Transcriptional Repression of the -Subunit Gene by Androgen Receptor Occurs Independently of DNA Binding but Requires the DNA-Binding and Ligand-Binding Domains of the Receptor

The pituitary glycoprotein hormones LH and FSH regulate the reproductive cycle and are sensitive to feedback by gonadal steroids. The common α-subunit shared by these hormones is transcriptionally repressed by androgen receptor (AR) in the presence of its ligand dihydrotestosterone. This identifies at least one mechanism that contributes to AR-dependent suppression of gonadotropin synthesis. Repression of α-subunit transcription by AR requires only the sequences within the first 480 bp of the promoter. While this region contains a high-affinity binding site for AR, this element does not mediate the suppressive effects of androgens. Instead, two other elements within the promoter-regulatory region (α-basal element and cAMP-regulatory element), which are important for expression of the α-subunit gene in gonadotropes, mediate the effects of AR. This suggests that AR inhibits activity of the α-subunit promoter by interfering with the transcriptional properties of the proteins that bind to α-basal element and the cAMP-regulatory elements. Furthermore, transfection analysis of various mutant ARs identified both the DNA-binding and ligand-binding domains of the receptor as critical for repression. Comparisons with the MMTV promoter revealed distinct structural requirements that underlie the trans-activation and transrepression properties of AR

The Cost of Improving Nutritional Outcomes Through Food‐Assisted Maternal and Child Health and Nutrition Programmes in Burundi and Guatemala

Evidence on the cost‐effectiveness of multisectoral maternal and child health and nutrition programmes is scarce. We conducted a prospective costing study of two food‐assisted maternal and child health and nutrition programmes targeted to pregnant women and children during the first 1,000 days (pregnancy to 2 years). Each was paired with a cluster‐randomized controlled trial to evaluate impact and compare the optimal quantity and composition of food rations (Guatemala, five treatment arms) and their optimal timing and duration (Burundi, three treatment arms). We calculated the total and per beneficiary cost, conducted cost consequence analyses, and estimated the cost savings from extending the programme for 2 years. In Guatemala, the programme model with the lowest cost per percentage point reduction in stunting provided the full‐size family ration with an individual ration of corn–soy blend or micronutrient powder. Reducing family ration size lowered costs but failed to reduce stunting. In Burundi, providing food assistance for the full 1,000 days led to the lowest cost per percentage point reduction in stunting. Reducing the duration of ration eligibility reduced per beneficiary costs but was less effective. A 2‐year extension could have saved 11% per beneficiary in Guatemala and 18% in Burundi. We found that investments in multisectoral nutrition programmes do not scale linearly. Programmes providing smaller rations or rations for shorter durations, although less expensive per beneficiary, may not provide the necessary dose to improve (biological) outcomes. Lastly, delivering effective programmes for longer periods can generate cost savings by dispersing start‐up costs and lengthening peak operating capacity

Transcriptional repression of the glycoprotein hormone alpha subunit gene by androgen may involve direct binding of androgen receptor to the proximal promoter.

Testicular androgens suppress the synthesis and secretion of the pituitary gonadotropins, in particular, luteinizing hormone. This suppressive effect includes transcription of both the common a subunit gene and the unique β subunit genes. Herein, we demonstrate that 1600 base pairs (bp) of proximal 5'-flanking region derived from the human α subunit gene and a shorter 315-bp segment of the bovine α subunit gene confer negative regulation by androgen to the gene encoding bacterial chloramphenicol acetyltransferase in transgenic mice.Testicular androgens suppress the synthesis and secretion of the pituitary gonadotropins, in particular, luteinizing hormone. This suppressive effect includes transcription of both the common a subunit gene and the unique β subunit genes. Herein, we demonstrate that 1600 base pairs (bp) of proximal 5'-flanking region derived from the human α subunit gene and a shorter 315-bp segment of the bovine α subunit gene confer negative regulation by androgen to the gene encoding bacterial chloramphenicol acetyltransferase in transgenic mice

Gender and sexuality II: Activism

This report considers genders and sexualities within and across spaces of activism. Geographers concerned with social belonging, equity, human rights, civic duties, and gendered and sexed identities often engage in activism through participatory research and/or direct action. This report brings together geographical scholarship on feminist and queer (lesbian, gay, bisexual, transgender, intersex, queer) – LGBTIQ – activism to examine the construction of transformative geographical knowledges. Feminist and queer activist geographers can be powerful forces for positive social change and challenge heteronormativity. They may also, however, reinforce normalizations and hierarchies within and beyond activist spaces. I bring together references that position geographers at the centre of activism, genders, sexualities and place

PhillydotMap: The Shape of Philadelphia

This book is the outgrowth of a working group entitled, “Modeling Urban Environmental Impacts on Health, Development, and Behavior sponsored by the University of Pennsylvania Institute for Urban Research. The purpose of the working gropu was to engage faculty from across campus and to encourage their collaborative use of GIS technology in the modeling of urban form and function. These ten chapters represent a wide range of GIS applications, from community-based social services to public history to social science research

Women's empowerment, production choices, and crop diversity in Burkina Faso, India, Malawi, and Tanzania: a secondary analysis of cross-sectional data

BACKGROUND: Bolstering farm-level crop diversity is one strategy to strengthen food system resilience and achieve global food security. Women who live in rural areas play an essential role in food production; therefore, we aimed to assess the associations between women's empowerment and crop diversity. METHODS: In this secondary analysis of cross-sectional data, we used data from four cluster-randomised controlled trials done in Burkina Faso, India, Malawi, and Tanzania. We assessed women's empowerment using indicators from the Women's Empowerment in Agriculture Index. Farm-level crop diversity measures were the number of food crops grown, number of food groups grown, and if nutrient-dense crops were grown. We used a two-stage modelling approach. First, we analysed covariate-adjusted country-specific associations between women's empowerment and crop diversity indicators using multivariable generalised linear models. Second, we pooled country-specific associations using random-effects models. FINDINGS: The final analytic sample included 1735 women from Burkina Faso, 4450 women from India, 547 women from Malawi, and 574 women from Tanzania. Across all countries, compared with households in which women provided input into fewer productive decisions, households of women with greater input into productive decisions produced more food crops (mean difference 0·36 [95% CI 0·16-0·55]), a higher number of food groups (mean difference 0·16 [0·06-0·25]), and more nutrient-dense crops (percentage point difference 3 [95% CI 3-4]). Across all countries, each additional community group a woman actively participated in was associated with cultivating a higher number of food crops (mean difference 0·20 [0·04-0·35]) and a higher number of food groups (mean difference 0·11 [0·03-0·18]), but not more nutrient-dense crops. In pooled associations from Burkina Faso and India, asset ownership was associated with cultivating a higher number of food crops (mean difference 0·08 [0·04-0·12]) and a higher number of food groups (mean difference 0·05 [0·04-0·07]), but not more nutrient-dense crops. INTERPRETATION: Greater women's empowerment was associated with higher farm-level crop diversity among low-income agricultural households, suggesting that it could help enhance efforts to strengthen food system resilience. FUNDING: Bill & Melinda Gates Foundation

<i>RPA3-UMAD1</i> rs12702634 and rheumatoid arthritis-associated interstitial lung disease in European ancestry

Objective Recently, a genome-wide association study identified an association between RA-associated interstitial lung disease (ILD) and RPA3-UMAD1 rs12702634 in the Japanese population, especially for patients with a usual interstitial pneumonia (UIP) pattern. We aimed to replicate this association in a European population and test for interaction with MUC5B rs35705950.Methods In this genetic case-control association study, patients with RA and ILD and controls with RA and no ILD were included from France, the USA and the Netherlands. Only cases and controls from European genetic ancestries determined by principal components analysis were included in the analyses. RA was defined by the 1987 ACR or 2010 ACR/EULAR criteria and ILD by chest high-resolution CT scan, except in the control dataset from the Netherlands, where the absence of ILD was determined by chart review. Patients were genotyped for RPA3-UMAD1 rs12702634 and MUC5B rs35705950. Associations were tested using logistic regression adjusted for sex, age at RA onset, age at ILD onset or at certified absence of ILD, tobacco smoking status and country of origin.Results Among the 883 patients included, 322 were RA-ILD cases (36.5%). MUC5B rs35705950 was strongly associated with RA-ILD in all datasets {combined adjusted odds ratio [OR] 2.9 [95% CI 2.1, 3.9], P = 1.1 x 10-11. No association between RPA3-UMAD1 rs12702634 and RA-ILD was observed [combined OR 1.2 (95% CI 0.8, 1.6), P = 0.31. No interaction was found between RPA3-UMAD1 rs12702634 and MUC5B rs35705950 (P = 0.70).Conclusion Our findings did not support a contribution of RPA3-UMAD1 rs12702634 to the overall RA-ILD susceptibility in the European population.What does this mean for patients?Interstitial lung disease (ILD) can develop in 10-60% of patients with rheumatoid arthritis (RA) and is associated with an increased risk of death. We do not yet fully understand why RA-ILD occurs, but risk factors include genetics and environmental factors such as tobacco smoking. Identifying new genetic risk factors for RA-ILD may improve our understanding of how this disease occurs, help us categorize patients in terms of their risk level and help us to potentially identify new drug targets. A previous Japanese genetic study identified the RPA3-UMAD1 rs12702634 common genetic variant as a risk factor for RA-ILD. However, a second Japanese study failed to replicate these findings. In this international study including patients with European ancestry, we did not find that RPA3-UMAD1 rs12702634 contributed to the overall risk of RA-ILD. Our findings highlight the importance of conducting analyses that try to replicate the results of a study. We also emphasize that genetic associations-even those already reported-require rigorous testing in different groups of people before we can conclude that they contribute to disease risk. Ongoing collaboration and multi-ancestry genetic studies are essential in order to advance our understanding of the complex genetics underlying RA-ILD