicalTrials.gov, number NCT01989611. Between April 1, 2014, and July 8, 2016, 450 participants initiated PrEP, 375 (83%) of whom were retained until week 48. At week 48, 277 (74%) of 375 participants had protective drug concentrations consistent with at least four doses per week: 183 (82%) of 222 participants from São Paulo compared with 94 (63%) of 150 participants from Rio de Janeiro (adjusted odds ratio 1·88, 95% CI 1·06-3·34); 119 (80%) of 148 participants who reported sex with HIV-infected partners compared with 158 (70%) of 227 participants who did not (1·78, 1·03-3·08); 67 (87%) of 77 participants who used stimulants compared with 210 (71%) of 298 participants who did not (2·23, 1·02-4·92); and 232 (80%) of 289 participants who had protective concentrations of tenofovir disphosphate at week 4 compared with 42 (54%) of 78 participants who did not (3·28, 1·85-5·80). Overall, receptive anal sex with the last three partners increased from 45% at enrolment to 49% at week 48 (p=0·17), and the mean number of sexual partners in the previous 3 months decreased from 11·4 (SD 28·94) at enrolment to 8·3 (19·55) at week 48 (p<0·0013). Two individuals seroconverted during follow-up (HIV incidence 0·51 per 100 person-years, 95% CI 0·13-2·06); both of these patients had undetectable tenofovir concentrations at seroconversion. Our results support the effectiveness and feasibility of PrEP in a real-world setting. Offering PrEP at public health-care clinics in a middle-income setting can retain high numbers of participants and achieve high levels of adherence without risk compensation in the investigated populations. Brazilian Ministry of Health, Conselho Nacional de Desenvolvimento Científico e Tecnológico, Secretaria de Vigilancia em Saúde, Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro, and Fundação de Amparo à Pesquisa do Estado de São Paulo. Copyright © 2018 Elsevier Ltd. All rights reserved.

Molecular Dynamics Simulation Study on the Binding and Stabilization Mechanism of Antiprion Compounds to the "Hot Spot" Region of PrPC.

PubMed

Zhou, Shuangyan; Liu, Xuewei; An, Xiaoli; Yao, Xiaojun; Liu, Huanxiang

2017-11-15

Structural transitions in the prion protein from the cellular form, PrP C , into the pathological isoform, PrP Sc , are regarded as the main cause of the transmissible spongiform encephalopathies, also known as prion diseases. Hence, discovering and designing effective antiprion drugs that can inhibit PrP C to PrP Sc conversion is regarded as a promising way to cure prion disease. Among several strategies to inhibit PrP C to PrP Sc conversion, stabilizing the native PrP C via specific binding is believed to be one of the valuable approaches and many antiprion compounds have been reported based on this strategy. However, the detailed mechanism to stabilize the native PrP C is still unknown. As such, to unravel the stabilizing mechanism of these compounds to PrP C is valuable for the further design and discovery of antiprion compounds. In this study, by molecular dynamics simulation method, we investigated the stabilizing mechanism of several antiprion compounds on PrP C that were previously reported to have specific binding to the "hot spot" region of PrP C . Our simulation results reveal that the stabilization mechanism of specific binding compounds can be summarized as (I) to stabilize both the flexible C-terminal of α2 and the hydrophobic core, such as BMD42-29 and GN8; (II) to stabilize the hydrophobic core, such as J1 and GJP49; (III) to stabilize the overall structure of PrP C by high binding affinity, as NPR-056. In addition, as indicated by the H-bond analysis and decomposition analysis of binding free energy, the residues N159 and Q160 play an important role in the specific binding of the studied compounds and all these compounds interact with PrP C in a similar way with the key interacting residues L130 in the β1 strand, P158, N159, Q160, etc. in the α1-β2 loop, and H187, T190, T191, etc. in the α2 C-terminus although the compounds have large structural difference. As a whole, our obtained results can provide some insights into the specific binding mechanism of main antiprion compounds to the "hot spot" region of PrP C at the molecular level and also provide guidance for effective antiprion drug design in the future.

A cost utility analysis of simeprevir used with peginterferon + ribavirin in the management of genotype 1 hepatitis C virus infection, from the perspective of the UK National Health Service.

PubMed

Westerhout, Kirsten; Treur, Maarten; Mehnert, Angelika; Pascoe, Katie; Ladha, Imran; Belsey, Jonathan

2015-01-01

Triple therapy using a protease inhibitor (PI) with peginterferon and ribavirin (PR) is increasingly used in patients with chronic hepatitis C virus (HCV) infection. The most recently introduced PI, simeprevir (SMV), offers high levels of viral eradication combined with a reduced overall duration of therapy. The objective of this study was to compare the cost-effectiveness of SMV + PR vs PR alone or in combination with telaprevir (TVR) or boceprevir (BOC) in patients infected with genotype 1 HCV Method: A cost-utility model was constructed, incorporating two phases, capturing the efficacy of therapy in an initial treatment phase, followed by a long-term post-treatment Markov phase, capturing lifetime outcomes according to whether a sustained viral response (SVR) had been achieved on treatment. Dosage regimens were based on the EMA approved label for each treatment. SVR estimates and adverse event rates were derived from a mixed treatment comparison. Baseline characteristics were drawn from an analysis of a UK HCV data-set and clinician opinion. Health state transition probabilities, utilities, and health state costs were drawn from previously published economic analyses. The model considered direct health costs only, and the perspective was that of the UK National Health Service. The model yielded an ICER for SMV + PR vs PR alone of £9725/QALY for treatment-naïve and £7819/QALY for treatment-experienced. Benefit was driven by increased likelihood of achieving SVR, with consequent long-term utility gains. SMV + PR dominated TVR + PR and BOC + PR in both patient groups. This principally reflected the QALY benefit of an increased likelihood of SVR with SMV, combined with lower overall drug costs, due to reduced mean treatment duration. Compared to other currently licensed treatment options, SMV + PR represents a cost effective treatment option for patients with chronic genotype 1 HCV infection.

Fish-Derived Omega-3 Fatty Acids and Prostate Cancer: A Systematic Review.

PubMed

Aucoin, Monique; Cooley, Kieran; Knee, Christopher; Fritz, Heidi; Balneaves, Lynda G; Breau, Rodney; Fergusson, Dean; Skidmore, Becky; Wong, Raimond; Seely, Dugald

2017-03-01

The use of natural health products in prostate cancer (PrCa) is high despite a lack of evidence with respect to safety and efficacy. Fish-derived omega-3 fatty acids possess anti-inflammatory effects and preclinical data suggest a protective effect on PrCa incidence and progression; however, human studies have yielded conflicting results. A search of OVID MEDLINE, Pre-MEDLINE, Embase, and the Allied and Complementary Medicine Database (AMED) was completed for human interventional or observational data assessing the safety and efficacy of fish-derived omega-3 fatty acids in the incidence and progression of PrCa. Of 1776 citations screened, 54 publications reporting on 44 studies were included for review and analysis: 4 reports of 3 randomized controlled trials, 1 nonrandomized clinical trial, 20 reports of 14 cohort studies, 26 reports of 23 case-control studies, and 3 case-cohort studies. The interventional studies using fish oil supplements in patients with PrCa showed no impact on prostate-specific antigen levels; however, 2 studies showed a decrease in inflammatory or other cancer markers. A small number of mild adverse events were reported and interactions with other interventions were not assessed. Cohort and case-control studies assessing the relationship between dietary fish intake and the risk of PrCa were equivocal. Cohort studies assessing the risk of PrCa mortality suggested an association between higher intake of fish and decreased risk of prostate cancer-related death. Current evidence is insufficient to suggest a relationship between fish-derived omega-3 fatty acid and risk of PrCa. An association between higher omega-3 intake and decreased PrCa mortality may be present but more research is needed. More intervention trials or observational studies with precisely measured exposure are needed to assess the impact of fish oil supplements and dietary fish-derived omega-3 fatty acid intake on safety, PrCa incidence, treatment, and progression.

Fish-Derived Omega-3 Fatty Acids and Prostate Cancer: A Systematic Review

PubMed Central

Aucoin, Monique; Cooley, Kieran; Knee, Christopher; Fritz, Heidi; Balneaves, Lynda G.; Breau, Rodney; Fergusson, Dean; Skidmore, Becky; Wong, Raimond; Seely, Dugald

2016-01-01

Background. The use of natural health products in prostate cancer (PrCa) is high despite a lack of evidence with respect to safety and efficacy. Fish-derived omega-3 fatty acids possess anti-inflammatory effects and preclinical data suggest a protective effect on PrCa incidence and progression; however, human studies have yielded conflicting results. Methods. A search of OVID MEDLINE, Pre-MEDLINE, Embase, and the Allied and Complementary Medicine Database (AMED) was completed for human interventional or observational data assessing the safety and efficacy of fish-derived omega-3 fatty acids in the incidence and progression of PrCa. Results. Of 1776 citations screened, 54 publications reporting on 44 studies were included for review and analysis: 4 reports of 3 randomized controlled trials, 1 nonrandomized clinical trial, 20 reports of 14 cohort studies, 26 reports of 23 case-control studies, and 3 case-cohort studies. The interventional studies using fish oil supplements in patients with PrCa showed no impact on prostate-specific antigen levels; however, 2 studies showed a decrease in inflammatory or other cancer markers. A small number of mild adverse events were reported and interactions with other interventions were not assessed. Cohort and case-control studies assessing the relationship between dietary fish intake and the risk of PrCa were equivocal. Cohort studies assessing the risk of PrCa mortality suggested an association between higher intake of fish and decreased risk of prostate cancer–related death. Conclusions. Current evidence is insufficient to suggest a relationship between fish-derived omega-3 fatty acid and risk of PrCa. An association between higher omega-3 intake and decreased PrCa mortality may be present but more research is needed. More intervention trials or observational studies with precisely measured exposure are needed to assess the impact of fish oil supplements and dietary fish-derived omega-3 fatty acid intake on safety, PrCa incidence, treatment, and progression. PMID:27365385

A Functional Interplay between Human Immunodeficiency Virus Type 1 Protease Residues 77 and 93 Involved in Differential Regulation of Precursor Autoprocessing and Mature Protease Activity

PubMed Central

Counts, Christopher J.; Ho, P. Shing; Donlin, Maureen J.; Tavis, John E.; Chen, Chaoping

2015-01-01

HIV-1 protease (PR) is a viral enzyme vital to the production of infectious virions. It is initially synthesized as part of the Gag-Pol polyprotein precursor in the infected cell. The free mature PR is liberated as a result of precursor autoprocessing upon virion release. We previously described a model system to examine autoprocessing in transfected mammalian cells. Here, we report that a covariance analysis of miniprecursor (p6*-PR) sequences derived from drug naïve patients identified a series of amino acid pairs that vary together across independent viral isolates. These covariance pairs were used to build the first topology map of the miniprecursor that suggests high levels of interaction between the p6* peptide and the mature PR. Additionally, several PR-PR covariance pairs are located far from each other (>12 Å Cα to Cα) relative to their positions in the mature PR structure. Biochemical characterization of one such covariance pair (77–93) revealed that each residue shows distinct preference for one of three alkyl amino acids (V, I, and L) and that a polar or charged amino acid at either of these two positions abolishes precursor autoprocessing. The most commonly observed 77V is preferred by the most commonly observed 93I, but the 77I variant is preferred by other 93 variances (L, V, or M) in supporting precursor autoprocessing. Furthermore, the 77I93V covariant enhanced precursor autoprocessing and Gag polyprotein processing but decreased the mature PR activity. Therefore, both covariance and biochemical analyses support a functional association between residues 77 and 93, which are spatially distant from each other in the mature PR structure. Our data also suggests that these covariance pairs differentially regulate precursor autoprocessing and the mature protease activity. PMID:25893662

Lifestyle, socioeconomic characteristics, and medical history of elderly persons who receive seasonal influenza vaccination in a tax-supported healthcare system.

PubMed

Hellfritzsch, Maja; Thomsen, Reimar Wernich; Baggesen, Lisbeth Munksgård; Larsen, Finn Breinholt; Sørensen, Henrik Toft; Christiansen, Christian Fynbo

2017-04-25

Observational studies on effectiveness of influenza vaccination in the elderly are thought to be biased by healthier lifestyles and higher socioeconomic status among vaccinated vs. unvaccinated persons. We examined this hypothesis in a uniform tax-supported health care system with free-of-charge influenza vaccination to the elderly. We conducted a cross-sectional study among Danes aged 65-79years participating in a survey. We compared elderly persons with and without a recent (within six months) influenza vaccination in terms of (i) lifestyle and socioeconomic characteristics obtained from the survey and (ii) health factors including medical history provided by Danish registries. We compared the prevalence of study variables among vaccinated and unvaccinated persons using age- and sex-adjusted prevalence ratios (aPRs) with 95% confidence intervals (CIs). Among the 4237 elderly persons completing the survey, 1718 (41%) had received an influenza vaccination. Vaccinated persons had more comorbidity than unvaccinated persons (aPR for high comorbidity level: 1.51 95% CI 1.24-1.84), were less likely to never have smoked (aPR: 0.88, 95% CI 0.80-0.97), and had a higher prevalence of physical inactivity (aPR: 1.08, 95% CI 1.03-1.13). Levels of education and income were similar in the two groups. Vaccinated persons had a higher prevalence of major physical limitations (aPR: 1.40, 95% CI 1.17-1.66) and need for assistance with activities of daily living (aPR: 1.29, 95% CI 1.13-1.47). Elderly influenza vaccinated persons were not healthier in terms of lifestyle and burden of disease, did not have a higher socioeconomic status, and were more frail than unvaccinated persons. Copyright © 2017 Elsevier Ltd. All rights reserved.

LED therapy or cryotherapy between exercise intervals in Wistar rats: anti-inflammatory and ergogenic effects.

PubMed

da Costa Santos, Vanessa Batista; de Paula Ramos, Solange; Milanez, Vinícius Flávio; Corrêa, Julio Cesar Molina; de Andrade Alves, Rubens Igor; Dias, Ivan Frederico Lupiano; Nakamura, Fábio Yuzo

2014-03-01

The aim of this study was to test, between two bouts of exercise, the effects of light-emitting diode (LED) therapy and cryotherapy regarding muscle damage, inflammation, and performance. Male Wistar rats were allocated in four groups: control, passive recovery (PR), cryotherapy (Cryo), and LED therapy. The animals were submitted to 45 min of swimming exercise followed by 25 min of recovery and then a second bout of either 45 min of exercise (muscle damage analysis) or time to exhaustion (performance). During the rest intervals, the rats were kept in passive rest (PR), submitted to cold water immersion (10 min, 10 °C) or LED therapy (940 nm, 4 J/cm(2)) of the gastrocnemius muscle. Blood samples were collected to analyze creatine kinase activity (CK), C-reactive protein (CRP), and leukocyte counts. The soleus muscles were evaluated histologically. Time to exhaustion was recorded during the second bout of exercise. After a second bout of 45 min, the results demonstrated leukocytosis in the PR and Cryo groups. Neutrophil counts were increased in all test groups. CK levels were increased in the Cryo group. CRP was increased in PR animals. The PR group presented a high frequency of necrosis, but the LED group had fewer necrotic areas. Edema formation was prevented, and fewer areas of inflammatory cells were observed in the LED group. The time to exhaustion was greater in both the LED and Cryo groups, without differences in CK levels. CRP was decreased in LED animals. We conclude that LED therapy and cryotherapy can improve performance, although LED therapy is more efficient in preventing muscle damage and local and systemic inflammation.

High fasting blood glucose and obesity significantly and independently increase risk of breast cancer death in hormone receptor-positive disease.

PubMed

Minicozzi, Pamela; Berrino, Franco; Sebastiani, Federica; Falcini, Fabio; Vattiato, Rosa; Cioccoloni, Francesca; Calagreti, Gioia; Fusco, Mario; Vitale, Maria Francesca; Tumino, Rosario; Sigona, Aurora; Budroni, Mario; Cesaraccio, Rosaria; Candela, Giuseppa; Scuderi, Tiziana; Zarcone, Maurizio; Campisi, Ildegarda; Sant, Milena

2013-12-01

We investigated the effect of fasting blood glucose and body mass index (BMI) at diagnosis on risk of breast cancer death for cases diagnosed in five Italian cancer registries in 2003-2005 and followed up to the end of 2008. For 1607 Italian women (≥15 years) with information on BMI or blood glucose or diabetes, we analysed the risk of breast cancer death in relation to glucose tertiles (≤84.0, 84.1-94.0, >94.0 mg/dl) plus diabetic and unspecified categories; BMI tertiles (≤23.4, 23.5-27.3, >27.3 kg/m(2), unspecified), stage (T1-3N0M0, T1-3N+M0 plus T4anyNM0, M1, unspecified), oestrogen (ER) and progesterone (PR) status (ER+PR+, ER-PR-, ER and PR unspecified, other), age, chemotherapy and endocrine therapy, using multiple regression models. Separate models for ER+PR+ and ER-PR- cases were also run. Patients often had T1-3N0M0, ER+PR+ cancers and received chemotherapy or endocrine therapy; only 6% were M1 and 17% ER-PR-. Diabetic patients were older and had more often high BMI (>27 kg/m(2)), ER-PR-, M1 cancers than other patients. For ER+PR+ cases, with adjustment for other variables, breast cancer mortality was higher in women with high BMI than those with BMI 23.5-27.3 kg/m(2) (hazard ratio (HR)=2.9, 95% confidence interval (CI) 1.2-6.9). Breast cancer mortality was also higher in women with high (>94 mg/dl) blood glucose compared to those with glucose 84.1-94.0mg/dl (HR=2.6, 95% CI 1.2-5.7). Our results provide evidence that in ER+PR+ patients, high blood glucose and high BMI are independently associated with increased risk of breast cancer death. Detection and correction of these factors in such patients may improve prognosis. Copyright © 2013 Elsevier Ltd. All rights reserved.

HIV Pre-Exposure Prophylaxis Stigma as a Multidimensional Barrier to Uptake Among Women Who Attend Planned Parenthood.

PubMed

Calabrese, Sarah K; Dovidio, John F; Tekeste, Mehrit; Taggart, Tamara; Galvao, Rachel W; Safon, Cara B; Willie, Tiara C; Caldwell, Abigail; Kaplan, Clair; Kershaw, Trace S

2018-05-22

PrEP uptake has lagged among US women. PrEP stigma is a recognized barrier to uptake among MSM but remains largely unexplored among women. This study examined the pervasiveness of PrEP stigma among US women and its implications for uptake. Setting/Methods: In a 2017 online survey of Planned Parenthood patients drawn from the three cities with the highest numbers of new HIV infections in Connecticut, 597 heterosexually-active, HIV-negative, PrEP-inexperienced women reported background characteristics, two dimensions of anticipated PrEP stigma (PrEP-user stereotypes and PrEP disapproval by others), and three indicators of potential PrEP uptake (interest in learning more about PrEP, intention to use PrEP, and comfort discussing PrEP with a provider). Participants commonly perceived PrEP-user stereotypes, with many believing that others would regard them as promiscuous (37%), HIV-positive (32%), bad (14%), or gay (11%) if they used PrEP. Thirty percent would feel ashamed to disclose PrEP use. Many participants expected disapproval by family (36%), sex partners (34%), and friends (25%). In adjusted analyses, perception of PrEP-user stereotypes was uniquely associated with lower comfort discussing PrEP with a provider. Expected PrEP disapproval by others was uniquely associated with less PrEP interest, less intention to use PrEP, and less comfort discussing PrEP with a provider. Exploratory moderation analyses suggested intention to use PrEP was greatest when participants anticipated low levels of both PrEP-user stereotypes and PrEP disapproval by others. Findings highlight the need for positive messaging targeting potential PrEP users and their social networks to increase PrEP acceptance and uptake.

A study of photomodulated reflectance on staircase-like, n-doped GaAs/AlxGa1−xAs quantum well structures

PubMed Central

2012-01-01

In this study, photomodulated reflectance (PR) technique was employed on two different quantum well infrared photodetector (QWIP) structures, which consist of n-doped GaAs quantum wells (QWs) between undoped AlxGa1−xAs barriers with three different x compositions. Therefore, the barrier profile is in the form of a staircase-like barrier. The main difference between the two structures is the doping profile and the doping concentration of the QWs. PR spectra were taken at room temperature using a He-Ne laser as a modulation source and a broadband tungsten halogen lamp as a probe light. The PR spectra were analyzed using Aspnes’ third derivative functional form. Since the barriers are staircase-like, the structure has different ground state energies; therefore, several optical transitions take place in the spectrum which cannot be resolved in a conventional photoluminescence technique at room temperature. To analyze the experimental results, all energy levels in the conduction and in the valance band were calculated using transfer matrix technique, taking into account the effective mass and the parabolic band approximations. A comparison of the PR results with the calculated optical transition energies showed an excellent agreement. Several optical transition energies of the QWIP structures were resolved from PR measurements. It is concluded that PR spectroscopy is a very useful experimental tool to characterize complicated structures with a high accuracy at room temperature. PMID:23146126

A study of photomodulated reflectance on staircase-like, n-doped GaAs/AlxGa1-xAs quantum well structures.

PubMed

Donmez, Omer; Nutku, Ferhat; Erol, Ayse; Arikan, Cetin M; Ergun, Yuksel

2012-11-12

In this study, photomodulated reflectance (PR) technique was employed on two different quantum well infrared photodetector (QWIP) structures, which consist of n-doped GaAs quantum wells (QWs) between undoped AlxGa1-xAs barriers with three different x compositions. Therefore, the barrier profile is in the form of a staircase-like barrier. The main difference between the two structures is the doping profile and the doping concentration of the QWs. PR spectra were taken at room temperature using a He-Ne laser as a modulation source and a broadband tungsten halogen lamp as a probe light. The PR spectra were analyzed using Aspnes' third derivative functional form.Since the barriers are staircase-like, the structure has different ground state energies; therefore, several optical transitions take place in the spectrum which cannot be resolved in a conventional photoluminescence technique at room temperature. To analyze the experimental results, all energy levels in the conduction and in the valance band were calculated using transfer matrix technique, taking into account the effective mass and the parabolic band approximations. A comparison of the PR results with the calculated optical transition energies showed an excellent agreement. Several optical transition energies of the QWIP structures were resolved from PR measurements. It is concluded that PR spectroscopy is a very useful experimental tool to characterize complicated structures with a high accuracy at room temperature.

A study of photomodulated reflectance on staircase-like, n-doped GaAs/Al x Ga1- x As quantum well structures

NASA Astrophysics Data System (ADS)

Donmez, Omer; Nutku, Ferhat; Erol, Ayse; Arikan, Cetin M.; Ergun, Yuksel

2012-11-01

In this study, photomodulated reflectance (PR) technique was employed on two different quantum well infrared photodetector (QWIP) structures, which consist of n-doped GaAs quantum wells (QWs) between undoped Al x Ga1- x As barriers with three different x compositions. Therefore, the barrier profile is in the form of a staircase-like barrier. The main difference between the two structures is the doping profile and the doping concentration of the QWs. PR spectra were taken at room temperature using a He-Ne laser as a modulation source and a broadband tungsten halogen lamp as a probe light. The PR spectra were analyzed using Aspnes' third derivative functional form. Since the barriers are staircase-like, the structure has different ground state energies; therefore, several optical transitions take place in the spectrum which cannot be resolved in a conventional photoluminescence technique at room temperature. To analyze the experimental results, all energy levels in the conduction and in the valance band were calculated using transfer matrix technique, taking into account the effective mass and the parabolic band approximations. A comparison of the PR results with the calculated optical transition energies showed an excellent agreement. Several optical transition energies of the QWIP structures were resolved from PR measurements. It is concluded that PR spectroscopy is a very useful experimental tool to characterize complicated structures with a high accuracy at room temperature.

Factors associated with caries: a survey of students from southern Brazil

PubMed Central

Borges, Tássia Silvana; Schwanke, Natalí Lippert; Reuter, Cézane Priscila; Neto, Léo Kraether; Burgos, Miria Suzana

2016-01-01

Abstract Objective: To describe the factors associated with dental caries among students from Santa Cruz do Sul, Rio Grande do Sul, Brazil. Methods: A cross-sectional study was conducted in a random sample of 623 students of both genders, aged 10-17 years old. Tooth decay was performed using the index of the World Health Organization (1997), DMFT (permanent dentition) that expresses the sum of decayed, missing and filled teeth per person. The maternal educational level was rated using criteria of the Brazilian Association of Market Research Companies. The remaining variables were obtained by a structured questionnaire. Poisson regression analysis was used to test the association between variables using robust models and a subsequently adjusted model. Data were expressed as prevalence ratio (PR). Results: Multivariate analysis identified the following factors related to the experience of dental caries: residence in rural municipalities (PR: 1.15; 95%CI: 1.0-1.3), attending a city school (PR: 3.30; 95%CI: 1.1-9.4) or a state school (PR: 3.40; 95%CI: 1.1-9.6); and having an illiterate mother or a mother that only attended up to the 4th year of school (PR: 1.67; 95%CI: 1.1-2.4) or high school (PR: 1.54; 95%CI: 1.1-2.2). Conclusions: The presence of caries in students in southern Brazil was associated with residence in rural areas, mother with little education and attendance to a public school. PMID:27477791

Nerve Growth Factor Increases mRNA Levels for the Prion Protein and the β -amyloid Protein Precursor in Developing Hamster Brain

NASA Astrophysics Data System (ADS)

Mobley, William C.; Neve, Rachael L.; Prusiner, Stanley B.; McKinley, Michael P.

1988-12-01

Deposition of amyloid filaments serves as a pathologic hallmark for some neurodegenerative disorders. The prion protein (PrP) is found in amyloid of animals with scrapie and humans with Creutzfeldt-Jakob disease; the β protein is present in amyloid deposits in Alzheimer disease and Down syndrome patients. These two proteins are derived from precursors that in the brain are expressed primarily in neurons and are membrane bound. We found that gene expression for PrP and the β -protein precursor (β -PP) is regulated in developing hamster brain. Specific brain regions showed distinct patterns of ontogenesis for PrP and β -PP mRNAs. The increases in PrP and β -PP mRNAs in developing basal forebrain coincided with an increase in choline acetyltransferase activity, raising the possibility that these markers might be coordinately controlled in cholinergic neurons and regulated by nerve growth factor (NGF). Injections of NGF into the brains of neonatal hamsters increased both PrP and β -PP mRNA levels. Increased PrP and β -PP mRNA levels induced by NGF were confined to regions that contain NGF-responsive cholinergic neurons and were accompanied by elevations in choline acetyltransferase. It remains to be established whether or not exogenous NGF acts to increase PrP and β -PP gene expression selectively in forebrain cholinergic neurons in the developing hamster and endogenous NGF regulates expression of these genes.

Phylogenetic analysis of PR genes in some pome fruit species with the emphasis on transcriptional analysis and ROS response under Erwinia amylovora inoculation in apple.

PubMed

Hassani, Maryam; Salami, Seyed Alireza; Nasiri, Jaber; Abdollahi, Hamid; Ghahremani, Zahra

2016-02-01

Attempts were made to identify eight pathogenesis related (PR) genes (i.e., PR-1a, PR3-ch1, PR3-Ch2, PR3-Ch3, PR3-Ch4, PR3-Ch5, PR-5 and PR-8) from 27 genotypes of apple, quince and pear, which are induced in response to inoculation with the pathogen Erwinia amylovora, the causal agent of fire blight. Totally, 32 PR genes of different families were obtained, excepting PR3-Ch2 (amplified only in apple) and PR3-Ch4 (amplified only in apple and pear), the others were successfully amplified in all the genotypes of apple, quince and pear. Evolutionary, the genes of each family exhibited significant homology with each other, as the corresponded phylogenetic neighbor-joining-based dendrograms were taken into consideration. Meanwhile, according to the expression assay, it was deduced that the pathogen activity can significantly affect the expression levels of some selected PR genes of PR3-Ch2, PR3-Ch4, PR3-Ch5 and particularly Cat I in both resistant (MM-111) and semi-susceptible (MM-106) apple rootstocks. Lastly, it was concluded that the pathogen E. amylovora is able to stimulate ROS response, particularly using generation of hydrogen peroxide (H2O2) in both aforementioned apple rootstock.

Inverse Relationship between Progesterone Receptor and Myc in Endometrial Cancer

PubMed Central

Dai, Donghai; Meng, Xiangbing; Thiel, Kristina W.; Leslie, Kimberly K.; Yang, Shujie

2016-01-01

Endometrial cancer, the most common gynecologic malignancy, is a hormonally-regulated disease. Response to progestin therapy positively correlates with hormone receptor expression, in particular progesterone receptor (PR). However, many advanced tumors lose PR expression. We recently reported that the efficacy of progestin therapy can be significantly enhanced by combining progestin with epigenetic modulators, which we term “molecularly enhanced progestin therapy.” What remained unclear was the mechanism of action and if estrogen receptor α (ERα), the principle inducer of PR, is necessary to restore functional expression of PR via molecularly enhanced progestin therapy. Therefore, we modeled advanced endometrial tumors that have lost both ERα and PR expression by generating ERα-null endometrial cancer cell lines. CRISPR-Cas9 technology was used to delete ERα at the genomic level. Our data demonstrate that treatment with a histone deacetylase inhibitor (HDACi) was sufficient to restore functional PR expression, even in cells devoid of ERα. Our studies also revealed that HDACi treatment results in marked downregulation of the oncogene Myc. We established that PR is a negative transcriptional regulator of Myc in endometrial cancer in the presence or absence of ERα, which is in contrast to studies in breast cancer cells. First, estrogen stimulation augmented PR expression and decreased Myc in endometrial cancer cell lines. Second, progesterone increased PR activity yet blunted Myc mRNA and protein expression. Finally, overexpression of PR by adenoviral transduction in ERα-null endometrial cancer cells significantly decreased expression of Myc and Myc-regulated genes. Analysis of the Cancer Genome Atlas (TCGA) database of endometrial tumors identified an inverse correlation between PR and Myc mRNA levels, with a corresponding inverse correlation between PR and Myc downstream transcriptional targets SRD5A1, CDK2 and CCNB1. Together, these data reveal a previously unanticipated inverse relationship between the tumor suppressor PR and the oncogene Myc in endometrial cancer. PMID:26859414

Variability of hydrological extreme events in East Asia and their dynamical control: a comparison between observations and two high-resolution global climate models

NASA Astrophysics Data System (ADS)

Freychet, N.; Duchez, A.; Wu, C.-H.; Chen, C.-A.; Hsu, H.-H.; Hirschi, J.; Forryan, A.; Sinha, B.; New, A. L.; Graham, T.; Andrews, M. B.; Tu, C.-Y.; Lin, S.-J.

2017-02-01

This work investigates the variability of extreme weather events (drought spells, DS15, and daily heavy rainfall, PR99) over East Asia. It particularly focuses on the large scale atmospheric circulation associated with high levels of the occurrence of these extreme events. Two observational datasets (APHRODITE and PERSIANN) are compared with two high-resolution global climate models (HiRAM and HadGEM3-GC2) and an ensemble of other lower resolution climate models from CMIP5. We first evaluate the performance of the high resolution models. They both exhibit good skill in reproducing extreme events, especially when compared with CMIP5 results. Significant differences exist between the two observational datasets, highlighting the difficulty of having a clear estimate of extreme events. The link between the variability of the extremes and the large scale circulation is investigated, on monthly and interannual timescales, using composite and correlation analyses. Both extreme indices DS15 and PR99 are significantly linked to the low level wind intensity over East Asia, i.e. the monsoon circulation. It is also found that DS15 events are strongly linked to the surface temperature over the Siberian region and to the land-sea pressure contrast, while PR99 events are linked to the sea surface temperature anomalies over the West North Pacific. These results illustrate the importance of the monsoon circulation on extremes over East Asia. The dependencies on of the surface temperature over the continent and the sea surface temperature raise the question as to what extent they could affect the occurrence of extremes over tropical regions in future projections.

Expression of cellular prion protein in the frontal and occipital lobe in Alzheimer's disease, diffuse Lewy body disease, and in normal brain: an immunohistochemical study.

PubMed

Rezaie, Payam; Pontikis, Charlie C; Hudson, Lance; Cairns, Nigel J; Lantos, Peter L

2005-08-01

Cellular prion protein (PrP(c)) is a glycoprotein expressed at low to moderate levels within the nervous system. Recent studies suggest that PrP(c) may possess neuroprotective functions and that its expression is upregulated in certain neurodegenerative disorders. We investigated whether PrP(c) expression is altered in the frontal and occipital cortex in two well-characterized neurodegenerative disorders--Alzheimer's disease (AD) and diffuse Lewy body disease (DLBD)--compared with that in normal human brain using immunohistochemistry and computerized image analysis. The distribution of PrP(c) was further tested for correlation with glial reactivity. We found that PrP(c) was localized mainly in the gray matter (predominantly in neurons) and expressed at higher levels within the occipital cortex in the normal human brain. Image analysis revealed no significant variability in PrP(c) expression between DLBD and control cases. However, blood vessels within the white matter of DLBD cases showed immunoreactivity to PrP(c). By contrast, this protein was differentially expressed in the frontal and occipital cortex of AD cases; it was markedly overexpressed in the former and significantly reduced in the latter. Epitope specificity of antibodies appeared important when detecting PrP(c). The distribution of PrP(c) did not correlate with glial immunoreactivity. In conclusion, this study supports the proposal that regional changes in expression of PrP(c) may occur in certain neurodegenerative disorders such as AD, but not in other disorders such as DLBD.

Proximity of SCG10 and prion protein in membrane rafts.

PubMed

Iwamaru, Yoshifumi; Kitani, Hiroshi; Okada, Hiroyuki; Takenouchi, Takato; Shimizu, Yoshihisa; Imamura, Morikazu; Miyazawa, Kohtaro; Murayama, Yuichi; Hoover, Edward A; Yokoyama, Takashi

2015-12-10

The conversion of normal cellular prion protein (PrPC) into its pathogenic isoform (PrPSc) is an essential event in prion pathogenesis. In culture models, membrane rafts are suggested to play a critical role in PrPSc formation. To identify the candidate molecules capable of interacting with PrPC and facilitating PrPSc formation in membrane rafts, we applied a novel biochemical labelling method termed 'enzyme-mediated activation of radical sources (EMARS)'. EMARS was applied to the Lubrol WX insoluble detergent-resistant membrane fractions from mouse neuroblastoma (N2a) cells in which the surface PrPC was labeled with HRP-conjugated anti-PrP antibody. Two-dimensional Western blots of these preparations revealed biotinylated spots of approximately 20 kDa with an isoelectric point of 8.0-9.0. Liquid chromatography-tandem mass spectrometry analysis resulted in the identification of peptides containing SCG10, the neuron-specific microtubule regulator. Proximity of SCG10 and PrPC was confirmed using proximity ligation assay and co-immunoprecipitation assay. Transfection of persistently 22L prion infected N2a cells with SCG10 small interfering RNA reduced SCG10 expression but did not prevent PrPSc accumulation, indicating that SCG10 appears to be unrelated to PrPSc formation of 22L prion. Immunofluorescence and Western blot analyses showed reduced levels of SCG10 in the hippocampus of prion-infected mice, suggesting a possible association between SCG10 levels and the prion neuropathogenesis. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Sex effects in mouse prion disease incubation time.

PubMed

Akhtar, Shaheen; Wenborn, Adam; Brandner, Sebastian; Collinge, John; Lloyd, Sarah E

2011-01-01

Prion disease incubation time in mice is determined by many factors including PrP expression level, Prnp alleles, genetic background, prion strain and route of inoculation. Sex differences have been described in age of onset for vCJD and in disease duration for both vCJD and sporadic CJD and have also been shown in experimental models. The sex effects reported for mouse incubation times are often contradictory and detail only one strain of mice or prions, resulting in broad generalisations and a confusing picture. To clarify the effect of sex on prion disease incubation time in mice we have compared male and female transmission data from twelve different inbred lines of mice inoculated with at least two prion strains, representing both mouse-adapted scrapie and BSE. Our data show that sex can have a highly significant difference on incubation time. However, this is limited to particular mouse and prion strain combinations. No sex differences were seen in endogenous PrP(C) levels nor in the neuropathological markers of prion disease: PrP(Sc) distribution, spongiosis, neuronal loss and gliosis. These data suggest that when comparing incubation times between experimental groups, such as testing the effects of modifier genes or therapeutics, single sex groups should be used.

Molecular Regulation of Parturition: A Myometrial Perspective

PubMed Central

Renthal, Nora E.; Williams, Koriand’r C.; Montalbano, Alina P.; Chen, Chien-Cheng; Gao, Lu; Mendelson, Carole R.

2015-01-01

The molecular mechanisms that maintain quiescence of the myometrium throughout most of pregnancy and promote its transformation to a highly coordinated contractile unit culminating in labor are complex and intertwined. During pregnancy, progesterone (P4) produced by the placenta and/or ovary serves a dominant role in maintaining myometrial quiescence by blocking proinflammatory response pathways and expression of so-called “contractile” genes. In the majority of placental mammals, increased uterine contractility near term is heralded by an increase in circulating estradiol-17β (E2) and/or increased estrogen receptor α (ERα) activity and a sharp decline in circulating P4 levels. However, in women, circulating levels of P4 and progesterone receptors (PR) in myometrium remain elevated throughout pregnancy and into labor. This has led to the concept that increased uterine contractility leading to term and preterm labor is mediated, in part, by a decline in PR function. The biochemical mechanisms for this decrease in PR function are also multifaceted and interwoven. In this paper, we focus on the molecular mechanisms that mediate myometrial quiescence and contractility and their regulation by the two central hormones of pregnancy, P4 and estradiol-17β. The integrative roles of microRNAs also are considered. PMID:26337112

The Two-Component System PhoPR of Clostridium acetobutylicum Is Involved in Phosphate-Dependent Gene Regulation ▿

PubMed Central

Fiedler, Tomas; Mix, Maren; Meyer, Uta; Mikkat, Stefan; Glocker, Michael O.; Bahl, Hubert; Fischer, Ralf-Jörg

2008-01-01

The phoPR gene locus of Clostridium acetobutylicum ATCC 824 comprises two genes, phoP and phoR. Deduced proteins are predicted to represent a response regulator and sensor kinase of a phosphate-dependent two-component regulatory system. We analyzed the expression patterns of phoPR in Pi-limited chemostat cultures and in response to Pi pulses. A basic transcription level under high-phosphate conditions was shown, and a significant increase in mRNA transcript levels was found when external Pi concentrations dropped below 0.3 mM. In two-dimensional gel electrophoresis experiments, a 2.5-fold increase in PhoP was observed under Pi-limiting growth conditions compared to growth with an excess of Pi. At least three different transcription start points for phoP were determined by primer extension analyses. Proteins PhoP and an N-terminally truncated *PhoR were individually expressed heterologously in Escherichia coli and purified. Autophosphorylation of *PhoR and phosphorylation of PhoP were shown in vitro. Electromobility shift assays proved that there was a specific binding of PhoP to the promoter region of the phosphate-regulated pst operon of C. acetobutylicum. PMID:18689481

Three-dimensional fusion of spaceborne and ground radar reflectivity data using a neural network-based approach

NASA Astrophysics Data System (ADS)

Kou, Leilei; Wang, Zhuihui; Xu, Fen

2018-03-01

The spaceborne precipitation radar onboard the Tropical Rainfall Measuring Mission satellite (TRMM PR) can provide good measurement of the vertical structure of reflectivity, while ground radar (GR) has a relatively high horizontal resolution and greater sensitivity. Fusion of TRMM PR and GR reflectivity data may maximize the advantages from both instruments. In this paper, TRMM PR and GR reflectivity data are fused using a neural network (NN)-based approach. The main steps included are: quality control of TRMM PR and GR reflectivity data; spatiotemporal matchup; GR calibration bias correction; conversion of TRMM PR data from Ku to S band; fusion of TRMM PR and GR reflectivity data with an NN method; interpolation of reflectivity data that are below PR's sensitivity; blind areas compensation with a distance weighting-based merging approach; combination of three types of data: data with the NN method, data below PR's sensitivity and data within compensated blind areas. During the NN fusion step, the TRMM PR data are taken as targets of the training NNs, and gridded GR data after horizontal downsampling at different heights are used as the input. The trained NNs are then used to obtain 3D high-resolution reflectivity from the original GR gridded data. After 3D fusion of the TRMM PR and GR reflectivity data, a more complete and finer-scale 3D radar reflectivity dataset incorporating characteristics from both the TRMM PR and GR observations can be obtained. The fused reflectivity data are evaluated based on a convective precipitation event through comparison with the high resolution TRMM PR and GR data with an interpolation algorithm.

The severity of dental caries in adults aged 35 to 44 years residing in the metropolitan area of a large city in Brazil: a cross-sectional study.

PubMed

Costa, Simone M; Vasconcelos, Mara; Haddad, João Paulo A; Abreu, Mauro Henrique N G

2012-07-31

In recent decades, studies in the field of public health have increasingly focused on social determinants that affect the health-illness process. The epidemiological perspective considers oral health to be a reflection of socioeconomic and environmental aspects, and it is particularly influenced by the social context. The aim of the present study was to assess the association between the severity of dental caries among adults aged 35 to 44 years and characteristics on the different levels at which the determinants of caries operate (individual, social structure and social context). A home-based, cross-sectional field study was carried out involving a sample of 1,150 adults (35 to 44 years of age) residing in metropolitan Belo Horizonte, Brazil. The DMFT (decayed, missing, filled tooth) index (≥14) was used to determine the severity of dental caries. Bivariate and multivariate analyses were carried out using the Poisson regression model with the level of significance set at 5% (p < 0.05) and 95% confidence intervals. The majority of the participants (68.5%) had high caries severity. The rate of high-severity caries in the group between 40 and 44 years of age was 1.15-fold (CI: 1.04-1.26) greater than that among those aged 35 to 39 years. A greater prevalence of high caries severity was found among those who frequently visited the dentist (PR = 1.18; CI: 1.07-1.30), those with a lower income (PR = 1.11; CI: 1.01-1.23), those who reported that their neighborhood did not come together in the previous year to petition political leaders for benefits (PR = 1.16; CI: 1.05-1.28) and those who are unable to make decisions (without empowerment) (PR = 1.12; CI: 1.01-1.24). The present study revealed high dental caries severity in adults, which was associated with individual characteristics, health-related behavior and social structure and contextual variables. These findings underscore the importance of considering social determinants involved in the health-illness process when carrying out epidemiological studies on dental caries.

Rapid and sensitive ultra-high-pressure liquid chromatography-tandem mass spectrometry analysis of the novel anticancer agent PR-104 and its major metabolites in human plasma: Application to a pharmacokinetic study.

PubMed

Gu, Yongchuan; Wilson, William R

2009-10-01

PR-104 is a dinitrobenzamide mustard currently in clinical trial as a hypoxia-activated prodrug. It is converted systemically to the corresponding alcohol, PR-104A, which is activated by nitroreduction to the hydroxylamine (PR-104H) and amine (PR-104M). PR-104A is also metabolised to the O-glucuronide (PR-104G), and by oxidative debromoethylation to the semi-mustard PR-104S. We now report a validated ultra-high-pressure liquid chromatography and tandem mass spectrometry (UHPLC-MS/MS) method for the determination of these metabolites in human plasma. Plasma proteins were precipitated with acidified methanol and the supernatant diluted into water. Aliquots were analysed by UHPLC-MS/MS using a Zorbax Eclipse XDB-C18 Rapid Resolution HT (50mmx2.1mm, 1.8microm) column and gradient of acetonitrile and 0.01% formic acid with a 6min run time. The method had a linear range of 0.1-50microM for PR-104, PR-104A and PR-104G, 0.05-5microM for PR-104H, 0.025-2.5microM for PR-104M and 0.01-1microM for PR-104S. The intra-day and inter-day precision and accuracy were within 14%. The extraction recovery of all analytes was over 87%. The validated method was illustrated by using it to study the pharmacokinetics of PR-104 and its metabolites in a human patient.

Search for new phases in the Praseodymium-Silicon system

NASA Astrophysics Data System (ADS)

de La Venta, Jose; Basaran, Ali C.; Grant, Ted; Gallardo-Amores, J.; Ramirez, J. G.; Suchomel, M. R.; Alario-Franco, M. A.; Fisk, Zachary; Schuller, Ivan K.

2013-03-01

We searched for new superconducting and magnetic phases in the Pr-Si system using high-pressure high-temperature and conventional arc melting syntheses. High pressure synthesis is a unique technique which allows incorporation of elements into compounds which otherwise cannot be synthesized at ambient pressure Both high and low Si concentration areas of the phase diagram were explored. To investigate the high Si concentration compounds, PrSi2 with an excess of Si was subjected to HP-HT synthesis. To explore the high Pr concentration binary compound Pr5Si3, we have synthesized undoped Pr5Si3 as well as different samples doped with C or B. High resolution X-ray powder diffraction, Magnetic Field Modulated Microwave Spectroscopy and magnetic characterization found that the addition of C gave rise to multiple previously-unknown ferromagnetic phases. Furthermore, X-ray refinement of the undoped samples confirmed the existence of the so far unconfirmed Pr3Si2 phase. Work supported by AFOSR MURI #F49550-09-1-0577 dedicated to Search for New Superconductors for Energy and Power A. Use of the Advanced Photon Source at ANL was supported by the U. S. DoE, Office of Basic Energy Sciences, Contract No. DE-AC02-06CH11357.

Daily short message service surveys to measure sexual behavior and pre-exposure prophylaxis use among Kenyan men and women.

PubMed

Curran, Kathryn; Mugo, Nelly R; Kurth, Ann; Ngure, Kenneth; Heffron, Renee; Donnell, Deborah; Celum, Connie; Baeten, Jared M

2013-11-01

Pre-exposure prophylaxis (PrEP) is a novel HIV prevention strategy which requires high adherence. We tested the use of daily short message service (i.e., SMS/text message) surveys to measure sexual behavior and PrEP adherence in Kenya. Ninety-six HIV-uninfected adult individuals, taking daily oral PrEP in a clinical trial, received daily SMS surveys for 60 days. Most participants (96.9 %) reported taking PrEP on ≥80 % days, but 69.8 % missed at least one dose. Unprotected sex was reported on 4.9 % of days; however, 47.9 % of participants reported unprotected sex at least once. Unprotected sex was not correlated with PrEP use (OR = 0.95). Participants reporting more sex were less likely to report PrEP non-adherence and those reporting no sex were most likely to report missing a PrEP dose (adjusted OR = 1.87). PrEP adherence was high, missed doses were correlated with sexual abstinence, and unprotected sex was not associated with decreased PrEP adherence.

Semiautomated cell-free conversion of prion protein: applications for high-throughput screening of potential antiprion drugs.

PubMed

Breydo, Leonid; Bocharova, Olga V; Baskakov, Ilia V

2005-04-01

Transmissible spongiform encephalitis (TSE) is a lethal illness with no known treatment. Conversion of the cellular prion protein (PrP(C)) into the infectious isoform (PrP(Sc)) is believed to be the central event in the development of this disease. Recombinant PrP (rPrP) protein folded into the amyloid conformation was shown to cause the transmissible form of prion disease in transgenic mice and can be used as a surrogate model for PrP(Sc). Here, we introduced a semiautomated assay of in vitro conversion of rPrP protein to the amyloid conformation. We have examined the effect of known inhibitors of prion propagation on this conversion and found good correlation between their activity in this assay and that in other in vitro assays. We thus propose that the conversion of rPrP to the amyloid isoform can serve as a high-throughput screen for possible inhibitors of PrP(Sc) formation and potential anti-TSE drugs.

Endogenous Opioid Signaling in the Medial Prefrontal Cortex is Required for the Expression of Hunger-Induced Impulsive Action.

PubMed

Selleck, Ryan A; Lake, Curtis; Estrada, Viridiana; Riederer, Justin; Andrzejewski, Matthew; Sadeghian, Ken; Baldo, Brian A

2015-09-01

Opioid transmission and dysregulated prefrontal cortex (PFC) activity have both been implicated in the inhibitory-control deficits associated with addiction and binge-type eating disorders. What remains unknown, however, is whether endogenous opioid transmission within the PFC modulates inhibitory control. Here, we compared intra-PFC opioid manipulations with a monoamine manipulation (d-amphetamine), in two sucrose-reinforced tasks: progressive ratio (PR), which assays the motivational value of an incentive, and differential reinforcement of low response rates (DRLs), a test of inhibitory control. Intra-PFC methylnaloxonium (M-NX, a limited diffusion opioid antagonist) was given to rats in a 'low-drive' condition (2-h food deprivation), and also after a motivational shift to a 'high-drive' condition (18-h food deprivation). Intra-PFC DAMGO (D-[Ala2,N-MePhe4, Gly-ol]-enkephalin; a μ-opioid agonist) and d-amphetamine were also tested in both tasks, under the low-drive condition. Intra-PFC M-NX nearly eliminated impulsive action in DRL engendered by hunger, at a dose (1 μg) that significantly affected neither hunger-induced PR enhancement nor hyperactivity. At a higher dose (3 μg), M-NX eliminated impulsive action and returned PR breakpoint to low-drive levels. Conversely, intra-PFC DAMGO engendered 'high-drive-like' effects: enhancement of PR and impairment of DRL performance. Intra-PFC d-amphetamine failed to produce effects in either task. These results establish that endogenous PFC opioid transmission is both necessary and sufficient for the expression of impulsive action in a high-arousal, high-drive appetitive state, and that PFC-based opioid systems enact functionally unique effects on food impulsivity and motivation relative to PFC-based monoamine systems. Opioid antagonists may represent effective treatments for a range of psychiatric disorders with impulsivity features.

PrE (Person-Relative-to-Event) Theory of Coping with Threat.

ERIC Educational Resources Information Center

Mulilis, John-Paul; Duval, T. Shelley

The generalizability of Person-Relative-to-Event (PrE) theory, originally applied to disaster-related situations, is investigated in a non-disaster simulation. The PrE theory of coping with threat emphasizes the relationship between level of appraised threat relative to person resources and personal responsibility. This theory has previously been…

Paths to Upper Level Positions in Public Relations

ERIC Educational Resources Information Center

Bishop, Patrick J.

2010-01-01

Preparation for a career in the field of public relations (PR) is based on a set of unique core competencies typically found in liberal arts. Though PR professionals rarely gain business degrees, they acquire knowledge, skills, perspectives, and strategies well-suited to executive-level positions in business. Additionally, managerial positions in…

A cost-effectiveness analysis of HIV preexposure prophylaxis for men who have sex with men in Australia.

PubMed

Schneider, Karen; Gray, Richard T; Wilson, David P

2014-04-01

Antiretroviral therapy (ART) used as preexposure prophylaxis (PrEP) by human immunodeficiency virus (HIV)-seronegative individuals reduces the risk of acquiring HIV. However, the population-level impact and cost-effectiveness of using PrEP as a public health intervention remains debated. We used a stochastic agent-based model of HIV transmission and progression to simulate the clinical and cost outcomes of different strategies of providing PrEP to men who have sex with men (MSM) in New South Wales (NSW), Australia. Model outcomes were reported as incremental cost-effectiveness ratios (ICERs) in 2013 Australian dollars per quality-adjusted life-year gained (QALYG). The use of PrEP in 10%-30% of the entire NSW MSM population was projected to cost an additional $316-$952 million over the course of 10 years, and cost >$400 000 per QALYG compared with the status quo. Targeting MSM with sexual partners ranging between >10 to >50 partners within 6 months cost an additional $31-$331 million dollars, and cost >$110 000 per QALYG compared with the status quo. We found that preexposure prophylaxis is most cost-effective when targeted for HIV-negative MSM in a discordant regular partnership. The ICERs ranged between $8399 and $11 575, for coverage ranging between 15% and 30%, respectively. Targeting HIV-negative MSM in a discordant regular partnership is a cost-effective intervention. However, this highly targeted strategy would not have large population-level impact. Other scenarios are unlikely to be cost-effective.

Perceptions of and intentions to adopt HIV pre-exposure prophylaxis among black men who have sex with men in Los Angeles.

PubMed

Brooks, Ronald A; Landovitz, Raphael J; Regan, Rotrease; Lee, Sung-Jae; Allen, Vincent C

2015-12-01

This study assessed perceptions of pre-exposure prophylaxis (PrEP) and their association with PrEP adoption intention among a convenience sample of 224 low socioeconomic status black men who have sex with men (BMSM) residing in Los Angeles. Participants received educational information about PrEP and completed an in-person interview. More than half (60%) of the participants indicated a high intention to adopt PrEP. Younger BMSM (18-29 years) were twice as likely to report a high intention to adopt PrEP compared to older BMSM (30+ years). Only 33% of participants were aware of PrEP and no participant had ever used PrEP. Negative perceptions were associated with a lower PrEP adoption intention and included being uncomfortable taking an HIV medicine when HIV-negative and not knowing if there are long-term side effects of taking an HIV medication. These findings suggest that BMSM may adopt PrEP but that negative perceptions may limit its uptake among this population. In order to facilitate PrEP adoption among BMSM targeted educational and community awareness programmes are needed to provide accurate information on the benefits of PrEP and to address the negative perceptions of PrEP held by local BMSM populations. © The Author(s) 2015.

What people want from sex and preexposure prophylaxis.

PubMed

Grant, Robert M; Koester, Kimberly A

2016-01-01

As demand for preexposure prophylaxis (PrEP) increases, we are learning more about what people want from sex and PrEP. PrEP demand has reached a tipping point in the USA and is increasing rapidly. Although the primary benefit of PrEP use is biological, to reduce risk of HIV infection, PrEP users often express an alternative set of social and emotional benefits that are provided by PrEP. These collateral benefits of PrEP have salience, affect, and are experienced in the present, which are compelling drivers of human behavior. PrEP use has been associated with feeling safe during sex, usually in contrast to ruminations related to fear of HIV or intimate partner violence or control. PrEP can create empowerment, or agency, defined as the capacity and autonomy to act on one's own behalf, because it provides control over one's vulnerability to HIV and relief to women and men who may otherwise worry about whether their partners will use a condom, take antiretroviral therapy, or disclose their HIV status accurately. Planning for sexual and social goals in calm moments is also empowering. These highly desired collateral benefits of PrEP could be undermined, or eliminated, if PrEP is implemented in ways that are coercive or that foment fear of sexual risk compensation, drug resistance, toxicity, or moral judgment. Current PrEP implementation provides direct and indirect benefits that are highly desired.

Photoluminescent emission of Pr 3+ ions in different zirconia crystalline forms

NASA Astrophysics Data System (ADS)

Ramos-Brito, F.; Alejo-Armenta, C.; García-Hipólito, M.; Camarillo, E.; Hernández A, J.; Murrieta S, H.; Falcony, C.

2008-08-01

Polycrystalline praseodymium doped-zirconia powders were synthesized by crystallization of a saturated solution and annealed in air at T a = 950 °C. Monoclinic, tetragonal and cubic crystalline phases of zirconia were obtained. EDS studies showed homogeneous chemical composition over all the powders particles and chemical elemental contents in good agreement with the incorporation of Pr 3+ ion in Zr 4+ sites. XRD patterns showed stabilization of tetragonal and cubic phases at 1.28 and 2.87 at.% of Pr 3+ doping concentrations, respectively. Both unit cells expand when Pr 3+ content increases. All samples showed a crystallite size lower than 27 nm. Diffuse reflectance studies exhibited the presence of the 4f5d absorption band of Pr 3+, and absorption peaks in 440-610 nm region associated with 4f inter-level electronic transitions in Pr 3+ ion. Low temperature (20 K) photo-luminescent spectroscopic measurements over excitation of 488 nm for praseodymium doped zirconia, showed multiple emission peaks in the 520-900 nm range of the electromagnetic spectrum, associated with typical 4f inter-level electronic transition in Pr 3+. Incorporation of Pr 3+ in more than one zirconia crystalline phase and the incorporation in cubic C 2 sites, were observed. Zirconia powders presented significant differences in its emission spectra as a function of the type of crystalline phase compounds.

The multivesicular body is the major internal site of prion conversion

PubMed Central

Yim, Yang-In; Park, Bum-Chan; Yadavalli, Rajgopal; Zhao, Xiaohong; Eisenberg, Evan; Greene, Lois E.

2015-01-01

ABSTRACT The conversion of the properly folded prion protein, PrPc, to its misfolded amyloid form, PrPsc, occurs as the two proteins traffic along the endocytic pathway and PrPc is exposed to PrPsc. To determine the specific site of prion conversion, we knocked down various proteins in the endocytic pathway including Rab7a, Tsg101 and Hrs (also known as HGS). PrPsc was markedly reduced in two chronically infected cell lines by preventing the maturation of the multivesicular body, a process that begins in the early endosome and ends with the sorting of cargo to the lysosome. By contrast, knocking down proteins in the retromer complex, which diverts cargo away from the multivesicular body caused an increase in PrPsc levels. These results suggest that the multivesicular body is the major site for intracellular conversion of PrPc to PrPsc. PMID:25663703

Antioxidant potential of mulberry and non-mulberry silk sericin and its implications in biomedicine.

PubMed

Kumar, Jadi Praveen; Mandal, Biman B

2017-07-01

Sericin, a principal constituent of silk, is widely used in various biomedical applications. In addition, conferring protection against free radicals and oxidative damage add more value to its therapeutic potential. However, the antioxidant (AO) properties of silk sericin (SS) remains contingent on extraction procedures. In the present study, we have evaluated the effect of different extraction methods (conventional, autoclaving, urea, alkali and acid-degradation) on AO properties of SS from three Indian silk varieties [Antheraea assamensis (AA), Philosamia ricini (PR) and Bombyx mori (BM)]. The physico-chemical characterization studies revealed that the molecular weight of SS isolates of each method ranged from 10 to 220kDa along with varied protein structural biochemistry. SS extracts using urea-degradation (BM, PR and AA), conventional method and alkali-degradation (BM) displayed high percentage of β-sheets, random coils and turns. Acid-degraded SS (PR, followed by AA and BM) showed the highest total flavonoid content while conventional method (PR), autoclaving (AA) and alkali-degradation (BM) displayed lowest flavonoid levels. Interestingly, SS extracted by autoclaving (BM and AA), acid-degradation (PR), conventional and alkali-degradation (BM, AA and PR) methods exhibited 50% reduction of 2, 2-diphenyl-1-picrylhydrazyl (DPPH) radical. Moreover, the efficacy of antioxidant potential of SS extracted by different methods was found to be in the order of "alkali>autoclaving>conventional" as demonstrated in L929 cells. Correspondingly, the anti-lipid peroxidation activity of SS extracted by alkali method (AA, BM and PR) further confirmed better AO properties amid others. Thus, the present study demonstrates that the extraction methods may significantly affect AO activity of SS which might be of importance for potential cosmetic applications. Copyright © 2017 Elsevier Inc. All rights reserved.

Conformation-dependent epitopes recognized by prion protein antibodies probed using mutational scanning and deep sequencing.

PubMed

Doolan, Kyle M; Colby, David W

2015-01-30

Prion diseases are caused by a structural rearrangement of the cellular prion protein, PrP(C), into a disease-associated conformation, PrP(Sc), which may be distinguished from one another using conformation-specific antibodies. We used mutational scanning by cell-surface display to screen 1341 PrP single point mutants for attenuated interaction with four anti-PrP antibodies, including several with conformational specificity. Single-molecule real-time gene sequencing was used to quantify enrichment of mutants, returning 26,000 high-quality full-length reads for each screened population on average. Relative enrichment of mutants correlated to the magnitude of the change in binding affinity. Mutations that diminished binding of the antibody ICSM18 represented the core of contact residues in the published crystal structure of its complex. A similarly located binding site was identified for D18, comprising discontinuous residues in helix 1 of PrP, brought into close proximity to one another only when the alpha helix is intact. The specificity of these antibodies for the normal form of PrP likely arises from loss of this conformational feature after conversion to the disease-associated form. Intriguingly, 6H4 binding was found to depend on interaction with the same residues, among others, suggesting that its ability to recognize both forms of PrP depends on a structural rearrangement of the antigen. The application of mutational scanning and deep sequencing provides residue-level resolution of positions in the protein-protein interaction interface that are critical for binding, as well as a quantitative measure of the impact of mutations on binding affinity. Copyright © 2014 Elsevier Ltd. All rights reserved.

Theobroma cacao L. pathogenesis-related gene tandem array members show diverse expression dynamics in response to pathogen colonization.

PubMed

Fister, Andrew S; Mejia, Luis C; Zhang, Yufan; Herre, Edward Allen; Maximova, Siela N; Guiltinan, Mark J

2016-05-17

The pathogenesis-related (PR) group of proteins are operationally defined as polypeptides that increase in concentration in plant tissues upon contact with a pathogen. To date, 17 classes of highly divergent proteins have been described that act through multiple mechanisms of pathogen resistance. Characterizing these families in cacao, an economically important tree crop, and comparing the families to those in other species, is an important step in understanding cacao's immune response. Using publically available resources, all members of the 17 recognized pathogenesis-related gene families in the genome of Theobroma cacao were identified and annotated resulting in a set of ~350 members in both published cacao genomes. Approximately 50 % of these genes are organized in tandem arrays scattered throughout the genome. This feature was observed in five additional plant taxa (three dicots and two monocots), suggesting that tandem duplication has played an important role in the evolution of the PR genes in higher plants. Expression profiling captured the dynamics and complexity of PR genes expression at basal levels and after induction by two cacao pathogens (the oomycete, Phytophthora palmivora, and the fungus, Colletotrichum theobromicola), identifying specific genes within families that are more responsive to pathogen challenge. Subsequent qRT-PCR validated the induction of several PR-1, PR-3, PR-4, and PR-10 family members, with greater than 1000 fold induction detected for specific genes. We describe candidate genes that are likely to be involved in cacao's defense against Phytophthora and Colletotrichum infection and could be potentially useful for marker-assisted selection for breeding of disease resistant cacao varieties. The data presented here, along with existing cacao-omics resources, will enable targeted functional genetic screening of defense genes likely to play critical functions in cacao's defense against its pathogens.

Risk Transmission Indicator of Schistosomiasis Japonicum Considering Human Activities in Lake and Marshland Regions- A Case Study of Poyang Lake, Jiangxi Province, P.R. China

NASA Astrophysics Data System (ADS)

Marie, Tiphanie; Yesou, Herve; Huber, Claire; De Fraipont, Paul; Uribe, Carlos; Lacaux, Jean-Pierre; Lafaye, Murielle; Lai, Xijun; Desnos, Yves-Louis

2013-01-01

This paper present the method used to determine the areas where schistosomiasis transmission is the higher. A primary work was necessary to this study: identification of potential presence of schistosomiasis japonicum’s vector in Poyang lakeshore area (Jiangxi Province, P.R. China). Results obtained from its first work were crossing with the most risky human activities and with villages to elaborate a level of transmission risk. The first parameter determined concern fishing, which was identified like the most risky activity for schistosomiasis transmission, and fish traps were digitalized using a very high resolution ALOS data. The second parameter is about the risky areas for buffalo grazing, and vector potential presence areas were crossed with village proximity to determine the most risky areas for human transmission. The third parameter built is a level of risk for each village digitalized around Poyang Lake, taking into account the proximity and level of potential presence of vector’s areas.

Is self interdental cleaning associated with dental plaque levels, dental calculus, gingivitis and periodontal disease?

PubMed

Crocombe, L A; Brennan, D S; Slade, G D; Loc, D O

2012-04-01

To ascertain whether interdental cleaning behaviours of Australian adults were associated with lower levels of plaque, gingivitis and periodontal disease. Data were obtained from the National Survey of Adult Oral Health 2004-06. Outcome variables were three indicators of oral hygiene outcomes (the presence or not of dental plaque, dental calculus and gingivitis) and two of periodontal disease (the presence or not of at least one tooth with a periodontal pocket or clinical attachment loss of ≥ 4 mm). The independent variable was classified into the following three groups: regularly clean interproximally 'at least daily' (daily+); 'less than daily' (< daily); and 'do not regularly clean interproximally' (reference group). Poisson regression with robust variance estimation was used to calculate prevalence ratios (PRs) and 95% confidence intervals (95% CIs) relative to the reference group, adjusted for covariates. Regular self interdental cleaning was associated with less dental plaque (< daily, PR = 0.89, 95% CI = 0.84, 0.95; and daily+, PR = 0.89, 95% CI = 0.82, 0.96), less dental calculus (< daily, PR = 0.88, 95% CI = 0.80, 0.97; and daily+, PR = 0.79, 95% CI = 0.70, 0.89) and lower levels of moderate/severe gingivitis (daily+, PR = 0.85, 95% CI = 0.77, 0.94). Periodontal pocketing was less likely for the < daily group (PR = 0.61, 95% CI = 0.46, 0.82), but was not associated with daily+ cleaning (PR = 0.99, 95% CI = 0.663, 1.49). There was not a significant association between interdental cleaning and clinical attachment loss (< daily, PR = 0.90, 95% CI = 0.77, 1.05; and daily+, PR = 1.17, 95% CI = 0.95, 1.44). Regular interdental cleaning was associated with better oral hygiene outcomes, such as dental plaque and gingivitis, although there was no significant association between regular interdental cleaning and clinical attachment loss. © 2011 John Wiley & Sons A/S.

Prevention of Rectal SHIV Transmission in Macaques by Daily or Intermittent Prophylaxis with Emtricitabine and Tenofovir

PubMed Central

García-Lerma, J. Gerardo; Otten, Ron A; Qari, Shoukat H; Jackson, Eddie; Cong, Mian-er; Masciotra, Silvina; Luo, Wei; Kim, Caryn; Adams, Debra R; Monsour, Michael; Lipscomb, Jonathan; Johnson, Jeffrey A; Delinsky, David; Schinazi, Raymond F; Janssen, Robert; Folks, Thomas M; Heneine, Walid

2008-01-01

Background In the absence of an effective vaccine, HIV continues to spread globally, emphasizing the need for novel strategies to limit its transmission. Pre-exposure prophylaxis (PrEP) with antiretroviral drugs could prove to be an effective intervention strategy if highly efficacious and cost-effective PrEP modalities are identified. We evaluated daily and intermittent PrEP regimens of increasing antiviral activity in a macaque model that closely resembles human transmission. Methods and Findings We used a repeat-exposure macaque model with 14 weekly rectal virus challenges. Three drug treatments were given once daily, each to a different group of six rhesus macaques. Group 1 was treated subcutaneously with a human-equivalent dose of emtricitabine (FTC), group 2 received orally the human-equivalent dosing of both FTC and tenofovir-disoproxil fumarate (TDF), and group 3 received subcutaneously a similar dosing of FTC and a higher dose of tenofovir. A fourth group of six rhesus macaques (group 4) received intermittently a PrEP regimen similar to group 3 only 2 h before and 24 h after each weekly virus challenge. Results were compared to 18 control macaques that did not receive any drug treatment. The risk of infection in macaques treated in groups 1 and 2 was 3.8- and 7.8-fold lower than in untreated macaques (p = 0.02 and p = 0.008, respectively). All six macaques in group 3 were protected. Breakthrough infections had blunted acute viremias; drug resistance was seen in two of six animals. All six animals in group 4 that received intermittent PrEP were protected. Conclusions This model suggests that single drugs for daily PrEP can be protective but a combination of antiretroviral drugs may be required to increase the level of protection. Short but potent intermittent PrEP can provide protection comparable to that of daily PrEP in this SHIV/macaque model. These findings support PrEP trials for HIV prevention in humans and identify promising PrEP modalities. PMID:18254653

Turbulent convective flows in a cubic cavity at high Prandtl number

NASA Astrophysics Data System (ADS)

Vasiliev, A.; Sukhanovskii, A.; Frick, P.

2016-10-01

Characteristics of turbulent convective flows in a cubic cell is studied experimentally for high values of Prandtl number. The first set was carriied out with propylene glycol (Pr = 64 and the second one with 25% water solution of propylene glycol (Pr = 24). It was found that increasing of Pr from 6.1 to 24 leads only to the slight change of intensity of the flow but during the next increasing of Pr from 24 to 64 the flow changes its structure.

Clinical significance of CXCL16/CXCR6 expression in patients with prostate cancer.

PubMed

Ha, Hong Koo; Lee, Wan; Park, Hyun Jun; Lee, Sang Don; Lee, Jeong Zoo; Chung, Moon Kee

2011-01-01

We hypothesized that the CXCL16-CXCR6 ligand-receptor system may play an important role in prostate cancer progression. Levels of CXCL16 and CXCR6 expression were evaluated in prostate cancer cell lines (PC-3 and LNCaP) and normal prostate epithelial cells (PrEC), as well as in tissues from 354 patients. The immunohistochemical expression of CXCL16/CXCR6 was greater in the PC-3/LNCaP cells than in the PrEC cell line. The expression of CXCL16/CXCR6 was significantly higher in prostate cancer than in benign prostatic hypertrophy. Using RT-PCR, the expression of CXCL16/CXCR6 was found to be greater in the PC-3/LNCaP cells than in the PrEC cell line. CXCL16/CXCR6 was weakly detected in lung and liver tissues, whereas CXCL16 was highly expressed in specimens of bone metastasis. CXCL16 immunostaining was related to Gleason score, T stage, tumor volume, perineural invasion and lymph node metastasis. However, biochemical PSA recurrence was not related to the expression of CXCL16/CXCR6. High CXCL16/CXCR6 expression may be related to aggressive cancer behavior, and high CXCL16 expression to bone metastases.

Sexual partnerships and considerations for HIV antiretroviral pre-exposure prophylaxis utilization among high-risk substance using men who have sex with men.

PubMed

Mimiaga, Matthew J; Closson, Elizabeth F; Kothary, Vishesh; Mitty, Jennifer A

2014-01-01

Men who have sex with men (MSM) remain at great risk of HIV in the United States, representing 65 % of incident HIV infections. One factor contributing to the high rate of HIV infection among MSM is use of "recreational" drugs that are highly associated with unprotected anal sex. Pre-exposure chemoprophylaxis (PrEP) is a novel biomedical HIV prevention strategy that has the potential to reduce HIV transmission in MSM. Main and casual sex partners play a role in HIV prevention efforts for MSM. The study aimed to qualitatively explore the perceived influences of sexual relationships on promoting and inhibiting PrEP use among high-risk MSM who report regular drug use. Semi-structured qualitative interviews were conducted with 40 participants recruited in Boston, Massachusetts. Data were analyzed using descriptive qualitative analysis. Casual partners presented a distinct set of concerns from primary partnerships. MSM generally viewed main partners as a potential source of support for taking PrEP. Given their informal and often temporary nature, PrEP disclosure to casual partners was considered unnecessary. HIV-related stigma and substance use were also perceived as barriers to discussing PrEP use with casual partners. MSM articulated a high degree of personal agency regarding their ability to take PrEP. Findings suggest that behavioral interventions to improve PrEP utilization and adherence for high-risk MSM should be tailored to sex partner type and the parameters established between sex partners. Approaches to PrEP disclosure and partner engagement should be informed by the relative benefits and limitations characterized by these different types of relationships.

Pre-exposure prophylaxis for HIV-negative persons with partners living with HIV: uptake, use, and effectiveness in an open-label demonstration project in East Africa

PubMed Central

Heffron, Renee; Ngure, Kenneth; Odoyo, Josephine; Bulya, Nulu; Tindimwebwa, Edna; Hong, Ting; Kidoguchi, Lara; Donnell, Deborah; Mugo, Nelly R.; Bukusi, Elizabeth A.; Katabira, Elly; Asiimwe, Stephen; Morton, Jennifer; Morrison, Susan; Haugen, Harald; Mujugira, Andrew; Haberer, Jessica E.; Ware, Norma C.; Wyatt, Monique A.; Marzinke, Mark A.; Frenkel, Lisa M.; Celum, Connie; Baeten, Jared M.

2017-01-01

Introduction: Pre-exposure prophylaxis (PrEP) can provide high protection against HIV infection and is a recommended intervention for HIV-negative persons with substantial HIV risk, such as individuals with a partner living with HIV.  Demonstration projects of PrEP have been conducted in diverse settings worldwide to illustrate practical examples of how PrEP can be delivered.  Methods: We evaluated delivery of PrEP for HIV-negative partners within heterosexual HIV serodiscordant couples in an open-label demonstration project in East Africa.  The delivery model integrated PrEP into HIV treatment services, prioritizing PrEP for HIV-negative partners within serodiscordant couples prior to and during the first 6 months after the partner living with HIV initiated antiretroviral therapy (ART).  We measured adherence to PrEP through medication event monitoring system (MEMS) bottle caps and quantification of tenofovir in plasma among a random sample of participants. We estimated HIV infections prevented using a counterfactual cohort simulated from the placebo arm of a previous PrEP clinical trial. Results: We enrolled 1,010 HIV serodiscordant couples that were naïve to ART and PrEP.  Ninety-seven percent (97%) of HIV-negative partners initiated PrEP, and when PrEP was dispensed, objective measures suggest high adherence: 71% of HIV-negative participants took ≥80% of expected doses, as recorded via MEMS, and 81% of plasma samples had tenofovir detected.  A total of 4 incident HIV infections were observed (incidence rate=0.24 per 100 person-years), a 95% reduction (95% CI 86-98%, p<0.0001) in HIV incidence, relative to estimated HIV incidence for the population in the absence of PrEP integrated into HIV treatment services.   Conclusions: PrEP uptake and adherence were high and incident HIV was rare in this PrEP demonstration project for African HIV-negative individuals whose partners were known to be living with HIV.  Delivery of PrEP to HIV-negative partners within HIV serodiscordant couples was feasible and should be prioritized for wide-scale implementation. PMID:29355231

Pre-exposure prophylaxis for HIV-negative persons with partners living with HIV: uptake, use, and effectiveness in an open-label demonstration project in East Africa.

PubMed

Heffron, Renee; Ngure, Kenneth; Odoyo, Josephine; Bulya, Nulu; Tindimwebwa, Edna; Hong, Ting; Kidoguchi, Lara; Donnell, Deborah; Mugo, Nelly R; Bukusi, Elizabeth A; Katabira, Elly; Asiimwe, Stephen; Morton, Jennifer; Morrison, Susan; Haugen, Harald; Mujugira, Andrew; Haberer, Jessica E; Ware, Norma C; Wyatt, Monique A; Marzinke, Mark A; Frenkel, Lisa M; Celum, Connie; Baeten, Jared M

2017-11-06

Introduction : Pre-exposure prophylaxis (PrEP) can provide high protection against HIV infection and is a recommended intervention for HIV-negative persons with substantial HIV risk, such as individuals with a partner living with HIV.  Demonstration projects of PrEP have been conducted in diverse settings worldwide to illustrate practical examples of how PrEP can be delivered.  Methods : We evaluated delivery of PrEP for HIV-negative partners within heterosexual HIV serodiscordant couples in an open-label demonstration project in East Africa.  The delivery model integrated PrEP into HIV treatment services, prioritizing PrEP for HIV-negative partners within serodiscordant couples prior to and during the first 6 months after the partner living with HIV initiated antiretroviral therapy (ART).  We measured adherence to PrEP through medication event monitoring system (MEMS) bottle caps and quantification of tenofovir in plasma among a random sample of participants. We estimated HIV infections prevented using a counterfactual cohort simulated from the placebo arm of a previous PrEP clinical trial. Results : We enrolled 1,010 HIV serodiscordant couples that were naïve to ART and PrEP.  Ninety-seven percent (97%) of HIV-negative partners initiated PrEP, and when PrEP was dispensed, objective measures suggest high adherence: 71% of HIV-negative participants took ≥80% of expected doses, as recorded via MEMS, and 81% of plasma samples had tenofovir detected.  A total of 4 incident HIV infections were observed (incidence rate=0.24 per 100 person-years), a 95% reduction (95% CI 86-98%, p<0.0001) in HIV incidence, relative to estimated HIV incidence for the population in the absence of PrEP integrated into HIV treatment services.   Conclusions : PrEP uptake and adherence were high and incident HIV was rare in this PrEP demonstration project for African HIV-negative individuals whose partners were known to be living with HIV.  Delivery of PrEP to HIV-negative partners within HIV serodiscordant couples was feasible and should be prioritized for wide-scale implementation.

Domain structures and Prco antisite point defects in double-perovskite PrBaCo2O5+δ and PrBa0.8Ca0.2Co2O5+δ.

PubMed

Ding, Yong; Chen, Yu; Pradel, Ken C; Zhang, Weilin; Liu, Meilin; Wang, Zhong Lin

2018-06-15

Owing to the excellent mixed-ionic and electronic conductivity and fast oxygen kinetics at reduced temperature (<800 °C), double-perovskite oxides such as PrBaCo 2 O 5+δ exhibit excellent properties as an oxygen electrode for solid oxide fuel cells (SOFCs). Using transmission electron microscopy (TEM), we revealed high-density antiphase domain boundaries (APBs) and 90° domain walls in PrBaCo 2 O 5+δ grains. Besides the regular lamellar 90° domain walls in {021} planes, irregular fine 90° domains are attached to the curved APBs. Electron energy-loss spectroscopy (EELS) reveals the composition variation across some of the 90° domain walls. There are fewer Co and more Ba ions approaching the 90° domain walls, while the changes in Pr and O ions are not detectable. We assume that the extra Ba 2+ cations replace the Pr 3+ cations, while the Pr 3+ cations go to the Co site to form Pr Co antisite point defects and become Pr 4+ . In this case, the Pr 4+ cations will help to balance the local charges and have compatible ionic radius with that of Co 3+ . The local strain field around the 90° domain walls play a crucial role in the stabilization of such Pr Co antisite point defects. The antisite point defects have been observed in our high-resolution TEM images and aberration-corrected high-angle annular dark-field (HAADF) scanning TEM images. After Ca 2+ doped into PrBaCo 2 O 5+δ to improve the structure stability, we observed tweed structures in the PrBa 0.8 Ca 0.2 Co 2 O 5+δ grain. The tweed structure is composed of high-density intersected needle-shaped 90° domain walls, which is linked to a strong local strain field and composition variation. Even when the temperature is increased to 750 °C, the domain structures are still stable as revealed by our in situ TEM investigation. Therefore, the influence of the domain structures and the Pr Co antisite defects on the ionic and electric conductivities must be considered. Copyright © 2018. Published by Elsevier B.V.

Intercomparison of spaceborne precipitation radars and its applications in examining precipitation-topography relationships in the Tibetan Plateau

NASA Astrophysics Data System (ADS)

Tang, G.; Gao, J.; Long, D.

2017-12-01

Precipitation is one of the most important components in the water and energy cycles. Spaceborne radars are considered the most direct technology for observing precipitation from space since 1998. This study compares and evaluates the only three existing spaceborne precipitation radars, i.e., the Ku-band precipitation radar (TRMM PR), the W-band Cloud Profiling Radar (CloudSat CPR), and the Ku/Ka-band Dual-frequency Precipitation Radar (GPM DPR). In addition, TRMM PR and GPM DPR are evaluated against hourly rain gauge data in Mainland China. The Tibetan Plateau (TP) is known as the Earth's third pole where precipitation is affected profoundly by topography. However, ground gauges are extremely sparse in the TP, and spaceborne radars can provide valuable data with relatively high accuracy. The relationships between precipitation and topography over the TP are investigated using 17-year TRMM PR data and 2-year GPM DPR data, in combination with rain gauge data. Results indicate that: (1) DPR and PR agree with each other and correlate very well with gauges in Mainland China. DPR improves light precipitation detectability significantly compared with PR. However, DPR high sensitivity scans (HS) deviates from DPR normal and matched scans (NS and MS) and PR in the comparison based on global coincident events and rain gauges in China; (2) CPR outperforms the other two radars in terms of light precipitation detection. In terms of global snowfall estimation, DPR and CPR show very different global snowfall distributions originating from different frequencies, retrieval algorithms, and sampling characteristics; and (3) Precipitation generally decreases exponentially with increasing elevation in the TP. The precipitation-topography relationships are regressed using exponential fitting in seventeen river basins in the TP with good coefficients of determination. Due to the short time span of GPM DPR, the relationships based on GPM DPR data are less robust than those derived from TRMM PR data. The Level-3 precipitation products, i.e., GPM IMERG and GSMaP, can reproduce the general pattern on how precipitation varies with elevation but misrepresent some important details.

The chemistry of prions: small molecules, protein conformers and mass spectrometry

USDA-ARS?s Scientific Manuscript database

Background/Introduction. Prions propagate by converting a normal cellular isoform (PrPC) into the prion isoform (PrPSc) in a template-driven process. The lysines in PrPC are highly conserved and strongly influence prion propagation, based on studies using natural polymorphisms of PrPC and transg...

Loss of prion protein is associated with the development of insulin resistance and obesity.

PubMed

de Brito, Giovanna; Lupinacci, Fernanda C; Beraldo, Flávio H; Santos, Tiago G; Roffé, Martín; Lopes, Marilene H; de Lima, Vladmir C; Martins, Vilma R; Hajj, Glaucia N

2017-08-17

Prion protein (PrP C ) was initially described due to its involvement in transmissible spongiform encephalopathies. It was subsequently demonstrated to be a cell surface molecule involved in many physiological processes, such as vesicle trafficking. Here, we investigated the roles of PrP C in the response to insulin and obesity development. Two independent PrP C knockout (KO) and one PrP C overexpressing (TG20) mouse models were fed high-fat diets, and the development of insulin resistance and obesity was monitored. PrP C KO mice fed high-fat diets presented all of the symptoms associated with the development of insulin resistance: hyperglycemia, hyperinsulinemia, and obesity. Conversely, TG20 animals fed high-fat diets showed reduced weight and insulin resistance. Accordingly, the expression of peroxisome proliferator-activated receptor gamma (PPARγ) was reduced in PrP C KO mice and increased in TG20 animals. PrP C KO cells also presented reduced glucose uptake upon insulin stimulation, due to reduced translocation of the glucose transporter Glut4. Thus, our results suggest that PrP C reflects susceptibility to the development of insulin resistance and metabolic syndrome. © 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

Absolute quantification of prion protein (90-231) using stable isotope-labeled chymotryptic peptide standards in a LC-MRM AQUA workflow.

PubMed

Sturm, Robert; Sheynkman, Gloria; Booth, Clarissa; Smith, Lloyd M; Pedersen, Joel A; Li, Lingjun

2012-09-01

Substantial evidence indicates that the disease-associated conformer of the prion protein (PrP(TSE)) constitutes the etiologic agent in prion diseases. These diseases affect multiple mammalian species. PrP(TSE) has the ability to convert the conformation of the normal prion protein (PrP(C)) into a β-sheet rich form resistant to proteinase K digestion. Common immunological techniques lack the sensitivity to detect PrP(TSE) at subfemtomole levels, whereas animal bioassays, cell culture, and in vitro conversion assays offer higher sensitivity but lack the high-throughput the immunological assays offer. Mass spectrometry is an attractive alternative to the above assays as it offers high-throughput, direct measurement of a protein's signature peptide, often with subfemtomole sensitivities. Although a liquid chromatography-multiple reaction monitoring (LC-MRM) method has been reported for PrP(TSE), the chemical composition and lack of amino acid sequence conservation of the signature peptide may compromise its accuracy and make it difficult to apply to multiple species. Here, we demonstrate that an alternative protease (chymotrypsin) can produce signature peptides suitable for a LC-MRM absolute quantification (AQUA) experiment. The new method offers several advantages, including: (1) a chymotryptic signature peptide lacking chemically active residues (Cys, Met) that can confound assay accuracy; (2) low attomole limits of detection and quantitation (LOD and LOQ); and (3) a signature peptide retaining the same amino acid sequence across most mammals naturally susceptible to prion infection as well as important laboratory models. To the authors' knowledge, this is the first report on the use of a non-tryptic peptide in a LC-MRM AQUA workflow.

Absolute quantification of prion protein (90-231) using stable isotope-labeled chymotryptic peptide standards in a LC-MRM AQUA workflow

PubMed Central

Sturm, Robert; Kreitinger, Gloria; Booth, Clarissa; Smith, Lloyd; Pedersen, Joel; Li, Lingjun

2012-01-01

Substantial evidence indicates that the disease-associated conformer of the prion protein (PrPTSE) constitutes the etiological agent in prion diseases. These diseases affect multiple mammalian species. PrPTSE has the ability to convert the conformation of the normal prion protein (PrPC) into a β-sheet rich form resistant to proteinase K digestion. Common immunological techniques lack the sensitivity to detect PrPTSE at sub-femtomole levels while animal bioassays, cell culture, and in vitro conversion assays offer ultrasensitivity but lack the high-throughput the immunological assays offer. Mass spectrometry is an attractive alternative to the above assays as it offers high-throughput, direct measurement of a protein’s signature peptide, often with sub-femtomole sensitivities. Although a liquid chromatography-multiple reaction monitoring (LC-MRM) method has been reported for PrPTSE, the chemical composition and lack of amino acid sequence conservation of the signature peptide may compromise its accuracy and make it difficult to apply to multiple species. Here, we demonstrate that an alternative protease (chymotrypsin) can produce signature peptides suitable for a LC-MRM absolute quantification (AQUA) experiment. The new method offers several advantages, including: (1) a chymotryptic signature peptide lacking chemically active residues (Cys, Met) that can confound assay accuracy; (2) low attomole limits of detection and quantitation (LOD and LOQ); and (3) a signature peptide retaining the same amino acid sequence across most mammals naturally susceptible to prion infection as well as important laboratory models. To the authors’ knowledge, this is the first report of the use of a non-tryptic peptide in a LC-MRM AQUA workflow. PMID:22714949

Absolute Quantification of Prion Protein (90-231) Using Stable Isotope-Labeled Chymotryptic Peptide Standards in a LC-MRM AQUA Workflow

NASA Astrophysics Data System (ADS)

Sturm, Robert; Sheynkman, Gloria; Booth, Clarissa; Smith, Lloyd M.; Pedersen, Joel A.; Li, Lingjun

2012-09-01

Substantial evidence indicates that the disease-associated conformer of the prion protein (PrPTSE) constitutes the etiologic agent in prion diseases. These diseases affect multiple mammalian species. PrPTSE has the ability to convert the conformation of the normal prion protein (PrPC) into a β-sheet rich form resistant to proteinase K digestion. Common immunological techniques lack the sensitivity to detect PrPTSE at subfemtomole levels, whereas animal bioassays, cell culture, and in vitro conversion assays offer higher sensitivity but lack the high-throughput the immunological assays offer. Mass spectrometry is an attractive alternative to the above assays as it offers high-throughput, direct measurement of a protein's signature peptide, often with subfemtomole sensitivities. Although a liquid chromatography-multiple reaction monitoring (LC-MRM) method has been reported for PrPTSE, the chemical composition and lack of amino acid sequence conservation of the signature peptide may compromise its accuracy and make it difficult to apply to multiple species. Here, we demonstrate that an alternative protease (chymotrypsin) can produce signature peptides suitable for a LC-MRM absolute quantification (AQUA) experiment. The new method offers several advantages, including: (1) a chymotryptic signature peptide lacking chemically active residues (Cys, Met) that can confound assay accuracy; (2) low attomole limits of detection and quantitation (LOD and LOQ); and (3) a signature peptide retaining the same amino acid sequence across most mammals naturally susceptible to prion infection as well as important laboratory models. To the authors' knowledge, this is the first report on the use of a non-tryptic peptide in a LC-MRM AQUA workflow.

Compound-specific Isotope Analysis of Cyanobacterial Pure cultures and Microbial Mats: Effects of Photorespiration?

NASA Technical Reports Server (NTRS)

Jahnke, L. L.; Summons, R. E.

2006-01-01

Microbial mats are considered modern homologs of Precambrian stromatolites. The carbon isotopic compositions of organic matter and biomarker lipids provide clues to the depositional environments of ancient mat ecosystems. As the source of primary carbon fixation for over two billion years, an understanding of cyanobacterial lipid biosynthesis, associated isotopic discriminations, and the influence of physiological factors on growth and isotope expression is essential to help us compare modern microbial ecosystems to their ancient counterparts. Here, we report on the effects of photorespiration (PR) on the isotopic composition of cyanobacteria and biomarker lipids, and on potential PR effects associated with the composition of various microbial mats. The high light, high O2 and limiting CO2 conditions often present at the surface of microbial mats are known to support PR in cyanobacteria. The oxygenase function of ribulose bisphosphate carboxylase/oxygenase can result in photoexcretion of glycolate and subsequent degration by heterotrophic bacteria. We have found evidence which supports an isotopic depletion (increased apparent E) scaled to O2 level associated with growth of Phormidium luridum at low CO2 concentrations (less than 0.04%). Similar to previous studies, isotopic differences between biomass and lipid biomarkers, and between lipid classes were positively correlated with overall fractionation, and should provide a means of estimating the influence of PR on overall isotopic composition of microbial mats. Several examples of microbial mats growing in the hydrothermal waters of Yellowstone National Park and the hypersaline marine evaporation ponds at Guerrero Negro, Baja Sur Mexico will be compared with a view to PR as a possible explanation of the relatively heavy C-isotope composition of hypersaline mats.

Detection of potential (anti)progestagenic endocrine disruptors using a recombinant human progesterone receptor binding and transactivation assay.

PubMed

Viswanath, Gunda; Halder, Sujata; Divya, Gunda; Majumder, Chandrajeet B; Roy, Partha

2008-11-25

The present work describes the identification of (anti)progestin endocrine disrupting chemicals (EDC) using a two step screening system. In the first step a competitive binding assay was developed using recombinant human progesterone receptor (hPR). The tested chemicals were of various classes like insecticides, their metabolites, industrial chemicals and waste water treatment plant (WWTP) effluents. All the tested chemicals demonstrated a high affinity binding for hPR. The average IC50 values of the test chemicals were within the range of 1-25microM. In the second step of screening, a mammalian cell-based hPR transactivation assay was developed where HEK 293 cells were co-transfected with hPR and luciferase reporter gene under the control of progesterone-response element. Stimulation of the cells with progesterone resulted in about 25-fold up regulation of luciferase activity, with EC50 value of 4nM. Potent anti-progesterone, RU486, significantly inhibited progesterone-induced transactivation and non-progestagenic steroids failed to transactivate hPR till 1microM concentrations. The chemicals showing high binding affinities in competitive binding assays were then tested in transactivation assay and all of them were found to be anti-progestative except WWTP effluents. Transactivation assays using extracted water samples from five different WWTP effluents showed that it was rich in progestative compounds. The levels of induction caused by these effluents were in the range of 15-25% of induction by progesterone and they represented about 6ng/l equivalent progesterone activities. In conclusion, we demonstrated that this two step assay provides an efficient screening tool for the detection of (anti)progestative EDC in various samples.

Inhibition of neutral endopeptidase potentiates neutrophil activation during Mg-deficiency in the rat

PubMed Central

Mak, I. T.; Kramer, J. H.; Chmielinska, J. J.; Khalid, M. H.; Landgraf, K. M.; Weglicki, W. B.

2013-01-01

Neutral endopeptidase (NEP), which degrades substance P (SP), may regulate neutrophil activation during Mg-deficiency (MgD). Male Sprague-Dawley rats (180g) were fed MgD (~50 mg Mg/kg) or Mg-sufficient (MgS, 608 mg Mg/kg) diets for 7 days ± NEP inhibitor phosphoramidon (PR, 5 mg/kg/day, s. c.). MgD alone induced a 9-fold (vs. MgS, p <0.01) elevation in plasma SP; MgD+PR enhanced it further to 18-fold (p <0.001). Neutrophils from MgD+PR rats displayed a 3.9-fold higher (p <0.01) basal ·O2- generation, but those from MgD or PR alone were not activated. Plasma PGE2-metabolite levels rose 2.67- (p <0.01) and 1.56- (p <0.05) fold, respectively, in MgD+PR and MgD groups; the corresponding red blood cell glutathione levels were decreased 21 % (p <0.025) and 7 % (NS). MgD+PR significantly reduced neutrophil NEP activity by 48 % (p <0.02); PR or MgD alone only reduced this activity 26 % and 15 %, respectively. We conclude that NEP inhibition potentiates SP-mediated neutrophil ·O2- production and may promote other inflammatory activities during MgD. PMID:18607539

Inhibition of neutral endopeptidase potentiates neutrophil activation during Mg-deficiency in the rat.

PubMed

Mak, I T; Kramer, J H; Chmielinska, J J; Khalid, M H; Landgraf, K M; Weglicki, W B

2008-07-01

Neutral endopeptidase (NEP), which degrades substance P (SP), may regulate neutrophil activation during Mg-deficiency (MgD). Male Sprague-Dawley rats (180g) were fed MgD (approximately 50 mg Mg/kg) or Mg-sufficient (MgS, 608 mg Mg/kg) diets for 7 days +/- NEP inhibitor phosphoramidon (PR, 5 mg/kg/day, s.c.). MgD alone induced a 9-fold (vs. MgS, p <0.01) elevation in plasma SP; MgD+PR enhanced it further to 18-fold (p <0.001). Neutrophils from MgD+PR rats displayed a 3.9-fold higher (p <0.01) basal .O(2-) generation, but those from MgD or PR alone were not activated. Plasma PGE2-metabolite levels rose 2.67- (p <0.01) and 1.56- (p <0.05) fold, respectively, in MgD+PR and MgD groups; the corresponding red blood cell glutathione levels were decreased 21% (p <0.025) and 7% (NS). MgD+PR significantly reduced neutrophil NEP activity by 48% (p <0.02); PR or MgD alone only reduced this activity 26% and 15%, respectively. We conclude that NEP inhibition potentiates SP-mediated neutrophil .O(2-) production and may promote other inflammatory activities during MgD.

The Vaginal Microbiome and its Potential to Impact Efficacy of HIV Pre-exposure Prophylaxis for Women.

PubMed

Velloza, Jennifer; Heffron, Renee

2017-10-01

This review describes existing evidence addressing the potential modulation of pre-exposure prophylaxis (PrEP) products, specifically 1% tenofovir (TFV) gel and oral tenofovir-based PrEP, by vaginal dysbiosis and discusses future considerations for delivering novel, long-acting PrEP products to women at high risk for vaginal dysbiosis and HIV. We describe results from analyses investigating the modification of PrEP efficacy by vaginal dysbiosis and studies of biological mechanisms that could render PrEP ineffective in the presence of specific microbiota. A secondary analysis from the CAPRISA-004 cohort demonstrated that there is no effect of the 1% TFV gel in the presence of non-Lactobacillus dominant microbiota. Another recent analysis comparing oral tenofovir-based PrEP efficacy among women with and without bacterial vaginosis in the Partners PrEP Study found that oral PrEP efficacy is not modified by bacterial vaginosis. Gardnerella vaginalis, commonly present in women with vaginal dysbiosis, can rapidly metabolize TFV particularly when it is locally applied and thereby prevent TFV integration into cells. Given that vaginal dysbiosis appears to modulate efficacy for 1% TFV gel but not for oral tenofovir-based PrEP, vaginal dysbiosis is potentially less consequential to HIV protection from TFV in the context of systemic drug delivery and high product adherence. Vaginal dysbiosis may undermine the efficacy of 1% TFV gel to protect women from HIV but not the efficacy of oral PrEP. Ongoing development of novel ring, injectable, and film-based PrEP products should investigate whether vaginal dysbiosis can reduce efficacy of these products, even in the presence of high adherence.

Insect Cell-Derived Cofactors Become Fully Functional after Proteinase K and Heat Treatment for High-Fidelity Amplification of Glycosylphosphatidylinositol-Anchored Recombinant Scrapie and BSE Prion Proteins

PubMed Central

Imamura, Morikazu; Kato, Nobuko; Okada, Hiroyuki; Yoshioka, Miyako; Iwamaru, Yoshifumi; Shimizu, Yoshihisa; Mohri, Shirou; Yokoyama, Takashi; Murayama, Yuichi

2013-01-01

The central event in prion infection is the conformational conversion of host-encoded cellular prion protein (PrPC) into the pathogenic isoform (PrPSc). Diverse mammalian species possess the cofactors required for in vitro replication of PrPSc by protein-misfolding cyclic amplification (PMCA), but lower organisms, such as bacteria, yeasts, and insects, reportedly lack the essential cofactors. Various cellular components, such as RNA, lipids, and other identified cofactor molecules, are commonly distributed in both eukaryotes and prokaryotes, but the reasons for the absence of cofactor activity in lower organisms remain to be elucidated. Previously, we reported that brain-derived factors were necessary for the in vitro replication of glycosylphosphatidylinositol-anchored baculovirus-derived recombinant PrP (Bac-PrP). Here, we demonstrate that following protease digestion and heat treatment, insect cell lysates had the functional cofactor activity required for Bac-PrP replication by PMCA. Mammalian PrPSc seeds and Bac-PrPSc generated by PMCA using Bac-PrP and insect cell-derived cofactors showed similar pathogenicity and produced very similar lesions in the brains of inoculated mice. These results suggested that the essential cofactors required for the high-fidelity replication of mammalian PrPSc were present in the insect cells but that the cofactor activity was masked or inhibited in the native state. We suggest that not only RNA, but also DNA, are the key components of PMCA, although other cellular factors were necessary for the expression of the cofactor activity of nucleic acids. PMCA using only insect cell-derived substances (iPMCA) was highly useful for the ultrasensitive detection of PrPSc of some prion strains. PMID:24367521

Plasma and cerebrospinal fluid pharmacokinetic parameters after single-dose administration of intravenous, oral, or rectal acetaminophen.

PubMed

Singla, Neil K; Parulan, Cherri; Samson, Roselle; Hutchinson, Joel; Bushnell, Rick; Beja, Evelyn G; Ang, Robert; Royal, Mike A

2012-09-01

This is the first study to compare plasma and cerebrospinal fluid (CSF) pharmacokinetics of intravenous (IV), oral (PO), or rectal (PR) formulations of acetaminophen. Healthy male subjects (N = 6) were randomized to receive a single dose of IV (OFIRMEV(®) ; Cadence) 1,000 mg (15 minute infusion), PO (2 Tylenol(®) 500 mg caplets; McNeil Consumer Healthcare), or PR acetaminophen (2 Feverall(®) 650 mg suppositories; Actavis) with a 1-day washout period between doses. The 1,300 mg PR concentrations were standardized to 1,000 mg. Acetaminophen plasma and CSF levels were obtained at T0, 0.25, 0.5, 0.75, 1, 2, 3, 4, and 6 hours. IV acetaminophen showed earlier and higher plasma and CSF levels compared with PO or PR administration. CSF bioavailability over 6 hours (AUC(0-6)) for IV, PO, and PR 1 g was 24.9, 14.2, and 10.3 μg·h/mL, respectively. No treatment-related adverse events were reported. One subject was replaced because of premature failure of his lumbar spinal catheter. The mean CSF level in the IV group was similar to plasma from 3 to 4 hours and higher from 4 hours on. Absorption phase, variability in plasma, and CSF were greater in PO and PR groups than variability with IV administration. These results demonstrate that earlier and greater CSF penetration occurs as a result of the earlier and higher plasma peak with IV administration compared with PO or PR. © 2012 Lotus Clinical Research, LLC. Pain Practice © 2012 World Institute of Pain.

Human Tonsil-Derived Follicular Dendritic-Like Cells are Refractory to Human Prion Infection in Vitro and Traffic Disease-Associated Prion Protein to Lysosomes

PubMed Central

Krejciova, Zuzana; De Sousa, Paul; Manson, Jean; Ironside, James W.; Head, Mark W.

2014-01-01

The molecular mechanisms involved in human cellular susceptibility to prion infection remain poorly defined. This is due, in part, to the absence of any well characterized and relevant cultured human cells susceptible to infection with human prions, such as those involved in Creutzfeldt-Jakob disease. In variant Creutzfeldt-Jakob disease, prion replication is thought to occur first in the lymphoreticular system and then spread into the brain. We have, therefore, examined the susceptibility of a human tonsil-derived follicular dendritic cell-like cell line (HK) to prion infection. HK cells were found to display a readily detectable, time-dependent increase in cell-associated abnormal prion protein (PrPTSE) when exposed to medium spiked with Creutzfeldt-Jakob disease brain homogenate, resulting in a coarse granular perinuclear PrPTSE staining pattern. Despite their high level of cellular prion protein expression, HK cells failed to support infection, as judged by longer term maintenance of PrPTSE accumulation. Colocalization studies revealed that exposure of HK cells to brain homogenate resulted in increased numbers of detectable lysosomes and that these structures immunostained intensely for PrPTSE after exposure to Creutzfeldt-Jakob disease brain homogenate. Our data suggest that human follicular dendritic-like cells and perhaps other human cell types are able to avoid prion infection by efficient lysosomal degradation of PrPTSE. PMID:24183781

Identification, purification, and expression patterns of chitinase from psychrotolerant Pedobacter sp. PR-M6 and antifungal activity in vitro.

PubMed

Song, Yong-Su; Seo, Dong-Jun; Jung, Woo-Jin

2017-06-01

In this study, a novel psychrotolerant chitinolytic bacterium Pedobacter sp. PR-M6 that displayed strong chitinolytic activity on 0.5% colloidal chitin was isolated from the soil of a decayed mushroom. Chitinase activity of PR-M6 at 25 °C (C25) after 6 days of incubation with colloidal chitin increased rapidly to a maximum level (31.3 U/mg proteins). Three chitinase isozymes (chiII, chiIII, and chiIV) from the crude enzyme at 25 °C (C25) incubation were expressed on SDS-PAGE gels at 25 °C. After purification by chitin-affinity chromatography, six chitinase isozymes (chiI, chiII, chiIII, chiIV, chiV, and chiVI) from C25-fractions were expressed on SDS-PAGE gels at 25 °C. Major bands of chitinase isozymes (chiI, chiII, and chiIII) from C4-fractions were strongly expressed on SDS-PAGE gels at 25 °C. Pedobacter sp. PR-M6 showed high inhibition rate of 60.9% and 57.5% against Rhizoctonia solani and Botrytis cinerea, respectively. These results indicated that psychrotolerant Pedobacter sp. PR-M6 could be applied widely as a microorganism agent for the biocontrol of agricultural phytopathogens at low temperatures. Copyright © 2017 Elsevier Ltd. All rights reserved.

Acceptability of Daily Use of Free Oral Pre-exposure Prophylaxis (PrEP) Among Transgender Women Sex Workers in Shenyang, China.

PubMed

Wang, Zixin; Lau, Joseph T F; Yang, Xueying; Cai, Yong; Gross, Danielle L; Ma, Tiecheng; Liu, Yan

2017-12-01

This study investigated the acceptability of daily use of free oral pre-exposure prophylaxis (PrEP) and associated factors among transgender women sex workers in Shenyang, China, following a briefing on PrEP. A total of 183 HIV negative or sero-status unknown participants completed the cross-sectional survey. The prevalence of acceptability of daily use of free oral PrEP was 61.2%. Adjusting for education level and monthly income, variables on negative attitudes toward PrEP (i.e., having concerns about the side-effects of PrEP) [Adjusted odds ratios (AOR): 0.26], perceived subjective norms (i.e., perceiving support from male partners to take PrEP) (AOR: 2.08), and perceived behavioral control (e.g., perceiving complete control over using PrEP) (AOR: 2.10-16.72) were significantly associated with acceptability of daily use of free oral PrEP. In addition, experiencing violence during sex work, perceived risk of contracting HIV from clients and probable anxiety were also significant. Future PrEP promotion campaigns should consider these factors.

Sphingosine-1-Phosphate Signaling and Metabolism Gene Signature in Pediatric Inflammatory Bowel Disease: A Matched-case Control Pilot Study

PubMed Central

Suh, Jung H.; Degagné, Émilie; Gleghorn, Elizabeth E.; Setty, Mala; Rodriguez, Alexis; Park, K. T.; Verstraete, Sofia G.; Heyman, Melvin B.; Patel, Ashish S.; Irek, Melissa; Gildengorin, Ginny L.; Hubbard, Neil E.; Borowsky, Alexander D.; Saba, Julie D.

2018-01-01

Goal The aim of this study was to investigate gene expression levels of proteins involved in sphingosine-1-phosphate (S1P) metabolism and signaling in a pediatric inflammatory bowel disease (IBD) patient population. Background IBD is a debilitating disease affecting 0.4% of the US population. The incidence of IBD in childhood is rising. Identifying effective targeted therapies that can be used safely in young patients and developing tools for selecting specific candidates for targeted therapies are important goals. Clinical IBD trials now underway target S1PR1, a receptor for the pro-inflammatory sphingolipid S1P. However, circulating and tissue sphingolipid levels and S1P-related gene expression have not been characterized in pediatric IBD. Methods Pediatric IBD patients and controls were recruited in a four-site study. Patients received a clinical score using PUCAI or PCDAI evaluation. Colon biopsies were collected during endoscopy. Gene expression was measured by qRT-PCR. Plasma and gut tissue sphingolipids were measured by LC-MS/MS. Results Genes of S1P synthesis (SPHK1, SPHK2), degradation (SGPL1), and signaling (S1PR1, S1PR2, and S1PR4) were significantly upregulated in colon biopsies of IBD patients with moderate/severe symptoms compared with controls or patients in remission. Tissue ceramide, dihydroceramide, and ceramide-1-phosphate (C1P) levels were significantly elevated in IBD patients compared with controls. Conclusions A signature of elevated S1P-related gene expression in colon tissues of pediatric IBD patients correlates with active disease and normalizes in remission. Biopsied gut tissue from symptomatic IBD patients contains high levels of pro-apoptotic and pro-inflammatory sphingolipids. A combined analysis of gut tissue sphingolipid profiles with this S1P-related gene signature may be useful for monitoring response to conventional therapy. PMID:29788359

Global Precipitation Measurement (GPM) Validation Network

NASA Technical Reports Server (NTRS)

Schwaller, Mathew; Moris, K. Robert

2010-01-01

The method averages the minimum TRMM PR and Ground Radar (GR) sample volumes needed to match-up spatially/temporally coincident PR and GR data types. PR and GR averages are calculated at the geometric intersection of the PR rays with the individual Ground Radar(GR)sweeps. Along-ray PR data are averaged only in the vertical, GR data are averaged only in the horizontal. Small difference in PR & GR reflectivity high in the atmosphere, relatively larger differences. Version 6 TRMM PR underestimates rainfall in the case of convective rain in the lower part of the atmosphere by 30 to 40 percent.

Home-based pre-exposure prophylaxis (PrEP) services for gay and bisexual men: An opportunity to address barriers to PrEP uptake and persistence

PubMed Central

Rendina, H. Jonathon; Grov, Christian

2017-01-01

Gay, bisexual, and other men who have sex with men (GBM) are disproportionately affected by the HIV epidemic. Despite the promise of pre-exposure prophylaxis (PrEP) in reducing HIV transmission risk, barriers for uptake and persistence exist. We sought to identify whether GBM in a nationwide cohort who have not yet initiated PrEP (n = 906) would prefer to get PrEP-related care from a primary care provider (PCP) compared to a specialist clinic or provider. We then sought to identify their level of interest and factors associated with preference for using home-based PrEP services (i.e., HB-PrEP), defined to participants as conducting HIV/STI self-testing from home with PrEP prescription mailing after an initial in-person clinic visit. We examined the associations of demographics, sexual HIV transmission risk, concern about frequent medical checkups associated with PrEP, health care access, and PrEP intentions with preferences for healthcare provider type and HB-PrEP. Concern about frequent medical checkups were associated with preferring a PCP for PrEP-related care, but men who perceived a barrier to bringing up the topic of PrEP with a doctor preferred a specialist clinic or provider more than a PCP. HB-PrEP was more appealing for younger men and those engaged in sexual HIV transmission risk, suggesting HB-PrEP could help reach GBM most vulnerable to HIV and in need of PrEP. HB-PrEP expansion has potential to increase PrEP uptake and persistence among GBM, particularly for men with barriers to clinic-based care and higher intentions to initiate PrEP. Clinical guidelines regarding HB-PrEP are needed to expand its use. PMID:29281688

Back Pain Prevalence and Its Associated Factors in Brazilian Athletes from Public High Schools: A Cross-Sectional Study.

PubMed

Noll, Matias; de Avelar, Ivan Silveira; Lehnen, Georgia Cristina; Vieira, Marcus Fraga

2016-01-01

Most studies on the prevalence of back pain have evaluated it in developed countries (Human Development Index--HDI > 0.808), and their conclusions may not hold for developing countries. The aim of this study was to identify the prevalence of back pain in representative Brazilian athletes from public high schools. This cross-sectional study was performed during the state phase of the 2015 Jogos dos Institutos Federais (JIF), or Federal Institutes Games, in Brazil (HDI = 0.744), and it enrolled 251 athletes, 173 males and 78 females (14-20 years old). The dependent variable was back pain, and the independent variables were demographic, socioeconomic, psychosocial, hereditary, exercise-level, anthropometric, strength, behavioral, and postural factors. The prevalence ratio (PR) was calculated using multivariable analysis according to the Poisson regression model (α = 0.05). The prevalence of back pain in the three months prior to the study was 43.7% (n = 104), and 26% of the athletes reported feeling back pain only once. Multivariable analysis showed that back pain was associated with demographic (sex), psychosocial (loneliness and loss of sleep in the previous year), hereditary (ethnicity, parental back pain), strength (lumbar and hand forces), anthropometric (body mass index), behavioral (sleeping time per night, reading and studying in bed, smoking habits in the previous month), and postural (sitting posture while writing, while on a bench, and while using a computer) variables. Participants who recorded higher levels of lumbar and manual forces reported a lower prevalence of back pain (PR < 0.79), whereas feeling lonely in the previous year, obesity, and ethnicity exhibited the highest prevalence ratio (PR > 1.30). In conclusion, there is no association between exercise levels and back pain but there is an association between back pain and non-exercise related variables.

HIV pre-exposure prophylaxis and health and community systems in the Global South: Thailand case study.

PubMed

Colby, Donn; Srithanaviboonchai, Kriengkrai; Vanichseni, Suphak; Ongwandee, Sumet; Phanuphak, Nittaya; Martin, Michael; Choopanya, Kachit; Chariyalertsak, Suwat; van Griensven, Frits

2015-01-01

Pre-exposure prophylaxis (PrEP) is recommended by the World Health Organization as an effective method of HIV prevention for individuals at risk for infection. In this paper, we describe the unique role that Thailand has played in the global effort to combat the HIV epidemic, including its role in proving the efficacy of PrEP, and discuss the opportunities and challenges of implementing PrEP in a middle-income country. Thailand was one of the first countries in the world to successfully reverse a generalized HIV epidemic. Despite this early success, HIV prevalence has remained high among people who inject drugs and has surged among men who have sex with men (MSM) and transgender women (TGW). Two pivotal trials that showed that the use of oral antiretroviral medication as PrEP can reduce HIV transmission were conducted partially or entirely at Thai sites. Demonstration projects of PrEP, as well as clinical trials of alternative PrEP regimens, began or will begin in 2014-2015 in Thailand and will provide additional data and experience on how to best implement PrEP for high-risk individuals in the community. Financing of drug costs, the need for routine laboratory monitoring and lack of awareness about PrEP among at-risk groups all present challenges to the wider implementation of PrEP for HIV prevention in Thailand. Although significant challenges to wider use remain, PrEP holds promise as a safe and highly effective method to be used as part of a combined HIV prevention strategy for MSM and TGW in Thailand.

Glycoform-independent prion conversion by highly efficient, cell-based, protein misfolding cyclic amplification

PubMed Central

Moudjou, Mohammed; Chapuis, Jérôme; Mekrouti, Mériem; Reine, Fabienne; Herzog, Laetitia; Sibille, Pierre; Laude, Hubert; Vilette, Didier; Andréoletti, Olivier; Rezaei, Human; Dron, Michel; Béringue, Vincent

2016-01-01

Prions are formed of misfolded assemblies (PrPSc) of the variably N-glycosylated cellular prion protein (PrPC). In infected species, prions replicate by seeding the conversion and polymerization of host PrPC. Distinct prion strains can be recognized, exhibiting defined PrPSc biochemical properties such as the glycotype and specific biological traits. While strain information is encoded within the conformation of PrPSc assemblies, the storage of the structural information and the molecular requirements for self-perpetuation remain uncertain. Here, we investigated the specific role of PrPC glycosylation status. First, we developed an efficient protein misfolding cyclic amplification method using cells expressing the PrPC species of interest as substrate. Applying the technique to PrPC glycosylation mutants expressing cells revealed that neither PrPC nor PrPSc glycoform stoichiometry was instrumental to PrPSc formation and strainness perpetuation. Our study supports the view that strain properties, including PrPSc glycotype are enciphered within PrPSc structural backbone, not in the attached glycans. PMID:27384922

Cuticle-degrading proteases produced by the entomopathogenic fungus Beauveria bassiana in the presence of coffee berry borer cuticle

PubMed Central

Dias, B.A.; Neves, P.M.O.J.; Furlaneto-Maia, L.; Furlaneto, M.C.

2008-01-01

A Brazilian isolate of Beauveria bassiana (CG425) that shows high virulence against the coffee berry borer (CBB) was examined for the production of subtilisin-like (Pr1) and trypsin-like (Pr2) cuticle-degrading proteases. Fungal growth was either in nitrate-medium or in CBB cuticle-containing medium under both buffered and unbuffered conditions. In unbuffered medium supplemented with cuticle, the pH of cultures dropped and Pr1 and Pr2 activities were detected in high amounts only at a pH of 5.5 or higher. In buffered cultures, Pr1 and Pr2 activities were higher in medium supplemented with cuticle compared to activities with nitrate-medium. The Pr1 and Pr2 activities detected were mostly in the culture supernatant. These data suggest that Pr1 and Pr2 proteases produced by strain CG425 are induced by components of CBB cuticle, and that the culture pH influences the expression of these proteases, indicating the occurrence of an efficient mechanism of protein secretion in this fungus. The results obtained in this study extend the knowledge about protease production in B. bassiana CG425, opening new avenues for studying the role of secreted proteases in virulence against the coffee berry borer during the infection process. PMID:24031220

Blood safety implications of donors using HIV pre-exposure prophylaxis.

PubMed

Seed, C R; Yang, H; Lee, J F

2017-07-01

HIV pre-exposure prophylaxis (PrEP) is the use of one or more antiretroviral medications (in combination) to prevent HIV infection. The most commonly used PrEP medication (Truvada ® , Gilead Sciences, Inc.) acts by inhibiting HIV-1 reverse transcriptase. If someone who is using PrEP unknowingly becomes HIV infected (termed 'PrEP breakthrough infection'), there may be suppressed viral replication resulting in a virus level undetectable by the most sensitive HIV NAT. Failure to seroconvert and seroreversion (loss of previously detectable HIV antibodies) have also both been observed with 2nd, 3rd and 4th generation screening immunoassays, as well as Western blot assays. If such a person was tested in the course of donating blood, the results may therefore be difficult to interpret. The index of suspicion for possible PrEP 'interference' should be highest in the context of concomitant low-level positive or 'greyzone' reactivity on HIV NAT and serological tests, which is an unusual pattern in acutely HIV-infected blood donors. Another possibility is detectable HIV RNA with negative HIV serology (i.e. a potential 'NAT yield' case) but without subsequent HIV seroconversion (or disappearance of HIV RNA). Excluding antiretroviral therapy or PrEP use by the donor in such circumstances would be important. The current rarity of PrEP breakthrough infection indicates that any potential safety risk is likely very small. However, considering the increasing use of PrEP we feel it is prudent for those interpreting HIV donor screening test results to consider the potential for PrEP interference. © 2017 International Society of Blood Transfusion.

Synthesis, characterization and optical properties of ATiO{sub 3}–Pr thin films prepared by a photochemical method (where A = Ba and Ca)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cabello, G., E-mail: gerardocabelloguzman@hotmail.com; Lillo, L.; Caro, C.

2015-10-15

Highlights: • A method of photochemical deposition has been used to the preparation of (Ba,Ca)TiO{sub 3} thin films doped Pr(III). • The (Ba,Ca)TiO{sub 3}/Pr(III) films under 375 nm excitation shows emissions attributable to {sup 1}D{sub 2} → {sup 3}H{sub 4} transition of Pr ion. • These PL signals decreased above 10 mol% of Pr(III). • Analysis suggests the presence of intermediate energy levels in the band gap influences in the PL processes. - Abstract: This article reports the characterization and optical properties of (Ba,Ca)TiO{sub 3} thin films doped with Pr at different proportions (0–15 mol%). The films were deposited onmore » Si (1 0 0) and quartz substrates using a photochemical method and post-annealed at 900 °C. The evaluation of photo-reactivity of the precursor complexes was monitored by UV–vis and FT-IR spectroscopy. The obtained films were characterized by X-ray diffraction and X-ray photoelectron spectroscopy. The results indicate that Ba, Ca, Ti, O and Pr are present in the form of perovskite. Under UV light excitation (375 nm) the (Ba,Ca)TiO{sub 3}–Pr films show the characteristic emissions ascribed to {sup 1}D{sub 2} → {sup 3}H{sub 4} transition of Pr{sup 3+} ion. The optical measurements show the presence of intermediate energy levels in the band gap which influence the emission processes.« less

The expression of sphingosine-1 phosphate receptor-1 in chronic lymphocytic leukemia cells is impaired by tumor microenvironmental signals and enhanced by piceatannol and R406.

PubMed

Borge, Mercedes; Remes Lenicov, Federico; Nannini, Paula R; de los Ríos Alicandú, María M; Podaza, Enrique; Ceballos, Ana; Fernández Grecco, Horacio; Cabrejo, María; Bezares, Raimundo F; Morande, Pablo E; Oppezzo, Pablo; Giordano, Mirta; Gamberale, Romina

2014-09-15

Chronic lymphocytic leukemia (CLL) is characterized by the progressive accumulation of clonal B lymphocytes. Proliferation occurs in lymphoid tissues upon interaction of leukemic cells with a supportive microenvironment. Therefore, the mobilization of tissue-resident CLL cells into the circulation is a useful therapeutic strategy to minimize the reservoir of tumor cells within survival niches. Because the exit of normal lymphocytes from lymphoid tissues depends on the presence of sphingosine-1 phosphate (S1P) and the regulated expression of S1P receptor-1 (S1PR1), we investigated whether the expression and function of S1PR1 can be modulated by key microenvironment signals. We found that activation of CLL cells with CXCL12, fibroblast CD40L(+), BCR cross-linking, or autologous nurse-like cells reduces their S1PR1 expression and the migratory response toward S1P. Moreover, we found that S1PR1 expression was reduced in the proliferative/activated subset of leukemic cells compared with the quiescent subset from the same patient. Similarly, bone marrow-resident CLL cells expressing high levels of the activation marker CD38 showed a lower expression of S1PR1 compared with CD38(low) counterparts. Finally, given that treatment with BCR-associated kinase inhibitors induces a transient redistribution of leukemic cells from lymphoid tissues to circulation, we studied the effect of the Syk inhibitors piceatannol and R406 on S1PR1 expression and function. We found that they enhance S1PR1 expression in CLL cells and their migratory response toward S1P. Based on our results, we suggest that the regulated expression of S1PR1 might modulate the egress of the leukemic clone from lymphoid tissues. Copyright © 2014 by The American Association of Immunologists, Inc.

PrP(C) homodimerization stimulates the production of PrPC cleaved fragments PrPN1 and PrPC1.

PubMed

Béland, Maxime; Motard, Julie; Barbarin, Alice; Roucou, Xavier

2012-09-19

An endoproteolytic cleavage termed α-cleavage between residues 111/112 is a characteristic feature of the cellular prion protein (PrP(C)). This cleavage generates a soluble N-terminal fragment (PrPN1) and a glycosylphosphatidylinositol-anchored C-terminal fragment (PrPC1). Independent studies demonstrate that modulating PrP(C) α-cleavage represents a potential therapeutic strategy in prion diseases. The regulation of PrP(C) α-cleavage is unclear. The only known domain that is essential for the α-cleavage to occur is a hydrophobic domain (HD). Importantly, the HD is also essential for the formation of PrP(C) homodimers. To explore the role of PrP(C) homodimerization on the α-cleavage, we used a well described inducible dimerization strategy whereby a chimeric PrP(C) composed of a modified FK506-binding protein (Fv) fused with PrP(C) and termed Fv-PrP is incubated in the presence of a dimerizer AP20187 ligand. We show that homodimerization leads to a considerable increase of PrP(C) α-cleavage in cultured cells and release of PrPN1 and PrPC1. Interestingly, enforced homodimerization increased PrP(C) levels at the plasma membrane, and preventing PrP(C) trafficking to the cell surface inhibited dimerization-induced α-cleavage. These observations were confirmed in primary hippocampal neurons from transgenic mice expressing Fv-PrP. The proteases responsible for the α-cleavage are still elusive, and in contrast to initial studies we confirm more recent investigations that neither ADAM10 nor ADAM17 are involved. Importantly, PrPN1 produced after PrP(C) homodimerization protects against toxic amyloid-β (Aβ) oligomers. Thus, our results show that PrP(C) homodimerization is an important regulator of PrP(C) α-cleavage and may represent a potential therapeutic avenue against Aβ toxicity in Alzheimer's disease.

Pre-Exposure Prophylaxis (PrEP) as an Additional Tool for HIV Prevention Among Men Who Have Sex With Men in Belgium: The Be-PrEP-ared Study Protocol

PubMed Central

Nöstlinger, Christiana; Wouters, Kristien; Fransen, Katrien; Crucitti, Tania; Kenyon, Chris; Buyze, Jozefien; Schurmans, Céline; Laga, Marie; Vuylsteke, Bea

2017-01-01

Background Pre-exposure prophylaxis (PrEP) is a promising and effective tool to prevent HIV. With the approval of Truvada as daily PrEP by the European Commission in August 2016, individual European Member states prepare themselves for PrEP implementation following the examples of France and Norway. However, context-specific data to guide optimal implementation is currently lacking. Objective With this demonstration project we evaluate whether daily and event-driven PrEP, provided within a comprehensive prevention package, is a feasible and acceptable additional prevention tool for men who have sex with men (MSM) at high risk of acquiring HIV in Belgium. The study’s primary objective is to document the uptake, acceptability, and adherence to both daily and event-driven PrEP, while several secondary objectives have been formulated including impact of PrEP use on sexual behavior. Methods The Be-PrEP-ared study is a phase 3, single-site, open-label prospective cohort study with a large social science component embedded in the trial. A total of 200 participants choose between daily or event-driven PrEP use and may switch, discontinue, or restart their regimen at the 3-monthly visits for a duration of 18 months. Data are collected on several platforms: an electronic case report form, a Web-based tool where participants register their sexual behavior and pill use, a more detailed electronic self-administered questionnaire completed during study visits on a tablet computer, and in-depth interviews among a selected sample of participants. To answer the primary objective, the recruitment rate, (un)safe sex behavior during the last 6 months, percentage of reported intention to use PrEP in the future, retention rates in different regimens, and attitudes towards PrEP use will be analyzed. Adherence will be monitored using self-reported adherence, pill count, tenofovir drug levels in blood samples, and the perceived skills to adhere. Results All participants are currently enrolled, and the last study visit is planned to take place around Q3 2018. Conclusions As PrEP is not yet available in Belgium for use, this study will provide insights into how to optimally implement PrEP within the current health care provision and will shape national and European guidelines with regard to the place of PrEP in HIV prevention strategies. ClinicalTrial EU Clinical Trial 2015-000054-37; https://www.clinicaltrialsregister.eu/ctr-search/trial/2015-000054-37/BE (Archived by WebCite at http://www.webcitation.org/6nacjSdmM). PMID:28135199

Rare earth substitutional impurities in germanium: A hybrid density functional theory study

NASA Astrophysics Data System (ADS)

Igumbor, E.; Omotoso, E.; Tunhuma, S. M.; Danga, H. T.; Meyer, W. E.

2017-10-01

The Heyd, Scuseria, and Ernzerhof (HSE06) hybrid functional by means of density functional theory has been used to model the electronic and structural properties of rare earth (RE) substitutional impurities in germanium (REGe) . The formation and charge state transition energies for the REGe (RE = Ce, Pr, Er and Eu) were calculated. The energy of formation for the neutral charge state of the REGe lies between -0.14 and 3.13 eV. The formation energy result shows that the Pr dopant in Ge (PrGe) has the lowest formation energy of -0.14 eV, and is most energetically favourable under equilibrium conditions. The REGe induced charge state transition levels within the band gap of Ge. Shallow acceptor levels were induced by both the Eu (EuGe) and Pr (PrGe) dopants in Ge. The CeGe and ErGe exhibited properties of negative-U ordering with effective-U values of -0.85 and -1.07 eV, respectively.

Up-conversion multiwave (White) luminescence in the visible spectral range under excitation by IR laser diodes in the active BaY2F8:Yb3+,Pr3+ medium

NASA Astrophysics Data System (ADS)

Pushkar', A. A.; Uvarova, T. V.; Kiiko, V. V.

2011-08-01

The possibilities of occupying high-lying 4 f states of Pr3+ ions in the active BaY2F8:Yb3+,Pr3+ medium according to the photon avalanche and step-by-step sensitization mechanisms are compared. It is shown that the photon avalanche is unlikely to occur in the BaY2F8:Yb3+,Pr3+ crystal. The multiband luminescence spectra in the visible spectral range (white emission) under single- and multiwave pumping of BaY2F8:Yb3+,Pr3+ crystal by IR laser diodes are reported.

Integrative data mining of high-throughput in vitro screens, in vivo data, and disease information to identify Adverse Outcome Pathway (AOP) signatures:ToxCast high-throughput screening data and Comparative Toxicogenomics Database (CTD) as a case study.

EPA Science Inventory

The Adverse Outcome Pathway (AOP) framework provides a systematic way to describe linkages between molecular and cellular processes and organism or population level effects. The current AOP assembly methods however, are inefficient. Our goal is to generate computationally-pr...

WebPrInSeS: automated full-length clone sequence identification and verification using high-throughput sequencing data.

PubMed

Massouras, Andreas; Decouttere, Frederik; Hens, Korneel; Deplancke, Bart

2010-07-01

High-throughput sequencing (HTS) is revolutionizing our ability to obtain cheap, fast and reliable sequence information. Many experimental approaches are expected to benefit from the incorporation of such sequencing features in their pipeline. Consequently, software tools that facilitate such an incorporation should be of great interest. In this context, we developed WebPrInSeS, a web server tool allowing automated full-length clone sequence identification and verification using HTS data. WebPrInSeS encompasses two separate software applications. The first is WebPrInSeS-C which performs automated sequence verification of user-defined open-reading frame (ORF) clone libraries. The second is WebPrInSeS-E, which identifies positive hits in cDNA or ORF-based library screening experiments such as yeast one- or two-hybrid assays. Both tools perform de novo assembly using HTS data from any of the three major sequencing platforms. Thus, WebPrInSeS provides a highly integrated, cost-effective and efficient way to sequence-verify or identify clones of interest. WebPrInSeS is available at http://webprinses.epfl.ch/ and is open to all users.

WebPrInSeS: automated full-length clone sequence identification and verification using high-throughput sequencing data

PubMed Central

Massouras, Andreas; Decouttere, Frederik; Hens, Korneel; Deplancke, Bart

2010-01-01

High-throughput sequencing (HTS) is revolutionizing our ability to obtain cheap, fast and reliable sequence information. Many experimental approaches are expected to benefit from the incorporation of such sequencing features in their pipeline. Consequently, software tools that facilitate such an incorporation should be of great interest. In this context, we developed WebPrInSeS, a web server tool allowing automated full-length clone sequence identification and verification using HTS data. WebPrInSeS encompasses two separate software applications. The first is WebPrInSeS-C which performs automated sequence verification of user-defined open-reading frame (ORF) clone libraries. The second is WebPrInSeS-E, which identifies positive hits in cDNA or ORF-based library screening experiments such as yeast one- or two-hybrid assays. Both tools perform de novo assembly using HTS data from any of the three major sequencing platforms. Thus, WebPrInSeS provides a highly integrated, cost-effective and efficient way to sequence-verify or identify clones of interest. WebPrInSeS is available at http://webprinses.epfl.ch/ and is open to all users. PMID:20501601

Volume collapse phase transitions in cerium-praseodymium alloys under high pressure

DOE Office of Scientific and Technical Information (OSTI.GOV)

Perreault, Christopher S.; Velisavljevic, Nenad; Samudrala, Gopi K.

Cerium-12at%Praseodymium(Ce 0.88Pr 0.12) and Ce-50at%Praseodymium(Ce 0.50Pr 0.50) alloy samples that contain a random solid-solution of Ce (4f1 (J=5/2)) and Pr (4f2 (J=4)) localized f-states have been studied by angle dispersive x-ray diffraction in a diamond anvil cell to a pressure of 65 GPa and 150 GPa respectively using a synchrotron source. Ce 0.88Pr 0.12 alloy crystallizes in a face-centered cubic (γ-phase) structure at ambient conditions, while Ce 0.50Pr 0.50 alloy crystallizes in the double hexagonal close packed (dhcp) structure at ambient conditions. Two distinct volume collapse transitions are observed in Ce 0.88Pr 0.12 alloy at 1.5 GPa and 18 GPamore » with volume change of 8.5% and 3% respectively. In contrast, Ce 0.50Pr 0.50 alloy shows only a single volume collapse of 5.6% at 20 GPa on phase transformation to α-Uranium structure under high pressure. Electrical transport measurements under high pressure show anomalies in electrical resistance at phase transitions for both compositions of this alloy.« less

Volume collapse phase transitions in cerium-praseodymium alloys under high pressure

DOE PAGES

Perreault, Christopher S.; Velisavljevic, Nenad; Samudrala, Gopi K.; ...

2018-06-08

Cerium-12at%Praseodymium(Ce 0.88Pr 0.12) and Ce-50at%Praseodymium(Ce 0.50Pr 0.50) alloy samples that contain a random solid-solution of Ce (4f1 (J=5/2)) and Pr (4f2 (J=4)) localized f-states have been studied by angle dispersive x-ray diffraction in a diamond anvil cell to a pressure of 65 GPa and 150 GPa respectively using a synchrotron source. Ce 0.88Pr 0.12 alloy crystallizes in a face-centered cubic (γ-phase) structure at ambient conditions, while Ce 0.50Pr 0.50 alloy crystallizes in the double hexagonal close packed (dhcp) structure at ambient conditions. Two distinct volume collapse transitions are observed in Ce 0.88Pr 0.12 alloy at 1.5 GPa and 18 GPamore » with volume change of 8.5% and 3% respectively. In contrast, Ce 0.50Pr 0.50 alloy shows only a single volume collapse of 5.6% at 20 GPa on phase transformation to α-Uranium structure under high pressure. Electrical transport measurements under high pressure show anomalies in electrical resistance at phase transitions for both compositions of this alloy.« less

Awareness and Willingness to Use Pre-exposure Prophylaxis (PrEP) Among Men Who Have Sex with Men and Transgender Women in Brazil.

PubMed

Hoagland, Brenda; De Boni, Raquel B; Moreira, Ronaldo I; Madruga, José Valdez; Kallas, Esper G; Goulart, Silvia Pereira; Cerqueira, Natalia; Torres, Thiago S; Luz, Paula M; Fernandes, Nilo Martinez; Liu, Albert Y; Grinsztejn, Beatriz; Veloso, Valdilea G

2017-05-01

Antiretroviral pre-exposure prophylaxis (PrEP) is recommended to prevent HIV infection among high-risk men who have sex with men (MSM) though not available in Brazil where the HIV epidemic persists unabated in this group. This cross-sectional study describes PrEP awareness and willingness and associated factors among MSM and transvestite/transgender women (trans women) pre-screened for the PrEP Brasil study. Awareness was reported by 61.3 % of the participants and was associated with age, education, site, study period and prior HIV testing. Most participants (82.1 %) were willing to use PrEP, which was associated with site, study period, number of male condomless anal sexual partners and anal sex with HIV positive/unknown partners. PrEP information is need among young and less educated individuals. Willingness to use PrEP was high and future studies should be conducted to confirm PrEP acceptability and the characteristics of the population who chose to adopt this intervention.

Primary Care Physicians' Willingness to Prescribe HIV Pre-exposure Prophylaxis for People who Inject Drugs.

PubMed

Edelman, E Jennifer; Moore, Brent A; Calabrese, Sarah K; Berkenblit, Gail; Cunningham, Chinazo; Patel, Viraj; Phillips, Karran; Tetrault, Jeanette M; Shah, Minesh; Fiellin, David A; Blackstock, Oni

2017-04-01

Pre-exposure prophylaxis for HIV (PrEP) is recommended for people who inject drugs (PWID). Despite their central role in disease prevention, willingness to prescribe PrEP to PWID among primary care physicians (PCPs) is largely understudied. We conducted an online survey (April-May 2015) of members of a society for academic general internists regarding PrEP. Among 250 respondents, 74% (n = 185) of PCPs reported high willingness to prescribe PrEP to PWID. PCPs were more likely to report high willingness to prescribe PrEP to all other HIV risk groups (p's < 0.03 for all pair comparisons). Compared with PCPs delivering care to more HIV-infected clinic patients, PCPs delivering care to fewer HIV-infected patients were more likely to report low willingness to prescribe PrEP to PWID (Odds Ratio [95% CI] = 6.38 [1.48-27.47]). PCP and practice characteristics were not otherwise associated with low willingness to prescribe PrEP to PWID. Interventions to improve PCPs' willingness to prescribe PrEP to PWID are needed.

Perceived HIV risk, actual sexual HIV risk and willingness to take pre-exposure prophylaxis among men who have sex with men in Toronto, Canada.

PubMed

Kesler, Maya A; Kaul, Rupert; Myers, Ted; Liu, Juan; Loutfy, Mona; Remis, Robert S; Gesink, Dionne

2016-11-01

Pre-exposure prophylaxis (PrEP) reduces HIV acquisition. Our goal was to determine the willingness of men who have sex with men (MSM) to take PrEP given perceived and actual HIV risk. HIV-negative MSM were recruited from September 2010 to June 2012 and asked about PrEP willingness and perceived HIV risk. Actual sexual HIV risk was measured by three condom-use components generated through principal components analysis. General HIV risk was measured using the HIV Incidence Risk Index for MSM (HIRI-MSM). Model 1 measured PrEP willingness given perceived and actual sexual HIV risk. Model 2 included actual HIV sexual risk, perceived HIV risk and general HIV risk. Model 3 removed actual sexual HIV risk. We recruited 150 HIV-negative MSM. About 55% were willing to take PrEP. Reasons for PrEP unwillingness were: low perceived risk (64%), side-effect concerns (44%), daily pill burden (16%) and efficacy concerns (4%). Model 1: MSM with high compared to low actual sexual HIV risk were more willing to use PrEP (OR 27.11, 95% CI 1.33-554.43) after adjusting for perceived risk, which was not significantly associated with PrEP willingness (OR 4.79, 95% CI 0.72-31.96). Model 2: MSM with high compared to low actual sexual HIV risk were more willing to use PrEP (OR 29.85, 95% CI 1.39-640.53) after adjusting for perceived and general HIV risk, neither of which was significantly associated with PrEP willingness (OR 5.07, 95% CI 0.73-35.09) and (OR 1.58, 95% CI 0.37-6.79), respectively. Model 3: After removing actual sexual HIV risk, MSM with high compared to low perceived risk were more willing to use PrEP (OR 6.85, 95% CI 1.23-38.05), and the HIRI-MSM general risk index was not associated with PrEP willingness (OR 1.87, 95% CI 0.54-6.54). Therefore, actual sexual HIV risk was the best predictor of PrEP willingness and general HIV risk did not inform PrEP willingness.

High-resolution, time-resolved MRA provides superior definition of lower-extremity arterial segments compared to 2D time-of-flight imaging.

PubMed

Thornton, F J; Du, J; Suleiman, S A; Dieter, R; Tefera, G; Pillai, K R; Korosec, F R; Mistretta, C A; Grist, T M

2006-08-01

To evaluate a novel time-resolved contrast-enhanced (CE) projection reconstruction (PR) magnetic resonance angiography (MRA) method for identifying potential bypass graft target vessels in patients with Class II-IV peripheral vascular disease. Twenty patients (M:F = 15:5, mean age = 58 years, range = 48-83 years), were recruited from routine MRA referrals. All imaging was performed on a 1.5 T MRI system with fast gradients (Signa LX; GE Healthcare, Waukesha, WI). Images were acquired with a novel technique that combined undersampled PR with a time-resolved acquisition to yield an MRA method with high temporal and spatial resolution. The method is called PR hyper time-resolved imaging of contrast kinetics (PR-hyperTRICKS). Quantitative and qualitative analyses were used to compare two-dimensional (2D) time-of-flight (TOF) and PR-hyperTRICKS in 13 arterial segments per lower extremity. Statistical analysis was performed with the Wilcoxon signed-rank test. Fifteen percent (77/517) of the vessels were scored as missing or nondiagnostic with 2D TOF, but were scored as diagnostic with PR-hyperTRICKS. Image quality was superior with PR-hyperTRICKS vs. 2D TOF (on a four-point scale, mean rank = 3.3 +/- 1.2 vs. 2.9 +/- 1.2, P < 0.0001). PR-hyperTRICKS produced images with high contrast-to-noise ratios (CNR) and high spatial and temporal resolution. 2D TOF images were of inferior quality due to moderate spatial resolution, inferior CNR, greater flow-related artifacts, and absence of temporal resolution. PR-hyperTRICKS provides superior preoperative assessment of lower limb ischemia compared to 2D TOF.

Paving the way to a full chip gate level double patterning application

NASA Astrophysics Data System (ADS)

Haffner, Henning; Meiring, Jason; Baum, Zachary; Halle, Scott

2007-10-01

Double patterning lithography processes can offer significant yield enhancement for challenging circuit designs. Many decomposition (i.e. the process of dividing the layout design into first and second exposures) techniques are possible, but the focus of this paper is on the use of a secondary "cut" mask to trim away extraneous features left from the first exposure. This approach has the advantage that each exposure only needs to support a subset of critical features (e.g. dense lines with the first exposure, isolated spaces with the second one). The extraneous features ("printing assist features" or PrAFs) are designed to support the process window of critical features much like the role of the subresolution assist features (SRAFs) in conventional processes. However, the printing nature of PrAFs leads to many more design options, and hence a greater process and decomposition parameter exploration space, than are available for SRAFs. A decomposition scheme using PRAFs was developed for a gate level process. A critical driver of the work was to deliver improved across-chip linewidth variation (ACLV) performance versus an optimized single exposure process while providing support for a larger range of critical features. A variety of PRAF techniques were investigated by simulation, with a PrAF scheme similar to standard SRAF rules being chosen as the optimal solution [1]. This paper discusses aspects of the code development for an automated PrAF generation and placement scheme and the subsequent decomposition of a layout into two mask levels. While PrAF placement and decomposition is straightforward for layouts with pitch and orientation restrictions, it becomes rather complex for unrestricted layout styles. Because this higher complexity yields more irregularly shaped PrAFs, mask making becomes another critical driver of the optimum placement and clean-up strategies. Examples are given of how those challenges are met or can be successfully circumvented. During subsequent decomposition of the PrAF-enhanced layout into two independent mask levels, various geometric decomposition parameters have to be considered. As an example, the removal of PrAFs has to be guaranteed by a minimum required overlap of the cut mask opening past any PrAF edge. It is discussed that process assumptions such as CD tolerances and overlay as well as inter-level relationship ground rules need to be considered to successfully optimize the final decomposition scheme. Furthermore, simulation and experimental results regarding not only ACLV but also across-device linewidth variation (ADLV) are analyzed.

A comparative molecular dynamics study on thermostability of human and chicken prion proteins

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ji, Hong-Fang; Zhang, Hong-Yu

To compare the thermostabilities of human and chicken normal cellular prion proteins (HuPrP{sup C} and CkPrP{sup C}), molecular dynamics (MD) simulations were performed for both proteins at an ensemble level (10 parallel simulations at 400 K and 5 parallel simulations at 300 K as a control). It is found that the thermostability of HuPrP{sup C} is comparable with that of CkPrP{sup C}, which implicates that the non-occurrence of prion diseases in non-mammals cannot be completely attributed to the thermodynamic properties of non-mammalian PrP{sup C}.

High-resolution structure of infectious prion protein: the final frontier

PubMed Central

Diaz-Espinoza, Rodrigo; Soto, Claudio

2014-01-01

Prions are the proteinaceous infectious agents responsible for the transmission of prion diseases. The main or sole component of prions is the misfolded prion protein (PrPSc), which is able to template the conversion of the host’s natively folded form of the protein (PrPC). The detailed mechanism of prion replication and the high-resolution structure of PrPSc are unknown. The currently available information on PrPSc structure comes mostly from low-resolution biophysical techniques, which have resulted in quite divergent models. Recent advances in the production of infectious prions, using very pure recombinant protein, offer new hope for PrPSc structural studies. This review highlights the importance of, challenges for and recent progress toward elucidating the elusive structure of PrPSc, arguably the major pending milestone to reach in understanding prions. PMID:22472622

Prions amplify through degradation of the VPS10P sorting receptor sortilin.

PubMed

Uchiyama, Keiji; Tomita, Mitsuru; Yano, Masashi; Chida, Junji; Hara, Hideyuki; Das, Nandita Rani; Nykjaer, Anders; Sakaguchi, Suehiro

2017-06-01

Prion diseases are a group of fatal neurodegenerative disorders caused by prions, which consist mainly of the abnormally folded isoform of prion protein, PrPSc. A pivotal pathogenic event in prion disease is progressive accumulation of prions, or PrPSc, in brains through constitutive conformational conversion of the cellular prion protein, PrPC, into PrPSc. However, the cellular mechanism by which PrPSc is progressively accumulated in prion-infected neurons remains unknown. Here, we show that PrPSc is progressively accumulated in prion-infected cells through degradation of the VPS10P sorting receptor sortilin. We first show that sortilin interacts with PrPC and PrPSc and sorts them to lysosomes for degradation. Consistently, sortilin-knockdown increased PrPSc accumulation in prion-infected cells. In contrast, overexpression of sortilin reduced PrPSc accumulation in prion-infected cells. These results indicate that sortilin negatively regulates PrPSc accumulation in prion-infected cells. The negative role of sortilin in PrPSc accumulation was further confirmed in sortilin-knockout mice infected with prions. The infected mice had accelerated prion disease with early accumulation of PrPSc in their brains. Interestingly, sortilin was reduced in prion-infected cells and mouse brains. Treatment of prion-infected cells with lysosomal inhibitors, but not proteasomal inhibitors, increased the levels of sortilin. Moreover, sortilin was reduced following PrPSc becoming detectable in cells after infection with prions. These results indicate that PrPSc accumulation stimulates sortilin degradation in lysosomes. Taken together, these results show that PrPSc accumulation of itself could impair the sortilin-mediated sorting of PrPC and PrPSc to lysosomes for degradation by stimulating lysosomal degradation of sortilin, eventually leading to progressive accumulation of PrPSc in prion-infected cells.

Willingness to use pre-exposure prophylaxis (PrEP) for HIV prevention among men who have sex with men (MSM) in Malaysia: findings from a qualitative study

PubMed Central

Bourne, Adam; Cassolato, Matteo; Thuan Wei, Clayton Koh; Wang, Bangyuan; Pang, Joselyn; Lim, Sin How; Azwa, Iskandar; Yee, Ilias; Mburu, Gitau

2017-01-01

Abstract Background: Men who have sex with men (MSM) continue to be disproportionately affected by HIV in Malaysia. Recent success has been observed within demonstration projects examining the efficacy of HIV pre-exposure prophylaxis (PrEP), an antiretroviral -based medication taken by HIV-negative men to prevent sero-conversion. In order for such promising findings to be translated in real-world settings, it is important to understand the acceptability of PrEP, including perceived barriers to access or uptake. Methods: As part of a larger mixed-methods study exploring acceptability and willingness to use PrEP among MSM in Malaysia, 19 men took part in audio-recorded focus group discussions hosted by a community-based HIV organization and facilitated by a trained researcher. Discussions focussed on awareness and potential information management, general perceptions of PrEP and potential motivations or barriers to the use of PrEP, including those at the personal, social, health system or structural level. Data were transcribed verbatim and underwent a detailed thematic analysis. Results: Rather than perceiving PrEP as a replacement for condoms in terms of having safer sex, many participants viewed it as an additional layer protection, serving as a crucial barrier to infection on occasions where condom use was intended, but did not occur. It was also perceived as more valuable to “at-risk” men, such as those in HIV sero-discordant relationships or those with a higher number of sexual partners. Elements of discussion tended to suggest that some men taking PrEP may be subject to stigma from others, on the assumption they may be promiscuous or engage in high-risk sexual behaviours. Conclusions: This qualitative study indicates that, broadly speaking, PrEP may be acceptable to MSM in Malaysia. However, in order for its potential to be realized, and uptake achieved, educative interventions are required to inform the target population as to the efficacy and potential, positive impact of PrEP. Given concerns for how those taking it may be stigmatized, it is crucial that the use of PrEP is presented as a responsible course of action, and one of a range of strategies that men can use to keep themselves safe from HIV. PMID:28782336

Willingness to use pre-exposure prophylaxis (PrEP) for HIV prevention among men who have sex with men (MSM) in Malaysia: findings from a qualitative study.

PubMed

Bourne, Adam; Cassolato, Matteo; Thuan Wei, Clayton Koh; Wang, Bangyuan; Pang, Joselyn; Lim, Sin How; Azwa, Iskandar; Yee, Ilias; Mburu, Gitau

2017-08-02

Men who have sex with men (MSM) continue to be disproportionately affected by HIV in Malaysia. Recent success has been observed within demonstration projects examining the efficacy of HIV pre-exposure prophylaxis (PrEP), an antiretroviral -based medication taken by HIV-negative men to prevent sero-conversion. In order for such promising findings to be translated in real-world settings, it is important to understand the acceptability of PrEP, including perceived barriers to access or uptake. As part of a larger mixed-methods study exploring acceptability and willingness to use PrEP among MSM in Malaysia, 19 men took part in audio-recorded focus group discussions hosted by a community-based HIV organization and facilitated by a trained researcher. Discussions focussed on awareness and potential information management, general perceptions of PrEP and potential motivations or barriers to the use of PrEP, including those at the personal, social, health system or structural level. Data were transcribed verbatim and underwent a detailed thematic analysis. Rather than perceiving PrEP as a replacement for condoms in terms of having safer sex, many participants viewed it as an additional layer protection, serving as a crucial barrier to infection on occasions where condom use was intended, but did not occur. It was also perceived as more valuable to "at-risk" men, such as those in HIV sero-discordant relationships or those with a higher number of sexual partners. Elements of discussion tended to suggest that some men taking PrEP may be subject to stigma from others, on the assumption they may be promiscuous or engage in high-risk sexual behaviours. This qualitative study indicates that, broadly speaking, PrEP may be acceptable to MSM in Malaysia. However, in order for its potential to be realized, and uptake achieved, educative interventions are required to inform the target population as to the efficacy and potential, positive impact of PrEP. Given concerns for how those taking it may be stigmatized, it is crucial that the use of PrEP is presented as a responsible course of action, and one of a range of strategies that men can use to keep themselves safe from HIV.

Association between the proportion of sampled transition cows with increased nonesterified fatty acids and beta-hydroxybutyrate and disease incidence, pregnancy rate, and milk production at the herd level.

PubMed

Ospina, P A; Nydam, D V; Stokol, T; Overton, T R

2010-08-01

In this study the herd alarm level was defined as the proportion of sampled transition cows per herd with increased prepartum nonesterified fatty acid (NEFA), postpartum beta-hydroxybutyrate (BHBA), or NEFA concentrations that were associated with herd-level incidence of displaced abomasum (DA) or clinical ketosis (CK), pregnancy rate (PR), and milk production. The objectives were to 1) identify the herd alarm level for excessive negative energy balance and 2) describe the herd-level prevalence of this proportion. This was a prospective cohort study of 60 free-stall herds fed total mixed rations in the northeast United States. Two cohorts of approximately 15 animals were assessed for prepartum NEFA and postpartum BHBA and NEFA. The herd alarm level (i.e., the proportion of sampled animals above a certain metabolite threshold) was as follows: 15% had prepartum NEFA of 0.27 mEq/L; 15 and 20% had BHBA of 10 and 12 mg/dL, respectively; and 15% had postpartum NEFA of 0.60 and 0.70 mEq/L. The different herd alarm levels correspond to differences between the metabolites and respective herd-level effect. The herd-level effects for herds above the herd alarm level for prepartum NEFA were 3.6% increase in DA and CK incidence, 1.2% decrease in PR, and 282 kg decrease in average mature equivalent 305-d (ME 305) milk. For BHBA, the herd-level effects were a 1.8% increase in DA and CK, 0.8% decrease in PR, and 534 and 358 kg decrease in projected ME 305 milk yield for heifers and cows, respectively. For postpartum NEFA, the herd-level effects were 1.7% increase in DA and CK, 0.9% decrease in PR, and 288 and 593 kg decrease in projected ME 305 milk yield for heifers and cows, respectively. The prevalence of herds in which more than 15% of animals sampled had prepartum NEFA concentration >or=0.30 mEq/L was 75%, BHBA >or=12 mg/dL was 40%, and postpartum NEFA >or=0.70 mEq/L was 65%. This study showed that there were detrimental herd-level effects if a large enough proportion of cows had increased metabolite concentrations, and further demonstrated that a high prevalence of herds have opportunity for improvement. Copyright (c) 2010 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Factors associated with last dental visit or not to visit the dentist by Brazilian adolescents: A population-based study

PubMed Central

Frias, Antonio C.; Mialhe, Fábio L.; Pereira, Antonio C.; Meneghim, Marcelo de C.

2017-01-01

Objectives We investigated the factors associated with no dental visit within the last two years by adolescents in the state of São Paulo, Brazil, by using data from the Oral Health Conditions of São Paulo state population Project (SBSP-2015) conducted in 2015. Methods This was a cross-sectional epidemiological study with a representative sample of adolescents aged 15 to higher years residing in São Paulo State. The examiners were calibrated and dental visits were measured categorically as 1- Less than 1 year, 2- One to two years, 3 - Three years or more, 4- I have never visited the dentist. Based on the literature we dichotomized the outcome in two groups: response 1 plus 2 against response 3 plus 4. Then, Multilevel Poisson Regression (MPR) was used to estimate the prevalence ratios of last dental visit three years or had never been to a dentist by adolescents compared with those who had visited the dentist within the past two years, with contextual variables as the distal level; sociodemographic variables, mesial; and individual variables, proximal level. Results A high percentage of adolescents (84.9%) reported visiting the dentist in the last 2 years. Whereas, 626 (11.6%) had not visited the dentist for over 3 years and 188 (3.4%) had never been. A significantly higher proportion of females than males reported visiting the dentist in the past 2 years (p = 0.003). The oral and dental condition was reported as satisfactory by 4,350 respondents (80.6%), and when they accessed the health service, 2,286 (42.3%) went to the public service. Lower mean family income (1.62PR;95%CI;1.36–1.94); ≥ 1,000 inhabitant/Dental Surgeons (1.25PR;95%IC;1.03–1.56);male (1.26PR;95%CI; 1.11–1.43) non-Caucasian ethnicity (Mulatto:1.30PR;95%CI;1.13–1.50 and Black:1.58PR;95%CI;1.29–1.93); dissatisfaction with the oral health condition (1.20PR;95%CI;1.01–1.45),last visit to the public service versus private service (2.26PR; 95%CI;1.91–2.65) and presenting with periodontal disease in the form of dental calculus as the worst situation (1.38PR; 95%CI; 1.16–1.53) were associated with last visit to the dentist. Conclusions A high proportion of adolescents had visited the dentist in the last two years. No dental visit within the last two years by adolescents were associated with contextual, health care system, sociodemographic, personal and oral health status, demonstrating that this is a complex phenomenon. Actions to promote regular dental visits by adolescents in Brazil should take these factors into consideration. PMID:28859102

High polymorphism in Est-SSR loci for cellulose synthase and β-amylase of sugarcane varieties (Saccharum spp.) used by the industrial sector for ethanol production.

PubMed

Augusto, Raphael; Maranho, Rone Charles; Mangolin, Claudete Aparecida; Pires da Silva Machado, Maria de Fátima

2015-01-01

High and low polymorphisms in simple sequence repeats of expressed sequence tag (EST-SSR) for specific proteins and enzymes, such as β-amylase, cellulose synthase, xyloglucan endotransglucosylase, fructose 1,6-bisphosphate aldolase, and fructose 1,6-bisphosphatase, were used to illustrate the genetic divergence within and between varieties of sugarcane (Saccharum spp.) and to guide the technological paths to optimize ethanol production from lignocellulose biomass. The varieties RB72454, RB867515, RB92579, and SP813250 on the second stage of cutting, all grown in the state of Paraná (PR), and the varieties RB92579 and SP813250 cultured in the PR state and in Northeastern Brazil, state of Pernambuco (PE), were analyzed using five EST-SSR primers for EstC66, EstC67, EstC68, EstC69, and EstC91 loci. Genetic divergence was evident in the EstC67 and EstC69 loci for β-amylase and cellulose synthase, respectively, among the four sugarcane varieties. An extremely high level of genetic differentiation was also detected in the EstC67 locus from the RB82579 and SP813250 varieties cultured in the PR and PE states. High polymorphism in SSR of the cellulose synthase locus may explain the high variability of substrates used in pretreatment and enzymatic hydrolysis processes, which has been an obstacle to effective industrial adaptations.

RNA-Seq and molecular docking reveal multi-level pesticide resistance in the bed bug

PubMed Central

2012-01-01

Background Bed bugs (Cimex lectularius) are hematophagous nocturnal parasites of humans that have attained high impact status due to their worldwide resurgence. The sudden and rampant resurgence of C. lectularius has been attributed to numerous factors including frequent international travel, narrower pest management practices, and insecticide resistance. Results We performed a next-generation RNA sequencing (RNA-Seq) experiment to find differentially expressed genes between pesticide-resistant (PR) and pesticide-susceptible (PS) strains of C. lectularius. A reference transcriptome database of 51,492 expressed sequence tags (ESTs) was created by combining the databases derived from de novo assembled mRNA-Seq tags (30,404 ESTs) and our previous 454 pyrosequenced database (21,088 ESTs). The two-way GLMseq analysis revealed ~15,000 highly significant differentially expressed ESTs between the PR and PS strains. Among the top 5,000 differentially expressed ESTs, 109 putative defense genes (cuticular proteins, cytochrome P450s, antioxidant genes, ABC transporters, glutathione S-transferases, carboxylesterases and acetyl cholinesterase) involved in penetration resistance and metabolic resistance were identified. Tissue and development-specific expression of P450 CYP3 clan members showed high mRNA levels in the cuticle, Malpighian tubules, and midgut; and in early instar nymphs, respectively. Lastly, molecular modeling and docking of a candidate cytochrome P450 (CYP397A1V2) revealed the flexibility of the deduced protein to metabolize a broad range of insecticide substrates including DDT, deltamethrin, permethrin, and imidacloprid. Conclusions We developed significant molecular resources for C. lectularius putatively involved in metabolic resistance as well as those participating in other modes of insecticide resistance. RNA-Seq profiles of PR strains combined with tissue-specific profiles and molecular docking revealed multi-level insecticide resistance in C. lectularius. Future research that is targeted towards RNA interference (RNAi) on the identified metabolic targets such as cytochrome P450s and cuticular proteins could lay the foundation for a better understanding of the genetic basis of insecticide resistance in C. lectularius. PMID:22226239

Puerariae radix isoflavones and their metabolites inhibit growth and induce apoptosis in breast cancer cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lin, Y.-J.; Department of Biotechnology, Asia University, Taichung, Taiwan; Graduate Institute of Chinese Medical Science, China Medical University, Taichung, Taiwan

2009-01-23

Puerariae radix (PR) is a popular natural herb and a traditional food in Asia, which has antithrombotic and anti-allergic properties and stimulates estrogenic activity. In the present study, we investigated the effects of the PR isoflavones puerarin, daidzein, and genistein on the growth of breast cancer cells. Our data revealed that after treatment with PR isoflavones, a dose-dependent inhibition of cell growth occurred in HS578T, MDA-MB-231, and MCF-7 cell lines. Results from cell cycle distribution and apoptosis assays revealed that PR isoflavones induced cell apoptosis through a caspase-3-dependent pathway and mediated cell cycle arrest in the G2/M phase. Furthermore, wemore » observed that the serum metabolites of PR (daidzein sulfates/glucuronides) inhibited proliferation of the breast cancer cells at a 50% cell growth inhibition (GI{sub 50}) concentration of 2.35 {mu}M. These results indicate that the daidzein constituent of PR can be metabolized to daidzein sulfates or daidzein glucuronides that exhibit anticancer activities. The protein expression levels of the active forms of caspase-9 and Bax in breast cancer cells were significantly increased by treatment with PR metabolites. These metabolites also increased the protein expression levels of p53 and p21. We therefore suggest that PR may act as a chemopreventive and/or chemotherapeutic agent against breast cancer by reducing cell viability and inducing apoptosis.« less

Degradation of the disease-associated prion protein by a serine protease from lichens.

USGS Publications Warehouse

Johnson, C.J.; Bennett, J.P.; Biro, S.M.; Duque-Velasquez, J. C.; Rodriguez, C.M.; Bessen, R.A.; Rocke, T.E.

2011-01-01

The disease-associated prion protein (PrPTSE), the probable etiological agent of the transmissible spongiform encephalopathies (TSEs), is resistant to degradation and can persist in the environment. Lichens, mutualistic symbioses containing fungi, algae, bacteria and occasionally cyanobacteria, are ubiquitous in the environment and have evolved unique biological activities allowing their survival in challenging ecological niches. We investigated PrPTSE inactivation by lichens and found acetone extracts of three lichen species (Parmelia sulcata, Cladonia rangiferina and Lobaria pulmonaria) have the ability to degrade prion protein (PrP) from TSE-infected hamsters, mice and deer. Immunoblots measuring PrP levels and protein misfolding cyclic amplification indicated at least two logs of reductions in PrPTSE. Degradative activity was not found in closely related lichen species or in algae or a cyanobacterium that inhabit lichens. Degradation was blocked by Pefabloc SC, a serine protease inhibitor, but not inhibitors of other proteases or enzymes. Additionally, we found that PrP levels in PrPTSE-enriched preps or infected brain homogenates are also reduced following exposure to freshly-collected P. sulcata or an aqueous extract of the lichen. Our findings indicate that these lichen extracts efficiently degrade PrPTSE and suggest that some lichens could have potential to inactivate TSE infectivity on the landscape or be a source for agents to degrade prions. Further work to clone and characterize the protease, assess its effect on TSE infectivity and determine which organism or organisms present in lichens produce or influence the protease activity is warranted.

Degradation of the disease-associated prion protein by a serine protease from lichens

USGS Publications Warehouse

Johnson, Christopher J.; Bennett, James P.; Biro, S.M.; Duque-Velasquez, J. C.; Rodriguez, Cynthia M.; Bessen, R.A.; Rocke, Tonie E.

2011-01-01

The disease-associated prion protein (PrPTSE), the probable etiological agent of the transmissible spongiform encephalopathies (TSEs), is resistant to degradation and can persist in the environment. Lichens, mutualistic symbioses containing fungi, algae, bacteria and occasionally cyanobacteria, are ubiquitous in the environment and have evolved unique biological activities allowing their survival in challenging ecological niches. We investigated PrPTSE inactivation by lichens and found acetone extracts of three lichen species (Parmelia sulcata, Cladonia rangiferina and Lobaria pulmonaria) have the ability to degrade prion protein (PrP) from TSE-infected hamsters, mice and deer. Immunoblots measuring PrP levels and protein misfolding cyclic amplification indicated at least two logs of reductions in PrPTSE. Degradative activity was not found in closely related lichen species or in algae or a cyanobacterium that inhabit lichens. Degradation was blocked by Pefabloc SC, a serine protease inhibitor, but not inhibitors of other proteases or enzymes. Additionally, we found that PrP levels in PrPTSE-enriched preps or infected brain homogenates are also reduced following exposure to freshly-collected P. sulcata or an aqueous extract of the lichen. Our findings indicate that these lichen extracts efficiently degrade PrPTSE and suggest that some lichens could have potential to inactivate TSE infectivity on the landscape or be a source for agents to degrade prions. Further work to clone and characterize the protease, assess its effect on TSE infectivity and determine which organism or organisms present in lichens produce or influence the protease activity is warranted.

Cell-surface prion protein interacts with glycosaminoglycans.

PubMed Central

Pan, Tao; Wong, Boon-Seng; Liu, Tong; Li, Ruliang; Petersen, Robert B; Sy, Man-Sun

2002-01-01

We used ELISA and flow cytometry to study the binding of prion protein PrP to glycosaminoglycans (GAGs). We found that recombinant human PrP (rPrP) binds GAGs including chondroitin sulphate A, chondroitin sulphate B, hyaluronic acid, and heparin. rPrP binding to GAGs occurs via the N-terminus, a region known to bind divalent cations. Additionally, rPrP binding to GAGs is enhanced in the presence of Cu2+ and Zn2+, but not Ca2+ and Mn2+. rPrP binds heparin strongest, and the binding is inhibited by certain heparin analogues, including heparin disaccharide and sulphate-containing monosaccharides, but not by acetylated heparin. Full-length normal cellular prion protein (PrPC), but not N-terminally truncated PrPC species, from human brain bind GAGs in a similar Cu2+/Zn2+-enhanced fashion. We found that GAGs specifically bind to a synthetic peptide corresponding to amino acid residues 23-35 in the N-terminus of rPrP. We further demonstrated that while both wild-type PrPC and an octapeptide-repeat-deleted mutant PrP produced by transfected cells bound heparin at the cell surface, the PrP N-terminal deletion mutant and non-transfectant control failed to bind heparin. Binding of heparin to wild-type PrPC on the cell surface results in a reduction of the level of cell-surface PrPC. These results provide strong evidence that PrPC is a surface receptor for GAGs. PMID:12186633

High spin states in {sup 151,153}Pr, {sup 157}Sm, and {sup 93}Kr

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hwang, J. K.; Ramayya, A. V.; Hamilton, J. H.

2010-09-15

High spin states are observed for the first time in the neutron-rich nuclei {sup 151,153}Pr, {sup 157}Sm, and {sup 93}Kr from the spontaneous fission of {sup 252}Cf. Twenty new transitions in {sup 151}Pr, twelve in {sup 153}Pr, five in {sup 157}Sm, and four in {sup 93}Kr were identified by using x-ray(Pr/Sm)-{gamma}-{gamma} and {gamma}-{gamma}-{gamma} triple coincidences. From the measured total internal conversion coefficients {alpha}{sub T} of four low-energy transitions in {sup 151,153}Pr, we determine that two bands in each nucleus have opposite parity. The interlacing E1 transitions between the bands suggest a form of parity doubling in {sup 151,153}Pr. New bandsmore » in {sup 157}Sm and {sup 93}Kr are reported. The half-life of the 354.8 keV state in {sup 93}Kr is measured to be 10(2) ns.« less

Growth of a Lightly Doped Pr^3+:LaCl3 Crystal to Determine Radiative Transition Rates

NASA Astrophysics Data System (ADS)

Watters, J. Michael; Ganem, Joseph; Shaw, L. B.; Bowman, S. R.; Feldman, B. J.

1996-03-01

The recent demontration of 5.2 and 7.2 micron lasers using Pr^3+:LaCl3 ,(S. R. Bowman, Joseph Ganem, B. J. Feldman and A. W. Kueny, IEEE J. Quant. Elect. 30, 2925(1994).)^,(S. R. Bowman, L. B. Shaw, B. J. Feldman and Joseph Ganem, postdeadline paper CPD 26 at CLEO(1995).) the longest known wavelengths for any rare earth solid-state laser, has motivated further studies of this material. Design of mid-infrared lasers that use Pr^3+:LaCl3 would benefit from the ability to model population dynamics under different pumping conditions of the lower levels of the Pr^3+ ion. The lower levels, that are the basis for the new mid-infrared lasers, have many energetic overlaps resulting in several competing energy transfer processes when Pr^3+ concentrations approach 1 percent or higher. To minimize these processes we have grown and studied a lightly doped Pr^3+:LaCl3 crystal in order to determine the underlying radiative transition rates. We report how knowledge of the radiative rates can be incorporated into a model describing energy transfer processes in more heavily doped crystals.

Event-level analysis of alcohol consumption and condom use in partnership contexts among men who have sex with men and transgender women in Lima, Peru.

PubMed

Delgado, Jeanne R; Segura, Eddy R; Lake, Jordan E; Sanchez, Jorge; Lama, Javier R; Clark, Jesse L

2017-01-01

We explored the association between alcohol use and condomless receptive (CRAI) and insertive (CIAI) anal intercourse within partnership contexts of men who have sex with men (MSM) and transgender women (TGW) in Lima, Peru. From 2012-2014, we surveyed men and TGW (n=1607) who reported anal intercourse with ≥1 male or TGW. Alcohol use with up to 3 sexual partners during the prior 90days was evaluated. Bivariate and multivariate analyses used generalized estimating equations to assess event-level associations between alcohol use, CRAI, CIAI, and partnership characteristics while adjusting for participant clustering from multiple partners. Of 4774 sexual partnerships reported, 48% were casual, 34% primary, 10% anonymous, and 8% commercial. Alcohol use preceding sex was significantly (p<0.05) associated with CRAI (PR=1.26) and CIAI (PR=1.37). Partnership characteristics significantly associated with alcohol use included commercial sex work (PR=2.21) and trended (p<0.10) towards alcohol use with casual (PR=1.16), transgender (PR=1.48), and moderno ("versatile"; PR=1.17) partners. CRAI and CIAI were more common among participants who reported knowing they (PR=1.52; PR=1.41, respectively) or their partner (PR=1.47; PR=1.44, respectively) was HIV-uninfected. Yet, only CIAI (PR=1.42) was more commonly reported with known HIV-infected partners. Participants who drank alcohol prior to sex were less likely to know their partner's HIV serostatus. Alcohol use prior to intercourse was associated with CRAI and CIAI, varied by partnership type, and may impair knowledge of partner HIV serostatus. Detailed knowledge of alcohol use within partner-specific contexts is essential for informing condom-based and alternative HIV prevention strategies for MSM and TGW in Peru. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Production of a soluble recombinant prion protein fused to blue fluorescent protein without refolding or detergents in Escherichia coli cells.

PubMed

Arii, Yasuhiro; Yamaguchi, Hidenori; Fukuoka, Shin-Ichi

2007-10-01

The physiological function of prion proteins (PrP) remains unclear. To investigate the physiological relevance of PrP, we constructed a fusion protein of PrP with enhanced blue fluorescent protein (PrP-EBFP) to quantify the interaction of PrP with other molecules. Production of soluble PrP-EBFP was achieved by lowering the expression temperature in Escherichia coli (E. coli) cells to 15 degrees C. Soluble PrP-EBFP was purified on cation exchange and heparin-affinity columns to yield high purity protein. This is the first report of the preparation of soluble recombinant PrP without refolding following solubilization using denaturants or disruption using detergents. To confirm the integrity of PrP-EBFP, anisotropy was estimated under physiological conditions in the presence of heparin, which interacts with PrP. The dissociation constant was determined to be 0.88+/-0.07 microM. PrP-EBFP should be useful in the quantification of PrP interactions with other molecules.

Tin doped PrBaFe 2O 5+δ anode material for solid oxide fuel cells

DOE PAGES

Dong, Guohui; Yang, Chunyang; He, Fei; ...

2017-04-25

Ceramic anodes have many advantages over cermet anodes for solid oxide fuel cells. We report the synthesis and characterization of Sn doped double perovskite PrBaFe (2-x)Sn xO 5+δ (x = 0–0.3) anode materials. Different crystal structures were observed depending on the Sn doping level and gas atmosphere. The materials demonstrated excellent stability in both reducing and redox atmospheres at elevated temperatures. The oxygen content in the as-prepared PrBaFe (2-x)Sn xO 5+δ was nonlinearly correlated to the Sn doping level and reached maximum values around x = 0.1. After the reducing treatment, the oxygen content linearly decreased with increasing Sn dopingmore » level. The electrical conductivity of bulk PrBaFe (2-x)Sn xO 5+δ (x = 0.1) reached 63.6 S cm -1 at 800 °C in humidified hydrogen. At 750 °C, the surface exchange coefficient and bulk diffusivity of PrBaFe (2-x)Sn xO 5+δ reached the maximum values of 4.42 × 10 -6 m s -1 and 6.04 × 10 -7 m 2 s -1, respectively, in the reducing process when the Sn doping level was x = 0.1. The activation energies of surface exchange coefficient and bulk diffusivity of PrBaFe (2-x)Sn xO 5+δ (x = 0.1) were 0.22 eV and 0.16 eV, respectively, in the reducing process. The area specific resistance of the PrBaFe (2-x)Sn xO 5+δ (x = 0.1) anode was 0.095–0.285 Ω cm 2 from 850–750 °C in humidified hydrogen, better than or comparable to the best ceramic anodes in the literature.« less

Laser induced fluorescence spectroscopy used for the investigation of Landé gJ- factors of praseodymium energy levels

NASA Astrophysics Data System (ADS)

Sobolewski, Ł. M.; Windholz, L.; Kwela, J.

2017-06-01

Laser induced fluorescence (LIF) spectroscopy was used for the investigation of structures of 52 spectral lines of Pr I in the wavelength range 561.3 - 613.9 nm. As a source of free Pr atoms a hollow cathode discharge lamp was used. We monitored selected LIF signals appearing when the laser beam excites the hollow cathode plasma. LIF spectra were recorded in the presence of a magnetic field of about 800 G produced by a permanent magnet for two linear polarizations of the exciting laser beam. We have determined for the first time Landé gJ- factors for 71 levels of neutral Pr and reinvestigated data for several other levels.

The activities of progesterone receptor isoform A and B are differentially modulated by their ligands in a gene-selective manner.

PubMed

Leo, Joyce C L; Lin, Valerie C L

2008-01-01

It is known that progesterone receptor (PR) isoform A (PR-A) and isoform B (PR-B) may mediate different effects of progesterone. The objective of this study was to determine if the functions of PR isoforms also vary in response to different PR modulators (PRM). The effects of 7 synthetic PRM were tested in MDA-MB-231 cells engineered to express PR-A, PR-B, or both PR isoforms. The effects of progesterone were similar in cells expressing PR-A or PR-B in which it inhibited growth and induced focal adhesion. On the other hand, synthetic PRM modulated the activity of the PR isoforms differently. RU486, CDB4124, 17alpha-hydroxy CDB4124 and VA2914 exerted agonist activities on cell growth and adhesion via PR-B. Via PR-A, however, these compounds displayed agonist effect on cell growth but induced stellate morphology which was distinct from the agonist's effect. Their dual properties via PR-A were also displayed at the gene expression level: the compounds acted as agonists on cell cycle genes but exhibited antagonistic effect on cell adhesion genes. Introduction of ERalpha by adenoviral vector to these cells did not change PR-A or PR-B mediated effect of PRM radically, but it causes significant cell rounding and modified the magnitudes of the responses to PRM. The findings suggest that the activities of PR isoforms may be modulated by different PRM through gene-specific regulatory mechanisms. This raises an interesting possibility that PRM may be designed to be PR isoform and cellular pathway selective to achieve targeted therapy in breast cancer. Copyright 2007 Wiley-Liss, Inc.

Solubility and cation exchange in phosphate rock and saturated clinoptilolite mixtures

NASA Technical Reports Server (NTRS)

Allen, E. R.; Hossner, L. R.; Ming, D. W.; Henninger, D. L.

1993-01-01

Mixtures of zeolite and phosphate rock (PR) have the potential to provide slow-release fertilization of plants in synthetic soils by dissolution and ion-exchange reactions. This study was conducted to examine solubility and cation-exchange relationships in mixtures of PR and NH4- and K-saturated clinoptilolite (Cp). Batch-equilibration experiments were designed to investigate the effect of PR source, the proportion of exchangeable K and NH4, and the Cp to PR ratio on solution N, P, K, and Ca concentrations. The dissolution and cation-exchange reactions that occurred after mixing NH4- and K-saturated Cp with PR increased the solubility of the PR and simultaneously released NH4 and K into solution. The more reactive North Carolina (NC) PR rendered higher solution concentrations of NH4 and K when mixed with Cp than did Tennessee (TN) PR. Solution P concentrations for the Cp-NC PR mixture and the Cp-TN PR mixture were similar. Solution concentrations of N, P, K, and Ca and the ratios of these nutrients in solution varied predictably with the type of PR, the Cp/PR ratio, and the proportions of exchangeable K and NH4 on the Cp. Our research indicated that slow-release fertilization using Cp/PR media may provide adequate levels of N, P, and K to support plant growth. Solution Ca concentrations were lower than optimum for plant growth.

An open and configurable embedded system for EMG pattern recognition implementation for artificial arms.

PubMed

Jun Liu; Fan Zhang; Huang, He Helen

2014-01-01

Pattern recognition (PR) based on electromyographic (EMG) signals has been developed for multifunctional artificial arms for decades. However, assessment of EMG PR control for daily prosthesis use is still limited. One of the major barriers is the lack of a portable and configurable embedded system to implement the EMG PR control. This paper aimed to design an open and configurable embedded system for EMG PR implementation so that researchers can easily modify and optimize the control algorithms upon our designed platform and test the EMG PR control outside of the lab environments. The open platform was built on an open source embedded Linux Operating System running a high-performance Gumstix board. Both the hardware and software system framework were openly designed. The system was highly flexible in terms of number of inputs/outputs and calibration interfaces used. Such flexibility enabled easy integration of our embedded system with different types of commercialized or prototypic artificial arms. Thus far, our system was portable for take-home use. Additionally, compared with previously reported embedded systems for EMG PR implementation, our system demonstrated improved processing efficiency and high system precision. Our long-term goals are (1) to develop a wearable and practical EMG PR-based control for multifunctional artificial arms, and (2) to quantify the benefits of EMG PR-based control over conventional myoelectric prosthesis control in a home setting.

Relationship between microstructural and magnetic properties of PrCo-based films prepared by the vacuum evaporation method

NASA Astrophysics Data System (ADS)

Fersi, R.; Bouzidi, W.; Bezergheanu, A.; Cizmas, C. B.; Bessais, L.; Mliki, N.

2018-04-01

In this work, Ce2Ni7 type structural PrCo-based films were deposited on Si(1 0 0) substrate by ultra-high (UHV) vacuum evaporation process. The structural and magnetic properties of these films have been performed using X-ray diffraction (XRD), atomic force microscopy (AFM), vibrating sample magnetometer (VSM) and magnetic force microscopy (MFM) techniques. Two effects on structural and magnetic properties of PrCo films have been investigated: the effect of the annealing temperature (Ta) and the effect of the variation of the magnetic X-layer thickness. The as deposited PrCo films have a magnetic coercivity (Hc) of about 40-100 Oe. But after annealing at 600 °C, Hc has increased hight about 9.5 kOe for PrCo(X = 20 nm) and 10.2 kOe for PrCo(X = 50 nm) were observed. The magnetic properties were affected by the thickness due to the morphology, also the relationship between the intergrain exchange coupling (IEC), the size and quantity of the PrCo grains. The hight extrinsic properties of Hc = 10.2 kOe, maximum energy product (BH)max of 5.12 MGOe and remanence ratio Mr /Ms = 0.53 are reported for the PrCo(X = 50 nm) films. These properties are highly desirable for extremely high-density magnetic recording media applications.

HIV pre-exposure prophylaxis and early antiretroviral treatment among female sex workers in South Africa: Results from a prospective observational demonstration project.

PubMed

Eakle, Robyn; Gomez, Gabriela B; Naicker, Niven; Bothma, Rutendo; Mbogua, Judie; Cabrera Escobar, Maria A; Saayman, Elaine; Moorhouse, Michelle; Venter, W D Francois; Rees, Helen

2017-11-01

Operational research is required to design delivery of pre-exposure prophylaxis (PrEP) and early antiretroviral treatment (ART). This paper presents the primary analysis of programmatic data, as well as demographic, behavioural, and clinical data, from the TAPS Demonstration Project, which offered both interventions to female sex workers (FSWs) at 2 urban clinic sites in South Africa. The TAPS study was conducted between 30 March 2015 and 30 June 2017, with the enrolment period ending on 31 July 2016. TAPS was a prospective observational cohort study with 2 groups receiving interventions delivered in existing service settings: (1) PrEP as part of combination prevention for HIV-negative FSWs and (2) early ART for HIV-positive FSWs. The main outcome was programme retention at 12 months of follow-up. Of the 947 FSWs initially seen in clinic, 692 were HIV tested. HIV prevalence was 49%. Among those returning to clinic after HIV testing and clinical screening, 93% of the women who were HIV-negative were confirmed as clinically eligible for PrEP (n = 224/241), and 41% (n = 110/270) of the women who were HIV-positive had CD4 counts within National Department of Health ART initiation guidelines at assessment. Of the remaining women who were HIV-positive, 93% were eligible for early ART (n = 148/160). From those eligible, 98% (n = 219/224) and 94% (n = 139/148) took up PrEP and early ART, respectively. At baseline, a substantial fraction of women had a steady partner, worked in brothels, and were born in Zimbabwe. Of those enrolled, 22% on PrEP (n = 49/219) and 60% on early ART (n = 83/139) were seen at 12 months; we observed high rates of loss to follow-up: 71% (n = 156/219) and 30% (n = 42/139) in the PrEP and early ART groups, respectively. Little change over time was reported in consistent condom use or the number of sexual partners in the last 7 days, with high levels of consistent condom use with clients and low use with steady partners in both study groups. There were no seroconversions on PrEP and 7 virological failures on early ART among women remaining in the study. Reported adherence to PrEP varied over time between 70% and 85%, whereas over 90% of participants reported taking pills daily while on early ART. Data on provider-side costs were also collected and analysed. The total cost of service delivery was approximately US$126 for PrEP and US$406 for early ART per person-year. The main limitations of this study include the lack of a control group, which was not included due to ethical considerations; clinical study requirements imposed when PrEP was not approved through the regulatory system, which could have affected uptake; and the timing of the implementation of a national sex worker HIV programme, which could have also affected uptake and retention. PrEP and early ART services can be implemented within FSW routine services in high prevalence, urban settings. We observed good uptake for both PrEP and early ART; however, retention rates for PrEP were low. Retention rates for early ART were similar to retention rates for the current standard of care. While the cost of the interventions was higher than previously published, there is potential for cost reduction at scale. The TAPS Demonstration Project results provided the basis for the first government PrEP and early ART guidelines and the rollout of the national sex worker HIV programme in South Africa.

HIV pre-exposure prophylaxis and early antiretroviral treatment among female sex workers in South Africa: Results from a prospective observational demonstration project

PubMed Central

Naicker, Niven; Bothma, Rutendo; Mbogua, Judie; Cabrera Escobar, Maria A.; Moorhouse, Michelle; Venter, W. D. Francois

2017-01-01

Background Operational research is required to design delivery of pre-exposure prophylaxis (PrEP) and early antiretroviral treatment (ART). This paper presents the primary analysis of programmatic data, as well as demographic, behavioural, and clinical data, from the TAPS Demonstration Project, which offered both interventions to female sex workers (FSWs) at 2 urban clinic sites in South Africa. Methods and findings The TAPS study was conducted between 30 March 2015 and 30 June 2017, with the enrolment period ending on 31 July 2016. TAPS was a prospective observational cohort study with 2 groups receiving interventions delivered in existing service settings: (1) PrEP as part of combination prevention for HIV-negative FSWs and (2) early ART for HIV-positive FSWs. The main outcome was programme retention at 12 months of follow-up. Of the 947 FSWs initially seen in clinic, 692 were HIV tested. HIV prevalence was 49%. Among those returning to clinic after HIV testing and clinical screening, 93% of the women who were HIV-negative were confirmed as clinically eligible for PrEP (n = 224/241), and 41% (n = 110/270) of the women who were HIV-positive had CD4 counts within National Department of Health ART initiation guidelines at assessment. Of the remaining women who were HIV-positive, 93% were eligible for early ART (n = 148/160). From those eligible, 98% (n = 219/224) and 94% (n = 139/148) took up PrEP and early ART, respectively. At baseline, a substantial fraction of women had a steady partner, worked in brothels, and were born in Zimbabwe. Of those enrolled, 22% on PrEP (n = 49/219) and 60% on early ART (n = 83/139) were seen at 12 months; we observed high rates of loss to follow-up: 71% (n = 156/219) and 30% (n = 42/139) in the PrEP and early ART groups, respectively. Little change over time was reported in consistent condom use or the number of sexual partners in the last 7 days, with high levels of consistent condom use with clients and low use with steady partners in both study groups. There were no seroconversions on PrEP and 7 virological failures on early ART among women remaining in the study. Reported adherence to PrEP varied over time between 70% and 85%, whereas over 90% of participants reported taking pills daily while on early ART. Data on provider-side costs were also collected and analysed. The total cost of service delivery was approximately US$126 for PrEP and US$406 for early ART per person-year. The main limitations of this study include the lack of a control group, which was not included due to ethical considerations; clinical study requirements imposed when PrEP was not approved through the regulatory system, which could have affected uptake; and the timing of the implementation of a national sex worker HIV programme, which could have also affected uptake and retention. Conclusions PrEP and early ART services can be implemented within FSW routine services in high prevalence, urban settings. We observed good uptake for both PrEP and early ART; however, retention rates for PrEP were low. Retention rates for early ART were similar to retention rates for the current standard of care. While the cost of the interventions was higher than previously published, there is potential for cost reduction at scale. The TAPS Demonstration Project results provided the basis for the first government PrEP and early ART guidelines and the rollout of the national sex worker HIV programme in South Africa. PMID:29161256

Combination HIV prevention among MSM in South Africa: results from agent-based modeling.

PubMed

Brookmeyer, Ron; Boren, David; Baral, Stefan D; Bekker, Linda-Gail; Phaswana-Mafuya, Nancy; Beyrer, Chris; Sullivan, Patrick S

2014-01-01

HIV prevention trials have demonstrated the effectiveness of a number of behavioral and biomedical interventions. HIV prevention packages are combinations of interventions and offer potential to significantly increase the effectiveness of any single intervention. Estimates of the effectiveness of prevention packages are important for guiding the development of prevention strategies and for characterizing effect sizes before embarking on large scale trials. Unfortunately, most research to date has focused on testing single interventions rather than HIV prevention packages. Here we report the results from agent-based modeling of the effectiveness of HIV prevention packages for men who have sex with men (MSM) in South Africa. We consider packages consisting of four components: antiretroviral therapy for HIV infected persons with CD4 count <350; PrEP for high risk uninfected persons; behavioral interventions to reduce rates of unprotected anal intercourse (UAI); and campaigns to increase HIV testing. We considered 163 HIV prevention packages corresponding to different intensity levels of the four components. We performed 2252 simulation runs of our agent-based model to evaluate those packages. We found that a four component package consisting of a 15% reduction in the rate of UAI, 50% PrEP coverage of high risk uninfected persons, 50% reduction in persons who never test for HIV, and 50% ART coverage over and above persons already receiving ART at baseline, could prevent 33.9% of infections over 5 years (95% confidence interval, 31.5, 36.3). The package components with the largest incremental prevention effects were UAI reduction and PrEP coverage. The impact of increased HIV testing was magnified in the presence of PrEP. We find that HIV prevention packages that include both behavioral and biomedical components can in combination prevent significant numbers of infections with levels of coverage, acceptance and adherence that are potentially achievable among MSM in South Africa.

Prognostic value of estrogen receptor and progesterone receptor tumor expression in Danish ovarian cancer patients: from the 'MALOVA' ovarian cancer study.

PubMed

Høgdall, Estrid V S; Christensen, Lise; Høgdall, Claus K; Blaakaer, Jan; Gayther, Simon; Jacobs, Ian J; Christensen, Ib Jarle; Kjaer, Susanne K

2007-11-01

Estrogen and progesterone are important hormones secreted by the ovary acting through specific receptors. Tumor tissue expression profiles of these have demonstrated prognostic value in malignancies such as breast, uterine and prostate cancer. In this study, including tissue samples from 773 Danish patients with an ovarian tumor, we evaluated whether estrogen receptor (ER) and progesterone receptor (PR) expression correlated with clinico-pathological parameters, and a possible prognostic impact on ovarian cancer (OC) patients was investigated. Using tissue array and immunohistochemistry, we analyzed the ER and PR expression levels in tissues from 582 women with OC and 191 women with low malignancy potential (LMP) ovarian tumors. Our results demonstrated that ER was expressed in 30 of the 191 LMP tumors (16%) and in 207 of the 582 OC (36%). PR was expressed in 38 LMP tumors (20%) and in 115 OC (20%). For both tumor types an excess of positive tumors was found in the serous compared to the mucinous subtype (p< or =0.00001). The frequency of ER expression-positive OC increased with increasing FIGO stage (p=0.0003), and the frequency of PR-positive tumors increased with increasing histological grade (p=0.0006). In a Cox survival analysis, a tissue ER and PR expression 10% or higher was found to imply an independent significant advantageous course of patient disease-specific survival (ER: hazard ratio (HR), 0.80; 95% confidence interval (CI), 0.63-0.99; PR: HR, 0.69; 95% CI, 0.51-0.94) together with FIGO stage, residual tumor after primary surgery, age at diagnosis and other histological types vs. serous adenocarcinoma. The histological grade of tumor was found to have no independent prognostic value. The prognostic value of ER and PR was found additive with a HR for patients with high ER and PR expression of 0.48 (95% CI, 0.31-0.74) compared to patients with <10% expression for both receptors. In conclusion, our results predict that an elevated expression of ER and PR, alone and in combination, point to a favorable outcome for patients with OC.

In Vitro Approach To Identify Key Amino Acids in Low Susceptibility of Rabbit Prion Protein to Misfolding

PubMed Central

Eraña, Hasier; Fernández-Borges, Natalia; Elezgarai, Saioa R.; Harrathi, Chafik; Charco, Jorge M.; Chianini, Francesca; Dagleish, Mark P.; Ortega, Gabriel; Millet, Óscar

2017-01-01

ABSTRACT Prion diseases, or transmissible spongiform encephalopathies (TSEs), are a group of rare progressive neurodegenerative disorders caused by an abnormally folded prion protein (PrPSc). This is capable of transforming the normal cellular prion protein (PrPC) into new infectious PrPSc. Interspecies prion transmissibility studies performed by experimental challenge and the outbreak of bovine spongiform encephalopathy that occurred in the late 1980s and 1990s showed that while some species (sheep, mice, and cats) are readily susceptible to TSEs, others are apparently resistant (rabbits, dogs, and horses) to the same agent. To study the mechanisms of low susceptibility to TSEs of certain species, the mouse-rabbit transmission barrier was used as a model. To identify which specific amino acid residues determine high or low susceptibility to PrPSc propagation, protein misfolding cyclic amplification (PMCA), which mimics PrPC-to-PrPSc conversion with accelerated kinetics, was used. This allowed amino acid substitutions in rabbit PrP and accurate analysis of misfolding propensities. Wild-type rabbit recombinant PrP could not be misfolded into a protease-resistant self-propagating isoform in vitro despite seeding with at least 12 different infectious prions from diverse origins. Therefore, rabbit recombinant PrP mutants were designed to contain every single amino acid substitution that distinguishes rabbit recombinant PrP from mouse recombinant PrP. Key amino acid residue substitutions were identified that make rabbit recombinant PrP susceptible to misfolding, and using these, protease-resistant misfolded recombinant rabbit PrP was generated. Additional studies characterized the mechanisms by which these critical amino acid residue substitutions increased the misfolding susceptibility of rabbit PrP. IMPORTANCE Prion disorders are invariably fatal, untreatable diseases typically associated with long incubation periods and characteristic spongiform changes associated with neuronal loss in the brain. Development of any treatment or preventative measure is dependent upon a detailed understanding of the pathogenesis of these diseases, and understanding the mechanism by which certain species appear to be resistant to TSEs is critical. Rabbits are highly resistant to naturally acquired TSEs, and even under experimental conditions, induction of clinical disease is not easy. Using recombinant rabbit PrP as a model, this study describes critical molecular determinants that confer this high resistance to transmissible spongiform encephalopathies. PMID:28978705

HIV pre-exposure prophylaxis and health and community systems in the Global South: Thailand case study

PubMed Central

Colby, Donn; Srithanaviboonchai, Kriengkrai; Vanichseni, Suphak; Ongwandee, Sumet; Phanuphak, Nittaya; Martin, Michael; Choopanya, Kachit; Chariyalertsak, Suwat; van Griensven, Frits

2015-01-01

Introduction Pre-exposure prophylaxis (PrEP) is recommended by the World Health Organization as an effective method of HIV prevention for individuals at risk for infection. In this paper, we describe the unique role that Thailand has played in the global effort to combat the HIV epidemic, including its role in proving the efficacy of PrEP, and discuss the opportunities and challenges of implementing PrEP in a middle-income country. Discussion Thailand was one of the first countries in the world to successfully reverse a generalized HIV epidemic. Despite this early success, HIV prevalence has remained high among people who inject drugs and has surged among men who have sex with men (MSM) and transgender women (TGW). Two pivotal trials that showed that the use of oral antiretroviral medication as PrEP can reduce HIV transmission were conducted partially or entirely at Thai sites. Demonstration projects of PrEP, as well as clinical trials of alternative PrEP regimens, began or will begin in 2014–2015 in Thailand and will provide additional data and experience on how to best implement PrEP for high-risk individuals in the community. Financing of drug costs, the need for routine laboratory monitoring and lack of awareness about PrEP among at-risk groups all present challenges to the wider implementation of PrEP for HIV prevention in Thailand. Conclusions Although significant challenges to wider use remain, PrEP holds promise as a safe and highly effective method to be used as part of a combined HIV prevention strategy for MSM and TGW in Thailand. PMID:26198342

Provider Attitudes Toward Oral Preexposure Prophylaxis for HIV Prevention Among High-Risk Men Who Have Sex with Men in Lima, Peru

PubMed Central

Tang, Eric C.; Sobieszczyk, Magdalena E.; Shu, Eileen; Gonzales, Pedro; Sanchez, Jorge

2014-01-01

Abstract Oral preexposure prophylaxis (PrEP) was the first biomedical intervention to demonstrate efficacy in preventing HIV infection among men who have sex with men (MSM). Healthcare providers' attitudes toward PrEP will be critical in translating this finding into effective public health rollout programs. In a convenience sample of 186 healthcare providers in Peru, we assessed knowledge, barriers, and attitudes to prescribe and monitor HIV PrEP for high-risk MSM and transgender women, the populations with the highest HIV incidence in this setting. A total of 57.5% reported awareness of PrEP, and awareness was independently associated with caring for more than 50 MSM (OR: 3.67, p<0.002). Lack of local guidelines, concern about increased high-risk behavior, antiretroviral drug resistance, and limited availability of antiretrovirals for HIV-infected individuals were the most common barriers to prescribing PrEP. Of all physicians 44.6% indicated that they would be likely to prescribe oral PrEP now; likelihood to prescribe was higher if PrEP were supported by local guidelines (70.3%, p<0.001), if more trials supported its effectiveness (68.5%, p<0.001), and if intermittent use were shown to be effective (62.2%, p=0.019). Physicians were more likely to prescribe PrEP now if they care for more than 50 MSM (OR: 6.62, p=0.010). Infectious disease specialists were less likely to prescribe PrEP (OR: 0.10, p=0.003) than nonspecialists. Successful large-scale implementation of PrEP in Peru will require focused educational campaigns to increase awareness and address concerns among healthcare providers. PMID:24319983

An NMR strategy to detect conformational differences in a protein complexed with highly analogous inhibitors in solution.

PubMed

Persons, John D; Khan, Shahid N; Ishima, Rieko

2018-04-12

This manuscript presents an NMR strategy to investigate conformational differences in protein-inhibitor complexes, when the inhibitors tightly bind to a protein at sub-nanomolar dissociation constants and are highly analogous to each other. Using HIV-1 protease (PR), we previously evaluated amide chemical shift differences, ΔCSPs, of PR bound to darunavir (DRV) compared to PR bound to several DRV analogue inhibitors, to investigate subtle but significant long-distance conformation changes caused by the inhibitor's chemical moiety variation [Khan, S. N., Persons, J. D. Paulsen, J. L., Guerrero, M., Schiffer, C. A., Kurt-Yilmaz, N., and Ishima, R., Biochemistry, (2018), 57, 1652-1662]. However, ΔCSPs are not ideal for investigating subtle PR-inhibitor interface differences because intrinsic differences in the electron shielding of the inhibitors affect protein ΔCSPs. NMR relaxation is also not suitable as it is not sensitive enough to detect small conformational differences in rigid regions among similar PR-inhibitor complexes. Thus, to gain insight into conformational differences at the inhibitor-protein interface, we recorded 15 N-half filtered NOESY spectra of PR bound to two highly analogous inhibitors and assessed NOEs between PR amide protons and inhibitor protons, between PR amide protons and hydroxyl side chains, and between PR amide protons and water protons. We also verified the PR amide-water NOEs using 2D water-NOE/ROE experiments. Differences in water-amide proton NOE peaks, possibly due to amide-protein hydrogen bonds, were observed between subunit A and subunit B, and between the DRV-bound form and an analogous inhibitor-bound form, which may contribute to remote conformational changes. Copyright © 2018 Elsevier Inc. All rights reserved.

The Effect of PrEP on HIV Incidence Among Men Who Have Sex With Men in the Context of Condom Use, Treatment as Prevention, and Seroadaptive Practices.

PubMed

LeVasseur, Michael T; Goldstein, Neal D; Tabb, Loni P; Olivieri-Mui, Brianne L; Welles, Seth L

2018-01-01

HIV preexposure prophylaxis (PrEP) is an effective tool in preventing HIV infection among high-risk men who have sex with men (MSM). It is unknown how effective PrEP is in the context of other implemented HIV prevention strategies, including condom use, seroadaption, and treatment as prevention (TasP). We evaluate the impact of increasing uptake of PrEP in conjunction with established prevention strategies on HIV incidence in a high-risk population of MSM through simulation. Agent-based simulation models representing the sexual behavior of high-risk, urban MSM in the United States over the period of 1 year were used to evaluate the effect of PrEP on HIV infection rates. Simulations included data for 10,000 MSM and compared increasing rates of PrEP uptake under 8 prevention paradigms: no additional strategies, TasP, condom use, seroadaptive behavior, and combinations thereof. We observed a mean of 103.2 infections per 10,000 MSM in the absence of any prevention method. PrEP uptake at 25% without any additional prevention strategies prevented 30.7% of infections. In the absence of PrEP, TasP, condom use, and seroadaptive behavior independently prevented 27.1%, 48.8%, and 37.7% of infections, respectively, and together prevented 72.2%. The addition of PrEP to the 3 aforementioned prevention methods, at 25% uptake, prevented an additional 5.0% of infections. To achieve a 25% reduction in HIV infections by 2020, HIV prevention efforts should focus on significantly scaling up access to PrEP in addition to HIV testing, access to antiretroviral therapy, and promoting condom use.

Provider attitudes toward oral preexposure prophylaxis for HIV prevention among high-risk men who have sex with men in Lima, Peru.

PubMed

Tang, Eric C; Sobieszczyk, Magdalena E; Shu, Eileen; Gonzales, Pedro; Sanchez, Jorge; Lama, Javier R

2014-05-01

Oral preexposure prophylaxis (PrEP) was the first biomedical intervention to demonstrate efficacy in preventing HIV infection among men who have sex with men (MSM). Healthcare providers' attitudes toward PrEP will be critical in translating this finding into effective public health rollout programs. In a convenience sample of 186 healthcare providers in Peru, we assessed knowledge, barriers, and attitudes to prescribe and monitor HIV PrEP for high-risk MSM and transgender women, the populations with the highest HIV incidence in this setting. A total of 57.5% reported awareness of PrEP, and awareness was independently associated with caring for more than 50 MSM (OR: 3.67, p<0.002). Lack of local guidelines, concern about increased high-risk behavior, antiretroviral drug resistance, and limited availability of antiretrovirals for HIV-infected individuals were the most common barriers to prescribing PrEP. Of all physicians 44.6% indicated that they would be likely to prescribe oral PrEP now; likelihood to prescribe was higher if PrEP were supported by local guidelines (70.3%, p<0.001), if more trials supported its effectiveness (68.5%, p<0.001), and if intermittent use were shown to be effective (62.2%, p=0.019). Physicians were more likely to prescribe PrEP now if they care for more than 50 MSM (OR: 6.62, p=0.010). Infectious disease specialists were less likely to prescribe PrEP (OR: 0.10, p=0.003) than nonspecialists. Successful large-scale implementation of PrEP in Peru will require focused educational campaigns to increase awareness and address concerns among healthcare providers.

Selective killing of human immunodeficiency virus infected cells by non-nucleoside reverse transcriptase inhibitor-induced activation of HIV protease.

PubMed

Jochmans, Dirk; Anders, Maria; Keuleers, Inge; Smeulders, Liesbeth; Kräusslich, Hans-Georg; Kraus, Günter; Müller, Barbara

2010-10-15

Current antiretroviral therapy against human immunodeficiency virus (HIV-1) reduces viral load and thereby prevents viral spread, but it cannot eradicate proviral genomes from infected cells. Cells in immunological sanctuaries as well as cells producing low levels of virus apparently contribute to a reservoir that maintains HIV persistence in the presence of highly active antiretroviral therapy. Thus, accelerated elimination of virus producing cells may represent a complementary strategy to control HIV infection. Here we sought to exploit HIV protease (PR) related cytotoxicity in order to develop a strategy for drug induced killing of HIV producing cells. PR processes the viral Gag and Gag-Pol polyproteins during virus maturation, but is also implicated in killing of virus producing cells through off-target cleavage of host proteins. It has been observed previously that micromolar concentrations of certain non-nucleoside reverse transcriptase inhibitors (NNRTIs) can stimulate intracellular PR activity, presumably by enhancing Gag-Pol dimerization. Using a newly developed cell-based assay we compared the degree of PR activation displayed by various NNRTIs. We identified inhibitors showing higher potency with respect to PR activation than previously described for NNRTIs, with the most potent compounds resulting in ~2-fold increase of the Gag processing signal at 250 nM. The degree of enhancement of intracellular Gag processing correlated with the compound's ability to enhance RT dimerization in a mammalian two-hybrid assay. Compounds were analyzed for their potential to mediate specific killing of chronically infected MT-4 cells. Levels of cytotoxicity on HIV infected cells determined for the different NNRTIs corresponded to the relative degree of drug induced intracellular PR activation, with CC50 values ranging from ~0.3 μM to above the tested concentration range (10 μM). Specific cytotoxicity was reverted by addition of PR inhibitors. Two of the most active compounds, VRX-480773 and GW-678248, were also tested in primary human cells and mediated cytotoxicity on HIV-1 infected peripheral blood mononuclear cells. These data present proof of concept for targeted drug induced elimination of HIV producing cells. While NNRTIs themselves may not be sufficiently potent for therapeutic application, the results provide a basis for the development of drugs exploiting this mechanism of action.

Selective killing of human immunodeficiency virus infected cells by non-nucleoside reverse transcriptase inhibitor-induced activation of HIV protease

PubMed Central

2010-01-01

Background Current antiretroviral therapy against human immunodeficiency virus (HIV-1) reduces viral load and thereby prevents viral spread, but it cannot eradicate proviral genomes from infected cells. Cells in immunological sanctuaries as well as cells producing low levels of virus apparently contribute to a reservoir that maintains HIV persistence in the presence of highly active antiretroviral therapy. Thus, accelerated elimination of virus producing cells may represent a complementary strategy to control HIV infection. Here we sought to exploit HIV protease (PR) related cytotoxicity in order to develop a strategy for drug induced killing of HIV producing cells. PR processes the viral Gag and Gag-Pol polyproteins during virus maturation, but is also implicated in killing of virus producing cells through off-target cleavage of host proteins. It has been observed previously that micromolar concentrations of certain non-nucleoside reverse transcriptase inhibitors (NNRTIs) can stimulate intracellular PR activity, presumably by enhancing Gag-Pol dimerization. Results Using a newly developed cell-based assay we compared the degree of PR activation displayed by various NNRTIs. We identified inhibitors showing higher potency with respect to PR activation than previously described for NNRTIs, with the most potent compounds resulting in ~2-fold increase of the Gag processing signal at 250 nM. The degree of enhancement of intracellular Gag processing correlated with the compound's ability to enhance RT dimerization in a mammalian two-hybrid assay. Compounds were analyzed for their potential to mediate specific killing of chronically infected MT-4 cells. Levels of cytotoxicity on HIV infected cells determined for the different NNRTIs corresponded to the relative degree of drug induced intracellular PR activation, with CC50 values ranging from ~0.3 μM to above the tested concentration range (10 μM). Specific cytotoxicity was reverted by addition of PR inhibitors. Two of the most active compounds, VRX-480773 and GW-678248, were also tested in primary human cells and mediated cytotoxicity on HIV-1 infected peripheral blood mononuclear cells. Conclusion These data present proof of concept for targeted drug induced elimination of HIV producing cells. While NNRTIs themselves may not be sufficiently potent for therapeutic application, the results provide a basis for the development of drugs exploiting this mechanism of action. PMID:20950436

A thermal and chemical degradation approach to decipher pristane and phytane precursors in sedimentary organic matter

USGS Publications Warehouse

Koopmans, M.P.; Rijpstra, W.I.C.; Klapwijk, M.M.; De Leeuw, J. W.; Lewan, M.D.; Sinninghe, Damste J.S.

1999-01-01

A thermal and chemical degradation approach was followed to determine the precursors of pristane (Pr) and phytane (Ph) in samples from the Gessoso-solfifera, Ghareb and Green River Formations. Hydrous pyrolysis of these samples yields large amounts of Pr and Ph carbon skeletons, indicating that their precursors are predominantly sequestered in high-molecular-weight fractions. However, chemical degradation of the polar fraction and the kerogen of the unheated samples generally does not release large amounts of Pr and Ph. Additional information on the precursors of Pr and Ph is obtained from flash pyrolysis analyses of kerogens and residues after hydrous pyrolysis and after chemical degradation. Multiple precursors for Pr and Ph are recognised in these three samples. The main increase of the Pr/Ph ratio with increasing maturation temperature, which is associated with strongly increasing amounts of Pr and Ph, is probably due to the higher amount of precursors of Pr compared to Ph, and not to the different timing of generation of Pr and Ph.A thermal and chemical degradation approach was followed to determine the precursors of pristane (Pr) and phytane (Ph) in samples from the Gessoso-solfifera, Ghareb and Green River Formations. Hydrous pyrolysis of these samples yields large amounts of Pr and Ph carbon skeletons, indicating that their precursors are predominantly sequestered in high-molecular-weight fractions. However, chemical degradation of the polar fraction and the kerogen of the unheated samples generally does not release large amounts of Pr and Ph. Additional information on the precursors of Pr and Ph is obtained from flash pyrolysis analyses of kerogens and residues after hydrous pyrolysis and after chemical degradation. Multiple precursors for Pr and Ph are recognised in these three samples. The main increase of the Pr/Ph ratio with increasing maturation temperature, which is associated with strongly increasing amounts of Pr and Ph, is probably due to the higher amount of precursors of Pr compared to Ph, and not to the different timing of generation of Pr and Ph.

Application of Glycerol for Induced Powdery Mildew Resistance in Triticum aestivum L.

PubMed

Li, Yinghui; Song, Na; Zhao, Chuanzhi; Li, Feng; Geng, Miaomiao; Wang, Yuhui; Liu, Wanhui; Xie, Chaojie; Sun, Qixin

2016-01-01

Previous work has demonstrated that glycerol-3-phosphate (G3P) and oleic acid (18:1) are two important signal molecules associated with plant resistance to fungi. In this article, we provide evidence that a 3% glycerol spray application 1-2 days before powdery mildew infection and subsequent applications once every 4 days was sufficient to stimulate the plant defense responses without causing any significant damage to wheat leaves. We found that G3P and oleic acid levels were markedly induced by powdery mildew infection. In addition, TaGLI1 (encoding a glycerol kinase) and TaSSI2 (encoding a stearoylacyl carrier protein fatty acid desaturase), two genes associated with the glycerol and fatty acid (FA) pathways, respectively, were induced by powdery mildew infection, and their promoter regions contain some fungal response elements. Moreover, exogenous application of glycerol increased the G3P level and decreased the level of oleic acid (18:1). Glycerol application induced the expression of pathogenesis-related ( PR ) genes ( TaPR-1, TaPR-2, TaPR-3, TaPR-4 , and TaPR-5 ), induced the generation of reactive oxygen species (ROS) before powdery mildew infection, and induced salicylic acid (SA) accumulation in wheat leaves. Further, we sprayed glycerol in a wheat field and found that it significantly ( p < 0.05) reduced the severity of powdery mildew disease and lessened disease-associated kernel weight loss, all without causing any noticeable degradation in wheat seed quality.

Application of Glycerol for Induced Powdery Mildew Resistance in Triticum aestivum L.

PubMed Central

Li, Yinghui; Song, Na; Zhao, Chuanzhi; Li, Feng; Geng, Miaomiao; Wang, Yuhui; Liu, Wanhui; Xie, Chaojie; Sun, Qixin

2016-01-01

Previous work has demonstrated that glycerol-3-phosphate (G3P) and oleic acid (18:1) are two important signal molecules associated with plant resistance to fungi. In this article, we provide evidence that a 3% glycerol spray application 1–2 days before powdery mildew infection and subsequent applications once every 4 days was sufficient to stimulate the plant defense responses without causing any significant damage to wheat leaves. We found that G3P and oleic acid levels were markedly induced by powdery mildew infection. In addition, TaGLI1 (encoding a glycerol kinase) and TaSSI2 (encoding a stearoylacyl carrier protein fatty acid desaturase), two genes associated with the glycerol and fatty acid (FA) pathways, respectively, were induced by powdery mildew infection, and their promoter regions contain some fungal response elements. Moreover, exogenous application of glycerol increased the G3P level and decreased the level of oleic acid (18:1). Glycerol application induced the expression of pathogenesis-related (PR) genes (TaPR-1, TaPR-2, TaPR-3, TaPR-4, and TaPR-5), induced the generation of reactive oxygen species (ROS) before powdery mildew infection, and induced salicylic acid (SA) accumulation in wheat leaves. Further, we sprayed glycerol in a wheat field and found that it significantly (p < 0.05) reduced the severity of powdery mildew disease and lessened disease-associated kernel weight loss, all without causing any noticeable degradation in wheat seed quality. PMID:27708588

Effects of posture on upper and lower limb peripheral resistance following submaximal cycling.

PubMed

Swan, P D; Spitler, D L; Todd, M K; Maupin, J L; Lewis, C L; Darragh, P M

1989-09-01

The purpose of this study was to determine postural effects on upper and lower limb peripheral resistance (PR) after submaximal exercise. Twelve subjects (six men and six women) completed submaximal cycle ergometer tests (60% age-predicted maximum heart rate) in the supine and upright seated positions. Each test included 20 minutes of rest, 20 minutes of cycling, and 15 minutes of recovery. Stroke volume and heart rate were determined by impedance cardiography, and blood pressure was measured by auscultation during rest, immediately after exercise, and at minutes 1-5, 7.5, 10, 12.5, and 15 of recovery. Peripheral resistance was calculated from values of mean arterial pressure and cardiac output. No significant (p less than 0.05) postural differences in PR were noted during rest for either limb. Immediately after exercise, PR decreased (55% to 61%) from resting levels in both limbs, independent of posture. Recovery ankle PR values were significantly different between postures. Upright ankle PR returned to 92% of the resting level within four minutes of recovery, compared to 76% of the resting level after 15 minutes in the supine posture. Peripheral resistance values in the supine and upright arm were not affected by posture and demonstrated a gradual pattern of recovery similar to the supine ankle recovery response (85% to 88% of rest within 15 minutes). The accelerated recovery rate of PR after upright exercise may result from local vasoconstriction mediated by a central regulatory response to stimulation from gravitational pressure on lower body circulation.

Characterization of PrNiO3-δ as oxygen electrode for SOFCs

NASA Astrophysics Data System (ADS)

Vibhu, Vaibhav; Flura, Aurélien; Nicollet, Clément; Fourcade, Sébastien; Penin, Nicolas; Bassat, Jean-Marc; Grenier, Jean-Claude; Rougier, Aline; Pouchard, Michel

2018-07-01

The praseodymium nickelate PrNiO3-δ was recently identified as one of the decomposition products of Pr2NiO4+δ oxygen electrode, raising the question of the role of this perovskite compound on the Pr2NiO4+δ performance and ageing behaviour. Herein, the electrochemical properties of PrNiO3-δ as cathode for Solid Oxide Fuel Cells (SOFCs) is reported. PrNiO3-δ, synthesized from the citrate-nitrate route, cristallizes in an orthorhombic structure (S.G.: Pnma). Under air, a transition to high temperature rhombohedral structure (S.G.: R-3c) occurs at around 600 °C, while its oxygen vacancy amount increases from δ ≈ 0.05 at room temperature up to 0.10 at high temperature. Thermal gravimetry analysis (TGA) measurements coupled with X-ray diffraction (XRD) characterizations show that above 1000 °C, in air, PrNiO3-δ starts to decompose into Pr2NiO4+δ and NiO through an intermediate transformation into Pr4Ni3O10+δ. The value of the polarization resistance (Rp) of co-sintered GDC-PrNiO3-δ electrode, at 950 °C in air for 2 h, is 0.91 Ω cm2 at 600 °C under air. It remains much higher than that of co-sintered GDC-Pr2NiO4+δ electrode (Rp = 0.15 Ω cm2), which means that the perovskite does not play any significant role in the electrochemical performance during long term operation of the Pr2NiO4+δ electrode.

Pre-Exposure Prophylaxis (PrEP) as an Additional Tool for HIV Prevention Among Men Who Have Sex With Men in Belgium: The Be-PrEP-ared Study Protocol.

PubMed

De Baetselier, Irith; Reyniers, Thijs; Nöstlinger, Christiana; Wouters, Kristien; Fransen, Katrien; Crucitti, Tania; Kenyon, Chris; Buyze, Jozefien; Schurmans, Céline; Laga, Marie; Vuylsteke, Bea

2017-01-30

Pre-exposure prophylaxis (PrEP) is a promising and effective tool to prevent HIV. With the approval of Truvada as daily PrEP by the European Commission in August 2016, individual European Member states prepare themselves for PrEP implementation following the examples of France and Norway. However, context-specific data to guide optimal implementation is currently lacking. With this demonstration project we evaluate whether daily and event-driven PrEP, provided within a comprehensive prevention package, is a feasible and acceptable additional prevention tool for men who have sex with men (MSM) at high risk of acquiring HIV in Belgium. The study's primary objective is to document the uptake, acceptability, and adherence to both daily and event-driven PrEP, while several secondary objectives have been formulated including impact of PrEP use on sexual behavior. The Be-PrEP-ared study is a phase 3, single-site, open-label prospective cohort study with a large social science component embedded in the trial. A total of 200 participants choose between daily or event-driven PrEP use and may switch, discontinue, or restart their regimen at the 3-monthly visits for a duration of 18 months. Data are collected on several platforms: an electronic case report form, a Web-based tool where participants register their sexual behavior and pill use, a more detailed electronic self-administered questionnaire completed during study visits on a tablet computer, and in-depth interviews among a selected sample of participants. To answer the primary objective, the recruitment rate, (un)safe sex behavior during the last 6 months, percentage of reported intention to use PrEP in the future, retention rates in different regimens, and attitudes towards PrEP use will be analyzed. Adherence will be monitored using self-reported adherence, pill count, tenofovir drug levels in blood samples, and the perceived skills to adhere. All participants are currently enrolled, and the last study visit is planned to take place around Q3 2018. As PrEP is not yet available in Belgium for use, this study will provide insights into how to optimally implement PrEP within the current health care provision and will shape national and European guidelines with regard to the place of PrEP in HIV prevention strategies. EU Clinical Trial 2015-000054-37; https://www.clinicaltrialsregister.eu/ctr-search/trial/2015-000054-37/BE (Archived by WebCite at http://www.webcitation.org/6nacjSdmM). ©Irith De Baetselier, Thijs Reyniers, Christiana Nöstlinger, Kristien Wouters, Katrien Fransen, Tania Crucitti, Chris Kenyon, Jozefien Buyze, Céline Schurmans, Marie Laga, Bea Vuylsteke, Be-PrEP-Ared Study Group. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 30.01.2017.

[Family factors associated with co-dependency in nurses at a hospital in Cancun, Quintana Roo, México].

PubMed

Ramírez-Amaro, Margarita; Martínez-Torres, Jorge; Ureña Bogarín, Enrique Leobardo

2014-05-01

Identifying family factors associated with the presence of co-dependency in nurses of a regional hospital in Cancún, Quintana Roo, Mexico. Cross-sectional, comparative study. City of Cancun (México). A random sample of 200nurses who met the inclusion criteria (having a partner for over a year, to be at work on the day of the interview), and who gave informed consent, completed three questionnaires during different shifts. Age, educational level, socioeconomic status, type of family structure, life cycle stage, co-dependency and family functioning. A total of 200nurses, with mean age of 36±8years, took part. The most common socioeconomic status was high (48%), and 47.5% had graduate studies. A co-dependency level of 20.5% (95%CI: 15-26.5) was found. Family factors associated with the presence of co-dependency were; family dysfunction, prevalence ratio (PR)=9.62 (95%CI: 3.47-27.3), stage of independence, PR=3.41 (95%CI: 1.44-7.86), single parent, PR=6.35 (95%CI: 2.41-16.68), and time with partner less than 5 years, PR=3.41 (95%CI: 1.54-7.85). It was found that family dysfunction and being a single parent were significantly associated with co-dependency in hospital nurses, therefore, on being able to identify these factors, family physicians can improve their dynamics and functioning by family study, and improving effective communication with nursing staff and their families. Copyright © 2013 Elsevier España, S.L. All rights reserved.

Salicylic acid confers enhanced resistance to Glomerella leaf spot in apple.

PubMed

Zhang, Ying; Shi, Xiangpeng; Li, Baohua; Zhang, Qingming; Liang, Wenxing; Wang, Caixia

2016-09-01

Glomerella leaf spot (GLS) caused by Glomerella cingulata is a newly emergent disease that results in severe defoliation and fruit spots in apple. Currently, there are no effective means to control this disease except for the traditional fungicide sprays. Induced resistance by elicitors against pathogens infection is a widely accepted eco-friendly strategy. In the present study, we investigated whether exogenous application of salicylic acid (SA) could improve resistance to GLS in a highly susceptible apple cultivar (Malus domestica Borkh. cv. 'Gala') and the underlying mechanisms. The results showed that pretreatment with SA, at 0.1-1.0 mM, induced strong resistance against GLS in 'Gala' apple leaves, with SA treated leaves showing significant reduction in lesion numbers and disease index. Concurrent with the enhanced disease resistance, SA treatment markedly increased the total antioxidant capacity (T-AOC) and defence-related enzyme activities, including catalase (CAT), superoxide dismutase (SOD), peroxidase (POD), phenylalanine ammonia-lyase (PAL) and polyphenol oxidase (PPO). As expected, SA treatment also induced the expression levels of five pathogenesis-related (PR) genes including PR1, PR5, PR8, Chitinase and β-1,3-glucanase. Furthermore, the most pronounced and/or rapid increase was observed in leaves treated with SA and subsequently inoculated with G. cingulata compared to the treatment with SA or inoculation with the pathogen. Together, these results suggest that exogenous SA triggered increase in reactive oxygen species levels and the antioxidant system might be responsible for enhanced resistance against G. cingulata in 'Gala' apple leaves. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Glycoform-independent prion conversion by highly efficient, cell-based, protein misfolding cyclic amplification.

PubMed

Moudjou, Mohammed; Chapuis, Jérôme; Mekrouti, Mériem; Reine, Fabienne; Herzog, Laetitia; Sibille, Pierre; Laude, Hubert; Vilette, Didier; Andréoletti, Olivier; Rezaei, Human; Dron, Michel; Béringue, Vincent

2016-07-07

Prions are formed of misfolded assemblies (PrP(Sc)) of the variably N-glycosylated cellular prion protein (PrP(C)). In infected species, prions replicate by seeding the conversion and polymerization of host PrP(C). Distinct prion strains can be recognized, exhibiting defined PrP(Sc) biochemical properties such as the glycotype and specific biological traits. While strain information is encoded within the conformation of PrP(Sc) assemblies, the storage of the structural information and the molecular requirements for self-perpetuation remain uncertain. Here, we investigated the specific role of PrP(C) glycosylation status. First, we developed an efficient protein misfolding cyclic amplification method using cells expressing the PrP(C) species of interest as substrate. Applying the technique to PrP(C) glycosylation mutants expressing cells revealed that neither PrP(C) nor PrP(Sc) glycoform stoichiometry was instrumental to PrP(Sc) formation and strainness perpetuation. Our study supports the view that strain properties, including PrP(Sc) glycotype are enciphered within PrP(Sc) structural backbone, not in the attached glycans.

Microstructure and optical properties of TiO2 nanocrystallites-CaTiO3:Pr3+ hybrid thick films

NASA Astrophysics Data System (ADS)

Xia, Chang-Kui; Gao, Xiang-Dong; Yu, Changjiang; Yu, Aimin; Li, Xiaomin; Gao, Dongsheng; Shi, Ying

Long afterglow CaTiO3:Pr3+ ceramic powders were integrated with hydrothermal TiO2 nanocrystallites via “doctor-blade” and TiO2-CaTiO3:Pr3+ hybrid thick films on FTO substrate were fabricated. Effects of the Pr3+ doping level (0.06%, 0.3%) and the CaTiO3:Pr3+/TiO2 weight ratio (0.23, 0.92) on the crystallinity, morphologies, optical transmittance and photoluminescence (PL) properties were investigated. Results showed that the crystallinity of the hybrid films originated from both TiO2 nanocrystallites and CaTiO3:Pr3+ ceramic particles, affected little by the integrating process. The film surface became denser and coarser due to the incorporation of CaTiO3:Pr3+ micron/submicron particles, and the film thickness varied little (˜2.2μm). The optical transmittance of the hybrid film decreased sharply (<20% for 0.92 incorporation level) due to the scattering effects of the CaTiO3:Pr3+ micron/submicron particles to the incident light. All the hybrid films exhibited strong PL at ˜613nm when excited with 332-335nm, and the film with the Ca0.997TiO3:Pr0.0033+/TiO2 weight ratio of 0.23 showed the highest emission. In addition, the film exhibited a photoresponce to a broad ultraviolet excitation ranging from 288-369nm and a long emission decay time up to 30min at 613nm, possible for use in the ultraviolet detectors, solar cells and other photoelectrical devices.

Community member perspectives from transgender women and men who have sex with men on pre-exposure prophylaxis as an HIV prevention strategy: implications for implementation

PubMed Central

2012-01-01

Background An international randomized clinical trial (RCT) on pre-exposure prophylaxis (PrEP) as an human immunodeficiency virus (HIV)-prevention intervention found that taken on a daily basis, PrEP was safe and effective among men who have sex with men (MSM) and male-to-female transgender women. Within the context of the HIV epidemic in the United States (US), MSM and transgender women are the most appropriate groups to target for PrEP implementation at the population level; however, their perspectives on evidenced-based biomedical research and the results of this large trial remain virtually unknown. In this study, we examined the acceptability of individual daily use of PrEP and assessed potential barriers to community uptake. Methods We conducted semi-structured interviews with an ethnoracially diverse sample of thirty HIV-negative and unknown status MSM (n = 24) and transgender women (n = 6) in three California metropolitan areas. Given the burden of disease among ethnoracial minorities in the US, we purposefully oversampled for these groups. Thematic coding and analysis of data was conducted utilizing an approach rooted in grounded theory. Results While participants expressed general interest in PrEP availability, results demonstrate: a lack of community awareness and confusion about PrEP; reservations about PrEP utilization, even when informed of efficacious RCT results; and concerns regarding equity and the manner in which a PrEP intervention could be packaged and marketed in their communities. Conclusions In order to effectively reduce HIV health disparities at the population level, PrEP implementation must take into account the uptake concerns of those groups who would actually access and use this biomedical intervention as a prevention strategy. Recommendations addressing these concerns are provided. PMID:23181780

Boceprevir plus peginterferon/ribavirin for treatment of chronic hepatitis C in Russia.

PubMed

Isakov, Vasily; Nikitin, Igor; Chulanov, Vladimir; Ogurtsov, Pavel; Lukyanova, Ekaterina; Long, Jianmin; Wahl, Janice; Helmond, Frans A

2016-02-28

To evaluate addition of boceprevir to peginterferon/ribavirin (PR) in Russian patients with chronic hepatitis C virus (HCV). Treatment-naive (TN) and treatment-experienced (TE) patients (who had failed prior treatment with PR for ≥ 12 wk) with chronic HCV genotype 1 infection were enrolled in this placebo-controlled, double-blind study. All patients initially received PR for 4 wk. Patients randomized to control treatment then received PR for an additional 44 wk. TN patients randomized to triple therapy received boceprevir (800 mg three times daily) plus PR for 24 wk and then further therapy according to treatment week 8 (TW8) HCV RNA levels. TE patients received boceprevir plus PR for 32 wk and then further therapy according to TW8 HCV RNA levels. Treatment was discontinued for TN patients with detectable HCV RNA at TW24 and TE patients with detectable HCV RNA at TW12 because of futility. The primary efficacy end point was sustained virologic response (SVR) defined as undetectable HCV RNA 24 wk after completing all study therapy. SVR was 74.8% in the boceprevir plus PR arm compared with 46.2% in the control arm, with a stratification-adjusted treatment difference of 29.2% (95%CI: 16.4-41.5; P < 0.0001). Rates of SVR were higher in the boceprevir arm in both TN and TE patient groups (TN 78.4% vs 56.3%; TE 69.4% vs 30.0%). Within TE patients, the rates of SVR were higher with boceprevir plus PR compared with PR, regardless of treatment failure type (null responder, partial responder, and relapser). Most patients receiving boceprevir plus PR in both TN (86%) and TE (71%) populations were eligible for reduced treatment duration. Anemia was increased in patients receiving boceprevir plus PR vs PR alone (47.2% vs 24.4%); there was a corresponding increase in ribavirin dose reduction and erythropoietin use. Among patients receiving boceprevir plus PR, SVR rates were similar in patients with anemia (< 10 g/dL) and those without anemia (71.2% vs 77.4%). Regulatory approval has been obtained for boceprevir plus PR in Russian patients with HCV genotype 1 infection based on the results of this study.

Boceprevir plus peginterferon/ribavirin for treatment of chronic hepatitis C in Russia

PubMed Central

Isakov, Vasily; Nikitin, Igor; Chulanov, Vladimir; Ogurtsov, Pavel; Lukyanova, Ekaterina; Long, Jianmin; Wahl, Janice; Helmond, Frans A

2016-01-01

AIM: To evaluate addition of boceprevir to peginterferon/ribavirin (PR) in Russian patients with chronic hepatitis C virus (HCV). METHODS: Treatment-naive (TN) and treatment-experienced (TE) patients (who had failed prior treatment with PR for ≥ 12 wk) with chronic HCV genotype 1 infection were enrolled in this placebo-controlled, double-blind study. All patients initially received PR for 4 wk. Patients randomized to control treatment then received PR for an additional 44 wk. TN patients randomized to triple therapy received boceprevir (800 mg three times daily) plus PR for 24 wk and then further therapy according to treatment week 8 (TW8) HCV RNA levels. TE patients received boceprevir plus PR for 32 wk and then further therapy according to TW8 HCV RNA levels. Treatment was discontinued for TN patients with detectable HCV RNA at TW24 and TE patients with detectable HCV RNA at TW12 because of futility. The primary efficacy end point was sustained virologic response (SVR) defined as undetectable HCV RNA 24 wk after completing all study therapy. RESULTS: SVR was 74.8% in the boceprevir plus PR arm compared with 46.2% in the control arm, with a stratification-adjusted treatment difference of 29.2% (95%CI: 16.4-41.5; P < 0.0001). Rates of SVR were higher in the boceprevir arm in both TN and TE patient groups (TN 78.4% vs 56.3%; TE 69.4% vs 30.0%). Within TE patients, the rates of SVR were higher with boceprevir plus PR compared with PR, regardless of treatment failure type (null responder, partial responder, and relapser). Most patients receiving boceprevir plus PR in both TN (86%) and TE (71%) populations were eligible for reduced treatment duration. Anemia was increased in patients receiving boceprevir plus PR vs PR alone (47.2% vs 24.4%); there was a corresponding increase in ribavirin dose reduction and erythropoietin use. Among patients receiving boceprevir plus PR, SVR rates were similar in patients with anemia (< 10 g/dL) and those without anemia (71.2% vs 77.4%). CONCLUSION: Regulatory approval has been obtained for boceprevir plus PR in Russian patients with HCV genotype 1 infection based on the results of this study. PMID:26962399

Cellular prion protein promotes glucose uptake through the Fyn-HIF-2α-Glut1 pathway to support colorectal cancer cell survival.

PubMed

Li, Qing-Quan; Sun, Yan-Ping; Ruan, Can-Ping; Xu, Xin-Yun; Ge, Jun-Hui; He, Jin; Xu, Zu-De; Wang, Qiang; Gao, Wen-Chao

2011-02-01

Cellular prion protein (PrPc) is a glycosylphosphatidylinositol-anchored membrane protein that has various physical functions, including protection against apoptotic and oxidative stress, cellular uptake of copper ions, transmembrane signaling, and adhesion to the extracellular matrix. In this study, we show that PrPc is highly expressed in colorectal adenocarcinomas. Transcriptome profiling of PrPc-depleted DLD-1 cells revealed downregulation of glucose transporter 1 (Glut1). PrPc is shown to be involved in regulating Glut1 expression through the Fyn-HIF-2α pathway. As Glut1 is the natural transporter of glucose and is required for the high glycolytic rate seen in colorectal tumors, silencing of PrPc reduced the proliferation and survival rate of colorectal cancer cells in vitro. In vivo, knockdown of PrPc by hydrodynamic injection with a cocktail of PrPc-shRNA-encoding plasmids also inhibited tumorigenicity in a xenograft model in nude mice. In summary, our data characterize a novel molecular mechanism that links PrPc expression to the regulation of glycolysis. Targeting PrPc will therefore be a promising strategy to overcome the growth and survival advantage in colorectal tumors. © 2010 Japanese Cancer Association.

Mechanisms Controlling Carbon Turnover from Diverse Microbial Groups in Temperate and Tropical Forest Soils

NASA Astrophysics Data System (ADS)

Throckmorton, H.; Dane, L.; Bird, J. A.; Firestone, M. K.; Horwath, W. R.

2010-12-01

Microorganisms represent an important intermediate along the pathway of plant litter decomposition to the formation of soil organic matter (SOM); yet little is known of the fate and stability of microbial C in soils and the importance of microbial biochemistry as a factor influencing SOM dynamics. This research investigates mechanisms controlling microbial C stabilization in a temperate forest in the Sierra Nevada of California (CA) and a tropical forest in Puerto Rico (PR). Biochemically diverse microbial groups (fungi, actinomycetes, bacteria gram (+), and bacteria gram (-)) were isolated from both sites, grown in the laboratory with C13 media, killed, and nonliving residues were added back to soils as a reciprocal transplant of microbial groups. The native microbial community in CA is dominated by fungi and in PR is dominated by bacteria, which provides an opportunity to asses the metabolic response of distinct microbial communities to the diverse microbial additions. CA and PR soils were sampled five times over a 3 and 2 year period, respectively. In CA there was no significant difference in the mean residence time (MRT) of diverse C13 microbial treatments; whereas in PR there were significant differences, whereby temperate fungi, temperate Gram (+) bacteria, and tropical actinomycetes exhibited a significantly longer MRT as compared with tropical fungi and temperate Gram (-). These results suggest that a bacterial dominated microbial community discriminates more amongst diverse substrates than a fungal-dominated community. MRT for labeled-C in CA was 5.21 ± 1.11 years, and in PR was 2.22 ± 0.45. Despite substantial differences in MRT between sites, physical fractionation of soils into light (LF), aggregated-occluded (OF), and mineral-associated (MF) fractions provided evidence that accelerated decomposition in PR (presumably due to climate) operated primarily on labeled-C unassociated with the mineral matrix (LF); labeled-C occluded within aggregates (OF) or bound to the mineral matrix (MF) exhibited similar turnover dynamics for the two sites. Py-GC-MS-IRMS examined the fate of labeled temperate fungal residues at the molecular level in CA (30 days) and in PR (17 days) in whole soils and soil fractions. Results showed notably high enrichment of two polysaccharide biomarkers at both sites (2-furancarboxaldehyde, 5-methyl; and levoglucosanone); as well as an enol compound. These compounds did not occur in high abundance in the original fungal residues, suggesting selective preservation or secondary formation of these compounds in both CA and PR soils. Two additional lipid biomarkers exhibited notably high enrichment in CA but not PR soils, suggesting some distinct pathways of humification may be occurring at each site. Physical fractionation combined with molecular analysis suggests that protection by aggregate-occlusion (OF) and chemical complexation with soil mineral surfaces (MF) represent distinct protection mechanisms that operate on different microbial compounds.

Efficacy of oral pre-exposure prophylaxis (PrEP) for HIV among women with abnormal vaginal microbiota: a post-hoc analysis of the randomised, placebo-controlled Partners PrEP Study.

PubMed

Heffron, Renee; McClelland, R Scott; Balkus, Jennifer E; Celum, Connie; Cohen, Craig R; Mugo, Nelly; Bukusi, Elizabeth; Donnell, Deborah; Lingappa, Jairam; Kiarie, James; Fiedler, Tina; Munch, Matthew; Fredricks, David N; Baeten, Jared M

2017-10-01

Daily oral tenofovir-based pre-exposure prophylaxis (PrEP) is high efficacious for HIV prevention among women with high adherence. However, the effect of abnormal vaginal microbiota on PrEP efficacy is of concern. We investigated whether bacterial vaginosis modified the efficacy of oral PrEP. We used prospectively collected data from women in the Partners PrEP Study, a placebo-controlled trial of daily oral PrEP (either tenofovir monotherapy or a combination of tenofovir and emtricitabine) in HIV serodiscordant couples aged 18 years or older in Kenya and Uganda that showed high efficacy in women. We used Cox proportional hazards regression to assess PrEP efficacy among subgroups of women defined by bacterial vaginosis status based on yearly microscopy and Nugent scoring (0-3 indicated healthy microbiota, 4-6 intermediate, and 7-10 bacterial vaginosis). In separate efficacy analyses, we also investigated individual components of the score (ie, detection of Gardnerella vaginalis or Bacteroides spp and non-detection of Lactobacillus spp) as markers of abnormal microbiota. Of 1470 women (median age 33 years), 357 (24%) had bacterial vaginosis at enrolment. 45 women seroconverted to HIV. The HIV prevention efficacy of PrEP did not differ significantly among women with healthy microbiota (incidence 0·6 per 100 person years in PrEP group and 2·5 per 100 person-years in the placebo group; efficacy 76·55% [95% CI 43·09 to 90·37]), intermediate microbiota (HIV incidence 1·8 per 100 person-years in the PrEP group and 3·5 per 100 person-years in the placebo group; efficacy 62·72% [95% CI -66·59 to 91·66]), or bacterial vaginosis (HIV incidence 0·9 per 100 person-years in the PrEP group and 3·5 per 100 person-years in the placebo group; efficacy 72·50% [95% CI 5·98 to 91·95]; p interaction =0·871). PrEP efficacy was not significantly different between women with detected G vaginalis or Bacteroides spp morphotypes and those without these morphotypes (efficacy 68·62% vs 76·72%; p interaction =0·652); or between those with Lactobacillus spp morphotypes and those without (70·48% vs 74·08%; p interaction =0·86). Among African women with a high prevalence of bacterial vaginosis and high adherence to PrEP, the efficacy of daily oral PrEP for HIV prevention did not differ significantly among women with abnormal versus healthy vaginal microbiota as defined by Nugent score. These data are reassuring that oral PrEP delivery to women can continue without the need for concurrent testing for bacterial vaginosis or vaginal dysbiosis. Bill & Melinda Gates Foundation, Eunice Kennedy Shriver National Institute of Child Health and Human Development, and National Institute of Allergy and Infectious Diseases. Copyright © 2017 Elsevier Ltd. All rights reserved.

Nascer no Brasil: the presence of a companion favors the use of best practices in delivery care in the South region of Brazil.

PubMed

Monguilhott, Juliana Jacques da Costa; Brüggemann, Odaléa Maria; Freitas, Paulo Fontoura; d'Orsi, Eleonora

2018-01-01

OBJECTIVE To analyze if the presence of a companion favors the use of best practices in the delivery care in the South region of Brazil. METHODS This is a cross-sectional analysis of the longitudinal study Nascer no Brasil. We analyzed data from 2,070 women from the South region of Brazil who went into labor. The data were collected between February and August 2011, by interviews and medical records. We performed a bivariate and multivariate analysis, calculating the crude and adjusted prevalence ratios using Poisson regression with robust variance estimation. The level of significance adopted was 5%. RESULTS Most women had a companion during labor (51.7%), but few remained during delivery (39.4%) or cesarean section (34.8%). Less than half of the women had access to several recommended practices, while non-recommended practices continue to be performed. In the model adjusted for age, education level, source of payment for the delivery, parity, and score of the Brazilian Association of Market Research Institutes, the presence of a companion was statistically associated with a greater supply of liquids and food (aPR = 1.34), dietary prescription (aPR = 1.34), use of non-pharmacological methods for pain relief (aPR = 1.37), amniotomy (aPR = 1.10), epidural or spinal analgesia (aPR = 1.84), adoption of non-lithotomy position in the delivery (aPR = 1.77), stay in the same room during labor, delivery, and postpartum (aPR = 1.62), skin-to-skin contact in the delivery (aPR = 1.81) and cesarean section (PR = 2.43), as well as reduced use of the Kristeller maneuver (aPR = 0.67), trichotomy (aPR = 0.59), and enema (aPR = 0.49). CONCLUSIONS In the South region of Brazil, most women do not have access to the best practices in addition to undergoing several unnecessary interventions. The presence of a companion is associated with several beneficial practices and the reduction in some interventions, although other interventions are not impacted.

Nascer no Brasil: the presence of a companion favors the use of best practices in delivery care in the South region of Brazil

PubMed Central

Monguilhott, Juliana Jacques da Costa; Brüggemann, Odaléa Maria; Freitas, Paulo Fontoura; d'Orsi, Eleonora

2018-01-01

ABSTRACT OBJECTIVE To analyze if the presence of a companion favors the use of best practices in the delivery care in the South region of Brazil. METHODS This is a cross-sectional analysis of the longitudinal study Nascer no Brasil. We analyzed data from 2,070 women from the South region of Brazil who went into labor. The data were collected between February and August 2011, by interviews and medical records. We performed a bivariate and multivariate analysis, calculating the crude and adjusted prevalence ratios using Poisson regression with robust variance estimation. The level of significance adopted was 5%. RESULTS Most women had a companion during labor (51.7%), but few remained during delivery (39.4%) or cesarean section (34.8%). Less than half of the women had access to several recommended practices, while non-recommended practices continue to be performed. In the model adjusted for age, education level, source of payment for the delivery, parity, and score of the Brazilian Association of Market Research Institutes, the presence of a companion was statistically associated with a greater supply of liquids and food (aPR = 1.34), dietary prescription (aPR = 1.34), use of non-pharmacological methods for pain relief (aPR = 1.37), amniotomy (aPR = 1.10), epidural or spinal analgesia (aPR = 1.84), adoption of non-lithotomy position in the delivery (aPR = 1.77), stay in the same room during labor, delivery, and postpartum (aPR = 1.62), skin-to-skin contact in the delivery (aPR = 1.81) and cesarean section (PR = 2.43), as well as reduced use of the Kristeller maneuver (aPR = 0.67), trichotomy (aPR = 0.59), and enema (aPR = 0.49). CONCLUSIONS In the South region of Brazil, most women do not have access to the best practices in addition to undergoing several unnecessary interventions. The presence of a companion is associated with several beneficial practices and the reduction in some interventions, although other interventions are not impacted. PMID:29364356

Piperazine derivatives inhibit PrP/PrP(res) propagation in vitro and in vivo.

PubMed

Leidel, Fabienne; Eiden, Martin; Geissen, Markus; Hirschberger, Thomas; Tavan, Paul; Giese, Armin; Kretzschmar, Hans A; Schätzl, Hermann; Groschup, Martin H

2014-02-28

Prion diseases are fatal neurodegenerative disorders, which are not curable and no effective treatment exists so far. The major neuropathological change in diseased brains is the conversion of the normal cellular form of the prion protein PrPc(C) into a disease-associated isoform PrP(Sc). PrP(Sc) accumulates into multimeres and fibrillar aggregates, which leads to the formation of amyloid plaques. Increasing evidence indicates a fundamental role of PrP(Sc) species and its aggregation in the pathogenesis of prion diseases, which initiates the pathological cascade and leads to neurodegeneration accompanied by spongiform changes. In search of compounds that have the potential to interfere with PrP(Sc) formation and propagation, we used a cell based assay for the screening of potential aggregation inhibitors. The assay deals with a permanently prion infected cell line that was adapted for a high-throughput screening of a compound library composed of 10,000 compounds (DIVERset 2, ChemBridge). We could detect six different classes of highly potent inhibitors of PrP(Sc) propagation in vitro and identified piperazine derivatives as a new inhibitory lead structure, which increased incubation time of scrapie infected mice. Copyright © 2014 Elsevier Inc. All rights reserved.

Geographic and Individual Associations with PrEP Stigma: Results from the RADAR Cohort of Diverse Young Men Who have Sex with Men and Transgender Women.

PubMed

Mustanski, Brian; Ryan, Daniel T; Hayford, Christina; Phillips, Gregory; Newcomb, Michael E; Smith, Justin D

2018-05-22

Increasing the uptake of pre-exposure prophylaxis (PrEP) to prevent HIV acquisition among at-risk populations, such as young men who have sex with men (YMSM), is of vital importance to slowing the HIV epidemic. Stigma and negative injunctive norms, such as the so called "Truvada Whore" phenomenon, hamper this effort. We examined the prevalence and types of PrEP stigma and injunctive norm beliefs among YMSM and transgender women and associated individual and geospatial factors. A newly created measure of PrEP Stigma and Positive Attitudes was administered to 620 participants in an ongoing longitudinal cohort study. Results indicated lower stigma among White, compared to Black and Latino participants, and among participants not identifying as male. Prior knowledge about PrEP was associated with lower stigma and higher positive attitudes. PrEP stigma had significant geospatial clustering and hotspots were identified in neighborhoods with high HIV incidence and concentration of racial minorities, whereas coldspots were identified in areas with high HIV incidence and low LGBT stigma. These results provide important information about PrEP attitudes and how PrEP stigma differs between individuals and across communities.

“Life-Steps” for PrEP Adherence: Demonstration of a CBT-Based Intervention to Increase Adherence to Preexposure Prophylaxis (PrEP) Medication Among Sexual-Minority Men at High Risk for HIV Acquisition

PubMed Central

Taylor, S. Wade; Psaros, Christina; Pantalone, David W.; Tinsley, Jake; Elsesser, Steven A.; Mayer, Kenneth H.; Safren, Steven A.

2016-01-01

One dramatic advance in human immunodeficiency virus (HIV) prevention efforts has been the prescription of medications typically used for HIV treatment as prophylaxis against acquiring HIV. As a preventative agent, this practice is referred to as “preexposure prophylaxis” (PrEP). The U.S. Federal Drug Administration approved daily PrEP for adults at risk for HIV who do not consistently use condoms during sex with HIV-infected or unknown-status partners. In this paper, we describe a cognitive-behavioral therapy (CBT) PrEP adherence intervention developed for use in high-risk sexual-minority men in the United States, adapted from “Life-Steps,” an evidence-based CBT intervention to promote adherence to HIV treatment. Modules include creating a PrEP dosing schedule, adhering to daily PrEP, problem solving barriers to adherence, and sexual risk-reduction techniques. Supplemented with practical video vignettes, this novel intervention may help to enhance the clinical practice of health care providers in outpatient settings to increase PrEP adherence in sexual-minority men. PMID:28392673

AucPR: an AUC-based approach using penalized regression for disease prediction with high-dimensional omics data.

PubMed

Yu, Wenbao; Park, Taesung

2014-01-01

It is common to get an optimal combination of markers for disease classification and prediction when multiple markers are available. Many approaches based on the area under the receiver operating characteristic curve (AUC) have been proposed. Existing works based on AUC in a high-dimensional context depend mainly on a non-parametric, smooth approximation of AUC, with no work using a parametric AUC-based approach, for high-dimensional data. We propose an AUC-based approach using penalized regression (AucPR), which is a parametric method used for obtaining a linear combination for maximizing the AUC. To obtain the AUC maximizer in a high-dimensional context, we transform a classical parametric AUC maximizer, which is used in a low-dimensional context, into a regression framework and thus, apply the penalization regression approach directly. Two kinds of penalization, lasso and elastic net, are considered. The parametric approach can avoid some of the difficulties of a conventional non-parametric AUC-based approach, such as the lack of an appropriate concave objective function and a prudent choice of the smoothing parameter. We apply the proposed AucPR for gene selection and classification using four real microarray and synthetic data. Through numerical studies, AucPR is shown to perform better than the penalized logistic regression and the nonparametric AUC-based method, in the sense of AUC and sensitivity for a given specificity, particularly when there are many correlated genes. We propose a powerful parametric and easily-implementable linear classifier AucPR, for gene selection and disease prediction for high-dimensional data. AucPR is recommended for its good prediction performance. Beside gene expression microarray data, AucPR can be applied to other types of high-dimensional omics data, such as miRNA and protein data.

Introducing a Rigid Loop Structure from Deer into Mouse Prion Protein Increases Its Propensity for Misfolding In Vitro

PubMed Central

Kyle, Leah M.; John, Theodore R.; Schätzl, Hermann M.; Lewis, Randolph V.

2013-01-01

Prion diseases are fatal neurodegenerative disorders characterized by misfolding of the cellular prion protein (PrPc) into the disease-associated isoform (PrPSc) that has increased β-sheet content and partial resistance to proteolytic digestion. Prion diseases from different mammalian species have varying propensities for transmission upon exposure of an uninfected host to the infectious agent. Chronic Wasting Disease (CWD) is a highly transmissible prion disease that affects free ranging and farmed populations of cervids including deer, elk and moose, as well as other mammals in experimental settings. The molecular mechanisms allowing CWD to maintain comparatively high transmission rates have not been determined. Previous work has identified a unique structural feature in cervid PrP, a rigid loop between β-sheet 2 and α-helix 2 on the surface of the protein. This study was designed to test the hypothesis that the rigid loop has a direct influence on the misfolding process. The rigid loop was introduced into murine PrP as the result of two amino acid substitutions: S170N and N174T. Wild-type and rigid loop murine PrP were expressed in E. coli and purified. Misfolding propensity was compared for the two proteins using biochemical techniques and cell free misfolding and conversion systems. Murine PrP with a rigid loop misfolded in cell free systems with greater propensity than wild type murine PrP. In a lipid-based conversion assay, rigid loop PrP converted to a PK resistant, aggregated isoform at lower concentrations than wild-type PrP. Using both proteins as substrates in real time quaking-induced conversion, rigid loop PrP adopted a misfolded isoform more readily than wild type PrP. Taken together, these findings may help explain the high transmission rates observed for CWD within cervids. PMID:23825561

Correlates of willingness to initiate pre-exposure prophylaxis and anticipation of practicing safer drug- and sex-related behaviors among high-risk drug users on methadone treatment.

PubMed

Shrestha, Roman; Karki, Pramila; Altice, Frederick L; Huedo-Medina, Tania B; Meyer, Jaimie P; Madden, Lynn; Copenhaver, Michael

2017-04-01

Although people who use drugs (PWUD) are key populations recommended to receive pre-exposure prophylaxis (PrEP) to prevent HIV, few data are available to guide PrEP delivery in this underserved group. We therefore examined the willingness to initiate PrEP and the anticipation of HIV risk reduction while on PrEP among high-risk PWUD. In a cross-sectional study of 400 HIV-negative, opioid dependent persons enrolled in a methadone program and reporting recent risk behaviors, we examined independent correlates of being willing to initiate PrEP. While only 72 (18%) were aware of PrEP, after being given a description of it, 251 (62.7%) were willing to initiate PrEP. This outcome was associated with having neurocognitive impairment (aOR=3.184, p=0.004) and higher perceived HIV risk (aOR=8.044, p<0.001). Among those willing to initiate PrEP, only 12.5% and 28.2%, respectively, indicated that they would always use condoms and not share injection equipment while on PrEP. Consistent condom use was associated with higher income (aOR=8.315, p=0.016), always using condoms with casual partners (aOR=6.597, p=0.001), and inversely associated with ongoing drug injection (aOR=0.323, p=0.027). Consistent safe injection, however, was inversely associated with age (aOR=0.948, p=0.035), ongoing drug injection (aOR=0.342, p<0.001), and perceived HIV risk (aOR=0.191, p=0.019). While willingness to initiate PrEP was high and correlated with being at elevated risk for HIV, anticipated higher risk behaviors in this group even while on PrEP suggests that the next generation of HIV prevention approaches may need to combine biomedical and behavioral components to sustain HIV risk reduction over time. Copyright © 2017 Elsevier B.V. All rights reserved.

Overexpression of p62/SQSTM1 promotes the degradations of abnormally accumulated PrP mutants in cytoplasm and relieves the associated cytotoxicities via autophagy-lysosome-dependent way.

PubMed

Xu, Yin; Zhang, Jin; Tian, Chan; Ren, Ke; Yan, Yu-E; Wang, Ke; Wang, Hui; Chen, Cao; Wang, Jing; Shi, Qi; Dong, Xiao-Ping

2014-04-01

The protein of p62/sequestosome 1 (SQSTM1), a key cargo adaptor protein involved in autophagy-lysosome degradation, exhibits inclusion bodies structure in cytoplasm and plays a protective role in some models of neurodegenerative diseases. Some PrP mutants, such as PrP-CYTO and PrP-PG14, also form cytosolic inclusion bodies and trigger neuronal apoptosis either in cultured cells or in transgenic mice. Here, we demonstrated that the cellular p62/SQSTM1 incorporated into the inclusion bodies formed by expressing the abnormal PrP mutants, PrP-CYTO and PrP-PG14, in human embryonic kidney 293 cells. Overexpression of p62/SQSTM1 efficiently relieved the cytosolic aggregations and cell apoptosis induced by the abnormal PrPs. Autophagy-lysosome inhibitors instead of proteasome inhibitor sufficiently blocked the p62/SQSTM1-mediated degradations of abnormal PrPs. Overexpression of p62/SQSTM1 did not alter the levels of light chain 3 (LC3) in the cells expressing various PrPs. However, more complexes of p62/SQSTM1 with LC3 were detected in the cells expressing the misfolded PrPs. These data imply that p62/SQSTM1 plays an important role in the homeostasis of abnormal PrPs via autophagy-lysosome-dependent way.

Value redefined for inflammatory bowel disease patients: a choice-based conjoint analysis of patients' preferences.

PubMed

van Deen, Welmoed K; Nguyen, Dominic; Duran, Natalie E; Kane, Ellen; van Oijen, Martijn G H; Hommes, Daniel W

2017-02-01

Value-based healthcare is an upcoming field. The core idea is to evaluate care based on achieved outcomes divided by the costs. Unfortunately, the optimal way to evaluate outcomes is ill-defined. In this study, we aim to develop a single, preference based, outcome metric, which can be used to quantify overall health value in inflammatory bowel disease (IBD). IBD patients filled out a choice-based conjoint (CBC) questionnaire in which patients chose preferable outcome scenarios with different levels of disease control (DC), quality of life (QoL), and productivity (Pr). A CBC analysis was performed to estimate the relative value of DC, QoL, and Pr. A patient-centered composite score was developed which was weighted based on the stated preferences. We included 210 IBD patients. Large differences in stated preferences were observed. Increases from low to intermediate outcome levels were valued more than increases from intermediate to high outcome levels. Overall, QoL was more important to patients than DC or Pr. Individual outcome scores were calculated based on the stated preferences. This score was significantly different from a score not weighted based on patient preferences in patients with active disease. We showed the feasibility of creating a single outcome metric in IBD which incorporates patients' values using a CBC. Because this metric changes significantly when weighted according to patients' values, we propose that success in healthcare should be measured accordingly.

Degradation of the Disease-Associated Prion Protein by a Serine Protease from Lichens

PubMed Central

Johnson, Christopher J.; Bennett, James P.; Biro, Steven M.; Duque-Velasquez, Juan Camilo; Rodriguez, Cynthia M.; Bessen, Richard A.; Rocke, Tonie E.

2011-01-01

The disease-associated prion protein (PrPTSE), the probable etiological agent of the transmissible spongiform encephalopathies (TSEs), is resistant to degradation and can persist in the environment. Lichens, mutualistic symbioses containing fungi, algae, bacteria and occasionally cyanobacteria, are ubiquitous in the environment and have evolved unique biological activities allowing their survival in challenging ecological niches. We investigated PrPTSE inactivation by lichens and found acetone extracts of three lichen species (Parmelia sulcata, Cladonia rangiferina and Lobaria pulmonaria) have the ability to degrade prion protein (PrP) from TSE-infected hamsters, mice and deer. Immunoblots measuring PrP levels and protein misfolding cyclic amplification indicated at least two logs of reductions in PrPTSE. Degradative activity was not found in closely related lichen species or in algae or a cyanobacterium that inhabit lichens. Degradation was blocked by Pefabloc SC, a serine protease inhibitor, but not inhibitors of other proteases or enzymes. Additionally, we found that PrP levels in PrPTSE-enriched preps or infected brain homogenates are also reduced following exposure to freshly-collected P. sulcata or an aqueous extract of the lichen. Our findings indicate that these lichen extracts efficiently degrade PrPTSE and suggest that some lichens could have potential to inactivate TSE infectivity on the landscape or be a source for agents to degrade prions. Further work to clone and characterize the protease, assess its effect on TSE infectivity and determine which organism or organisms present in lichens produce or influence the protease activity is warranted. PMID:21589935

Degradation of the disease-associated prion protein by a serine protease from lichens

USGS Publications Warehouse

Johnson, C.J.; Bennett, J.P.; Biro, S.M.; Duque-Velasquez, J.C.; Rodriguez, C.M.; Bessen, R.A.; Rocke, T.E.; Bartz, Jason C.

2011-01-01

The disease-associated prion protein (PrP(TSE)), the probable etiological agent of the transmissible spongiform encephalopathies (TSEs), is resistant to degradation and can persist in the environment. Lichens, mutualistic symbioses containing fungi, algae, bacteria and occasionally cyanobacteria, are ubiquitous in the environment and have evolved unique biological activities allowing their survival in challenging ecological niches. We investigated PrP(TSE) inactivation by lichens and found acetone extracts of three lichen species (Parmelia sulcata, Cladonia rangiferina and Lobaria pulmonaria) have the ability to degrade prion protein (PrP) from TSE-infected hamsters, mice and deer. Immunoblots measuring PrP levels and protein misfolding cyclic amplification indicated at least two logs of reductions in PrP(TSE). Degradative activity was not found in closely related lichen species or in algae or a cyanobacterium that inhabit lichens. Degradation was blocked by Pefabloc SC, a serine protease inhibitor, but not inhibitors of other proteases or enzymes. Additionally, we found that PrP levels in PrP(TSE)-enriched preps or infected brain homogenates are also reduced following exposure to freshly-collected P. sulcata or an aqueous extract of the lichen. Our findings indicate that these lichen extracts efficiently degrade PrP(TSE) and suggest that some lichens could have potential to inactivate TSE infectivity on the landscape or be a source for agents to degrade prions. Further work to clone and characterize the protease, assess its effect on TSE infectivity and determine which organism or organisms present in lichens produce or influence the protease activity is warranted.

Prevalence and clinical impact of iron deficiency and anaemia among outpatients with chronic heart failure: The PrEP Registry.

PubMed

von Haehling, Stephan; Gremmler, Uwe; Krumm, Michael; Mibach, Frank; Schön, Norbert; Taggeselle, Jens; Dahm, Johannes B; Angermann, Christiane E

2017-06-01

Iron deficiency (ID) and anaemia are common in heart failure (HF). The prospective, observational PReP registry (Prävalenz des Eisenmangels bei Patienten mit Herzinsuffizienz) studied prevalence and clinical impact of ID and anaemia in HF outpatients attending cardiology practices in Germany. A total of 42 practices enrolled consecutive patients with chronic HF [left ventricular ejection fraction (LVEF) ≤45%]. ID was defined as serum ferritin <100 µg/l, or serum ferritin ≥100 µg/l/<300 µg/l plus transferrin saturation <20%, and anaemia as haemoglobin <13 g/dl (12 g/dl) in men (women). Exercise capacity was assessed using spiroergometry (69.4%) or 6-min walk test (30.4%). Amongst 1198 PReP-participants [69.0  ± 10.6 years, 25.3% female, New York Heart Association (NYHA) class 2.4  ± 0.5, LVEF 35.3 ± 7.2%], ID was found in 42.5% (previously unknown in all), and anaemia in 18.9% (previously known in 4.8%). ID was associated with female gender, lower body weight and haemoglobin, higher NYHA class and natriuretic peptide (NP) levels (all p < 0.05). ID was also more common in anaemic than non-anaemic patients (p < 0.0001), and 9.8% of PrEP-participants had both, ID and anaemia. On spiroergometry, ID independently predicted maximum exercise capacity even after multivariable adjustment, including anaemia (p = 0.0004). In all PrEP-participants, ID predicted reduced physical performance (adjusted for age, gender, anaemia, serum creatinine, C-reactive protein, LVEF, and NP level). Despite high prevalence, ID was previously unknown in all PrEP-participants, and anaemia was often unappreciated. Given the clinical relevance, treatability, and independent association with reduced physical performance, ID should be considered more in real-world ambulatory healthcare settings and ID-screening be advocated to cardiologists in such populations.

Protecting children from rabies with education and pre-exposure prophylaxis: A school-based campaign in El Nido, Palawan, Philippines

PubMed Central

Deray, Raffy; Rivera, Cesar; Gripon, Shiela; Ulanday, Corazon; Roces, Maria Concepcion; Attlan, Michael; Demont, Clarisse; Kieffer, Alexia; Miranda, Mary Elizabeth

2018-01-01

Background Rabies remains endemic in the Philippines. A study was conducted in El Nido, Palawan, Philippines to: (i) detect the true incidence of animal bites in school children aged 5–14 years using active surveillance and compare these data to estimates from the existing passive surveillance system, (ii) evaluate the impact of rabies prevention education and pre-exposure prophylaxis (PrEP) on animal bite incidence, and (iii) assess the health economic impact of the interventions. Methodology and principal findings A cohort of 4,700 school children was followed-up for any suspect rabies exposures between January 2011 and December 2012. Data on animal bite incidence from the study cohort were compared to that obtained from a review of consultation records at the Animal Bite Treatment Center (ABTC). PrEP was offered to children in all 27 public elementary schools in El Nido (in January to February 2012). Teachers were given a manual for integrating rabies in the public elementary school curriculum during the school year 2012–13. Active surveillance of the cohort revealed a higher incidence of suspect rabies exposures than that from passive surveillance. Despite a decrease in the number of Category III bites, there was no significant decrease in overall bite incidence as a result of the interventions. However, there was an increase in rabies awareness among school children in all grade levels. There was also a high level of acceptability of PrEP. Children who received PrEP and subsequently were bitten only needed two booster doses for post-exposure prophylaxis, resulting in substantial cost-savings. Conclusions/significance The true burden of animal bites remains underestimated in ABTC records. PrEP is advantageous in selected population groups, i.e. school-aged children in rabies endemic areas with limited access to animal and human rabies prevention services. Educating school children is beneficial. Strengthening veterinary interventions to target the disease at source is important. PMID:29293571

Protecting children from rabies with education and pre-exposure prophylaxis: A school-based campaign in El Nido, Palawan, Philippines.

PubMed

Deray, Raffy; Rivera, Cesar; Gripon, Shiela; Ulanday, Corazon; Roces, Maria Concepcion; Amparo, Anna Charinna; Attlan, Michael; Demont, Clarisse; Kieffer, Alexia; Miranda, Mary Elizabeth

2018-01-01

Rabies remains endemic in the Philippines. A study was conducted in El Nido, Palawan, Philippines to: (i) detect the true incidence of animal bites in school children aged 5-14 years using active surveillance and compare these data to estimates from the existing passive surveillance system, (ii) evaluate the impact of rabies prevention education and pre-exposure prophylaxis (PrEP) on animal bite incidence, and (iii) assess the health economic impact of the interventions. A cohort of 4,700 school children was followed-up for any suspect rabies exposures between January 2011 and December 2012. Data on animal bite incidence from the study cohort were compared to that obtained from a review of consultation records at the Animal Bite Treatment Center (ABTC). PrEP was offered to children in all 27 public elementary schools in El Nido (in January to February 2012). Teachers were given a manual for integrating rabies in the public elementary school curriculum during the school year 2012-13. Active surveillance of the cohort revealed a higher incidence of suspect rabies exposures than that from passive surveillance. Despite a decrease in the number of Category III bites, there was no significant decrease in overall bite incidence as a result of the interventions. However, there was an increase in rabies awareness among school children in all grade levels. There was also a high level of acceptability of PrEP. Children who received PrEP and subsequently were bitten only needed two booster doses for post-exposure prophylaxis, resulting in substantial cost-savings. The true burden of animal bites remains underestimated in ABTC records. PrEP is advantageous in selected population groups, i.e. school-aged children in rabies endemic areas with limited access to animal and human rabies prevention services. Educating school children is beneficial. Strengthening veterinary interventions to target the disease at source is important.

Female adolescent elite handball players are more susceptible to shoulder problems than their male counterparts.

PubMed

Asker, Martin; Holm, Lena W; Källberg, Henrik; Waldén, Markus; Skillgate, Eva

2018-02-10

Shoulder problems are frequent among senior elite handball players. The objective of this study was to assess the prevalence of shoulder problems among adolescent elite handball players and to investigate potential differences in gender, school grade, playing position and playing level. During the 2014 and 2015 pre-season periods, 471 players (age 15-18 years, 54% female) completed a comprehensive baseline questionnaire regarding history of any shoulder pain and shoulder problems experienced during the past season. The players were monitored weekly for one competition season (September-April) regarding shoulder problems and the amount of match and training. Generalised linear models with a binomial link function were used to calculate a prevalence ratio (PR) with 95% confidence interval (CI) to compare the subgroups of players. In total, 110 players (23%) reported having substantial shoulder problems (defined as moderate/severe reduction in training volume, or moderate/severe reduction in performance, or complete inability to participate) at some point during the follow-up season, of which almost half reported complete inability to participate. Of those players reporting substantial problems, 43% (95% CI 39-48) did so for at least 3 consecutive weeks during the season. The prevalence was significantly higher in female players (PR 1.46, 95% 1.04-2.06) and in backcourt players (PR 1.58, 95% CI 1.08-2.32), but no differences were found for school grade (PR 1.21 95% CI 0.88-1.67) or playing level (PR 1.09 95% CI 0.76-1.56). The prevalence of substantial shoulder problems in adolescent elite handball players is high, especially among females, and this warrants further studies on risk factors for shoulder injury and the development of prevention strategies in handball players already before the age of 15. These findings also highlight the importance of introducing a clinical monitoring programme on a routine basis and improving the medical support, taking gender-related aspects into consideration, at handball-profiled secondary schools. II.

Caprine PrP variants harboring Asp-146, His-154 and Gln-211 alleles display reduced convertibility upon interaction with pathogenic murine prion protein in scrapie infected cells.

PubMed

Kanata, Eirini; Arsenakis, Minas; Sklaviadis, Theodoros

2016-09-02

Scrapie, the prion disease of sheep and goats, is a devastating malady of small ruminants. Due to its infectious nature, epidemic outbreaks may occur in flocks/herds consisting of highly susceptible animals. Field studies identified scrapie-protective caprine PrP variants, harboring specific single amino acid changes (Met-142, Arg-143, Asp-146, Ser-146, His-154, Gln-211 and Lys-222). Their effects are under further evaluation, and aim to determine the most protective allele. We assessed some of these variants (Asp-146, His-154, Gln-211 and Lys-222), after their exogenous expression as murine-caprine chimeras in a scrapie- infected murine cell line. We report that exogenously expressed PrPs undergo conformational conversion upon interaction with the endogenous pathological murine prion protein (PrP SC ), which results in the detection of goat-specific and partially PK-resistant moieties. These moieties display a PK-resistance pattern distinct from the one detected in natural goat scrapie cases. Within this cellular model, distinct conformational conversion potentials were assigned to the tested variants. Molecules carrying the Asp-146, His-154 and Gln-211 alleles showed significantly lower conversion levels compared to wild type, confirming their protective effects against scrapie. Although we utilized a heterologous conversion system, this is to our knowledge, the first study of caprine PrP variants in a cellular context of scrapie, that confirms the protective effects of some of the studied alleles.

Release of Full-Length PrPC from Cultured Neurons Following Neurotoxic Challenge

PubMed Central

Wang, Kevin K. W.; Zoltewicz, J. Susie; Chiu, Allen; Zhang, Zhiqun; Rubenstein, Richard

2012-01-01

The susceptibility of the normal cellular prion protein isoform, cellular prion protein (PrPC), to proteolytic digestion has been well documented. In addition, a link between PrPC and the cytosolic protease, calpain, has been reported although the specifics of the interaction remain unclear. We performed in vitro and in cell-based studies to examine this relationship. We observed that human recombinant PrP (HrPrP) was readily cleaved by calpain-1 and -2, and we have identified and defined the targeted cleavage sites. In contrast, HrPrP was resistant to caspase-3 digestion. Unexpectedly, when brain lysates from PrPC-expressing mice were treated with calpain, no appreciable loss of the intact PrPC, nor the appearance of PrPC breakdown products (BDPs) were observed, even though alpha II-spectrin was converted to its signature calpain-induced BDPs. In addition, when rat cerebrocortical neuronal cultures (RtCNC) were subjected to the two neurotoxins at subacute levels, maitotoxin (MTX) and N-methyl-d-aspartate (NMDA), PrPC-BDPs were also not detectable. However, a novel finding from these cell-based studies is that apparently full-length, mature PrPC is released into culture media from RtCNC challenged with subacute doses of MTX and NMDA. Calpain inhibitor SNJ-1945 and caspase inhibitor IDN-6556 did not attenuate the release of PrPC. Similarly, the lysosomal protease inhibitor, NH4Cl, and the proteasome inhibitor, lactacystin, did not significantly alter the integrity of PrPC or its release from the RtCNC. In conclusion, rat neuronal PrPC is not a significant target for proteolytic modifications during MTX and NMDA neurotoxic challenges. However, the robust neurotoxin-mediated release of full-length PrPC into the cell culture media suggests an unidentified neuroprotective mechanism for PrPC. PMID:23093947

The tumor suppressor SirT2 regulates cell cycle progression and genome stability by modulating the mitotic deposition of H4K20 methylation

PubMed Central

Serrano, Lourdes; Martínez-Redondo, Paloma; Marazuela-Duque, Anna; Vazquez, Berta N.; Dooley, Scott J.; Voigt, Philipp; Beck, David B.; Kane-Goldsmith, Noriko; Tong, Qiang; Rabanal, Rosa M.; Fondevila, Dolors; Muñoz, Purificación; Krüger, Marcus; Tischfield, Jay A.; Vaquero, Alejandro

2013-01-01

The establishment of the epigenetic mark H4K20me1 (monomethylation of H4K20) by PR-Set7 during G2/M directly impacts S-phase progression and genome stability. However, the mechanisms involved in the regulation of this event are not well understood. Here we show that SirT2 regulates H4K20me1 deposition through the deacetylation of H4K16Ac (acetylation of H4K16) and determines the levels of H4K20me2/3 throughout the cell cycle. SirT2 binds and deacetylates PR-Set7 at K90, modulating its chromatin localization. Consistently, SirT2 depletion significantly reduces PR-Set7 chromatin levels, alters the size and number of PR-Set7 foci, and decreases the overall mitotic deposition of H4K20me1. Upon stress, the interaction between SirT2 and PR-Set7 increases along with the H4K20me1 levels, suggesting a novel mitotic checkpoint mechanism. SirT2 loss in mice induces significant defects associated with defective H4K20me1–3 levels. Accordingly, SirT2-deficient animals exhibit genomic instability and chromosomal aberrations and are prone to tumorigenesis. Our studies suggest that the dynamic cross-talk between the environment and the genome during mitosis determines the fate of the subsequent cell cycle. PMID:23468428

Expression Plasmids for Use in Candida glabrata

PubMed Central

Zordan, Rebecca E.; Ren, Yuxia; Pan, Shih-Jung; Rotondo, Giuseppe; Peñas, Alejandro De Las; Iluore, Joseph; Cormack, Brendan P.

2013-01-01

We describe a series of CEN/ARS episomal plasmids containing different Candida glabrata promoters, allowing for a range of constitutive or regulated expression of proteins in C. glabrata. The set of promoters includes three constitutive promoters (EGD2pr, HHT2pr, PDC1pr), two macrophage/phagocytosis-induced promoters (ACO2pr, LYS21pr), and one nutritionally regulated promoter (MET3pr). Each promoter was cloned into two plasmid backbones that differ in their selectable marker, URA3, or the dominant-selectable NAT1 gene, which confers resistance to the drug nourseothricin. Expression from the 12 resulting plasmids was assessed using GFP as a reporter and flow cytometry or quantitative reverse-transcription polymerase chain reaction to assess expression levels. Together this set of plasmids expands the toolkit of expression vectors available for use with C. glabrata. PMID:23934995

Attitudes and Acceptance of Oral and Parenteral HIV Preexposure Prophylaxis among Potential User Groups: A Multinational Study

PubMed Central

Gomez, Gabriela B.; Garnett, Geoffrey P.; Dybul, Mark R.; Piot, Peter K.

2012-01-01

Background The use of antiviral medications by HIV negative people to prevent acquisition of HIV or pre-exposure prophylaxis (PrEP) has shown promising results in recent trials. To understand the potential impact of PrEP for HIV prevention, in addition to efficacy data, we need to understand both the acceptability of PrEP among members of potential user groups and the factors likely to determine uptake. Methods and findings Surveys of willingness to use PrEP products were conducted with 1,790 members of potential user groups (FSWs, MSM, IDUs, SDCs and young women) in seven countries: Peru, Ukraine, India, Kenya, Botswana, Uganda and South Africa. Analyses of variance were used to assess levels of acceptance across different user groups and countries. Conjoint analysis was used to examine the attitudes and preferences towards hypothetical and known attributes of PrEP programs and medications. Overall, members of potential user groups were willing to consider taking PrEP (61% reported that they would definitely use PrEP). Current results demonstrate that key user groups in different countries perceived PrEP as giving them new possibilities in their lives and would consider using it as soon as it becomes available. These results were maintained when subjects were reminded of potential side effects, the need to combine condom use with PrEP, and for regular HIV testing. Across populations, route of administration was considered the most important attribute of the presented alternatives. Conclusions Despite multiple conceivable barriers, there was a general willingness to adopt PrEP in key populations, which suggests that if efficacious and affordable, it could be a useful tool in HIV prevention. There would be a willingness to experience inconvenience and expense at the levels included in the survey. The results suggest that delivery in a long lasting injection would be a good target in drug development. PMID:22247757

Obesity-stimulated aldosterone release is not related to an S1P-dependent mechanism.

PubMed

Werth, Stephan; Müller-Fielitz, Helge; Raasch, Walter

2017-12-01

Aldosterone has been identified as an important factor in obesity-associated hypertension. Here, we investigated whether sphingosine-1-phosphate (S1P), which has previously been linked to obesity, increases aldosterone release. S1P-induced aldosterone release was determined in NCI H295R cells in the presence of S1P receptor (S1PR) antagonists. In vivo release of S1P (100-300 µg/kg bw ) was investigated in pithed, lean Sprague Dawley (SD) rats, diet-obese spontaneous hypertensive rats (SHRs), as well as in lean or obese Zucker rats. Aldosterone secretion was increased in NCI H295R cells by S1P, the selective S1PR1 agonist SEW2871 and the selective S1PR2 antagonist JTE013. Treatment with the S1PR1 antagonist W146 or fingolimod and the S1PR1/3 antagonist VPbib2319 decreased baseline and/or S1P-stimulated aldosterone release. Compared to saline-treated SD rats, plasma aldosterone increased by ~50 pg/mL after infusing S1P. Baseline levels of S1P and aldosterone were higher in obese than in lean SHRs. Adrenal S1PR expression did not differ between chow- or CD-fed rats that had the highest S1PR1 and lowest S1PR4 levels. S1P induced a short-lasting increase in plasma aldosterone in obese, but not in lean SHRs. However, 2-ANOVA did not demonstrate any difference between lean and obese rats. S1P-induced aldosterone release was also similar between obese and lean Zucker rats. We conclude that S1P is a local regulator of aldosterone production. S1PR1 agonism induces an increase in aldosterone secretion, while stimulating adrenal S1PR2 receptor suppresses aldosterone production. A significant role of S1P in influencing aldosterone secretion in states of obesity seems unlikely. © 2017 Society for Endocrinology.

Epidemiology of Chronic Wasting Disease: PrPres Detection, Shedding, and Environmental Contamination

DTIC Science & Technology

2008-08-01

encephalopathies (TSEs) in that it occurs in free- ranging as well as captive wild ruminants and environmental contamination appears to play a...sensitivity and high specificity and second, dogma suggests that current assays for the detection of PrPres utilize protease digestion . Proving a highly...to achieve specificity as samples require protease digestion , protein precipitation, or extensive processing in order to distinguish PrPres from the

Integrity of Helix 2-Helix 3 Domain of the PrP Protein Is Not Mandatory for Prion Replication*

PubMed Central

Salamat, Khalid; Moudjou, Mohammed; Chapuis, Jérôme; Herzog, Laetitia; Jaumain, Emilie; Béringue, Vincent; Rezaei, Human; Pastore, Annalisa; Laude, Hubert; Dron, Michel

2012-01-01

The process of prion conversion is not yet well understood at the molecular level. The regions critical for the conformational change of PrP remain mostly debated and the extent of sequence change acceptable for prion conversion is poorly documented. To achieve progress on these issues, we applied a reverse genetic approach using the Rov cell system. This allowed us to test the susceptibility of a number of insertion mutants to conversion into prion in the absence of wild-type PrP molecules. We were able to propagate several prions with 8 to 16 extra amino acids, including a polyglycine stretch and His or FLAG tags, inserted in the middle of the protease-resistant fragment. These results demonstrate the possibility to increase the length of the loop between helices H2 and H3 up to 4-fold, without preventing prion replication. They also indicate that this loop probably remains unstructured in PrPSc. We also showed that bona fide prions can be produced following insertion of octapeptides in the two C-terminal turns of H2. These insertions do not interfere with the overall fold of the H2-H3 domain indicating that the highly conserved sequence of the terminal part of H2 is not critical for the conversion. Altogether these data showed that the amplitude of modifications acceptable for prion conversion in the core of the globular domain of PrP is much greater than one might have assumed. These observations should help to refine structural models of PrPSc and elucidate the conformational changes underlying prions generation. PMID:22511770

Integrity of helix 2-helix 3 domain of the PrP protein is not mandatory for prion replication.

PubMed

Salamat, Khalid; Moudjou, Mohammed; Chapuis, Jérôme; Herzog, Laetitia; Jaumain, Emilie; Béringue, Vincent; Rezaei, Human; Pastore, Annalisa; Laude, Hubert; Dron, Michel

2012-06-01

The process of prion conversion is not yet well understood at the molecular level. The regions critical for the conformational change of PrP remain mostly debated and the extent of sequence change acceptable for prion conversion is poorly documented. To achieve progress on these issues, we applied a reverse genetic approach using the Rov cell system. This allowed us to test the susceptibility of a number of insertion mutants to conversion into prion in the absence of wild-type PrP molecules. We were able to propagate several prions with 8 to 16 extra amino acids, including a polyglycine stretch and His or FLAG tags, inserted in the middle of the protease-resistant fragment. These results demonstrate the possibility to increase the length of the loop between helices H2 and H3 up to 4-fold, without preventing prion replication. They also indicate that this loop probably remains unstructured in PrP(Sc). We also showed that bona fide prions can be produced following insertion of octapeptides in the two C-terminal turns of H2. These insertions do not interfere with the overall fold of the H2-H3 domain indicating that the highly conserved sequence of the terminal part of H2 is not critical for the conversion. Altogether these data showed that the amplitude of modifications acceptable for prion conversion in the core of the globular domain of PrP is much greater than one might have assumed. These observations should help to refine structural models of PrP(Sc) and elucidate the conformational changes underlying prions generation.

Sulforaphane Preconditioning Sensitizes Human Colon Cancer Cells towards the Bioreductive Anticancer Prodrug PR-104A.

PubMed

Erzinger, Melanie M; Bovet, Cédric; Hecht, Katrin M; Senger, Sabine; Winiker, Pascale; Sobotzki, Nadine; Cristea, Simona; Beerenwinkel, Niko; Shay, Jerry W; Marra, Giancarlo; Wollscheid, Bernd; Sturla, Shana J

2016-01-01

The chemoprotective properties of sulforaphane (SF), derived from cruciferous vegetables, are widely acknowledged to arise from its potent induction of xenobiotic-metabolizing and antioxidant enzymes. However, much less is known about the impact of SF on the efficacy of cancer therapy through the modulation of drug-metabolizing enzymes. To identify proteins modulated by a low concentration of SF, we treated HT29 colon cancer cells with 2.5 μM SF. Protein abundance changes were detected by stable isotope labeling of amino acids in cell culture. Among 18 proteins found to be significantly up-regulated, aldo-keto reductase 1C3 (AKR1C3), bioactivating the DNA cross-linking prodrug PR-104A, was further characterized. Preconditioning HT29 cells with SF reduced the EC50 of PR-104A 3.6-fold. The increase in PR-104A cytotoxicity was linked to AKR1C3 abundance and activity, both induced by SF in a dose-dependent manner. This effect was reproducible in a second colon cancer cell line, SW620, but not in other colon cancer cell lines where AKR1C3 abundance and activity were absent or barely detectable and could not be induced by SF. Interestingly, SF had no significant influence on PR-104A cytotoxicity in non-cancerous, immortalized human colonic epithelial cell lines expressing either low or high levels of AKR1C3. In conclusion, the enhanced response of PR-104A after preconditioning with SF was apparent only in cancer cells provided that AKR1C3 is expressed, while its expression in non-cancerous cells did not elicit such a response. Therefore, a subset of cancers may be susceptible to combined food-derived component and prodrug treatments with no harm to normal tissues.

Predictors of Over-Reporting HIV Pre-exposure Prophylaxis (PrEP) Adherence Among Young Men Who Have Sex With Men (YMSM) in Self-Reported Versus Biomarker Data.

PubMed

Baker, Zoë; Javanbakht, Marjan; Mierzwa, Stan; Pavel, Craig; Lally, Michelle; Zimet, Gregory; Gorbach, Pamina

2018-04-01

Young men who have sex with men (YMSM) face a disproportionately high burden of HIV. Oral pre-exposure prophylaxis (PrEP) is effective in preventing HIV acquisition, but adherence to PrEP among YMSM may be inadequate. Medication adherence may be assessed via biomarkers, which are expensive and invasive, or via self-report through Audio Computer Assisted Self-Interview (ACASI), which may result in over-reporting of adherence. In this paper we assess the potential of a new method of self-report, the Interactive Questionnaire System (iQS), in validly estimating true adherence rates. PrEP adherence among 167 YMSM aged 15-23 was measured via dried blood spot (DBS), ACASI, and iQS twice over a 24-week study period. Both ACASI- and iQS-reported data revealed that over 40% of individuals self-reporting adequate PrEP adherence had DBS-estimated drug levels indicating inadequate adherence. Adjusted logistic repeated measures random intercept regression analyses indicated that younger YMSM had higher odds of over-reporting adherence than older YMSM-each 1 year increase in age was associated with 0.79 times the odds of over-reporting adherence (95% CI 0.63, 0.98; p value = 0.031), and being African American was associated with 3.22 times greater odds of over-reporting than non-African Americans (95% CI 1.51, 6.90; p-value = 0.0003). These results suggest that ACASI and iQS methods of self-report significantly overestimate true PrEP adherence rates among YMSM, and that the odds of over-reporting adherence may be affected by both age and race.

Steroid receptor profiling of vinclozolin and its primary metabolites.

PubMed

Molina-Molina, José-Manuel; Hillenweck, Anne; Jouanin, Isabelle; Zalko, Daniel; Cravedi, Jean-Pierre; Fernández, Mariana-Fátima; Pillon, Arnaud; Nicolas, Jean-Claude; Olea, Nicolás; Balaguer, Patrick

2006-10-01

Several pesticides and fungicides commonly used to control agricultural and indoor pests are highly suspected to display endocrine-disrupting effects in animals and humans. Endocrine disruption is mainly caused by the interference of chemicals at the level of steroid receptors: it is now well known that many of these chemicals can display estrogenic effects and/or anti-androgenic effects, but much less is known about the interaction of these compounds with other steroid receptors. Vinclozolin, a dicarboximide fungicide, like its primary metabolites 2-[[(3,5-dichlorophenyl)-carbamoyl]oxy]-2-methyl-3-butenoic acid (M1), and 3',5'-dichloro-2-hydroxy-2-methylbut-3-enanilide (M2), is known to bind androgen receptor (AR). Although vinclozolin and its metabolites were characterized as anti-androgens, relatively little is known about their effects on the function of the progesterone (PR), glucocorticoid (GR), mineralocorticoid (MR) or estrogen receptors (ERalpha and ERbeta). Objectives of the study were to determine the ability of vinclozolin and its two primary metabolites to activate AR, PR, GR, MR and ER. For this purpose, we used reporter cell lines bearing luciferase gene under the control of wild type or chimeric Gal4 fusion AR, PR, GR, MR or ERs. We confirmed that all three were antagonists for AR, whereas only M2 was found a partial agonist. Interestingly, M2 was also a PR, GR and MR antagonist (MR>PR>GR) while vinclozolin was an MR and PR antagonist. Vinclozolin, M1 and M2 were agonists for both ERs with a lower affinity for ERbeta. Although the potencies of the fungicide and its metabolites are low when compared to natural ligands, their ability to act via more than one mechanism and the potential for additive or synergistic effect must be taken into consideration in the risk assessment process.

Individual and contextual factors related to binge drinking among adolescents in Spain: a multilevel approach.

PubMed

Teixidó-Compañó, Ester; Sordo, Luis; Bosque-Prous, Marina; Puigcorbé, Susanna; Barrio, Gregorio; Brugal, M Teresa; Belza, María José J; Espelt, Albert

2018-01-15

The aim of this study was to estimate the prevalence of binge drinking by regions in Spain and assess the effect of individual and contextual factors related to this drinking pattern in adolescents. A cross-sectional study was performed with data from the 2014 Spanish School Survey on Drug Use (ESTUDES) in students aged 14-18 years (N = 34,259). The outcome was binge drinking in adolescents during the last 30 days. Individual independent variables were socioeconomic variables and variables related to access to alcohol and its availability. Contextual variables consisted of adult alcohol consumption, public policies on alcohol, and socioeconomic factors. Multilevel Poisson regression models with robust variance were estimated, obtaining prevalence ratios (PR) and their 95% confidence intervals.  The results showed that the prevalence of youth binge drinking by region of residence was similar for both sexes (r = 0.72). At the individual level, binge drinking was mainly associated with the perception of easy access to alcohol (PR: 1.38; 95% CI: 1.23-1.55), consumption in open areas [(PR: 3.82; 95% CI: 3.44-4.24) < once a month and (PR: 6.57; 95% CI: 5.85-7.37) ≥ once a month], at least one parent allowing alcohol consumption (PR: 1.42; 95% CI: 1.37-1.47), and receiving >30 euros weekly (PR :1.51; 95% CI: 1.37-1.67). Contextual variables were not associated with youth binge drinking when individual variables were considered. In conclusion, youth binge drinking was associated with individual variables related to high alcohol accessibility and availability, regardless of contextual variables. These variables explained the variability in binge drinking among Spanish regions.

SYMPTOMS OF ANXIETY ON BOTH SIDES OF THE US-MEXICO BORDER: THE ROLE OF IMMIGRATION

PubMed Central

Borges, Guilherme; Zamora, Beatriz; García, José; Orozco, Ricardo; Cherpitel, Cheryl J.; Zemore, Sarah E.; Breslau, Joshua

2014-01-01

Home to about 15 million people, the US-Mexico border area has suffered stresses from increased border security efforts and a costly drug war in Mexico. Whether immigration patterns add to increasing levels of anxiety for the Mexican population and the Mexican-origin individuals living in the US-Mexico border and near the border is unknown. We used the US-Mexico Study on Alcohol and Related Conditions (UMSARC), a cross-sectional survey (2011–2013) of individuals living in border and non-border cities of the US (n=2,336) and Mexico (n=2,460). In Mexico respondents were asked if they ever migrated to the US or have a family member living in the US (328) or not (2,124), while in the US respondents were asked if they were born in Mexico (697), born in the US with no US-born parents (second generation, 702) or born in the US with at least one US-born parent (third generation, 932). The prevalence and risk factors for symptoms of anxiety using the Beck Anxiety Inventory (>=10) were obtained. Mexicans with no migrant experience had a prevalence of anxiety and adjusted prevalence ratio (PR) within the last month of 6.7% (PR=reference), followed by Mexicans with migration experience of 13.1% (PR=1.8), Mexican-born respondents living in the US of 17.3% (PR=2.6), US born Mexican-Americans of 2nd generation of 18.6% (PR=3.3) and finally US born 3rd+ generation of 25.9% (PR=3.8). Results help to identify regions and migration patterns at high risk for anxiety and may help to unravel causal mechanisms that underlie this risk. PMID:25543519

Symptoms of anxiety on both sides of the US-Mexico border: the role of immigration.

PubMed

Borges, Guilherme; Zamora, Beatriz; García, José; Orozco, Ricardo; Cherpitel, Cheryl J; Zemore, Sarah E; Breslau, Joshua

2015-02-01

Home to about 15 million people, the US-Mexico border area has suffered stresses from increased border security efforts and a costly drug war in Mexico. Whether immigration patterns add to increasing levels of anxiety for the Mexican population and the Mexican-origin individuals living in the US-Mexico border and near the border is unknown. We used the US-Mexico Study on Alcohol and Related Conditions (UMSARC), a cross-sectional survey (2011-2013) of individuals living in border and non-border cities of the US (n = 2336) and Mexico (n = 2460). In Mexico respondents were asked if they ever migrated to the US or have a family member living in the US (328) or not (2124), while in the US respondents were asked if they were born in Mexico (697), born in the US with no US-born parents (second generation, 702) or born in the US with at least one US-born parent (third generation, 932). The prevalence and risk factors for symptoms of anxiety using the Beck Anxiety Inventory (>=10) were obtained. Mexicans with no migrant experience had a prevalence of anxiety and adjusted prevalence ratio (PR) within the last month of 6.7% (PR = reference), followed by Mexicans with migration experience of 13.1% (PR = 1.8), Mexican-born respondents living in the US of 17.3% (PR = 2.6), US born Mexican-Americans of 2nd generation of 18.6% (PR = 3.3) and finally US born 3rd + generation of 25.9% (PR = 3.8). Results help to identify regions and migration patterns at high risk for anxiety and may help to unravel causal mechanisms that underlie this risk. Copyright © 2014 Elsevier Ltd. All rights reserved.

A single amino acid (Asp159) from the dog prion protein suppresses the toxicity of the mouse prion protein in Drosophila

PubMed Central

Sanchez-Garcia, J; Jensen, K; Zhang, Y; Rincon-Limas, DE; Fernandez-Funez, P

2016-01-01

Misfolding of the prion protein (PrP) is the key step in the transmission of spongiform pathologies in humans and several animals. Although PrP is highly conserved in mammals, a few changes in the sequence of endogenous PrP are proposed to confer protection to dogs, which were highly exposed to prion during the mad-cow epidemics. D159 is a unique amino acid found in PrP from dogs and other canines that was shown to alter surface charge, but its functional relevance has never been tested in vivo. Here, we show in transgenic Drosophila that introducing the N159D substitution on mouse PrP decreases its turnover. Additionally, mouse PrP-N159D demonstrates no toxicity and accumulates no pathogenic conformations, suggesting that a single D159 substitution is sufficient to prevent PrP conformational change and pathogenesis. Understanding the mechanisms mediating the protective activity of D159 is likely to lessen the burden of prion diseases in humans and domestic animals. PMID:27477054

Cost-effectiveness Analysis of Nutritional Support for the Prevention of Pressure Ulcers in High-Risk Hospitalized Patients.

PubMed

Tuffaha, Haitham W; Roberts, Shelley; Chaboyer, Wendy; Gordon, Louisa G; Scuffham, Paul A

2016-06-01

To evaluate the cost-effectiveness of nutritional support compared with standard care in preventing pressure ulcers (PrUs) in high-risk hospitalized patients. An economic model using data from a systematic literature review. A meta-analysis of randomized controlled trials on the efficacy of nutritional support in reducing the incidence of PrUs was conducted. Modeled cohort of hospitalized patients at high risk of developing PrUs and malnutrition simulated during their hospital stay and up to 1 year. Standard care included PrU prevention strategies, such as redistribution surfaces, repositioning, and skin protection strategies, along with standard hospital diet. In addition to the standard care, the intervention group received nutritional support comprising patient education, nutrition goal setting, and the consumption of high-protein supplements. The analysis was from a healthcare payer perspective. Key outcomes of the model included the average costs and quality-adjusted life years. Model results were tested in univariate sensitivity analyses, and decision uncertainty was characterized using a probabilistic sensitivity analysis. Compared with standard care, nutritional support was cost saving at AU $425 per patient and marginally more effective with an average 0.005 quality-adjusted life years gained. The probability of nutritional support being cost-effective was 87%. Nutritional support to prevent PrUs in high-risk hospitalized patients is cost-effective with substantial cost savings predicted. Hospitals should implement the recommendations from the current PrU practice guidelines and offer nutritional support to high-risk patients.

PrEP as a feature in the optimal landscape of combination HIV prevention in sub-Saharan Africa

PubMed Central

McGillen, Jessica B; Anderson, Sarah-Jane; Hallett, Timothy B

2016-01-01

Introduction The new WHO guidelines recommend offering pre-exposure prophylaxis (PrEP) to people who are at substantial risk of HIV infection. However, where PrEP should be prioritised, and for which population groups, remains an open question. The HIV landscape in sub-Saharan Africa features limited prevention resources, multiple options for achieving cost saving, and epidemic heterogeneity. This paper examines what role PrEP should play in optimal prevention in this complex and dynamic landscape. Methods We use a model that was previously developed to capture subnational HIV transmission in sub-Saharan Africa. With this model, we can consider how prevention funds could be distributed across and within countries throughout sub-Saharan Africa to enable optimal HIV prevention (that is, avert the greatest number of infections for the lowest cost). Here, we focus on PrEP to elucidate where, and to whom, it would optimally be offered in portfolios of interventions (alongside voluntary medical male circumcision, treatment as prevention, and behaviour change communication). Over a range of continental expenditure levels, we use our model to explore prevention patterns that incorporate PrEP, exclude PrEP, or implement PrEP according to a fixed incidence threshold. Results At low-to-moderate levels of total prevention expenditure, we find that the optimal intervention portfolios would include PrEP in only a few regions and primarily for female sex workers (FSW). Prioritisation of PrEP would expand with increasing total expenditure, such that the optimal prevention portfolios would offer PrEP in more subnational regions and increasingly for men who have sex with men (MSM) and the lower incidence general population. The marginal benefit of including PrEP among the available interventions increases with overall expenditure by up to 14% (relative to excluding PrEP). The minimum baseline incidence for the optimal offer of PrEP declines for all population groups as expenditure increases. We find that using a fixed incidence benchmark to guide PrEP decisions would incur considerable losses in impact (up to 7%) compared with an approach that uses PrEP more flexibly in light of prevailing budget conditions. Conclusions Our findings suggest that, for an optimal distribution of prevention resources, choices of whether to implement PrEP in subnational regions should depend on the scope for impact of other possible interventions, local incidence in population groups, and total resources available. If prevention funding were to become restricted in the future, it may be suboptimal to use PrEP according to a fixed incidence benchmark, and other prevention modalities may be more cost-effective. In contrast, expansions in funding could permit PrEP to be used to its full potential in epidemiologically driven prevention portfolios and thereby enable a more cost-effective HIV response across Africa. PMID:27760682

In silico studies and fluorescence binding assays of potential anti-prion compounds reveal an important binding site for prion inhibition from PrP(C) to PrP(Sc).

PubMed

Pagadala, Nataraj S; Perez-Pineiro, Rolando; Wishart, David S; Tuszynski, Jack A

2015-02-16

To understand the pharmacophore properties of 2-aminothiazoles and design novel inhibitors against the prion protein, a highly predictive 3D quantitative structure-activity relationship (QSAR) has been developed by performing comparative molecular field analysis (CoMFA) and comparative similarity analysis (CoMSIA). Both CoMFA and CoMSIA maps reveal the presence of the oxymethyl groups in meta and para positions on the phenyl ring of compound 17 (N-[4-(3,4-dimethoxyphenyl)-1,3-thiazol-2-yl]quinolin-2-amine), is necessary for activity while electro-negative nitrogen of quinoline is highly favorable to enhance activity. The blind docking results for these compounds show that the compound with quinoline binds with higher affinity than isoquinoline and naphthalene groups. Out of 150 novel compounds retrieved using finger print analysis by pharmacophoric model predicted based on five test sets of compounds, five compounds with diverse scaffolds were selected for biological evaluation as possible PrP inhibitors. Molecular docking combined with fluorescence quenching studies show that these compounds bind to pocket-D of SHaPrP near Trp145. The new antiprion compounds 3 and 6, which bind with the interaction energies of -12.1 and -13.2 kcal/mol, respectively, show fluorescence quenching with binding constant (Kd) values of 15.5 and 44.14 μM, respectively. Further fluorescence binding assays with compound 5, which is similar to 2-aminothiazole as a positive control, also show that the molecule binds to the pocket-D with the binding constant (Kd) value of 84.7 μM. Finally, both molecular docking and a fluorescence binding assay of noscapine as a negative control reveals the same binding site on the surface of pocket-A near a rigid loop between β2 and α2 interacting with Arg164. This high level of correlation between molecular docking and fluorescence quenching studies confirm that these five compounds are likely to act as inhibitors for prion propagation while noscapine might act as a prion accelerator from PrP(C) to PrP(Sc). Copyright © 2014 Elsevier Masson SAS. All rights reserved.

The effect of Houttuynia cordata injection on pseudorabies herpesvirus (PrV) infection in vitro.

PubMed

Ren, Xiaofeng; Sui, Xiuwen; Yin, Jiechao

2011-02-01

Pseudorabies herpesvirus (PrV) belongs to the Alphaherpesvirinae. Piglets infected with PrV die within a few days. Development of effective antiviral agents is one alternative or complementary method to prevent PrV infection. Houttuynia cordata Thunb. (Saururaceae), H. cordata, a traditional Chinese medicine, is often used to relieve lung abnormal symptoms, infectious disease, refractory hemoptysis and malignant pleural effusion in China. The present study aimed to investigate the effect of H. cordata injection on cell infection by PrV using Vero cells (a monkey kidney cell line) and swine testis cells (ST) as models. The infectivity of PrV was determined by plaque assays when H. cordata was applied to the virus, to the virus infected cells, and to the cells prior to infection. The genomic DNA copies post-drug treatment were confirmed by PCR and reverse transcription PCR. The cell apoptosis caused by the virus was analyzed. H. cordata efficiently inhibited cell infection after incubating the drug with PrV. Nevertheless, H. cordata was more efficient in Vero cells than in ST cells in terms of its inhibitory effect. Low-dosage drug inhibited cell apoptosis induced by PrV; nevertheless, high-dosage drug alone resulted in cell apoptosis. H. cordata has a direct inhibitory activity against PrV in vitro. H. cordata may be used as an anti-PrV agent or combined with other anti-PrV agents. PrV infection induces cell apoptosis and H. cordata inhibits cell infection. The optimal administration dosage of H. cordata should be taken into account in the future, because high-dosage H. cordata alone causes cell apoptosis.

Gemella sanguinis endocarditis with c-ANCA/anti-PR-3-associated immune complex necrotizing glomerulonephritis with a ‘full-house’ pattern on immunofluorescence microscopy

PubMed Central

Rousseau-Gagnon, Mathieu; Riopel, Julie; Desjardins, Anne; Garceau, Daniel; Agharazii, Mohsen; Desmeules, Simon

2013-01-01

A 67-year-old man was evaluated for haematuria, with a rising creatinine level from 88 to 906 µmol/L and positive c-anti-neutrophil cytoplasm antibody (ANCA)/anti-proteinase 3 (anti-PR3). A kidney biopsy revealed necrotizing glomerulonephritis with a ‘full-house’ pattern on immunofluorescence microscopy. Echocardiography and blood cultures growing Gemella sanguinis diagnosed endocarditis. Dialysis was required for a month. Three months later, following valve replacement, glucocorticoids and 2 months of antibiotic therapy, the creatinine level decreased to 62 µmol/L and c-ANCA/anti-PR3 disappeared. This first case of c-ANCA/anti-PR3 positive glomerulonephritis with a ‘full-house’ immunofluorescence pattern due to bacterial endocarditis underlines the importance of ruling out infection with ANCA positivity or kidney biopsy suggestive of lupus nephritis. PMID:26064489

Cross section measurements of radiative KL2,3 RRS in 24Cr and L3M4,5 RRS in 59Pr for Mn Kα1,2 X-rays

NASA Astrophysics Data System (ADS)

Sharma, Veena; Upmanyu, Arun; Singh, Ranjit; Singh, Gurjot; Sharma, Hitesh; Kumar, Sanjeev; Mehta, D.

2017-06-01

The KL2,3 and L3M4,5 radiative resonant Raman scattering (RRS) cross sections have been measured for the quasimonochromatic Mn Kα1,2 X-rays (5.895 keV) in 24Cr (K-shell level width (ΓK) =1.08 eV) and 59 Pr (L3-subshell level width (ΓL3) =3.60 eV), respectively, using targets in metallic and various chemical forms. The incident Mn Kα1,2 X-ray energy is lower than the K-shell binding energy of 24Cr and L3-subshell binding energy of 59Pr by 94 ΓK (Cr) and 94 ΓL3 (Pr), respectively. The experimental measurements were performed with a low energy Ge detector (LEGe) and a radioactive 55Fe annular source in conjunction with 24Cr absorber. The measured cross section values for the 24Cr and 59 Pr elements in their various oxidation states are found to be same within experimental errors. The measurements were further extended to investigate alignment of the intermediate L3-subshell (J =3/2) virtual vacancy states in 59Pr through angular distribution measurements for RRS photon emission, which is found to be isotropic within experimental errors.

CNOP testimony on their understanding of training programs in optics

NASA Astrophysics Data System (ADS)

Lasagesse, Laétitia

2005-10-01

Within the National Commission for Training in Optics & Photonics (CNOP), the state of play in education for optics has been compiled at national level from primary & secondary level to University and technological training levels. Partners from CNOP propose to: - Present the www.optra.net Website webmastered by Opticsvalley, on which a list of optics training in Europe is available- Zoom in on Professional diplomas such as CQPM "optician de précision", CQPM "monteur de précision"- Present the existing baccalaureat (French A Level) concerning Optics - ...

Steroid hormone receptors ERalpha and PR characterised by immunohistochemistry in the mare adrenal gland.

PubMed

Alm, Ylva Hedberg; Sukjumlong, Sayamon; Kindahl, Hans; Dalin, Anne-Marie

2009-07-22

Sex steroid hormone receptors have been identified in the adrenal gland of rat, sheep and rhesus monkey, indicating a direct effect of sex steroids on adrenal gland function. In the present study, immunohistochemistry using two different mouse monoclonal antibodies was employed to determine the presence of oestrogen receptor alpha (ERalpha) and progesterone receptor (PR) in the mare adrenal gland. Adrenal glands from intact (n = 5) and ovariectomised (OVX) (n = 5) mares, as well as uterine tissue (n = 9), were collected after euthanasia. Three of the OVX mares were treated with a single intramuscular injection of oestradiol benzoate (2.5 mg) 18-22 hours prior to euthanasia and tissue collection (OVX+Oe). Uterine tissue was used as a positive control and showed positive staining for both ERalpha and PR. ERalpha staining was detected in the adrenal zona glomerulosa, fasciculata and reticularis of all mare groups. Ovariectomy increased cortical ERalpha staining intensity. In OVX mares and one intact mare, positive ERalpha staining was also detected in adrenal medullary cells. PR staining of weak intensity was present in a low proportion of cells in the zona fasciculata and reticularis of all mare groups. Weak PR staining was also found in a high proportion of adrenal medullary cells. In contrast to staining in the adrenal cortex, which was always located within the cell nuclei, medullary staining for both ERalpha and PR was observed only in the cell cytoplasm. The present results show the presence of ERalpha in the adrenal cortex, indicating oestradiol may have a direct effect on mare adrenal function. However, further studies are needed to confirm the presence of PR as staining in the present study was only weak and/or minor. Also, any possible effect of oestradiol treatment on the levels of steroid receptors cannot be determined by the present study, as treatment time was of a too short duration.

Transport and processing of the Rous sarcoma virus Gag protein in the endoplasmic reticulum.

PubMed Central

Krishna, N K; Weldon, R A; Wills, J W

1996-01-01

The Gag proteins of replication-competent retroviruses direct budding at the plasma membrane and are cleaved by the viral protease (PR) just before or very soon after particle release. In contrast, defective retroviruses that bud into the endoplasmic reticulum (ER) have been found, and morphologically these appear to contain uncleaved Gag proteins. From this, it has been proposed that activation of PR may depend upon a host factor found only at the plasma membrane. However, if Gag proteins were cleaved by PR before the particle could pinch off the ER membrane, then the only particles that would remain visible are those that packaged smaller-than-normal amounts of PR, and these would have an immature morphology. To distinguish between these two hypotheses, we made use of the Rous sarcoma virus (RSV) Gag protein, the PR of RSV IS included on each Gag molecule. To target Gag to the ER, a signal peptide was installed at its amino terminus in place of the plasma membrane-binding domain. An intervening, hydrophobic, transmembrane anchor was included to keep Gag extended into the cytoplasm. We found that PR-mediated processing occurred, although the cleavage products were rapidly degraded. When the anchor was removed, allowing the entire protein to be inserted into the lumen of the ER, Gag processing occurred with a high level of efficiency, and the cleavage products were quite stable. Thus, PR activation does not require targeting of Gag molecules to the plasma membrane. Unexpectedly, molecules lacking the transmembrane anchor were rapidly secreted from the cell in a nonmembrane-enclosed form and in a manner that was very sensitive to brefeldin A and monensin. In contrast, the wild-type RSV and Moloney murine leukemia virus Gag proteins were completely insensitive to these inhibitors, suggesting that the normal mechanism of transport to the plasma membrane does not require interactions with the secretory pathway. PMID:8627676

Periodontal status and neutrophilic enzyme levels in gingival crevicular fluid during pregnancy and postpartum.

PubMed

Gürsoy, Mervi; Könönen, Eija; Gürsoy, Ulvi K; Tervahartiala, Taina; Pajukanta, Riitta; Sorsa, Timo

2010-12-01

Pregnancy induces or enhances susceptibility to gingivitis; however, the presence and role of neutrophilic enzymes in pregnancy-related gingivitis are not well known. The present study demonstrates the relationship between neutrophilic enzymes in gingival crevicular fluid (GCF) and periodontal status during pregnancy and postpartum. At baseline, 30 periodontally healthy pregnant women (Pr group) and 24 non-pregnant women (N-Pr group) as their controls participated in the study. The Pr group was examined once per each trimester and twice during postpartum and the N-Pr group three times (on successive months). During each visit, GCF samples were collected from all first molars, and clinical measurements (visible plaque index, bleeding on probing [BOP], probing depth [PD], and clinical attachment level) were recorded. The samples were analyzed for matrix metalloproteinase (MMP)-8, polymorphonuclear neutrophil (PMN) elastase, myeloperoxidase (MPO), and tissue inhibitor of matrix metalloproteinase (TIMP)-1. Their levels were compared to the periodontal status at the collection site. In the Pr group, BOP and PD scores significantly increased between the first and second trimester, indicating pregnancy gingivitis. This increased inflammation was not reflected by the enzymes examined in GCF; the amounts of PMN elastase decreased continuously during the follow-up period, and those of MPO and MMP-8 did not increase until delivery, whereas TIMP-1 amounts remained stable throughout the follow-up period. In the N-Pr group, all parameters remained steady. Despite an increased susceptibility to gingivitis during mid-pregnancy, the host response does not seem to activate its own degradative enzymes.

Prion Protein Regulates Iron Transport by Functioning as a Ferrireductase

PubMed Central

Singh, Ajay; Haldar, Swati; Horback, Katharine; Tom, Cynthia; Zhou, Lan; Meyerson, Howard; Singh, Neena

2017-01-01

Prion protein (PrPC) is implicated in the pathogenesis of prion disorders, but its normal function is unclear. We demonstrate that PrPC is a ferrireductase (FR), and its absence causes systemic iron deficiency in PrP knock-out mice (PrP−/−). When exposed to non-transferrin-bound (NTB) radioactive-iron (59FeCl3) by gastric-gavage, PrP−/− mice absorb significantly more 59Fe from the intestinal lumen relative to controls, indicating appropriate systemic response to the iron deficiency. Chronic exposure to excess dietary iron corrects this deficiency, but unlike wild-type (PrP+/+) controls that remain iron over-loaded, PrP−/− mice revert back to the iron deficient phenotype after 5 months of chase on normal diet. Bone marrow (BM) preparations of PrP−/− mice on normal diet show relatively less stainable iron, and this phenotype is only partially corrected by intraperitoneal administration of excess iron-dextran. Cultured PrP−/− BM-macrophages incorporate significantly less NTB-59Fe in the absence or presence of excess extracellular iron, indicating reduced uptake and/or storage of available iron in the absence of PrPC. When expressed in neuroblastoma cells, PrPC exhibits NAD(P)H-dependent cell-surface and intracellular FR activity that requires the copper-binding octa-peptide-repeat region and linkage to the plasma membrane for optimal function. Incorporation of NTB-59Fe by neuroblastoma cells correlates with FR activity of PrPC, implicating PrPC in cellular iron uptake and metabolism. These observations explain the correlation between PrPC expression and cellular iron levels, and the cause of iron imbalance in sporadic-Creutzfeldt-Jakob-disease brains where PrPC accumulates as insoluble aggregates. PMID:23478311

In situ aromatase expression in primary tumor is associated with estrogen receptor expression but is not predictive of response to endocrine therapy in advanced breast cancer

PubMed Central

2009-01-01

Background New, third-generation aromatase inhibitors (AIs) have proven comparable or superior to the anti-estrogen tamoxifen for treatment of estrogen receptor (ER) and/or progesterone receptor (PR) positive breast cancer. AIs suppress total body and intratumoral estrogen levels. It is unclear whether in situ carcinoma cell aromatization is the primary source of estrogen production for tumor growth and whether the aromatase expression is predictive of response to endocrine therapy. Due to methodological difficulties in the determination of the aromatase protein, COX-2, an enzyme involved in the synthesis of aromatase, has been suggested as a surrogate marker for aromatase expression. Methods Primary tumor material was retrospectively collected from 88 patients who participated in a randomized clinical trial comparing the AI letrozole to the anti-estrogen tamoxifen for first-line treatment of advanced breast cancer. Semi-quantitative immunohistochemical (IHC) analysis was performed for ER, PR, COX-2 and aromatase using Tissue Microarrays (TMAs). Aromatase was also analyzed using whole sections (WS). Kappa analysis was applied to compare association of protein expression levels. Univariate Wilcoxon analysis and the Cox-analysis were performed to evaluate time to progression (TTP) in relation to marker expression. Results Aromatase expression was associated with ER, but not with PR or COX-2 expression in carcinoma cells. Measurements of aromatase in WS were not comparable to results from TMAs. Expression of COX-2 and aromatase did not predict response to endocrine therapy. Aromatase in combination with high PR expression may select letrozole treated patients with a longer TTP. Conclusion TMAs are not suitable for IHC analysis of in situ aromatase expression and we did not find COX-2 expression in carcinoma cells to be a surrogate marker for aromatase. In situ aromatase expression in tumor cells is associated with ER expression and may thus point towards good prognosis. Aromatase expression in cancer cells is not predictive of response to endocrine therapy, indicating that in situ estrogen synthesis may not be the major source of intratumoral estrogen. However, aromatase expression in combination with high PR expression may select letrozole treated patients with longer TTP. Trial registration Sub-study of trial P025 for advanced breast cancer. PMID:19531212

Association between ambient air pollution and proliferation of umbilical cord blood cells.

PubMed

Novack, L; Yitshak-Sade, M; Landau, D; Kloog, I; Sarov, B; Karakis, I

2016-11-01

It has been established as a common knowledge that ambient air pollution (AAP) has an adverse effect on human health. The pathophysiological mechanism of this impact is likely to be related to the oxidative stress. In the current study we estimate the association between AAP and cell proliferation (CP) of umbilical cord blood cells, representing maternal organism most proximal to the fetal body. Blood samples were tested for proliferation in 292 enrolled Arab-Bedouin women at delivery (July 2012-March 2013). The estimates of AAP were defined by a hybrid satellite based model predicting both PM 2.5 (particles<2.5µm in diameter) and PM 10 (particles<10µm in diameter) as well as monitoring stations for gaseous air pollutants. Risk estimates of pollution exposure were adjusted to medical history, household risk factors and meteorological factors on the day of delivery or one week prior. Ambient ozone (O 3 ) levels on 1, 2, 3and 4 days prior to delivery were associated with lower CP (Prevalence ratio (PR)=0.92, 0.92, 0.93, 0.93, respectively). Increase in inter-quartile range (IOR) of PM 2.5 one day before delivery was associated with 9% increase in CP levels (PR=1.09). The positive direction in association was changed to negative association with CP for PM 2.5 levels measured at more distant time periods (PR=0.90 and 0.93 for lags 5 and 6 days, respectively). Investigation of PM 10 levels indicated a similar pattern (PR=1.05 for pollution values recorded one day before delivery and 0.93 and 0.95 for lags of 5 and 6 days, respectively). Carbon monoxide (CO) levels were associated with lower CP on the day of delivery and 1day prior (PR=0.92 and PR=0.94). To conclude, the levels of cell proliferation of umbilical cord blood cells appear to be associated with the AAP. More studies are needed to support our findings. Copyright © 2016. Published by Elsevier Inc.

Influenza Viral Vectors Expressing Two Kinds of HA Proteins as Bivalent Vaccine Against Highly Pathogenic Avian Influenza Viruses of Clade 2.3.4.4 H5 and H7N9

PubMed Central

Li, Jinping; Hou, Guangyu; Wang, Yan; Wang, Suchun; Peng, Cheng; Yu, Xiaohui; Jiang, Wenming

2018-01-01

The H5 and H7N9 subtypes of highly pathogenic avian influenza viruses (HPAIVs) in China pose a serious challenge to public health and the poultry industry. In this study, a replication competent recombinant influenza A virus of the Í5N1 subtype expressing the H7 HA1 protein from a tri-cistronic NS segment was constructed. A heterologous dimerization domain was used to combine with the truncated NS1 protein of 73 amino acids to increase protein stability. H7 HA1, nuclear export protein coding region, and the truncated NS1 were fused in-frame into a single open reading frame via 2A self-cleaving peptides. The resulting PR8-H5-NS1(73)H7 stably expressed the H5 HA and H7 HA1 proteins, and exhibited similar growth kinetics as the parental PR8-H5 virus in vitro. PR8-H5-NS1(73)H7 induced specific hemagglutination inhibition (HI) antibody against H5, which was comparable to that of the combination vaccine of PR8-H5 and PR8-H7. The HI antibody titers against H7 virus were significantly lower than that by the combination vaccine. PR8-H5-NS1(73)H7 completely protected chickens from challenge with both H5 and H7 HPAIVs. These results suggest that PR8-H5-NS1(73)H7 is highly immunogenic and efficacious against both H5 and H7N9 HPAIVs in chickens. Highlights: - PR8-H5-NS1(73)H7 simultaneously expressed two HA proteins of different avian influenza virus subtypes. - PR8-H5-NS1(73)H7 was highly immunogenic in chickens. - PR8-H5-NS1(73)H7 provided complete protection against challenge with both H5 and H7N9 HPAIVs. PMID:29670587

Overcoming etch challenges related to EUV based patterning (Conference Presentation)

NASA Astrophysics Data System (ADS)

Metz, Andrew W.; Cottle, Hongyun; Honda, Masanobu; Morikita, Shinya; Kumar, Kaushik A.; Biolsi, Peter

2017-04-01

Research and development activities related to Extreme Ultra Violet [EUV] defined patterning continue to grow for < 40 nm pitch applications. The confluence of high cost and extreme process control challenges of Self-Aligned Quad Patterning [SAQP] with continued momentum for EUV ecosystem readiness could provide cost advantages in addition to improved intra-level overlay performance relative to multiple patterning approaches. However, Line Edge Roughness [LER] and Line Width Roughness [LWR] performance of EUV defined resist images are still far from meeting technology needs or ITRS spec performance. Furthermore, extreme resist height scaling to mitigate flop over exacerbates the plasma etch trade-offs related to traditional approaches of PR smoothing, descum implementation and maintaining 2D aspect ratios of short lines or elliptical contacts concurrent with ultra-high photo resist [PR] selectivity. In this paper we will discuss sources of LER/LWR, impact of material choice, integration, and innovative plasma process techniques and describe how TELTM VigusTM CCP Etchers can enhance PR selectivity, reduce LER/LWR, and maintain 2D aspect ratio of incoming patterns. Beyond traditional process approaches this paper will show the utility of: [1] DC Superposition in enhancing EUV resist hardening and selectivity, increasing resistance to stress induced PR line wiggle caused by CFx passivation, and mitigating organic planarizer wiggle; [2] Quasi Atomic Layer Etch [Q-ALE] for ARC open eliminating the tradeoffs between selectivity, CD, and shrink ratio control; and [3] ALD+Etch FUSION technology for feature independent CD shrink and LER reduction. Applicability of these concepts back transferred to 193i based lithography is also confirmed.

Association of Walkability With Obesity in Baltimore City, Maryland

PubMed Central

Gittelsohn, Joel; Zonderman, Alan B.; Evans, Michele K.; Gary-Webb, Tiffany L.

2011-01-01

Objectives. To investigate the association between walkability and obesity, we studied adults residing in Baltimore City, Maryland, in neighborhoods of varying racial and socioeconomic composition. Methods. We conducted a cross-sectional study of 3493 participants from the study Healthy Aging in Neighborhoods of Diversity across the Life Span. We used the Pedestrian Environment Data Scan to measure neighborhood walkability in 34 neighborhoods of diverse racial and socioeconomic composition in which the study participants lived. Confirmatory factor analysis was used to determine walkability scores. Multilevel modeling was used to determine prevalence ratios for the association between walkability and obesity. Results. Among individuals living in predominately White and high-socioeconomic status (SES) neighborhoods, residing in highly walkable neighborhoods was associated with a lower prevalence of obesity when compared with individuals living in poorly walkable neighborhoods, after adjusting for individual-level demographic variables (prevalence ratio–[PR] = 0.58; P = <.001 vs PR = 0.80; P = .004). Prevalence ratios were similar after controlling for the perception of crime, physical activity, and main mode of transportation. The association between walkability and obesity for individuals living in low-SES neighborhoods was not significant after accounting for main mode of transportation (PR = 0.85; P = .060). Conclusions. Future research is needed to determine how differences in associations by neighborhood characteristics may contribute to racial disparities in obesity. PMID:21164099

Psychological violence against pregnant women in a prenatal care cohort: rates and associated factors in São Luís, Brazil.

PubMed

Ribeiro, Marizélia Rodrigues Costa; da Silva, Antônio Augusto Moura; E Alves, Maria Teresa Seabra Soares de Britto; Batista, Rosângela Fernandes Lucena; de Rocha, Lourdes Maria Leitão Nunes; Schraiber, Lilia Blima; Medeiros, Nilzângela Lima; Costa, Danielle Cristina Silva; Bettiol, Heloisa; Barbieri, Marco Antônio

2014-02-12

Violence against pregnant women has been associated with gestational and perinatal disorders. Psychological violence is the type least investigated and its associated factors have been little studied. The present study was conducted in order to estimate prevalence rates and analyze the factors associated with exclusive and recurrent psychological violence in the municipality of São Luís, Brazil. Data regarding 982 pregnant women, aged from 14 to 45 years, interviewed in 2010 and 2011 in a prenatal cohort were used. A self-applied questionnaire was used to screen for violence. Pregnant women submitted to physical and sexual violence were excluded from the analysis of factors associated with exclusive psychological violence. Prevalence ratios and 95% confidence intervals were estimated by a Poisson regression model with a hierarchical approach at three levels. At level 1 of the theoretical-conceptual model, we analyzed demographic and socioeconomic characteristics and variables that express gender inequalities; at level 2, we analyzed social support received by the women, and at level 3, the life experiences of the pregnant women. Prevalence rate of exclusive psychological violence was 41.6% and of recurrent violence was 32.6%. Exclusive psychological violence was associated with pregnant women's age of 14 to 18 years (PR: 1.32 95% CI: 1.04 - 1.70), pregnant women's schooling superior to that of her intimate partner (PR: 1.54 95% CI: 1.09 - 2.16), inadequate social affective support/positive social interaction (PR: 1.34 95% CI: 1.11 - 1.62), use of illicit drugs by the pregnant women (PR: 1.80 95% CI: 1.16 - 2.81) and having had six or more intimate partners in life (PR: 1.52 95% CI: 1.18 - 1.96). Recurrent exclusive psychological violence was associated with inadequate social affective support/positive social interaction (PR: 1.47 95% CI: 1.15 - 1.87), use of illicit drugs by the pregnant women (PR: 2,28 95% CI: 1,40 - 3,71) and having had six or more intimate partners in life (PR: 1.47 95% CI: 1.06 - 2.03). Psychological violence was a common phenomenon in this population of pregnant women that was associated with gender inequalities, inadequate social support and illicit drug use and should be routinely investigated during prenatal visits at health care services.

Ex vivo mammalian prions are formed of paired double helical prion protein fibrils.

PubMed

Terry, Cassandra; Wenborn, Adam; Gros, Nathalie; Sells, Jessica; Joiner, Susan; Hosszu, Laszlo L P; Tattum, M Howard; Panico, Silvia; Clare, Daniel K; Collinge, John; Saibil, Helen R; Wadsworth, Jonathan D F

2016-05-01

Mammalian prions are hypothesized to be fibrillar or amyloid forms of prion protein (PrP), but structures observed to date have not been definitively correlated with infectivity and the three-dimensional structure of infectious prions has remained obscure. Recently, we developed novel methods to obtain exceptionally pure preparations of prions from mouse brain and showed that pathogenic PrP in these high-titre preparations is assembled into rod-like assemblies. Here, we have used precise cell culture-based prion infectivity assays to define the physical relationship between the PrP rods and prion infectivity and have used electron tomography to define their architecture. We show that infectious PrP rods isolated from multiple prion strains have a common hierarchical assembly comprising twisted pairs of short fibres with repeating substructure. The architecture of the PrP rods provides a new structural basis for understanding prion infectivity and can explain the inability to systematically generate high-titre synthetic prions from recombinant PrP. © 2016 The Authors.

Specific detection of rinderpest virus by real-time reverse transcription-PCR in preclincal and clinical samples of experimentally infected cattle

USDA-ARS?s Scientific Manuscript database

A highly sensitive detection test for Rinderpest virus (RPV), based on a real-time reverse transcription-PCR (RT-PR) system, was developed. Five different RPV genomic targets were examined, and one was selected and optimized to detect viral RNA in infected tissue culture fluid with a level of detec...

Phase diagram of the Pr-Mn-O system in composition-temperature-oxygen pressure coordinates

NASA Astrophysics Data System (ADS)

Vedmid', L. B.; Yankin, A. M.; Fedorova, O. M.; Kozin, V. M.

2016-05-01

The phase relations in the Pr-Mn-O system were studied by the static method at lowered oxygen pressure in combination with thermal analysis and high-temperature X-ray diffraction. The equilibrium oxygen pressure in dissociation of PrMn2O5 and PrMnO3 was measured, and the thermodynamic characteristics of formation of these compounds from elements were calculated. The P- T- x phase diagram of the Pr-Mn-O system was constructed in the "composition-oxygen pressure-temperature" coordinates.

Development of an Influenza A Master Virus for Generating High-Growth Reassortants for A/Anhui/1/2013(H7N9) Vaccine Production in Qualified MDCK Cells

PubMed Central

Suzuki, Yasushi; Odagiri, Takato; Tashiro, Masato; Nobusawa, Eri

2016-01-01

In 2013, the first case of human infection with an avian influenza A virus (H7N9) was reported in China, and the human infection with this virus has continued as of 2016. At the request of the WHO, we have successfully developed candidate reassortant vaccine virus using A/Anhui/1/2013 and the high egg-growth master virus A/PR/8/1934. Recent plans regarding influenza vaccine production include using cell-cultured systems in Japan and several other countries. However, egg-based vaccine viruses are not always suitable for cell-cultured vaccine production due to potential issues with growth, protein yield and antigenic stability. Therefore, in this study, we have developed a high-growth master virus (hg-PR8) adapted to qualified NIID-MDCK cells that are competent for vaccine production. The virus hg-PR8 was obtained after 20 serial passages of A/Puerto Rico/8/1934 (PR8) in NIID-MDCK cells. The viral titer of hg-PR8 was 108.6 plaque-forming units per milliliter (PFU/mL). Seven amino acid substitutions were identified in the amino acid sequences of PB2, PB1, PA, NA, M and NS of hg-PR8 compared to the sequence of the original PR8 (org-PR8) strain. The growth capacities of the reassortant viruses, which possess heterologous internal genes from hg-PR8 or org-PR8, indicated that the amino acid changes in PB2 and NS2 similarly affected growth capacity in NIID-MDCK cells. To assess the suitability of hg-PR8 as a master virus, we generated 6:2 reassortant viruses possessing the HA and NA segments from A/Anhui/1/2013 (H7N9) and the remaining segments from hg-PR8. The virus titers of the reassortant strains were 107−108 PFU/mL. The antigenicity of the viruses was stable during ten passages of the viruses in NIID-MDCK cells. In comparison with the egg-based reassortant vaccine viruses with identical HA and NA segments, the hg-PR8-based viruses showed 1.5- to 2-fold higher protein yields in NIID-MDCK cells. PMID:27454606

Sexually transmitted infections and pre-exposure prophylaxis: challenges and opportunities among men who have sex with men in the US.

PubMed

Scott, Hyman M; Klausner, Jeffrey D

2016-01-01

Pre-Exposure Prophylaxis (PrEP) has shown high efficacy in preventing human immunodeficiency virus (HIV) infection among men who have sex with men (MSM) in several large clinical trials, and more recently in "real world" reports of clinical implementation and a PrEP demonstration project. Those studies also demonstrated high bacterial sexually transmitted infection (STI) incidence and raised the discussion of how PrEP may impact STI control efforts, especially in the setting of increasing Neisseria gonorrhoeae antimicrobial resistance and the increase in syphilis cases among MSM. Here, we discuss STIs as a driver of HIV transmission risk among MSM, and the potential opportunities and challenges for STI control afforded by expanded PrEP implementation among high-risk MSM.

High-temperature fcc phase of Pr:  Negative thermal expansion and intermediate valence state

NASA Astrophysics Data System (ADS)

Kuznetsov, A. Yu.; Dmitriev, V. P.; Bandilet, O. I.; Weber, H.-P.

2003-08-01

A high-temperature angle-dispersive synchrotron radiation diffraction study has revealed the double hexagonal-close-packed-to-face-centered-cubic (dhcp-to-fcc) transformation in the Pr metal occurring martensitically between 575 and 1035 K. The high-temperature fcc phase shows a negative thermal expansion in the range 600 800 K, attributed to the 4f-electron delocalization. A phenomenological theory is developed, which explains consistently the observed effect in terms of the mean valence variation of the metal as a function of temperature; it also predicts the existence of an isostructural phase transition and of a critical end point of a gas-liquid type in compressed Pr. The analysis of published data on P-T variation of conductivity of Pr supports this prediction.

Association between ambient air pollution and proliferation of umbilical cord blood cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Novack, L., E-mail: novack@bgu.ac.il

It has been established as a common knowledge that ambient air pollution (AAP) has an adverse effect on human health. The pathophysiological mechanism of this impact is likely to be related to the oxidative stress. In the current study we estimate the association between AAP and cell proliferation (CP) of umbilical cord blood cells, representing maternal organism most proximal to the fetal body. Blood samples were tested for proliferation in 292 enrolled Arab-Bedouin women at delivery (July 2012–March 2013). The estimates of AAP were defined by a hybrid satellite based model predicting both PM{sub 2.5} (particles<2.5 µm in diameter) andmore » PM{sub 10} (particles<10 µm in diameter) as well as monitoring stations for gaseous air pollutants. Risk estimates of pollution exposure were adjusted to medical history, household risk factors and meteorological factors on the day of delivery or one week prior. Ambient ozone (O{sub 3}) levels on 1, 2, 3and 4 days prior to delivery were associated with lower CP (Prevalence ratio (PR)=0.92, 0.92, 0.93, 0.93, respectively). Increase in inter-quartile range (IOR) of PM{sub 2.5} one day before delivery was associated with 9% increase in CP levels (PR=1.09). The positive direction in association was changed to negative association with CP for PM{sub 2.5} levels measured at more distant time periods (PR=0.90 and 0.93 for lags 5 and 6 days, respectively). Investigation of PM{sub 10} levels indicated a similar pattern (PR=1.05 for pollution values recorded one day before delivery and 0.93 and 0.95 for lags of 5 and 6 days, respectively). Carbon monoxide (CO) levels were associated with lower CP on the day of delivery and 1 day prior (PR=0.92 and PR=0.94). To conclude, the levels of cell proliferation of umbilical cord blood cells appear to be associated with the AAP. More studies are needed to support our findings. - Highlights: • Ambient air pollutants were suggested to have an impact on cell proliferation (CP) of umbilical cord blood. • Ozone (O{sub 3}) and carbon monoxide (CO) levels days before delivery were associated with lower CP. • Particulate matter day before delivery was associated with increased CP levels; CP levels decreased for pollutants' levels more distant in time. • Change in directions of an association is likely to be related to different underlying pathophysiological mechanism of pollutants' effect on humans' body.« less

Photoemission study of the electronic structure (Pr 0.2La 0.8)(Ba 1.875La 0.125)Cu 3O 7- gd

NASA Astrophysics Data System (ADS)

Lindberg, P. A. P.; Shen, Z.-X.; Lindau, I.; Spicer, W. E.; Mitzi, D. B.; Kapitulnik, A.

1989-11-01

Photoemission results from the Pr and La doped 1 2 3 system (Pr 0.2La 0.8) (Ba 1.875La 0.125)Cu 3O 7-gd are reported. The core level spectra show strong resemblance to those of other compounds of the 1 2 3 and 2 1 4 systems. The Cu 2 p satellite intensity is found to be ˜ 35% of the main Cu 2 p line, and the O 1 s core level spectra, exhibiting a clear doublet, show evidence of extrinsic oxygen. The clear correlation between the intensities of certain features in the valence band and the amount of extrinsic oxygen, as monitored by the O 1 s core level spectra, is explicitly addressed.

Exploring the cause of initially reactive bovine brains on rapid tests for BSE

PubMed Central

Dudas, Sandor; James, Jace; Anderson, Renee; Czub, Stefanie

2015-01-01

ABSTRACT Bovine spongiform encephalopathy (BSE) is an invariably fatal prion disease of cattle. The identification of the zoonotic potential of BSE prompted safety officials to initiate surveillance testing for this disease. In Canada, BSE surveillance is primarily focused on high risk cattle including animals which are dead, down and unable to rise, diseased or distressed. This targeted surveillance results in the submission of brain samples with a wide range of tissue autolysis and associated contaminants. These contaminants have the potential to interfere with important steps of surveillance tests resulting in initially positive test results requiring additional testing to confirm the disease status of the animal. The current tests used for BSE screening in Canada utilize the relative protease resistance of the prion protein gained when it misfolds from PrPC to PrPSc as part of the disease process. Proteinase K completely digests PrPC in normal brains, but leaves most of the PrPSc in BSE positive brains intact which is detected using anti-prion antibodies. These tests are highly reliable but occasionally give rise to initially reactive/false positive results. Test results for these reactive samples were close to the positive/negative cut-off on a sub set of test platforms. This is in contrast to all of the previous Canadian positive samples whose numeric values on these same test platforms were 10 to 100 fold greater than the test positive/negative cut-off. Here we explore the potential reason why a sample is repeatedly positive on a sub-set of rapid surveillance tests, but negative on other test platforms. In order to better understand and identify what might cause these initial reactions, we have conducted a variety of rapid and confirmatory assays as well as bacterial isolation and identification on BSE positive, negative and initially reactive samples. We observed high levels of viable bacterial contamination in initially reactive samples suggesting that the reactivity may be related to bacterial factors. Several bacteria isolated from the initially reactive samples have characteristics of biofilm forming bacteria and this extracellular matrix might play a role in preventing complete digestion of PrPC in these samples. PMID:26689488

Hot News: Sexually Transmitted Infections on the Rise in PrEP Users.

PubMed

Barreiro, Pablo

2018-01-01

Pre-exposure prophylaxis (PrEP) with oral Truvada (tenofovir plus emtricitabine) is effective at preventing HIV infection in high-risk homosexual men. In the United States, PrEP was approved in 2012 and is reimbursed by Medicaid and the majority of private insurers. The situation is diverse and not uniform in the European Union, being PrEP more widely used in France than in the rest of countries. Concerns have been raised that PrEP use may be accompanied by the phenomena of risk compensation or behavioral disinhibition, whereby PrEP users' perception of decreased risk of HIV acquisition may lead them to engage in overall riskier sexual practices and increase their chances of acquiring sexually transmitted infections (STIs) (Blumenthal, et al. Virtual Mentor. 2014;16:909-15). Modifiable factors that may influence the acquisition of STI include condom use, number of partners, partner characteristics, and healthcare-seeking behaviors. In addition, MSM may alter HIV risk mitigation practices while on PrEP by decreasing seroadaptive practices such as serosorting that is seeking a partner of similar perceived serostatus (Khosopour, et al. AIDS Behav. 2017;21:2935-44). High rates of STI have been reported among PrEP users, as well as high rates of condomless sex, and increasing rates of STI over time (Liu, et al. JAMA Intern Med. 2016;176:75-84; Kojima, et al. AIDS, 2016;30:2251-2). In a new study conducted in Montreal, Canada, increases in the rates of STI in PrEP users were demonstrated measuring incidence rates of STI before and following the initiation of PrEP in the same cohort. The authors measured the incidence of gonorrhea, chlamydia, and/or syphilis in 109 HIV-seronegative homosexual men 12 months before and 12 months after beginning Truvada for HIV prevention (Nguyen, et al. AIDS. 2018;32:523-30). New episodes of gonorrhea, chlamydia, and/or syphilis rose in the cohort after providing Truvada, as shown in Figure 1. Moreover, the incidence of three or more STI increased from 3.7 to 9.2 cases per 100 personyears in this cohort. The Canadian study highlighted that the rate of STI with PrEP was also higher than in a group of 86 homosexual men that had undergone PEP in Montreal during 2010-2015. Other findings of the study we the high rate of STI with anorectal location, symptomless STI (e.g., chlamydia) and the frequency of sex partners contacted by internet. The increased rates of STI in PrEP users suggest a need to reinforce counseling and STI diagnosis and treatment efforts. Although PrEP may provide a public health benefit beyond the immediate prevention of HIV infection as result of bringing into care high-risk homosexual men who might not otherwise be seeking care for STI, doctors in charge must take this opportunity for informing adequately on STI and the risks inherent to multiple and occasional sexual contacts.

U.S. military service and the prevalence of metabolic syndrome: Findings from a cross-sectional analysis of the Cooper Center Longitudinal Study, 1979-2013.

PubMed

Janak, Jud C; Pérez, Adriana; Alamgir, Hasanat; Orman, Jean A; Cooper, Sharon P; Shuval, Kerem; DeFina, Laura; Barlow, Carolyn E; Gabriel, Kelley Pettee

2017-02-01

U.S. military service confers both health benefits and risks potentially associated with a clustering of cardiovascular risk factors called metabolic syndrome. However, the association between prior military service and metabolic syndrome has not sufficiently been examined. The purpose of the study was to compare the prevalence of metabolic syndrome by prior military service status. Among 42,370 men (887 with prior military service) examined from 1979 to 2013 at the Cooper Clinic (Dallas, TX), we used a cross-sectional study design to examine the association between military service and metabolic syndrome. First, an unadjusted log binomial regression model was performed by regressing the prevalence of metabolic syndrome on prior service. This was followed by performing Kleinbaum's modeling strategy for assessing confounding. The same methodology was used to explore the association between individual metabolic syndrome risk factors and prior service. Prior military service was not significantly associated with the prevalence of metabolic syndrome (PR=0.98, 0.89-1.07). None of the variables explored were identified as confounders. Participants with prior military service had lower prevalence of both elevated levels of triglycerides (PR=0.89, 0.80-0.99) and low levels of high-density lipoprotein-cholesterol (PR=0.78, 0.70-0.88). They had a higher prevalence of elevated resting systolic blood pressure (PR=1.23, 1.12-1.35). However, none of these associations were significant after adjusting for identified confounders: age; cardiorespiratory fitness; and exam year. Study findings indicate that military service was not independently associated with the prevalence of metabolic syndrome or its components. Future research is warranted longitudinally assessing the impact of military service on long-term outcomes. Copyright © 2016 Elsevier Inc. All rights reserved.

Self-Reported Impact of Chlamydia Testing on Subsequent Behavior: Results of an Online Survey of Young Adults in England.

PubMed

Hartney, Thomas; Baraitser, Paula; Nardone, Anthony

2015-09-01

The National Chlamydia Screening Programme performs 1.7 million tests annually among young adults in England. The effect of chlamydia screening on subsequent behavior is unknown. This study examined the self-reported impact of testing on young adults' subsequent health care-seeking and sexual behavior. We conducted a cross-sectional Web-based anonymous survey using an online panel to recruit 1521 young adults aged 16 to 24 years and resident in England. Survey questions were developed using the theory of planned behavior. Multivariate log-binomial regression was used to identify the variables associated with an impact on subsequent behavior after testing. Most respondents reported that being tested for chlamydia had a positive effect on their subsequent sexual behavior (68.6%; 422/615) or health care-seeking behavior (80.0%; 492/615). In multivariate analysis, being female and having a high level of engagement at last test were both associated with positive impacts on sexual behavior (72.7% [adjusted prevalence ratio {aPR}, 1.19; 95% confidence interval {CI}, 1.07-1.33] and 82.7% [aPR, 1.55; 95% CI, 1.27-1.89], respectively), and health care-seeking behavior (84.4% [aPR, 1.13; 95% Cl, 1.04-1.24] and 86.3% [aPR, 1.23; 95% CI, 1.07-1.41], respectively). Among respondents with minimum level of engagement, 72.4% (76/105) reported an increase in subsequent health care-seeking behavior. Chlamydia testing had a positive impact on young adults' self-reported health care-seeking and sexual behavior. This suggests that chlamydia screening has a wider effect on young adults' sexual health beyond that of treatment alone.

Light-promoted rhodopsin expression and starvation survival in the marine dinoflagellate Oxyrrhis marina.

PubMed

Guo, Zhiling; Zhang, Huan; Lin, Senjie

2014-01-01

The discovery of microbial rhodopsins in marine proteobacteria changed the dogma that photosynthesis is the only pathway to use the solar energy for biological utilization in the marine environment. Although homologs of these rhodopsins have been identified in dinoflagellates, the diversity of the encoding genes and their physiological roles remain unexplored. As an initial step toward addressing the gap, we conducted high-throughput transcriptome sequencing on Oxyrrhis marina to retrieve rhodopsin transcripts, rapid amplification of cDNA ends to isolate full-length cDNAs of dominant representatives, and quantitative reverse-transcription PCR to investigate their expression under varying conditions. Our phylogenetic analyses showed that O. marina contained both the proton-pumping type (PR) and sensory type (SR) rhodopsins, and the transcriptome data showed that the PR type dominated over the SR type. We compared rhodopsin gene expression for cultures kept under light: dark cycle and continuous darkness in a time course of 24 days without feeding. Although both types of rhodopsin were expressed under the two conditions, the expression levels of PR were much higher than SR, consistent with the transcriptomic data. Furthermore, relative to cultures kept in the dark, rhodopsin expression levels and cell survival rate were both higher in cultures grown in the light. This is the first report of light-dependent promotion of starvation survival and concomitant promotion of PR expression in a eukaryote. While direct evidence needs to come from functional test on rhodopsins in vitro or gene knockout/knockdown experiments, our results suggest that the proton-pumping rhodopsin might be responsible for the light-enhanced survival of O. marina, as previously demonstrated in bacteria.

What Primary Care Providers Need to Know about Pre-Exposure Prophylaxis (PrEP) for HIV Prevention: Narrative Review

PubMed Central

Krakower, Douglas; Mayer, Kenneth H.

2013-01-01

As HIV prevalence climbs globally, including more than 50,000 new infections per year in the United States, we need effective HIV prevention strategies. The use of antiretrovirals for pre-exposure prophylaxis (known as “PrEP”) among high-risk HIV-uninfected persons is emerging as one such strategy. Randomized controlled trials have demonstrated that once daily oral PrEP decreased HIV incidence among at-risk MSM and African heterosexuals, including HIV serodiscordant couples. An additional randomized control trial of a pericoital topical application of antiretroviral microbicide gel reduced HIV incidence among at-risk heterosexual South African women. Two other studies in African women did not demonstrate the efficacy of oral or topical PrEP, raising concerns about adherence patterns and efficacy in this population. The FDA Antiretroviral Advisory Panel reviewed these studies and additional data in May 2012 and recommended the approval of oral tenofovir-emtricitabine for PrEP in high-risk populations. Patients may seek PrEP from their primary care providers and those on PrEP require monitoring. Thus, primary care providers should become familiar with PrEP. This review outlines the current state of knowledge about PrEP as it pertains to primary care including identification of individuals likely to benefit from PrEP, counseling to maximize adherence and minimize potential increases in risky behavior, and monitoring for potential drug toxicities, HIV acquisition, and antiretroviral drug resistance. Issues related to cost and insurance coverage are also discussed. Recent data suggest that PrEP, in conjunction with other prevention strategies, holds promise in helping to curtail the HIV epidemic. PMID:22821365

Comprehensive Study of Pr-Doped GdBa2Cu3O7 - y System

NASA Astrophysics Data System (ADS)

Yamani, Z.; Akhavan, M.

1997-09-01

An extensive study of the magnetic, electrical transport, and structural properties of the normal and superconducting states of Gd1 - xPrxBa2Cu3O7 - y (GdPr-123) is presented. Ceramic compounds have been synthesized by the solid state reaction technique, and characterized by XRD, SEM, TGA, and DT techniques. The parent compound GdBa2Cu3O7 - y (Gd-123) is a high-Tc superconductor and the endpoint compound, PrBa2Cu3O7 - y (Pr-123) is a magnetic insulator, both having the crystal structures isomorphic to the 123 phase structure. The superconducting transition temperature is reduced with increasing Pr content in a non-linear manner, in contrast to the Abrikosov-Gorkov pair breaking theory. A metal-insulator transition is observed at the critical Pr content, xcr 0.45, at which superconductivity completely disappears. Magnetic susceptibility measurements show that the nominal Pr valence is 3.86+, independent of the Pr content. The metal-insulator transition in this system is similar to that in the oxygen-deficient RBa2Cu3O7 - y (R-123) system. Based on this resemblance, we suggest that Pr doping reduces the carrier concentration (either by hole filling/localization or changes in the band structure) similar to the deoxygenated case. Hence, the environment surrounding the Cu-O layers is important to high-Tc superconductivity (HTSC). In this sense, HTSC cannot completely be two dimensional feature. A chain-plane correlation (CPC) effect is plausible. The normal state conduction mechanism has been interpreted by the quantum percolation theory based on localized states. Localization is probably caused by the Pr valence fluctuations in the GdPr-123 system.

Interactions between inflammatory signals and the progesterone receptor in regulating gene expression in pregnant human uterine myocytes

PubMed Central

Lee, Yun; Sooranna, Suren R; Terzidou, Vasso; Christian, Mark; Brosens, Jan; Huhtinen, Kaisa; Poutanen, Matti; Barton, Geraint; Johnson, Mark R; Bennett, Phillip R

2012-01-01

The absence of a fall in circulating progesterone levels has led to the concept that human labour is associated with ‘functional progesterone withdrawal’ caused through changes in the expression or function of progesterone receptor (PR). At the time of labour, the human uterus is heavily infiltrated with inflammatory cells, which release cytokines to create a ‘myometrial inflammation’ via NF-κB activation. The negative interaction between NF-κB and PR, may represent a mechanism to account for ‘functional progesterone withdrawal’ at term. Conversely, PR may act to inhibit NF-κB function and so play a role in inhibition of myometrial inflammation during pregnancy. To model this inter-relationship, we have used small interfering (si) RNA-mediated knock-down of PR in human pregnant myocytes and whole genome microarray analysis to identify genes regulated through PR. We then activated myometrial inflammation using IL-1β stimulation to determine the role of PR in myometrial inflammation regulation. Through PR-knock-down, we found that PR regulates gene networks involved in myometrial quiescence and extracellular matrix integrity. Activation of myometrial inflammation was found to antagonize PR-induced gene expression, of genes normally upregulated via PR. We found that PR does not play a role in repression of pro-inflammatory gene networks induced by IL-1β and that only MMP10 was significantly regulated in opposite directions by IL-1β and PR. We conclude that progesterone acting through PR does not generally inhibit myometrial inflammation. Activation of myometrial inflammation does cause ‘functional progesterone withdrawal’ but only in the context of genes normally upregulated via PR. PMID:22435466

N-Acetyl-S-(n-Propyl)-L-Cysteine in Urine from Workers Exposed to 1-Bromopropane in Foam Cushion Spray Adhesives

PubMed Central

Hanley, Kevin W.; Petersen, Martin R.; Cheever, Kenneth L.; Luo, Lian

2009-01-01

1-Bromopropane (1-BP) has been marketed as an alternative for ozone depleting and other solvents; it is used in aerosol products, adhesives, metal, precision, and electronics cleaning solvents. Mechanisms of toxicity of 1-BP are not fully understood, but it may be a neurological and reproductive toxicant. Sparse exposure information prompted this study using 1-BP air sampling and urinary metabolites. Mercapturic acid conjugates are excreted in urine from 1-BP metabolism involving debromination. Research objectives were to evaluate the utility of urinary N-acetyl-S-(n-propyl)-L-cysteine (AcPrCys) for assessing exposure to 1-BP and compare it to urinary bromide [Br(−)] previously reported for these workers. Forty-eight-hour urine specimens were obtained from 30 workers at two factories where 1-BP spray adhesives were used to construct polyurethane foam seat cushions. Urine specimens were also obtained from 21 unexposed control subjects. All the workers' urine was collected into composite samples representing three time intervals: at work, after work but before bedtime, and upon awakening. Time-weighted average (TWA) geometric mean breathing zone concentrations were 92.4 and 10.5 p.p.m. for spraying and non-spraying jobs, respectively. Urinary AcPrCys showed the same trend as TWA exposures to 1-BP: higher levels were observed for sprayers. Associations of AcPrCys concentrations, adjusted for creatinine, with 1-BP TWA exposure were statistically significant for both sprayers (P < 0.05) and non-sprayers (P < 0.01). Spearman correlation coefficients for AcPrCys and Br(−) analyses determined from the same urine specimens were highly correlated (P < 0.0001). This study confirms that urinary AcPrCys is an important 1-BP metabolite and an effective biomarker for highly exposed foam cushion workers. PMID:19706636

Malus hupehensis NPR1 induces pathogenesis-related protein gene expression in transgenic tobacco.

PubMed

Zhang, J-Y; Qiao, Y-S; Lv, D; Gao, Z-H; Qu, S-C; Zhang, Z

2012-03-01

Most commercially grown apple cultivars are susceptible to fungal diseases. Malus hupehensis has high resistance to many diseases affecting apple cultivars. Understanding innate defence mechanisms would help to develop disease-resistant apple crops. Non-expressor of pathogenesis-related genes 1 (NPR1) plays a key role in regulating salicylic acid (SA)-mediated systemic acquired resistance (SAR). MhNPR1 cDNA, corresponding to genomic DNA and its 5' flanking sequences, was isolated from M. hupehensis. Sequence analysis showed that the regulatory mechanism for oligomer-monomer transition of the MhNPR1 protein in apple might be similar to that of GmNPR1 in soybean, but different from that of AtNPR1 in Arabidopsis. No significant differences in MhNPR1 expression were found in M. hupehensis after infection with Botryosphaeria berengeriana, showing that MhNPR1 might be regulated by pathogens at the protein level, as described for Arabidopsis and grapevine. SA treatment significantly induced MhNPR1 expression in leaves, stems and roots, while methyl jasmonate (MeJA) treatment induced MhNPR1 expression in roots, but not in leaves or stems. The expression of MhNPR1 was highly increased in roots, moderately in leaves, and did not change in stems after treatment with 1-aminocyclopropane-1-carboxylic acid (ACC). SAR marker genes (MhPR1 and MhPR5) were induced by SA, MeJA and ACC in leaves, stems and roots. Overexpression of MhNPR1 significantly induced the expression of pathogenesis-related genes (NtPR1, NtPR3 and NtPR5) in transgenic tobacco plants and resistance to the fungus Botrytis cinerea, suggesting that MhNPR1 orthologues are a component of the SA defence signalling pathway and SAR is induced in M. hupehensis. © 2011 German Botanical Society and The Royal Botanical Society of the Netherlands.

Very High-Temperature Reactor (VHTR) Proliferation Resistance and Physical Protection (PR&PP)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Moses, David Lewis

2011-10-01

This report documents the detailed background information that has been compiled to support the preparation of a much shorter white paper on the design features and fuel cycles of Very High-Temperature Reactors (VHTRs), including the proposed Next-Generation Nuclear Plant (NGNP), to identify the important proliferation resistance and physical protection (PR&PP) aspects of the proposed concepts. The shorter white paper derived from the information in this report was prepared for the Department of Energy Office of Nuclear Science and Technology for the Generation IV International Forum (GIF) VHTR Systems Steering Committee (SSC) as input to the GIF Proliferation Resistance and Physicalmore » Protection Working Group (PR&PPWG) (http://www.gen-4.org/Technology/horizontal/proliferation.htm). The short white paper was edited by the GIF VHTR SCC to address their concerns and thus may differ from the information presented in this supporting report. The GIF PR&PPWG will use the derived white paper based on this report along with other white papers on the six alternative Generation IV design concepts (http://www.gen-4.org/Technology/systems/index.htm) to employ an evaluation methodology that can be applied and will evolve from the earliest stages of design. This methodology will guide system designers, program policy makers, and external stakeholders in evaluating the response of each system, to determine each system's resistance to proliferation threats and robustness against sabotage and terrorism threats, and thereby guide future international cooperation on ensuring safeguards in the deployment of the Generation IV systems. The format and content of this report is that specified in a template prepared by the GIF PR&PPWG. Other than the level of detail, the key exception to the specified template format is the addition of Appendix C to document the history and status of coated-particle fuel reprocessing technologies, which fuel reprocessing technologies have yet to be deployed commercially and have only been demonstrated in testing at a laboratory scale.« less

Bayesian geostatistical modelling of soil-transmitted helminth survey data in the People's Republic of China.

PubMed

Lai, Ying-Si; Zhou, Xiao-Nong; Utzinger, Jürg; Vounatsou, Penelope

2013-12-18

Soil-transmitted helminth infections affect tens of millions of individuals in the People's Republic of China (P.R. China). There is a need for high-resolution estimates of at-risk areas and number of people infected to enhance spatial targeting of control interventions. However, such information is not yet available for P.R. China. A geo-referenced database compiling surveys pertaining to soil-transmitted helminthiasis, carried out from 2000 onwards in P.R. China, was established. Bayesian geostatistical models relating the observed survey data with potential climatic, environmental and socioeconomic predictors were developed and used to predict at-risk areas at high spatial resolution. Predictors were extracted from remote sensing and other readily accessible open-source databases. Advanced Bayesian variable selection methods were employed to develop a parsimonious model. Our results indicate that the prevalence of soil-transmitted helminth infections in P.R. China considerably decreased from 2005 onwards. Yet, some 144 million people were estimated to be infected in 2010. High prevalence (>20%) of the roundworm Ascaris lumbricoides infection was predicted for large areas of Guizhou province, the southern part of Hubei and Sichuan provinces, while the northern part and the south-eastern coastal-line areas of P.R. China had low prevalence (<5%). High infection prevalence (>20%) with hookworm was found in Hainan, the eastern part of Sichuan and the southern part of Yunnan provinces. High infection prevalence (>20%) with the whipworm Trichuris trichiura was found in a few small areas of south P.R. China. Very low prevalence (<0.1%) of hookworm and whipworm infections were predicted for the northern parts of P.R. China. We present the first model-based estimates for soil-transmitted helminth infections throughout P.R. China at high spatial resolution. Our prediction maps provide useful information for the spatial targeting of soil-transmitted helminthiasis control interventions and for long-term monitoring and surveillance in the frame of enhanced efforts to control and eliminate the public health burden of these parasitic worm infections.

Bayesian geostatistical modelling of soil-transmitted helminth survey data in the People’s Republic of China

PubMed Central

2013-01-01

Background Soil-transmitted helminth infections affect tens of millions of individuals in the People’s Republic of China (P.R. China). There is a need for high-resolution estimates of at-risk areas and number of people infected to enhance spatial targeting of control interventions. However, such information is not yet available for P.R. China. Methods A geo-referenced database compiling surveys pertaining to soil-transmitted helminthiasis, carried out from 2000 onwards in P.R. China, was established. Bayesian geostatistical models relating the observed survey data with potential climatic, environmental and socioeconomic predictors were developed and used to predict at-risk areas at high spatial resolution. Predictors were extracted from remote sensing and other readily accessible open-source databases. Advanced Bayesian variable selection methods were employed to develop a parsimonious model. Results Our results indicate that the prevalence of soil-transmitted helminth infections in P.R. China considerably decreased from 2005 onwards. Yet, some 144 million people were estimated to be infected in 2010. High prevalence (>20%) of the roundworm Ascaris lumbricoides infection was predicted for large areas of Guizhou province, the southern part of Hubei and Sichuan provinces, while the northern part and the south-eastern coastal-line areas of P.R. China had low prevalence (<5%). High infection prevalence (>20%) with hookworm was found in Hainan, the eastern part of Sichuan and the southern part of Yunnan provinces. High infection prevalence (>20%) with the whipworm Trichuris trichiura was found in a few small areas of south P.R. China. Very low prevalence (<0.1%) of hookworm and whipworm infections were predicted for the northern parts of P.R. China. Conclusions We present the first model-based estimates for soil-transmitted helminth infections throughout P.R. China at high spatial resolution. Our prediction maps provide useful information for the spatial targeting of soil-transmitted helminthiasis control interventions and for long-term monitoring and surveillance in the frame of enhanced efforts to control and eliminate the public health burden of these parasitic worm infections. PMID:24350825

AIDS vaccines and preexposure prophylaxis: is synergy possible?

PubMed

Excler, Jean-Louis; Rida, Wasima; Priddy, Frances; Gilmour, Jill; McDermott, Adrian B; Kamali, Anatoli; Anzala, Omu; Mutua, Gaudensia; Sanders, Eduard J; Koff, Wayne; Berkley, Seth; Fast, Patricia

2011-06-01

While the long-term goal is to develop highly effective AIDS vaccines, first generation vaccines may be only partially effective. Other HIV prevention modalities such as preexposure prophylaxis with antiretrovirals (PrEP) may have limited efficacy as well. The combined administration of vaccine and PrEP (VAXPREP), however, may have a synergistic effect leading to an overall benefit that is greater than the sum of the individual effects. We propose two test-of-concept trial designs for an AIDS vaccine plus oral or topical ARV. In one design, evidence that PrEP reduces the risk of HIV acquisition is assumed to justify offering it to all participants. A two-arm study comparing PrEP alone to VAXPREP is proposed in which 30 to 60 incident infections are observed to assess the additional benefit of vaccination on risk of infection and setpoint viral load. The demonstrated superiority of VAXPREP does not imply vaccine alone is efficacious. Similarly, the lack of superiority does not imply vaccine alone is ineffective, as antagonism could exist between vaccine and PrEP. In the other design, PrEP is assumed not to be in general use. A 2 × 2 factorial design is proposed in which high-risk individuals are randomized to one of four arms: placebo vaccine given with placebo PrEP, placebo vaccine given with PrEP, vaccine given with placebo PrEP, or VAXPREP. Between 60 and 210 infections are required to detect a benefit of vaccination with or without PrEP on risk of HIV acquisition or setpoint viral load, with fewer infections needed when synergy is present.

Resistance of Soil-Bound Prions to Rumen Digestion

PubMed Central

Saunders, Samuel E.; Bartelt-Hunt, Shannon L.; Bartz, Jason C.

2012-01-01

Before prion uptake and infection can occur in the lower gastrointestinal system, ingested prions are subjected to anaerobic digestion in the rumen of cervids and bovids. The susceptibility of soil-bound prions to rumen digestion has not been evaluated previously. In this study, prions from infectious brain homogenates as well as prions bound to a range of soils and soil minerals were subjected to in vitro rumen digestion, and changes in PrP levels were measured via western blot. Binding to clay appeared to protect noninfectious hamster PrPc from complete digestion, while both unbound and soil-bound infectious PrPSc proved highly resistant to rumen digestion. In addition, no change in intracerebral incubation period was observed following active rumen digestion of unbound hamster HY TME prions and HY TME prions bound to a silty clay loam soil. These results demonstrate that both unbound and soil-bound prions readily survive rumen digestion without a reduction in infectivity, further supporting the potential for soil-mediated transmission of chronic wasting disease (CWD) and scrapie in the environment. PMID:22937149

Antiretroviral drug resistance and phylogenetic diversity of HIV-1 in Chile.

PubMed

Ríos, Maritza; Delgado, Elena; Pérez-Alvarez, Lucía; Fernández, Jorge; Gálvez, Paula; de Parga, Elena Vázquez; Yung, Verónica; Thomson, Michael M; Nájera, Rafael

2007-06-01

This study reports the analysis of human immunodeficiency virus type 1 (HIV-1) protease (PR) and reverse transcriptase (RT) coding sequences from 136 HIV-1-infected subjects from Chile, 66 (49%) of them under antiretroviral (ARV) treatment. The prevalence of mutations conferring high or intermediate resistance levels to ARVs was 77% among treated patients and 2.5% among drug-naïve subjects. The distribution of resistance prevalence in treated patients by drug class was 61% to nucleoside RT inhibitors, 84% to nonnucleoside RT inhibitors, and 46% to PR inhibitors. Phylogenetic analysis revealed that 115 (85%) subjects were infected with subtype B viruses, 1 with a subtype F1 virus, and 20 (15%) carried BF intersubtype recombinants. Most BF recombinants grouped into two clusters, one related to CRF12_BF, while the other could represent a new circulating recombinant form (CRF). In conclusion, this is the first report analysing the prevalence of ARV resistance which includes patients under HAART from Chile. Additionally, phylogenetic analysis of the PR-RT coding sequences reveals the presence of BF intersubtype recombinants. (c) 2007 Wiley-Liss, Inc.

Coming Home at Paranal

NASA Astrophysics Data System (ADS)

2002-02-01

Unique "Residencia" Opens at the VLT Observatory Summary The Paranal Residencia at the ESO VLT Observatory is now ready and the staff and visitors have moved into their new home. This major architectural project has the form of a unique subterranean construction with a facade opening towards the Pacific Ocean , far below at a distance of about 12 km. Natural daylight is brought into the building through a 35-m wide glass-covered dome, a rectangular courtyard roof and various skylight hatches. Located in the middle of the Atacama Desert, one of the driest areas on Earth, the Residencia incorporates a small garden and a swimming pool, allowing the inhabitants to retreat from time to time from the harsh outside environment. Returning from long shifts at the VLT and other installations on the mountain, here they can breathe moist air and receive invigorating sensory impressions. With great originality of the design, it has been possible to create an interior with a feeling of open space - this is a true "home in the desert" . Moreover, with strict ecological power, air and water management , the Paranal Residencia has already become a symbol of innovative architecture in its own right. Constructed with robust, but inexpensive materials, it is an impressively elegant and utilitarian counterpart to the VLT high-tech facilities poised some two hundred meters above, on the top of the mountain. PR Photo 05a/02 : Aerial view of the Paranal Observatory area. PR Photo 05b/02 : Aerial view of the Paranal Residencia . PR Photo 05c/02 : Outside view of the Paranal Residencia . PR Photo 05d/02 : The Entry Hall (fisheye view). PR Photo 05e/02 : The Entry Hall with garden and pool. PR Photo 05f/02 : The Reception Area . PR Photo 05g/02 : The Reception Area - decoration. PR Photo 05h/02 : The Reception Area - decoration. PR Photo 05i/02 : The Reception Area - decoration. PR Photo 05j/02 : View towards the Cantine . PR Photo 05k/02 : View towards the Kitchen . PR Photo 05l/02 : View of the Corridors . PR Photo 05m/02 : A Bedroom . PR Photo 05n/02 : The main facade in evening light . PR Photo 05o/02 : View from the Observing Platform towards the Residencia in evening light. The Paranal Residencia ESO PR Photo 05a/02 ESO PR Photo 05a/02 [Preview - JPEG: 611 x 400 pix - 73k] [Normal - JPEG: 1222 x 800 pix - 936k] [HiRes - JPEG: 3000 x 1964 pix - 4.6M] ESO PR Photo 05b/02 ESO PR Photo 05b/02 [Preview - JPEG: 619 x 400 pix - 92k] [Normal - JPEG: 1238 x 800 pix - 944k] [HiRes - JPEG: 3000 x 1938 pix - 3.1M] Caption : PR Photo 05a/02 shows an aerial view of the Paranal Observatory. Below the observing platform at the top of the mountain - at a distance of about 3 km - is the Base Camp with the technical area (to the right of the road) and the new Residencia building (left of the road). To the extreme left is a temporary container camp of the construction company. PR Photo 05b/02 shows the Base Camp in more detail. In the course of 2002, many of the containers on the right side will be removed. The square building in the foreground to the left of the entrance gate is the future "Visitors' Centre".- A dummy 8.2-m concrete mirror is also placed here. These photos were made by ESO engineer Gert Hüdepohl during the final construction phase in late 2001. Ever since the construction of the ESO Very Large Telescope (VLT) at Paranal began in 1991, staff and visitors have resided in cramped containers in the "Base Camp". This is one of driest and most inhospitable areas in the Chilean Atacama Desert and eleven years is a long time to wait. However, there was never any doubt that the construction of the telescope itself must have absolute priority. Nevertheless, with the major technical installations in place, the time had come to develop a more comfortable and permanent base of living at Paranal, outside the telescope area. A unique architectural concept The concept for the Paranal Residencia emerged from a widely noted international architectural competition, won by Auer and Weber Freie Architekten from Munich (Germany), and with Dominik Schenkirz as principal designer. The interior furnishing and decoration was awarded to the Chilean architect Paula Gutierrez . The construction began in late 1998. Information about this work and several photos illustrating the progress have been published as PR Photos 31a-d/99 , PR Photo 43h/99 and PR Photos 04b-d/01 . Taking advantage of an existing depression in the ground, the architects created a unique subterranean construction with a single facade opening towards the Pacific Ocean , far below at a distance of about 12 km. It has the same colour as the desert and blends perfectly into the surroundings. The Paranal Residencia is elegant, with robust and inexpensive materials. Natural daylight is brought into the building through a 35-m wide glass-covered dome, a rectangular courtyard roof and various skylight hatches. The great originality of this design has made it possible to create an interior with a feeling of open space, despite the underground location. Some building characteristics are indicated below Facilities at the Residencia To the visitor who arrives at the Paranal Residencia from the harsh natural environment, the welcoming feeling under the dome is unexpected and instantly pleasant. This is a true "oasis" within coloured concrete walls and the air is agreeably warm and moist. There is a strong sense of calm and serenity and, above all, a feeling of coming home . At night, the lighting below the roofing closure fabric is spectacular and the impression on the mind is overwhelming. The various facilities are integrated over four floors below ground level. They include small, but nice and simple bedrooms, offices, meeting points, a restaurant, a library, a reception area, a cinema and other recreational areas. The natural focal point is located next to the reception at the entrance. The dining room articulates the building at the -2 level and view points through the facade form bridges between the surrounding Paranal desert and the interior. Simple, but elegant furnishing and specially manufactured carpeting complement a strong design of perspectives. The Republic of Chile, the host state for the ESO Paranal Observatory, is present with its emblematic painter Roberto Matta . Additional space is also provided for a regional art and activity display. The staff moved out of the containers and into their new home in mid-January 2002. Today, the Paranal Residencia has already become a symbol of innovative architecture in its own right, an impressively elegant and utilitarian counterpart to the VLT high-tech facilities poised some two hundred meters above, on the top of the mountain. Some building characteristics * Construction initiated in 1998 * Area: 10000 m 2 * Total cost: 12 Million Euro (less than 2% of the total cost of the VLT project), approx. 1200 Euro/m 2 * 108 bedrooms, each with 16 m 2 * Cantine capacity for 200 persons * 22 offices * 5 terraces/viewpoints * 70-seat cinema room * Multiple meeting areas * Double room library * Building management control for the environment and the lighting * Swimming pool; water treatment and grey water recirculation * Modular concept with potential for extension to 200 rooms * Completely light-tight and with a high level of sound insulation * Communication network with phone and TV-set in each room * Main contractors: Vial y Vives, Petricio Industrial, Koch The Paranal Residencia: A Photo Collection

Optical Material Researches for Frontier Optical Ceramics and Visible Fiber Laser Technologies

DTIC Science & Technology

2016-07-07

technology of visible fiber laser, Pr-doped waterproof fluoro-aluminate glass fiber (Pr:WPFGF) laser. The significant achievements are as follows; 1...greater than 1-W and multi-color visible fiber laser oscillations, 2) visible laser pulse generation in a Pr-doped waterproof fluoride glass fiber ...for more high power operation, fabrication of a Pr-doped double-clad structured waterproof fluoride glass fiber with a single-mode beam. These results

Gendered Differences in the Perceived Risks and Benefits of Oral PrEP Among HIV Serodiscordant Couples in Kenya

PubMed Central

Carroll, Jennifer J.; Ngure, Kenneth; Heffron, Renee; Curran, Kathryn; Mugo, Nelly R.

2016-01-01

Pre-exposure prophylaxis (PrEP) is effective for preventing HIV among HIV serodiscordant heterosexual couples. Gender roles may influence perceived personal and social risks related to HIV prevention behaviors and may affect use of PrEP. In this study, interviews and focus groups were conducted with 68 individuals from 34 mutually disclosed serodiscordant heterosexual partnerships in Thika, Kenya. Socio-cultural factors that affect adherence to PrEP were explored using grounded analysis. Three factors were identified, which shape perceptions of PrEP: gendered power dynamics and control over decision-making in the household; conflicts between risk reduction strategies and male sexual desire; culture bound definitions of women’s work. Adherence to PrEP in the Partners PrEP Study was high; however, participants articulated conflicting interests related to PrEP in connection with traditional gender roles. The successful delivery of PrEP will require understanding of key social factors, particularly related to gender and dyadic dynamics around HIV serostatus. PMID:26754017

Adolescent Human Immunodeficiency Virus Care Providers’ Attitudes Toward the Use of Oral Pre-Exposure Prophylaxis in Youth

PubMed Central

Zimet, Gregory; Lally, Michelle; Kahn, Jessica A.

2016-01-01

Abstract Oral pre-exposure prophylaxis (PrEP) for human immunodeficiency virus (HIV) prevention is currently indicated for use in adults in the United States and may soon be indicated for minor adolescents. However, implementation of PrEP use among minors may present unique barriers. We conducted 15 individual, semi-structured interviews among US clinicians caring for HIV-infected and at-risk youth. The theory-driven interview guide assessed demographics, perceived role of oral PrEP in HIV prevention among adolescents, perceived barriers to and facilitating factors for use of PrEP in adolescents, and clinician-reported likelihood of prescribing PrEP. Transcripts were analyzed using framework analysis. Overall, clinicians viewed PrEP as a time-limited intervention that is one part of a comprehensive approach to HIV prevention among adolescents. Perceived barriers to prescribing to minors included concerns about: confidentiality, legality of minors consenting to PrEP without parental involvement, ability of minors to understand the risks/benefits of PrEP, the possible impact of PrEP on bone accrual, off-label use of PrEP medication in minors, and the high costs associated with PrEP use. Clinician-reported facilitating factors for prescribing PrEP to youth included educating communities and other clinicians about PrEP, ensuring adequate financial resources and infrastructure for delivering PrEP, developing formal guidance on effective behavioral interventions that should be delivered with PrEP, and gaining personal experience with prescribing PrEP. Clinicians indicated greater comfort with prescribing PrEP to adults versus minors. For PrEP to become more widely available to youth at risk for HIV infection, barriers that are unique to PrEP use in minors must be addressed. PMID:27410497

Active FOXO1 is a Key Determinant of Isoform-Specific Progesterone Receptor Transactivation and Senescence Programming

PubMed Central

Diep, Caroline H.; Knutson, Todd P.; Lange, Carol A.

2015-01-01

Progesterone promotes differentiation coupled to proliferation and pro-survival in the breast, but inhibits estrogen-driven growth in the reproductive tract and ovaries. Herein, it is demonstrated, using progesterone receptor (PR) isoform-specific ovarian cancer model systems, that PR-A and PR-B promote distinct gene expression profiles that differ from PR-driven genes in breast cancer cells. In ovarian cancer models, PR-A primarily regulates genes independently of progestin, while PR-B is the dominant ligand-dependent isoform. Notably, FOXO1 and the PR/FOXO1 target-gene p21 (CDKN1A) are repressed by PR-A, but induced by PR-B. In the presence of progestin, PR-B, but not PR-A, robustly induced cellular senescence via FOXO1-dependent induction of p21 and p15 (CDKN2B). Chromatin immunoprecipitation (ChIP) assays performed on PR-isoform specific cells demonstrated that while each isoform is recruited to the same PRE-containing region of the p21 promoter in response to progestin, only PR-B elicits active chromatin marks. Overexpression of constitutively active FOXO1 in PR-A-expressing cells conferred robust ligand-dependent upregulation of the PR-B target genes GZMA, IGFBP1, and p21, and induced cellular senescence. In the presence of endogenous active FOXO1, PR-A was phosphorylated on Ser294 and transactivated PR-B at PR-B target genes; these events were blocked by the FOXO1 inhibitor (AS1842856). PR isoform-specific regulation of the FOXO1/p21 axis recapitulated in human primary ovarian tumor explants treated with progestin; loss of progestin sensitivity correlated with high AKT activity. PMID:26577046

Role of Country of Birth, Testing Site, and Neighborhood Characteristics on Nonlinkage to HIV Care Among Latinos.

PubMed

Sheehan, Diana M; Cosner, Chelsea; Fennie, Kristopher P; Gebrezgi, Merhawi T; Cyrus, Elena; Maddox, Lorene M; Levison, Julie H; Spencer, Emma C; Niyonsenga, Theophile; Trepka, Mary Jo

2018-04-01

The objective of this study was to estimate disparities in linkage to human immunodeficiency virus (HIV) care among Latinos by country/region of birth, HIV testing site, and neighborhood characteristics. A retrospective study was conducted using Florida HIV surveillance records of Latinos/Hispanics aged ≥13 diagnosed during 2014-2015. Linkage to HIV care was defined as a laboratory test (HIV viral load or CD4) within 3 months of HIV diagnosis. Multi-level Poisson regression models were used to estimate adjusted prevalence ratios (aPR) for nonlinkage to care. Of 2659 Latinos, 18.8% were not linked to care within 3 months. Compared with Latinos born in mainland United States, those born in Cuba [aPR 0.60, 95% confidence interval (CI) 0.47-0.76] and Puerto Rico (aPR 0.61, 95% CI 0.41-0.90) had a decreased prevalence of nonlinkage. Latinos diagnosed at blood banks (aPR 2.34, 95% CI 1.75-3.12), HIV case management and screening facilities (aPR 1.76, 95% CI 1.46-2.14), and hospitals (aPR 1.42, 95% CI 1.03-1.96) had an increased prevalence of nonlinkage compared with outpatient general, infectious disease, and tuberculosis/sexually transmitted diseases/family planning clinics. Latinos who resided in the lowest (aPR 1.57, 95% CI 1.19-2.07) and third lowest (aPR 1.33, 95% CI 1.01-1.76) quartiles of neighborhood socioeconomic status compared with the highest quartile were at increased prevalence. Latinos who resided in neighborhoods with <25% Latinos also had increased prevalence of nonlinkage (aPR 1.23, 95% CI 1.01-1.51). Testing site at diagnosis may be an important determinant of HIV care linkage among Latinos due to neighborhood or individual-level resources that determine location of HIV testing.

Experimental Investigation of the Cd-Pr Phase Diagram

PubMed Central

Reichmann, Thomas L.; Effenberger, Herta S.; Ipser, Herbert

2014-01-01

The complete Cd-Pr equilibrium phase diagram was investigated with a combination of powder-XRD, SEM and DTA. All intermetallic compounds within this system, already reported in literature, could be confirmed: CdPr, Cd2Pr, Cd3Pr, Cd45Pr11, Cd58Pr13, Cd6Pr and Cd11Pr. The corresponding phase boundaries were determined at distinct temperatures. The homogeneity range of the high-temperature allotropic modification of Pr could be determined precisely and a limited solubility of 22.1 at.% Cd was derived. Additionally, single-crystal X-ray diffraction was employed to investigate structural details of Cd2Pr; it is isotypic to the AlB2-type structure with a z value of the Cd site of 0.5. DTA results of alloys located in the adjacent two-phase fields of Cd2Pr suggested a phase transformation between 893 and 930°C. For the phase Cd3Pr it was found that the lattice parameter a changes linearly with increasing Cd content, following Vegard’s rule. The corresponding defect mechanism could be evaluated from structural data collected with single-crystal XRD. Introduction of a significant amount of vacancies on the Pr site and the reduction in symmetry of one Cd position (8c to 32f) resulted in a noticeable decrease of all R-values. PMID:24718502

Generic amyloidogenicity of mammalian prion proteins from species susceptible and resistant to prions.

PubMed

Nyström, Sofie; Hammarström, Per

2015-05-11

Prion diseases are lethal, infectious diseases associated with prion protein (PrP) misfolding. A large number of mammals are susceptible to both sporadic and acquired prion diseases. Although PrP is highly conserved and ubiquitously expressed in all mammals, not all species exhibit prion disease. By employing full length recombinant PrP from five known prion susceptible species (human, cattle, cat, mouse and hamster) and two species considered to be prion resistant (pig and dog) the amyloidogenicity of these PrPs has been delineated. All the mammalian PrPs, even from resistant species, were swiftly converted from the native state to amyloid-like structure when subjected to a native condition conversion assay. The PrPs displayed amyloidotypic tinctorial and ultrastructural hallmarks. Self-seeded conversion of the PrPs displayed significantly decreased lag phases demonstrating that nucleation dependent polymerization is a dominating mechanism in the fibrillation process. Fibrils from Aβ1-40, Aβ1-42, Lysozyme, Insulin and Transthyretin did not accelerate conversion of HuPrP whereas fibrils from HuPrP90-231 and HuPrP121-231 as well as full length PrPs of all PrPs efficiently seeded conversion showing specificity of the assay requiring the C-terminal PrP sequence. Our findings have implications for PrP misfolding and could have ramifications in the context of prion resistant species and silent carriers.

Ambiguity, ambivalence, and apprehensions of taking HIV-1 pre-exposure prophylaxis among male couples in San Francisco: a mixed methods study.

PubMed

Saberi, Parya; Gamarel, Kristi E; Neilands, Torsten B; Comfort, Megan; Sheon, Nicolas; Darbes, Lynae A; Johnson, Mallory O

2012-01-01

We conducted a mixed-methods study to examine serodiscordant and seroconcordant (HIV-positive/HIV-positive) male couples' PrEP awareness, concerns regarding health care providers offering PrEP to the community, and correlates of PrEP uptake by the HIV-negative member of the couple. Qualitative sub-study included one-on-one interviews to gain a deeper understanding of participants' awareness of and experiences with PrEP and concerns regarding health care providers offering PrEP to men who have sex with men (MSM). Quantitative analyses consisted of a cross-sectional study in which participants were asked about the likelihood of PrEP uptake by the HIV-negative member of the couple and level of agreement with health care providers offering PrEP to anyone requesting it. We used multivariable regression to examine associations between PrEP questions and covariates of interest and employed an inductive approach to identify key qualitative themes. Among 328 men (164 couples), 62% had heard about PrEP, but approximately one-quarter were mistaking it with post-exposure prophylaxis. The majority of participants had low endorsement of PrEP uptake and 40% were uncertain if health care providers should offer PrEP to anyone requesting it. Qualitative interviews with 32 men suggest that this uncertainty likely stems from concerns regarding increased risk compensation. Likelihood of future PrEP uptake by the HIV-negative member of the couple was positively associated with unprotected insertive anal intercourse but negatively correlated with unprotected receptive anal intercourse. Findings suggest that those at greatest risk may not be receptive of PrEP. Those who engage in moderate risk express more interest in PrEP; however, many voice concerns of increased risk behavior in tandem with PrEP use. Results indicate a need for further education of MSM communities and the need to determine appropriate populations in which PrEP can have the highest impact.

Does right lateral decubitus position change retroperitoneal oblique corridor? A radiographic evaluation from L1 to L5.

PubMed

Zhang, Fan; Xu, Haocheng; Yin, Bo; Tao, Hongyue; Yang, Shuo; Sun, Chi; Wang, Yitao; Yin, Jun; Shao, Minghao; Wang, Hongli; Xia, Xinlei; Ma, Xiaosheng; Lu, Feizhou; Jiang, Jianyuan

2017-03-01

To determine if the retroperitoneal oblique corridor will be affected by right lateral decubitus position. Forty volunteers were randomly enrolled and MRI scan was performed from L1 to L5 in supine and right lateral decubitus positions, respectively. In images across the center of each disc, O was defined as the center of a disc and A (supine) or A' (right lateral decubitus) was located in left lateral border of the aorta or the iliac artery; B (supine) or B' (right lateral decubitus) was on the anterior medial border of the psoas. The distance of AB and A'B' (Recorded as A-Ps and A-Pr, respectively) at each level was recorded and compared to each other. The relationships between A-Pr, sex, BMI and relative psoas cross-sectional area (PCSA) at each level were also evaluated. A-Pr was significantly smaller than A-Ps at L1/2, L2/3 and L3/4 (All p < 0.05); there was no significantly difference of A-Pr between all levels (p = 0.105), but L1/2 seemed to be larger than L3/4, followed by L2/3 and L4/5; A-Pr at each level was not affected by sex (All p > 0.05); linear relationships were found between A-Pr, BMI and PCSA at L1/2 and L3/4. ROC at L1/2, L2/3 and L3/4 will significantly decrease from supine to right lateral decubitus position and the reason may be due to the relaxed psoas deformation. Using MRI images in supine position for pre-operatively ROC evaluation is not accurate. Spine surgeon should also be more cautious when OLIF is performed at L4/5 where ROC is the smallest. Patients from Asia and those with strong psoas major at L1/2 and L3/4 are also associated with relatively narrow ROC.

Intracellular accumulation of a mild-denatured monomer of the human PrP fragment 90-231, as possible mechanism of its neurotoxic effects.

PubMed

Chiovitti, Katia; Corsaro, Alessandro; Thellung, Stefano; Villa, Valentina; Paludi, Domenico; D'Arrigo, Cristina; Russo, Claudio; Perico, Angelo; Ianieri, Adriana; Di Cola, Domenico; Vergara, Alberto; Aceto, Antonio; Florio, Tullio

2007-12-01

Because of high tendency of the prion protein (PrP) to aggregate, the exact PrP isoform responsible for prion diseases as well as the pathological mechanism that it activates remains still controversial. In this study, we show that a pre-fibrillar, monomeric or small oligomeric conformation of the human PrP fragment 90-231 (hPrP90-231), rather than soluble or fibrillar large aggregates, represents the neurotoxic species. In particular, we demonstrate that monomeric mild-denatured hPrP90-231 (incubated for 1 h at 53 degrees C) induces SH-SY5Y neuroblastoma cell death, while, when structured in large aggregates, it is ineffective. Using spectroscopic and cellular techniques we demonstrate that this toxic conformer is characterized by a high exposure of hydrophobic regions that favors the intracellular accumulation of the protein. Inside the cells hPrP90-231 is mainly compartmentalized into the lysosomes where it may trigger pro-apoptotic 'cell death' signals. The PrP toxic conformation, which we have obtained inducing a controlled in vitro conformational change of the protein, might mimic mild-unfolding events occurring in vivo, in the presence of specific mutations, oxidative reactions or proteolysis. Thus, in light of this model, we propose that novel therapeutic strategies, designed to inhibit the interaction of the toxic PrP with the plasmamembrane, could be beneficial to prevent the formation of intracellular neurotoxic aggregates and ultimately the neuronal death.

Evolution of structural, magnetic and transport behavior by Pr doping in SrRuO3

NASA Astrophysics Data System (ADS)

Gupta, Renu; Pramanik, A. K.

2018-05-01

Here we report the evolution of structural, magnetic and transport behavior in perovskite based ruthenates Sr1-xPrxRuO3 (x=0.0 and 0.1). The substitution of Pr on Sr site retains orthorhombic structure while we find the slight change in structural parameters. The SrRuO3 has itinerant ferromagnet (FM) type nature of ordering temperature ˜160 K and below the transition temperature showing large bifurcation between ZFC and FC magnetization. By Pr doping, the magnetic moment decreases with decreasing bifurcation of ZFC and FC. The ZFC data show three distinct peaks (three transition temperature; TM1,TM2 and TM3). The magnetization study of both the samples, at high temperature fitted with modified CWL showing the decreasing value of ordering temperature by Pr doping matches close to TM2. The low-temperature isothermal magnetization M (H) data show that the high field saturation moment has decreased by Pr doping. The Arrott plot gives spontaneous magnetization (Ms) which is also decreased by Pr substitution. Evolution of Rhodes-Wohlfarth ratio value increases, which suggests that FM in this system evolves toward the more itinerant type by Pr doping. The electrical resistivity ρ(T) of both the samples show metallic behavior, in the all temperature range and ρ(T) increases by Pr doping while around below 45 K, the resistivity decreases by Pr doping and this crossing temperature also matches with ZFC data.

Clinical Investigation Program Report Control Symbol MED 300.

DTIC Science & Technology

1982-10-01

Preeclampsia as an Aid to Further Management. (C) (PR) 41 1961 Use of C-Reactive Protein in Prediction of ARD Prog- nosiS, (C) (PR) 42 1981 The Assessment...37 Status: Completed * Title: Routine Use of Serum Uric Acid Levels at 36 Weeks Gestation as Screening Test for Preeclampsia as an Aid to Further...nvestigators: .amily Pr-&ctiU. CPT Ellis M. Knight, MC Key Words: Serum Uric Acid Preeclampsia Accumulative MZDCASI Eat Accumulative Periodic Mar 82 Cost: ]A

Newcastle disease virus-vectored West Nile fever vaccine is immunogenic in mammals and poultry.

PubMed

Wang, Jinliang; Yang, Jie; Ge, Jinying; Hua, Ronghong; Liu, Renqiang; Li, Xiaofeng; Wang, Xijun; Shao, Yu; Sun, Encheng; Wu, Donglai; Qin, Chengfeng; Wen, Zhiyuan; Bu, Zhigao

2016-06-24

West Nile virus (WNV) is an emerging zoonotic pathogen which is harmful to human and animal health. Effective vaccination in susceptible hosts should protect against WNV infection and significantly reduce viral transmission between animals and from animals to humans. A versatile vaccine suitable for different species that can be delivered via flexible routes remains an essential unmet medical need. In this study, we developed a recombinant avirulent Newcastle disease virus (NDV) LaSota strain expressing WNV premembrane/envelope (PrM/E) proteins (designated rLa-WNV-PrM/E) and evaluated its immunogenicity in mice, horses, chickens, ducks and geese. Mouse immunization experiments disclosed that rLa-WNV-PrM/E induces significant levels of WNV-neutralizing antibodies and E protein-specific CD4+ and CD8+ T-cell responses. Moreover, recombinant rLa-WNV-PrM/E elicited significant levels of WNV-specific IgG in horses upon delivery via intramuscular immunization, and in chickens, ducks and geese via intramuscular, oral or intranasal immunization. Our results collectively support the utility of rLa-WNV-PrM/E as a promising WNV veterinary vaccine candidate for mammals and poultry.

Memory Impairment in Transgenic Alzheimer Mice Requires Cellular Prion Protein

PubMed Central

Gimbel, David A.; Nygaard, Haakon B.; Coffey, Erin E.; Gunther, Erik C.; Laurén, Juha; Gimbel, Zachary A.; Strittmatter, Stephen M.

2012-01-01

Soluble oligomers of the amyloid-β (Aβ) peptide are thought to play a key role in the pathophysiology of Alzheimer’s disease (AD). Recently, we reported that synthetic Aβ oligomers bind to cellular prion protein (PrPC) and that this interaction is required for suppression of synaptic plasticity in hippocampal slices by oligomeric Aβ peptide. We hypothesized that PrPC is essential for the ability of brain-derived Aβ to suppress cognitive function. Here, we crossed familial AD transgenes encoding APPswe and PSen1ΔE9 into Prnp−/− mice to examine the necessity of PrPC for AD-related phenotypes. Neither APP expression nor Aβ level is altered by PrPC absence in this transgenic AD model, and astrogliosis is unchanged. However, deletion of PrPC expression rescues 5-HT axonal degeneration, loss of synaptic markers, and early death in APPswe/PSen1ΔE9 transgenic mice. The AD transgenic mice with intact PrPC expression exhibit deficits in spatial learning and memory. Mice lacking PrPC, but containing Aβ plaque derived from APPswe/PSen1ΔE9 transgenes, show no detectable impairment of spatial learning and memory. Thus, deletion of PrPC expression dissociates Aβ accumulation from behavioral impairment in these AD mice, with the cognitive deficits selectively requiring PrPC. PMID:20445063

The 7 × 1 Fermi Surface Reconstruction in a Two-dimensional f -electron Charge Density Wave System: PrTe 3

DOE PAGES

Lee, Eunsook; Kim, D. H.; Kim, Hyun Woo; ...

2016-07-25

The electronic structure of a charge density wave (CDW) system PrTe 3 and its modulated structure in the CDW phase have been investigated by employing ARPES, XAS, Pr 4 f RPES, and first-principles band structure calculation. Pr ions are found to be nearly trivalent, supporting the CDW instability in the metallic Te sheets through partial filling. Finite Pr 4 f spectral weight is observed near the Fermi level, suggesting the non-negligible Pr 4 f contribution to the CDW formation through the Pr 4 f -Te 5p hybridization. The two-fold symmetric features in the measured Fermi surface (FS) of PrTe 3more » are explained by the calculated FS for the assumed 7 × 1 CDW supercell formation in Te sheets. The shadow bands and the corresponding very weak FSs are observed, which originate from both the band folding due to the 3D interaction of Te sheets with neighboring Pr-Te layers and that due to the CDW-induced FS reconstruction. The straight vertical FSs are observed along k z, demonstrating the nearly 2D character for the near-EF states. The observed linear dichroism reveals the in-plane orbital character of the near-E F Te 5p states.« less

A Structural and Functional Comparison Between Infectious and Non-Infectious Autocatalytic Recombinant PrP Conformers

PubMed Central

Noble, Geoffrey P.; Wang, Daphne W.; Walsh, Daniel J.; Barone, Justin R.; Miller, Michael B.; Nishina, Koren A.; Li, Sheng; Supattapone, Surachai

2015-01-01

Infectious prions contain a self-propagating, misfolded conformer of the prion protein termed PrPSc. A critical prediction of the protein-only hypothesis is that autocatalytic PrPSc molecules should be infectious. However, some autocatalytic recombinant PrPSc molecules have low or undetectable levels of specific infectivity in bioassays, and the essential determinants of recombinant prion infectivity remain obscure. To identify structural and functional features specifically associated with infectivity, we compared the properties of two autocatalytic recombinant PrP conformers derived from the same original template, which differ by >105-fold in specific infectivity for wild-type mice. Structurally, hydrogen/deuterium exchange mass spectrometry (DXMS) studies revealed that solvent accessibility profiles of infectious and non-infectious autocatalytic recombinant PrP conformers are remarkably similar throughout their protease-resistant cores, except for two domains encompassing residues 91-115 and 144-163. Raman spectroscopy and immunoprecipitation studies confirm that these domains adopt distinct conformations within infectious versus non-infectious autocatalytic recombinant PrP conformers. Functionally, in vitro prion propagation experiments show that the non-infectious conformer is unable to seed mouse PrPC substrates containing a glycosylphosphatidylinositol (GPI) anchor, including native PrPC. Taken together, these results indicate that having a conformation that can be specifically adopted by post-translationally modified PrPC molecules is an essential determinant of biological infectivity for recombinant prions, and suggest that this ability is associated with discrete features of PrPSc structure. PMID:26125623

Red-backed vole brain promotes highly efficient in vitro amplification of abnormal prion protein from macaque and human brains infected with variant Creutzfeldt-Jakob disease agent.

USGS Publications Warehouse

Nemecek, Julie; Nag, Nabanita; Carlson, Christina M.; Schneider, Jay R.; Heisey, Dennis M.; Johnson, Christopher J.; Asher, David M.; Gregori, Luisa

2013-01-01

Rapid antemortem tests to detect individuals with transmissible spongiform encephalopathies (TSE) would contribute to public health. We investigated a technique known as protein misfolding cyclic amplification (PMCA) to amplify abnormal prion protein (PrPTSE) from highly diluted variant Creutzfeldt-Jakob disease (vCJD)-infected human and macaque brain homogenates, seeking to improve the rapid detection of PrPTSE in tissues and blood. Macaque vCJD PrPTSE did not amplify using normal macaque brain homogenate as substrate (intraspecies PMCA). Next, we tested interspecies PMCA with normal brain homogenate of the southern red-backed vole (RBV), a close relative of the bank vole, seeded with macaque vCJD PrPTSE. The RBV has a natural polymorphism at residue 170 of the PrP-encoding gene (N/N, S/S, and S/N). We investigated the effect of this polymorphism on amplification of human and macaque vCJD PrPTSE. Meadow vole brain (170N/N PrP genotype) was also included in the panel of substrates tested. Both humans and macaques have the same 170S/S PrP genotype. Macaque PrPTSE was best amplified with RBV 170S/S brain, although 170N/N and 170S/N were also competent substrates, while meadow vole brain was a poor substrate. In contrast, human PrPTSE demonstrated a striking narrow selectivity for PMCA substrate and was successfully amplified only with RBV 170S/S brain. These observations suggest that macaque PrPTSE was more permissive than human PrPTSE in selecting the competent RBV substrate. RBV 170S/S brain was used to assess the sensitivity of PMCA with PrPTSE from brains of humans and macaques with vCJD. PrPTSE signals were reproducibly detected by Western blot in dilutions through 10-12 of vCJD-infected 10% brain homogenates. This is the first report showing PrPTSE from vCJD-infected human and macaque brains efficiently amplified with RBV brain as the substrate. Based on our estimates, PMCA showed a sensitivity that might be sufficient to detect PrPTSE in vCJD-infected human and macaque blood.

Comparisons of Reflectivities from the TRMM Precipitation Radar and Ground-Based Radars

NASA Technical Reports Server (NTRS)

Wang, Jianxin; Wolff, David B.

2008-01-01

Given the decade long and highly successful Tropical Rainfall Measuring Mission (TRMM), it is now possible to provide quantitative comparisons between ground-based radars (GRs) with the space-borne TRMM precipitation radar (PR) with greater certainty over longer time scales in various tropical climatological regions. This study develops an automated methodology to match and compare simultaneous TRMM PR and GR reflectivities at four primary TRMM Ground Validation (GV) sites: Houston, Texas (HSTN); Melbourne, Florida (MELB); Kwajalein, Republic of the Marshall Islands (KWAJ); and Darwin, Australia (DARW). Data from each instrument are resampled into a three-dimensional Cartesian coordinate system. The horizontal displacement during the PR data resampling is corrected. Comparisons suggest that the PR suffers significant attenuation at lower levels especially in convective rain. The attenuation correction performs quite well for convective rain but appears to slightly over-correct in stratiform rain. The PR and GR observations at HSTN, MELB and KWAJ agree to about 1 dB on average with a few exceptions, while the GR at DARW requires +1 to -5 dB calibration corrections. One of the important findings of this study is that the GR calibration offset is dependent on the reflectivity magnitude. Hence, we propose that the calibration should be carried out using a regression correction, rather than simply adding an offset value to all GR reflectivities. This methodology is developed towards TRMM GV efforts to improve the accuracy of tropical rain estimates, and can also be applied to the proposed Global Precipitation Measurement and other related activities over the globe.

Effects of quantum interference between radiative and dielectronic recombination on photorecombination cross-section profiles for the He-like ions Ar{sup 16+} and Fe{sup 24+}

DOE Office of Scientific and Technical Information (OSTI.GOV)

Behar, Ehud; Jacobs, Verne L.; Oreg, Joseph

Total cross sections for electron-ion photorecombination (PR) processes are calculated using a projection-operator and resolvent-operator approach. This approach provides a unified quantum-mechanical description of the combined electron-ion PR process, including radiative and dielectronic recombination as coherent, interfering components. An especially adapted version of the Hebrew-University Lawrence-Livermore Atomic Code HULLAC is developed and employed for the calculations. In particular, PR cross sections for He-like argon and iron ions are calculated for incident-electron energies in the vicinity of the 1s2l2l{sup '} and 1s2l3l{sup '} doubly-excited, autoionizing levels of the Li-like ions. Significant effects of quantum interference between radiative and dielectronic recombination, inmore » the form of asymmetric PR cross-section profiles, are predicted, especially for weak transitions. The general behavior of the interference effect, as a function of the ion charge q and as a function of the principal quantum number n{sup '} of the outer electron in the autoionizing state, is investigated using a hydrogenic-scaling analysis. It is found that the degree of asymmetry in the PR cross-section profile can be substantial for close-to-neutral ions and also for very highly-charged ions. In the intermediate-charge regime, on the other hand, the asymmetry is anticipated to be less prominent. The dependence of the quantum-interference effect on n{sup '} is predicted to be much weaker.« less

Proteorhodopsin in living color: diversity of spectral properties within living bacterial cells.

PubMed

Kelemen, Bradley R; Du, Mai; Jensen, Rasmus B

2003-12-03

Proteorhodopsin is a family of over 50 proteins that provide phototrophic capability to marine bacteria by acting as light-powered proton pumps. The potential importance of proteorhodopsin to global ocean ecosystems and the possible applications of proteorhodopsin in optical data storage and optical signal processing have spurred diverse research in this new family of proteins. We show that proteorhodopsin expressed in Escherichia coli is functional and properly inserted in the membrane. At high expression levels, it appears to self-associate. We present a method for determining spectral properties of proteorhodopsin in intact E. coli cells that matches results obtained with detergent-solubilized, purified proteins. Using this method, we observe distinctly different spectra for protonated and deprotonated forms of 21 natural proteorhodopsin proteins in intact E. coli cells. Upon protonation, the wavelength maxima red shifts between 13 and 53 nm. We find that pKa values between 7.1 and 8.5 describe the pH-dependent spectral shift for all of the 21 natural variants of proteorhodopsin. The wavelength maxima of the deprotonated forms of the 21 natural proteorhodopsins cluster in two sequence-related groups: blue proteorhodopsins (B-PR) and green proteorhodopsins (G-PR). The site-directed substitution Leu105Gln in Bac31A8 proteorhodopsin shifts this G-PR's wavelength maximum to a wavelength maximum the same as that of the B-PR Hot75m1 proteorhodopsin. The site-directed substitution Gln107Leu in Hot75m1 proteorhodopsin shifts this B-PR's wavelength maximum to a wavelength maximum as that of Bac31A8 proteorhodopsin.

Differential Muscle Hypertrophy Is Associated with Satellite Cell Numbers and Akt Pathway Activation Following Activin Type IIB Receptor Inhibition in Mtm1 p.R69C Mice

PubMed Central

Lawlor, Michael W.; Viola, Marissa G.; Meng, Hui; Edelstein, Rachel V.; Liu, Fujun; Yan, Ke; Luna, Elizabeth J.; Lerch-Gaggl, Alexandra; Hoffmann, Raymond G.; Pierson, Christopher R.; Buj-Bello, Anna; Lachey, Jennifer L.; Pearsall, Scott; Yang, Lin; Hillard, Cecilia J.; Beggs, Alan H.

2015-01-01

X-linked myotubular myopathy is a congenital myopathy caused by deficiency of myotubularin. Patients often present with severe perinatal weakness, requiring mechanical ventilation to prevent death from respiratory failure. We recently reported that an activin receptor type IIB inhibitor produced hypertrophy of type 2b myofibers and modest increases of strength and life span in the severely myopathic Mtm1δ4 mouse model of X-linked myotubular myopathy. We have now performed a similar study in the less severely symptomatic Mtm1 p.R69C mouse in hopes of finding greater treatment efficacy. Activin receptor type IIB inhibitor treatment of Mtm1 p.R69C animals produced behavioral and histological evidence of hypertrophy in gastrocnemius muscles but not in quadriceps or triceps. The ability of the muscles to respond to activin receptor type IIB inhibitor treatment correlated with treatment-induced increases in satellite cell number and several muscle-specific abnormalities of hypertrophic signaling. Treatment-responsive Mtm1 p.R69C gastrocnemius muscles displayed lower levels of phosphorylated ribosomal protein S6 and higher levels of phosphorylated eukaryotic elongation factor 2 kinase than were observed in Mtm1 p.R69C quadriceps muscle or in muscles from wild-type littermates. Hypertrophy in the Mtm1 p.R69C gastrocnemius muscle was associated with increased levels of phosphorylated ribosomal protein S6. Our findings indicate that muscle-, fiber type-, and mutation-specific factors affect the response to hypertrophic therapies that will be important to assess in future therapeutic trials. PMID:24726641

PR-Set7 is degraded in a conditional Cul4A transgenic mouse model of lung cancer

DOE PAGES

Wang, Yang; Xu, Zhidong; Mao, Jian -Hua; ...

2015-06-01

Background and objective. Maintenance of genomic integrity is essential to ensure normal organismal development and to prevent diseases such as cancer. PR-Set7 (also known as Set8) is a cell cycle regulated enzyme that catalyses monomethylation of histone 4 at Lys20 (H4K20me1) to promote chromosome condensation and prevent DNA damage. Recent studies show that CRL4CDT2-mediated ubiquitylation of PR-Set7 leads to its degradation during S phase and after DNA damage. This might occur to ensure appropriate changes in chromosome structure during the cell cycle or to preserve genome integrity after DNA damage. Methods. We developed a new model of lung tumor developmentmore » in mice harboring a conditionally expressed allele of Cul4A. We have therefore used a mouse model to demonstrate for the first time that Cul4A is oncogenic in vivo. With this model, staining of PR-Set7 in the preneoplastic and tumor lesions in AdenoCre-induced mouse lungs was performed. Meanwhile we identified higher protein level changes of γ-tubulin and pericentrin by IHC. Results. The level of PR-Set7 down-regulated in the preneoplastic and adenocarcinomous lesions following over-expression of Cul4A. We also identified higher levels of the proteins pericentrin and γ-tubulin in Cul4A mouse lungs induced by AdenoCre. Conclusion. PR-Set7 is a direct target of Cul4A for degradation and involved in the formation of lung tumors in the conditional Cul4A transgenic mouse model.« less

PR-Set7 is degraded in a conditional Cul4A transgenic mouse model of lung cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Yang; Xu, Zhidong; Mao, Jian -Hua

Background and objective. Maintenance of genomic integrity is essential to ensure normal organismal development and to prevent diseases such as cancer. PR-Set7 (also known as Set8) is a cell cycle regulated enzyme that catalyses monomethylation of histone 4 at Lys20 (H4K20me1) to promote chromosome condensation and prevent DNA damage. Recent studies show that CRL4CDT2-mediated ubiquitylation of PR-Set7 leads to its degradation during S phase and after DNA damage. This might occur to ensure appropriate changes in chromosome structure during the cell cycle or to preserve genome integrity after DNA damage. Methods. We developed a new model of lung tumor developmentmore » in mice harboring a conditionally expressed allele of Cul4A. We have therefore used a mouse model to demonstrate for the first time that Cul4A is oncogenic in vivo. With this model, staining of PR-Set7 in the preneoplastic and tumor lesions in AdenoCre-induced mouse lungs was performed. Meanwhile we identified higher protein level changes of γ-tubulin and pericentrin by IHC. Results. The level of PR-Set7 down-regulated in the preneoplastic and adenocarcinomous lesions following over-expression of Cul4A. We also identified higher levels of the proteins pericentrin and γ-tubulin in Cul4A mouse lungs induced by AdenoCre. Conclusion. PR-Set7 is a direct target of Cul4A for degradation and involved in the formation of lung tumors in the conditional Cul4A transgenic mouse model.« less

Differential muscle hypertrophy is associated with satellite cell numbers and Akt pathway activation following activin type IIB receptor inhibition in Mtm1 p.R69C mice.

PubMed

Lawlor, Michael W; Viola, Marissa G; Meng, Hui; Edelstein, Rachel V; Liu, Fujun; Yan, Ke; Luna, Elizabeth J; Lerch-Gaggl, Alexandra; Hoffmann, Raymond G; Pierson, Christopher R; Buj-Bello, Anna; Lachey, Jennifer L; Pearsall, Scott; Yang, Lin; Hillard, Cecilia J; Beggs, Alan H

2014-06-01

X-linked myotubular myopathy is a congenital myopathy caused by deficiency of myotubularin. Patients often present with severe perinatal weakness, requiring mechanical ventilation to prevent death from respiratory failure. We recently reported that an activin receptor type IIB inhibitor produced hypertrophy of type 2b myofibers and modest increases of strength and life span in the severely myopathic Mtm1δ4 mouse model of X-linked myotubular myopathy. We have now performed a similar study in the less severely symptomatic Mtm1 p.R69C mouse in hopes of finding greater treatment efficacy. Activin receptor type IIB inhibitor treatment of Mtm1 p.R69C animals produced behavioral and histological evidence of hypertrophy in gastrocnemius muscles but not in quadriceps or triceps. The ability of the muscles to respond to activin receptor type IIB inhibitor treatment correlated with treatment-induced increases in satellite cell number and several muscle-specific abnormalities of hypertrophic signaling. Treatment-responsive Mtm1 p.R69C gastrocnemius muscles displayed lower levels of phosphorylated ribosomal protein S6 and higher levels of phosphorylated eukaryotic elongation factor 2 kinase than were observed in Mtm1 p.R69C quadriceps muscle or in muscles from wild-type littermates. Hypertrophy in the Mtm1 p.R69C gastrocnemius muscle was associated with increased levels of phosphorylated ribosomal protein S6. Our findings indicate that muscle-, fiber type-, and mutation-specific factors affect the response to hypertrophic therapies that will be important to assess in future therapeutic trials. Copyright © 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.