Homologous and heterologous desensitization of guanylyl cyclase-B signaling in GH3 somatolactotropes

The guanylyl cyclases, GC-A and GC-B, are selective receptors for atrial and C-type natriuretic peptides (ANP and CNP, respectively). In the anterior pituitary, CNP and GC-B are major regulators of cGMP production in gonadotropes and yet mouse models of disrupted CNP and GC-B indicate a potential role in growth hormone secretion. In the current study, we investigate the molecular and pharmacological properties of the CNP/GC-B system in somatotrope lineage cells. Primary rat pituitary and GH3 somatolactotropes expressed functional GC-A and GC-B receptors that had similar EC50 properties in terms of cGMP production. Interestingly, GC-B signaling underwent rapid homologous desensitization in a protein phosphatase 2A (PP2A)-dependent manner. Chronic exposure to either CNP or ANP caused a significant down-regulation of both GC-A- and GC-B-dependent cGMP accumulation in a ligand-specific manner. However, this down-regulation was not accompanied by alterations in the sub-cellular localization of these receptors. Heterologous desensitization of GC-B signaling occurred in GH3 cells following exposure to either sphingosine-1-phosphate or thyrotrophin-releasing hormone (TRH). This heterologous desensitization was protein kinase C (PKC)-dependent, as pre-treatment with GF109203X prevented the effect of TRH on CNP/GC-B signaling. Collectively, these data indicate common and distinct properties of particulate guanylyl cyclase receptors in somatotropes and reveal that independent mechanisms of homologous and heterologous desensitization occur involving either PP2A or PKC. Guanylyl cyclase receptors thus represent potential novel therapeutic targets for treating growth-hormone-associated disorders

Human Papillomavirus Risk Perceptions Among Young Adult Sexual Minority Cisgender Women and Nonbinary Individuals Assigned Female at Birth

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/148405/1/psrh12087_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/148405/2/psrh12087.pd

Roadmaps to Utopia: Tales of the Smart City

Notions of the Smart City are pervasive in urban development discourses. Various frameworks for the development of smart cities, often conceptualized as roadmaps, make a number of implicit claims about how smart city projects proceed but the legitimacy of those claims is unclear. This paper begins to address this gap in knowledge. We explore the development of a smart transport application, MotionMap, in the context of a £16M smart city programme taking place in Milton Keynes, UK. We examine how the idealized smart city narrative was locally inflected, and discuss the differences between the narrative and the processes and outcomes observed in Milton Keynes. The research shows that the vision of data-driven efficiency outlined in the roadmaps is not universally compelling, and that different approaches to the sensing and optimization of urban flows have potential for empowering or disempowering different actors. Roadmaps tend to emphasize the importance of delivering quick practical results. However, the benefits observed in Milton Keynes did not come from quick technical fixes but from a smart city narrative that reinforced existing city branding, mobilizing a growing network of actors towards the development of a smart region. Further research is needed to investigate this and other smart city developments, the significance of different smart city narratives, and how power relationships are reinforced and constructed through them

The role of the General Practitioner in weight management in primary care – a cross sectional study in General Practice

BACKGROUND: Obesity has become a global pandemic, considered the sixth leading cause of mortality by the WHO. As gatekeepers to the health system, General Practitioners are placed in an ideal position to manage obesity. Yet, very few consultations address weight management. This study aims to explore reasons why patients attending General Practice appointments are not engaging with their General Practitioner (GP) for weight management and their perception of the role of the GP in managing their weight. METHODS: In February 2006, 367 participants aged between 17 and 64 were recruited from three General Practices in Melbourne to complete a waiting room self - administered questionnaire. Questions included basic demographics, the role of the GP in weight management, the likelihood of bringing up weight management with their GP and reasons why they would not, and their nominated ideal person to consult for weight management. Physical measurements to determine weight status were then completed. The statistical methods included means and standard deviations to summarise continuous variables such as weight and height. Sub groups of weight and questionnaire answers were analysed using the chi2 test of significant differences taking p as < 0.05. RESULTS: The population sample had similar obesity co-morbidity rates to the National Heart Foundation data. 74% of patients were not likely to bring up weight management when they visit their GP. Negative reasons were time limitation on both the patient's and doctor's part and the doctor lacking experience. The GP was the least likely person to tell a patient to lose weight after partner, family and friends. Of the 14% that had been told by their GP to lose weight, 90% had cardiovascular obesity related co-morbidities. GPs (15%) were 4th in the list of ideal persons to manage weight after personal trainer CONCLUSION: Patients do not have confidence in their GPs for weight management, preferring other health professionals who may lack evidence based training. Concurrently, GPs target only those with obesity related co-morbidities. Further studies evaluating GPs' opinions about weight management, effective strategies that can be implemented in primary care and the co-ordination of the team approach need to be done

Predicting Bison Migration out of Yellowstone National Park Using Bayesian Models

Long distance migrations by ungulate species often surpass the boundaries of preservation areas where conflicts with various publics lead to management actions that can threaten populations. We chose the partially migratory bison (Bison bison) population in Yellowstone National Park as an example of integrating science into management policies to better conserve migratory ungulates. Approximately 60% of these bison have been exposed to bovine brucellosis and thousands of migrants exiting the park boundary have been culled during the past two decades to reduce the risk of disease transmission to cattle. Data were assimilated using models representing competing hypotheses of bison migration during 1990–2009 in a hierarchal Bayesian framework. Migration differed at the scale of herds, but a single unifying logistic model was useful for predicting migrations by both herds. Migration beyond the northern park boundary was affected by herd size, accumulated snow water equivalent, and aboveground dried biomass. Migration beyond the western park boundary was less influenced by these predictors and process model performance suggested an important control on recent migrations was excluded. Simulations of migrations over the next decade suggest that allowing increased numbers of bison beyond park boundaries during severe climate conditions may be the only means of avoiding episodic, large-scale reductions to the Yellowstone bison population in the foreseeable future. This research is an example of how long distance migration dynamics can be incorporated into improved management policies

Gene expression profile of the skin in the 'hairpoor' (HrHp) mice by microarray analysis

<p>Abstract</p> <p>Background</p> <p>The transcriptional cofactor, Hairless (HR), acts as one of the key regulators of hair follicle cycling; the loss of function mutations is the cause of the expression of the hairless phenotype in humans and mice. Recently, we reported a new <it>Hr </it>mutant mouse called 'Hairpoor' (<it>Hr^Hp</it>). These mutants harbor a gain of the function mutation, T403A, in the <it>Hr </it>gene. This confers the overexpression of HR and <it>Hr^Hp</it>is an animal model of Marie Unna hereditary hypotrichosis in humans. In the present study, the expression profile of <it>Hr^Hp/Hr^Hp</it>skin was investigated using microarray analysis to identify genes whose expression was affected by the overexpression of HR.</p> <p>Results</p> <p>From 45,282 mouse probes, differential expressions in 43 (>2-fold), 306 (>1.5-fold), and 1861 genes (>1.2-fold) in skin from <it>Hr^Hp/Hr^Hp</it>mice were discovered and compared with skin from wild-type mice. Among the 1861 genes with a > 1.2-fold increase in expression, further analysis showed that the expression of eight genes known to have a close relationship with hair follicle development, ascertained by conducting real-time PCR on skin RNA produced during hair follicle morphogenesis (P0-P14), indicated that four genes, <it>Wif1</it>, <it>Casp14</it>, <it>Krt71</it>, and <it>Sfrp1</it>, showed a consistent expression pattern with respect to HR overexpression in vivo.</p> <p>Conclusion</p> <p><it>Wif1 </it>and <it>Casp14 </it>were found to be upregulated, whereas <it>Krt71 </it>and <it>Sfrp1 </it>were downregulated in cells overexpressing HR in transient transfection experiments on keratinocytes, suggesting that HR may transcriptionally regulate these genes. Further studies are required to understand the mechanism of this regulation by the HR cofactor.</p

Advising overweight persons about diet and physical activity in primary health care: Lithuanian health behaviour monitoring study

BACKGROUND: Obesity is a globally spreading health problem. Behavioural interventions aimed at modifying dietary habits and physical activity patterns are essential in prevention and management of obesity. General practitioners (GP) have a unique opportunity to counsel overweight patients on weight control. The purpose of the study was to assess the level of giving advice on diet and physical activity by GPs using the data of Lithuanian health behaviour monitoring among adult population. METHODS: Data from cross-sectional postal surveys of 2000, 2002 and 2004 were analysed. Nationally representative random samples were drawn from the population register. Each sample consisted of 3000 persons aged 20–64 years. The response rates were 74.4% in 2000, 63.4% in 2002 and 61.7% in 2004. Self-reported body weight and height were used to calculate body mass index (BMI). Information on advising in primary health care was obtained asking whether GP advised overweight patients to change dietary habits and to increase physical activity. The odds of receiving advice on diet and physical activity were calculated using multiple logistic regression analyses according to a range of sociodemographic variables, perceived health, number of visits to GPs and body-weight status. RESULTS: Almost a half of respondents were overweight or obese. Only one fourth of respondents reported that they were advised to change diet. The proportion of persons who received advice on physical activity was even lower. The odds of receiving advice increased with age. A strong association was found between perceived health and receiving advice. The likelihood of receiving advice was related to BMI. GPs were more likely to give advice when BMI was high. More than a half of obese respondents (63.3%) reported that they had tried to lose weight. The association between receiving advice and self-reported attempt to lose weight was found. CONCLUSION: The low rate of dietary and physical activity advice reported by overweight patients implies that more lifestyle counselling should be provided in primary health care. There is an obvious need for improved training and education of GPs in counselling of overweight patients focusing on methods of giving dietary and physical activity advice

Natriuretic peptide activation of extracellular regulated kinase 1/2 (ERK1/2) pathway by particulate guanylyl cyclases in GH3 somatolactotropes.

The natriuretic peptides, Atrial-, B-type and C-type natriuretric peptides (ANP, BNP, CNP), are regulators of many endocrine tissues and exert their effects predominantly through the activation of their specific guanylyl cyclase receptors (GC-A and GC-B) to generate cGMP. Whereas cGMP-independent signalling has been reported in response to natriuretic peptides, this is mediated via either the clearance receptor (Npr-C) or a renal-specific NPR-Bi isoform, which both lack intrinsic guanylyl cyclase activity. Here, we report evidence of GC-B-dependent cGMP-independent signalling in pituitary GH3 cells. Stimulation of GH3 cells with CNP resulted in a rapid and sustained enhancement of ERK1/2 phosphorylation (P-ERK1/2), an effect that was not mimicked by dibutryl-cGMP. Furthermore, CNP-stimulated P-ERK1/2 occurred at concentrations below that required for cGMP accumulation. The effect of CNP on P-ERK1/2 was sensitive to pharmacological blockade of MEK (U0126) and Src kinases (PP2). Silencing of the GC-B1 and GC-B2 splice variants of the GC-B receptor by using targeted short interfering RNAs completely blocked the CNP effects on P-ERK1/2. CNP failed to alter GH3 cell proliferation or cell cycle distribution but caused a concentration-dependent increase in the activity of the human glycoprotein α-subunit promoter (αGSU) in a MEK-dependent manner. Finally, CNP also activated the p38 and JNK MAPK pathways in GH3 cells. These findings reveal an additional mechanism of GC-B signalling and suggest additional biological roles for CNP in its target tissues

Prospective and Mendelian randomization analyses on the association of circulating fatty acid binding protein 4 (FABP-4) and risk of colorectal cancer

BACKGROUND: Fatty acid binding protein 4 (FABP-4) is a lipid-binding adipokine upregulated in obesity, which may facilitate fatty acid supply for tumor growth and promote insulin resistance and inflammation and may thus play a role in colorectal cancer (CRC) development. We aimed to investigate the association between circulating FABP-4 and CRC and to assess potential causality using a Mendelian randomization (MR) approach. METHODS: The association between pre-diagnostic plasma measurements of FABP-4 and CRC risk was investigated in a nested case-control study in 1324 CRC cases and the same number of matched controls within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. A two-sample Mendelian randomization study was conducted based on three genetic variants (1 cis, 2 trans) associated with circulating FABP-4 identified in a published genome-wide association study (discovery n = 20,436) and data from 58,131 CRC cases and 67,347 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry. RESULTS: In conditional logistic regression models adjusted for potential confounders including body size, the estimated relative risk, RR (95% confidence interval, CI) per one standard deviation, SD (8.9 ng/mL) higher FABP-4 concentration was 1.01 (0.92, 1.12) overall, 0.95 (0.80, 1.13) in men and 1.09 (0.95, 1.25) in women. Genetically determined higher FABP-4 was not associated with colorectal cancer risk (RR per FABP-4 SD was 1.10 (0.95, 1.27) overall, 1.03 (0.84, 1.26) in men and 1.21 (0.98, 1.48) in women). However, in a cis-MR approach, a statistically significant association was observed in women (RR 1.56, 1.09, 2.23) but not overall (RR 1.23, 0.97, 1.57) or in men (0.99, 0.71, 1.37). CONCLUSIONS: Taken together, these analyses provide no support for a causal role of circulating FABP-4 in the development of CRC, although the cis-MR provides some evidence for a positive association in women, which may deserve to be investigated further

Italian network for obesity and cardiovascular disease surveillance: A pilot project

<p>Abstract</p> <p>Background</p> <p>Also in Mediterranean countries, which are considered a low risk population for cardiovascular disease (CVD), the increase in body mass index (BMI) has become a public health priority. To evaluate the feasibility of a CVD and obesity surveillance network, forty General Practitioners (GPs) were engaged to perform a screening to assess obesity, cardiovascular risk, lifestyle habits and medication use.</p> <p>Methods</p> <p>A total of 1,046 women and 1,044 men aged 35–74 years were randomly selected from GPs' lists stratifying by age decade and gender. Anthropometric and blood pressure measurements were performed by GPs using standardized methodologies. BMI was computed and categorized in normal weight (BMI 18.5–24.9 kg/m²), overweight (BMI 25.0–29.9 kg/m²) and obese (BMI ≥ 30 kg/m²). Food frequency (per day: fruits and vegetables; per week: meat, cheese, fish, pulses, chocolate, fried food, sweet, wholemeal food, rotisserie food and sugar drink) and physical activity (at work and during leisure time) were investigated through a questionnaire. CVD risk was assessed using the Italian CUORE Project risk function.</p> <p>Results</p> <p>The percentage of missing values was very low. Prevalence of overweight was 34% in women and 50% in men; prevalence of obesity was 23% in both men and women. Level of physical activity was mostly low or very low. BMI was inversely associated with consumption of pulses, rotisserie food, chocolate, sweets and physical activity during leisure time and directly associated with consumption of meat. Mean value of total cardiovascular risk was 4% in women and 11% in men. One percent of women and 16% of men were at high cardiovascular risk (≥ 20% in 10 years). Normal weight persons were four times more likely to be at low risk than obese persons.</p> <p>Conclusion</p> <p>This study demonstrated the feasibility of a surveillance network of GPs in Italy focusing on obesity and other CVD risk factors. It also provided information on lifestyle habits, such as diet and physical activity.</p