Architecture of androgen receptor pathways amplifying glucagon-like peptide-1 insulinotropic action in male pancreatic β cells

Male mice lacking the androgen receptor (AR) in pancreatic β cells exhibit blunted glucose-stimulated insulin secretion (GSIS), leading to hyperglycemia. Testosterone activates an extranuclear AR in β cells to amplify glucagon-like peptide-1 (GLP-1) insulinotropic action. Here, we examined the architecture of AR targets that regulate GLP-1 insulinotropic action in male β cells. Testosterone cooperates with GLP-1 to enhance cAMP production at the plasma membrane and endosomes via: (1) increased mitochondrial production of CO2, activating the HCO3--sensitive soluble adenylate cyclase; and (2) increased Gαs recruitment to GLP-1 receptor and AR complexes, activating transmembrane adenylate cyclase. Additionally, testosterone enhances GSIS in human islets via a focal adhesion kinase/SRC/phosphatidylinositol 3-kinase/mammalian target of rapamycin complex 2 actin remodeling cascade. We describe the testosterone-stimulated AR interactome, transcriptome, proteome, and metabolome that contribute to these effects. This study identifies AR genomic and non-genomic actions that enhance GLP-1-stimulated insulin exocytosis in male β cells

Architecture of Androgen Receptor Pathways Amplifying Glucagon-Like Peptide-1 Insulinotropic Action in Male Pancreatic β Cells

Male mice lacking the androgen receptor (AR) in pancreatic β cells exhibit blunted glucose-stimulated insulin secretion (GSIS), leading to hyperglycemia. Testosterone activates an extranuclear AR in β cells to amplify glucagon-like peptide-1 (GLP-1) insulinotropic action. Here, we examined the architecture of AR targets that regulate GLP-1 insulinotropic action in male β cells. Testosterone cooperates with GLP-1 to enhance cAMP production at the plasma membrane and endosomes via: (1) increased mitochondrial production of C

Protein Kinase A Negatively Regulates the Acetic Acid Stress Response in <i>S. cerevisiae</i>

Bioethanol fermentation from lignocellulosic hydrolysates is negatively affected by the presence of acetic acid. The budding yeast S. cerevisiae adapts to acetic acid stress partly by activating the transcription factor, Haa1. Haa1 induces the expression of many genes, which are responsible for increased fitness in the presence of acetic acid. Here, we show that protein kinase A (PKA) is a negative regulator of Haa1-dependent gene expression under both basal and acetic acid stress conditions. Deletions of RAS2, encoding a positive regulator of PKA, and PDE2, encoding a negative regulator of PKA, lead to an increased and decreased expression of Haa1-regulated genes, respectively. Importantly, the deletion of HAA1 largely reverses the effects of ras2∆. Additionally, the expression of a dominant, hyperactive RAS2A18V19 mutant allele also reduces the expression of Haa1-regulated genes. We found that both pde2Δ and RAS2A18V19 reduce cell fitness in response to acetic acid stress, while ras2Δ increases cellular adaptation. There are three PKA catalytic subunits in yeast, encoded by TPK1, TPK2, and TPK3. We show that single mutations in TPK1 and TPK3 lead to the increased expression of Haa1-regulated genes, while tpk2Δ reduces their expression. Among tpk double mutations, tpk1Δ tpk3Δ greatly increases the expression of Haa1-regulated genes. We found that acetic acid stress in a tpk1Δ tpk3Δ double mutant induces a flocculation phenotype, which is reversed by haa1Δ. Our findings reveal PKA to be a negative regulator of the acetic acid stress response and may help engineer yeast strains with increased efficiency of bioethanol fermentation

Prevalence of pulmonary tuberculosis amongst the tribal population of Madhya Pradesh, central India

Background: This was a prevalence survey of pulmonary tuberculosis (PTB) disease in the tribal population of Madhya Pradesh state, central India. Methods: A community-based cross-sectional tuberculosis (TB) disease prevalence survey was undertaken among adults aged 515 years in the tribal population of Madhya Pradesh. A multistage stratified cluster sampling was adopted. A representative random sample of villages predominated by tribal populations was selected from 11 districts. All eligible individuals were questioned for chest symptoms relating to TB. Sputum samples were collected from all eligible individuals, transported to the laboratory, and examined by Ziehl–Neelsen (ZN) smear microscopy and solid media culture methods. Results: Of the 23 411 individuals eligible for screening, 22 270 (95.1%) were screened for symptoms. The overall proportion of symptomatic individuals was 7.9%. Overall prevalence (culture and/or smear positive) of PTB was 387 [95% confidence interval (CI): 273–502] per 100 000 population. The prevalence increased with age and was also significantly higher among males (554/100 000; 95% CI: 415–693) as compared with females (233/100 000; 95% CI: 101–364) (P<0.001). Conclusion: The findings suggest that the TB situation amongst the tribal population is not that different from the situation among the non-tribal population in the country. However, TB remains a major public health problem amongst the tribal population and there is a need to maintain and further strengthen TB control measures on a sustained and long-term basis

Prevalence of pulmonary tuberculosis--a baseline survey in central India.

BACKGROUND: The present study provides an estimate of the prevalence of bacteriologially positive pulmonary tuberculosis in Jabalpur, a district in central India. METHODOLOGY/PRINCIPAL FINDINGS: A community based cross-sectional survey was undertaken in Jabalpur District of the central Indian state of Madhya Pradesh. A stratified cluster sampling design was adopted to select the sample. All eligible individuals were questioned for pulmonary symptoms suggestive of TB disease. Two sputum samples were collected from all eligible individuals and were examined by Ziehl-Neelsen smear microscopy and solid media culture methods. Of the 99,918 individuals eligible for screening, 95,071 (95.1%) individuals were screened. Of these, 7,916 (8.3%) were found to have symptoms and sputum was collected from 7,533 (95.2%) individuals. Overall prevalence of bacteriologically positive PTB was found to be 255.3 per 100,000 population (95% C.I: 195.3-315.4). Prevalence was significantly higher (p<0.001) amongst males (355.8; 95% C.I: 304.4-413.4) compared with females (109.0; 95% C.I: 81.2-143.3). Prevalence was also significantly higher in rural areas (348.9; 95% C.I: 292.6-412.8) as compared to the urban (153.9; 95% C.I: 123.2-190.1). CONCLUSIONS/SIGNIFICANCE: The TB situation in Jabalpur district, central India, is observed to be comparable to the TB situation at the national level (255.3 versus 249). There is however, a need to maintain and further strengthen TB control measures on a sustained and long term basis in the area to have a significant impact on the disease prevalence in the community

Tuberculous infection in Saharia, a primitive tribal community of Central India

A cross-sectional tuberculin survey was carried out to estimate the prevalence of tuberculous infection and the annual risk of tuberculosis infection (ARTI) among children of Saharia, a primitive ethnic group in Madhya Pradesh, Central India. A total of 1341 children aged 1—9 years were subjected to tuberculin testing with 1 TU of PPD RT 23 and the reaction sizes were read after 72 h. The proportion of BCG scar-positive children was 34.6%. The frequency distribution of children by reaction sizes indicated a clear-cut anti-mode at 11mm and a mode at 18mm at the right-hand side of the distribution. The prevalence of infection among children irrespective of BCG scar was estimated as 20.4% (95% CI 18.2—22.5%) and the ARTI was 3.9% (95% CI 3.5—4.3%). The corresponding figures were 21.1% (95% CI 18.3—23.8%) and 3.9% (95% CI 3.4—4.5%) among BCG scar-negative children and 19.0% (95% CI 15.4—22.5%) and 4.0% (95% CI 3.2—4.8%) among BCG scar-positive children. The findings of the present study show a high prevalence of tuberculous infection and high ARTI in this primitive ethnic group. There is an urgent need to further intensify tuberculosis control measures on a sustained and long-term basis in this area

Annual risk of tuberculosis infection among tribal population of central India

objective To estimate the annual risk of tuberculosis infection (ARTI) among tribal children of Madhya Pradesh, central India. methods Community-based, cross-sectional tuberculin survey among children aged 1–9 years in the tribal population of Madhya Pradesh. Multistage stratified cluster sampling was used to select a representative random sample of villages predominated by tribal population from selected districts. A total of 4802 children were tuberculin-tested with 1TU of PPD RT 23 and the reaction sizes read after 72 h. results A total of 3062 (64%) children had no BCG scar. The frequency distribution of children by reaction sizes indicated a fair mode at 18 mm in the right hand side of the distribution. By mirror-image technique, the prevalence of infection among children with no recognizable BCG scar was estimated as 6.8% (95% CI: 4.8–8.9%). The ARTI was computed as 1.3% (0.9–1.7%). The corresponding figures for children irrespective of scar status were 7.1% (95% CI: 5.5–8.8%) and 1.3% (1.0–1.7%) respectively. conclusions The risk of tuberculosis infection in tribal population of Madhya Pradesh, central India is not different from other areas of the country. There is, however, a need to further intensify tuberculosis control measures on a sustained and long-term basis