2,015,918 research outputs found
Proline-rich tyrosine kinase 2 mediates gonadotropin-releasing hormone signaling to a specific extracellularly regulated kinase-sensitive transcriptional locus in the luteinizing hormone beta-subunit gene
Full text linkG protein-coupled receptor regulation of gene transcription primarily occurs through the phosphorylation of transcription factors by MAPKs. This requires transduction of an activating signal via scaffold proteins that can ultimately determine the outcome by binding signaling kinases and adapter proteins with effects on the target transcription factor and locus of activation. By investigating these mechanisms, we have elucidated how pituitary gonadotrope cells decode an input GnRH signal into coherent transcriptional output from the LH beta-subunit gene promoter. We show that GnRH activates c-Src and multiple members of the MAPK family, c-Jun NH2-terminal kinase 1/2, p38MAPK, and ERK1/2. Using dominant-negative point mutations and chemical inhibitors, we identified that calcium-dependent proline-rich tyrosine kinase 2 specifically acts as a scaffold for a focal adhesion/cytoskeleton-dependent complex comprised of c-Src, Grb2, and mSos that translocates an ERK-activating signal to the nucleus. The locus of action of ERK was specifically mapped to early growth response-1 (Egr-1) DNA binding sites within the LH beta-subunit gene proximal promoter, which was also activated by p38MAPK, but not c-Jun NH2-terminal kinase 1/2. Egr-1 was confirmed as the transcription factor target of ERK and p38MAPK by blockade of protein expression, transcriptional activity, and DNA binding. We have identified a novel GnRH-activated proline-rich tyrosine kinase 2-dependent ERK-mediated signal transduction pathway that specifically regulates Egr-1 activation of the LH beta-subunit proximal gene promoter, and thus provide insight into the molecular mechanisms required for differential regulation of gonadotropin gene expression
External validation of anti-Müllerian hormone based prediction of live birth in assisted conception
Full text link<p>Background - Chronological age and oocyte yield are independent determinants of live birth in assisted conception. Anti-Müllerian hormone (AMH) is strongly associated with oocyte yield after controlled ovarian stimulation. We have previously assessed the ability of AMH and age to independently predict live birth in an Italian assisted conception cohort. Herein we report the external validation of the nomogram in 822 UK first in vitro fertilization (IVF) cycles.</p>
<p>Methods - Retrospective cohort consisting of 822 patients undergoing their first IVF treatment cycle at Glasgow Centre for Reproductive Medicine. Analyses were restricted to women aged between 25 and 42 years of age. All women had an AMH measured prior to commencing their first IVF cycle. The performance of the model was assessed; discrimination by the area under the receiver operator curve (ROCAUC) and model calibration by the predicted probability versus observed probability.</p>
<p>Results - Live births occurred in 29.4% of the cohort. The observed and predicted outcomes showed no evidence of miscalibration (p = 0.188). The ROCAUC was 0.64 (95% CI: 0.60, 0.68), suggesting moderate and similar discrimination to the original model. The ROCAUC for a continuous model of age and AMH was 0.65 (95% CI 0.61, 0.69), suggesting that the original categories of AMH were appropriate.</p>
<p>Conclusions - We confirm by external validation that AMH and age are independent predictors of live birth. Although the confidence intervals for each category are wide, our results support the assessment of AMH in larger cohorts with detailed baseline phenotyping for live birth prediction.</p>
Regulation of the juvenile hormone titre in the Colorado potato beetle
No full textThree main topics were investigated in regulation of the titre of juvenile hormone in haemolymph of the Colorado potato beetle ( Leptinotarsa decemlineata Say): enzymic breakdown of the hormone; binding and protection of the hormone by carrier proteins; the synthetic capacity of the corpora allata.Juvenile hormone was broken down by two major pathways: ester hydrolysis by esterases and hydration of the epoxide group by epoxide hydratases in tissue. In haemolymph of the beetle, juvenile hormone is solely broken down by juvenile hormone esterases. An in vitro method was developed to measure the catalytic activity of juvenile hormone esterase from haemolymph. High activities were observed in fourth-instar larvae and in beetles just before diapause. Lower activities were found in third- instar larvae and in beetles reared with long days, at diapause and after diapause. The juvenile hormone esterase was insensitive to diisopropylfluorophosphate (DFP), an inhibitor used to distinguish between carboxylesterases and esterases specific to juvenile hormone. Electrophoresis of the esterase from haemolymph showed one or more esterases specific to juvenile hormone.The short half-life of juvenile hormone measured in vivo and in vitro in the haemolymph and inhibition studies with Triton X-100 suggests that juvenile hormone esterases in haemolymph govern breakdown. Activities of juvenile hormone esterase correlate well with the juvenile hormone titre.The sharp changes in juvenile hormone esterase suggest that esterase activity is regulated. The mechanism was studied by supplying juvenile hormone and by microsurgery. Treatment of diapausing beetles with juvenile hormone itself or analogues caused an increase in activity of juvenile hormone esterase within 24 h. Ligation or removal of corpora allata suggested that this induction was an indirect effect of juvenile hormone. Transfer from short day to long day and treatment with hormone of beetles reared with short days prevented high activity of juvenile hormone esterase. Removal of corpora allata at emergence from beetles reared with short days resulted in the same. In beetles reared with short days the titre of hormone during the first days after adult emergence probably induces the rise in esterase. Esterase activity is thus most likely controlled indirectly by the hormone, via a centre in the brains (hormostate). The level of esterase activity is probably dependent on the sensitivity of this hormostate and on the titre of the juvenile hormone.In several insects juvenile hormone is transported bound to carrier proteins. In haemolymph of larval and adult Colorado potato beetles lipoproteins of high molecular weight (>100,00 daltons) were found, capable of binding juvenile hormone, its analogues, and palmitic acid. The lipoproteins were partially separated by gel permeation chromatography and electrophoresis on polyacrylamide gel. The binding characteristics of the lipoproteins indicate low affinity (K d ≈10 -5 M), low specificity and high binding capacity. The juvenile hormone complexed to lipoproteins was protected against esterases from haemolymph to some extent. Thus these carrier lipoproteins probably play little role in the regulation of the titre of juvenile hormone.In the last part of our investigations the activity of the corpora allata was measured in vitro. High activities were observed in beetles reared with long days and in beetles after emergence. In beetles reared with short days, amounts of hormone produced were intermediate until Day 6 after emergence, thereafter declining to a low value. During diapause, production remained low. The production by corpus allatum and the activity of juvenile hormone esterase were in good agreement with the titre of juvenile hormone. The corpora allata are probably the primary regulator of the hormone titre in the Colorado potato beetle.<p/
Longitudinal evidence of the impact of normal thyroid stimulating hormone variations on cognitive functioning in very old age
No full textThe purpose of this study was to examine longitudinal associations among thyroid stimulating hormone (TSH) levels and cognitive performance. Data collected at the first three assessment times, approximately 3 years apart, are reported for the survivors (n=45) from a previously published cross-sectional study. Participants were aged 75–93 years at baseline, and data reported were collected in the Kungsholmen Project, a longitudinal project investigating aging and dementia. Analyses revealed that although declining verbal fluency and visuospatial abilities were accompanied by simultaneously declining TSH levels, the pattern of cross-sectional and longitudinal results are interpreted such that declining TSH levels may have caused episodic memory deficits later on. These results were obtained in the examination of 6-year but not 3-year change, and after removal of the cognitive variation associated with depressive mood symptoms
Molecular biological studies on neuropeptides of the adipokinetic hormone/red pigment-concentrating hormone family and the neuroparsin family in the arthropod sister groups of insects and crustaceans
No full textIncludes abstract.Includes bibliographical references.This study describes the identification of three novel precursor transcripts which includes the adipokinetic hormone (AKH) / red pigment-concentrating hormone (RPCH) and the neuroparsin (NP) from the South African spiny lobster, Jasus lalandii, the RPCH and the RPCH receptor (RPCHR) from the water flea D. pulex and the NP from the southern green stinkbug, Nezara viridula. The study also investigates the localisation and expression profiles of the AKH/RPCH and NP transcripts within crustaceans and insects
Artificial Hormone Network for Adaptable Robots
Full text linkWith current robotic technologies, it generally remains unreliable to use fully autonomous robots in high-risk robotic applications such as search and rescue, surveillance or exploration in disaster scenarios. One of the main issues comes from the fact that unstructured real-world environments are dynamic and full of interventions. Therefore, for autonomous robots to operate in such environments, the ability to adapt to both internal and external environmental changes is crucial. Being unable to deal with such changes not only could downgrade the performance of the robots but also potentially cause devastating consequences in risky environments. Looking towards nature, it can be observed that biological organisms can cope well with the dynamic unpredictability of real-world environments. One of the key properties which assist biological organisms is the ability to adapt to changing environments by the utilization of hormones in response to environmental cues. This biological feature provides an inspiration for this research which investigates a novel Artificial Hormone Network architecture in providing adaptability for autonomous robots to deal with both internal and external environmental changes in simulations of unstructured real-world environments. The Artificial Hormone Network architecture proposes a new method which allows constructions and interactions of several hormones in order to provide adaptability for autonomous robots in different application scenarios. Two Artificial Hormone Networks (AHN1 and AHN2) are proposed and investigated in this research. Results from experiments correspondingly report better performance in dealing with considered internal and external environmental changes on a robot implemented with the Artificial Hormone Networks than a robot implemented without them. Another important aspect of the Artificial Hormone Network architecture is the ability to be constructed automatically to provide particular adaptability using Cartesian Genetic Programming. Experiment results show that the construction of Artificial Hormone Networks can be evolved and that this evolved system not only performed to a level of adaptability that was acceptable but actually performed better than the “hand-coded” system
Psychological well-being on thyroid hormone replacement
Full text linkDespite 100 years after the discovery of thyroxine, controversy still exists regarding optimal thyroid hormone replacement therapy. Several anecdotal reports suggest that thyroxine alone therapy does not normalise psychological wellbeing. My cross-sectional study (n=1922) provided the first evidence in support of the hypothesis that a small proportion of patients on thyroxine alone therapy have increased psychological morbidity despite having normal TSH (publication 1). My second study was the largest randomised placebo controlled study to date to compare the effects of thyroxine alone and combined T3/T4 therapy over a 12 months period. This categorically proved that thyroxine alone therapy should be the first choice for hypothyroid patients (publication 2). Further genetic analysis of the deiodinase genes showed that a sub-group of hypothyroid patients with an SNP on D2 gene do have reduced psychological wellbeing on thyroxine alone therapy and improve on combined T3/T4 therapy compared to those without (publication 5). Both these findings were shown only by our study and were possible because of the large size (n=700). Detailed analysis of the various thyroid hormones and their ratio from our study showed that in addition to TSH, free T4 should be taken into account when treating hypothyroid patients (publication 4). My pharmacokinetic study provided the crucial and first evidence of the profiles of thyroid hormones on once a day combined T3/T4 therapy, highlighting the need to use either slow-release T3 or multiple doses of T3 in a day (publication 3). Our invited commentary and review (publications 6-8 & 10) have highlighted the importance of “individualised set points” for thyroid hormones, the complexity of thyroid hormone transport and actions as well as an algorithm for approaching hypothyroid patients. My other work (publication 9) was the first to test the possibility and provided the first evidence of deiodinase gene polymorphisms affecting circulating thyroid hormone levels and their possible role in psychological wellbeing in normal population. Thus, my work in the area, “Psychological wellbeing in patients of thyroid hormone replacement therapy” has provided several landmark findings, resulting in 10 publications including 4 in JCEM, 2 in Lancet and 1 in Clinical Endocrinology
Decrease in adiponectin levels correlates to growth response in growth hormone-treated children
No full textBACKGROUND/AIMS: Adiponectin is secreted by adipose tissue and circulates in human plasma at high levels. Decreased adiponectin levels are associated with insulin resistance and obesity. The aim of this study was to investigate whether changes in serum adiponectin levels are related to the growth response, insulin levels and insulin resistance during growth hormone (GH) treatment. METHODS: The study included 94 short prepubertal children (19 girls and 75 boys). The mean age at the start of daily GH injections was 9.04 +/- 2.38 years. Adiponectin levels in serum were measured using an ELISA. RESULTS: At baseline, adiponectin correlated with the first-year growth response (r = 0.26, p = 0.012). Adiponectin decreased significantly after 1 week, 3 months and 1 year from 14.5 +/- 5.71 to 13.1 +/- 5.22 (p < 0.0001), 10.3 +/- 4.82 (p < 0.0001) and 12.5 +/- 5.34 microg/ml (p < 0.0001), respectively. There were significant correlations between the first-year growth response and the decrease in adiponectin levels after 3 months and 1 year (r = -0.38, p < 0.0001 and r = -0.47, p < 0.0001, respectively). No correlations between adiponectin, insulin and the homeostasis model assessment of insulin resistance were seen. CONCLUSIONS: GH treatment in prepubertal children decreases serum adiponectin levels, and the decrease is correlated to the growth response. No correlations between adiponectin and insulin levels or insulin resistance were found
Investigating the role of growth hormone receptor in oesophageal squamous-cell carcinoma.
No full textIncludes abstract.Includes bibliographical references.Squamous-cell carcinoma of the oesophagus is a formidable disease which poses a significant health risk in developing countries where incidence is high and survival is low. Investigating the poorly understood mechanisms involved in oesophageal tumourigenesis may provide a platform to develop improved diagnostic techniques and therapies. The growth hormone (GH) signalling axis is important for proper cellular and organ system function. The axis has been shown to play a role in a number of cancers
Hormone replacement therapy: perspectives from women, medicine and sociology
Full text linkDeveloped on the boundary between medicine and sociology, this thesis develops a critique of the perspectives of these disciplines through analysis of a study of women's perspectives on hormone replacement therapy. Women's perspectives are explored through a postal questionnaire survey and a study using individual interviews and focus groups. The survey results provide a measure of women’s attitudes towards, and knowledge of, hormone replacement therapy. The individual interviews detail the way women move towards a decision about the therapy and identifies common themes, particularly women's fears and what influences their fears. The focus groups explore contrasting themes including women's control and choice in decisions about therapy, contrary themes in women’s attitudes and the different ways of thinking used by the women. The results of the studies are assessed for their implications for clinical general practice. The thesis also takes a sociological perspective on women and HRT and on the research process, in particular exploring two themes. Firstly, the interaction between the social context, the research subject and the research process. This includes the social factors influencing the development of the research and choice of research methods, and the influence of the research methods on the results obtained. The second theme is the perspectives and levels of analysis used by the main disciplines contributing to the thesis; biomedicine, biostatistics, general practice and sociology. The thesis explores how the different perspectives and levels of analysis influence research and how they are used to manage the social context. These explorations are used to suggest future directions for research on hormone replacement therapy and for general practice
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