Publications by authors named "Ariel Wang"

13 Publications

  • Page 1 of 1

Azithromycin versus standard care in patients with mild-to-moderate COVID-19 (ATOMIC2): an open-label, randomised trial.

Lancet Respir Med 2021 Jul 9. Epub 2021 Jul 9.

Respiratory Medicine Unit and National Institute for Health Research Oxford Biomedical Research Centre, Nuffield Department of Medicine Experimental Medicine, University of Oxford, Oxford, UK.

Background: The antibacterial, anti-inflammatory, and antiviral properties of azithromycin suggest therapeutic potential against COVID-19. Randomised data in mild-to-moderate disease are not available. We assessed whether azithromycin is effective in reducing hospital admission in patients with mild-to-moderate COVID-19.

Methods: This prospective, open-label, randomised superiority trial was done at 19 hospitals in the UK. We enrolled adults aged at least 18 years presenting to hospitals with clinically diagnosed, highly probable or confirmed COVID-19 infection, with fewer than 14 days of symptoms, who were considered suitable for initial ambulatory management. Patients were randomly assigned (1:1) to azithromycin (500 mg once daily orally for 14 days) plus standard care or to standard care alone. The primary outcome was death or hospital admission from any cause over the 28 days from randomisation. The primary and safety outcomes were assessed according to the intention-to-treat principle. This trial is registered at ClinicalTrials.gov (NCT04381962) and recruitment is closed.

Findings: 298 participants were enrolled from June 3, 2020, to Jan 29, 2021. Three participants withdrew consent and requested removal of all data, and three further participants withdrew consent after randomisation, thus, the primary outcome was assessed in 292 participants (145 in the azithromycin group and 147 in the standard care group). The mean age of the participants was 45·9 years (SD 14·9). 15 (10%) participants in the azithromycin group and 17 (12%) in the standard care group were admitted to hospital or died during the study (adjusted OR 0·91 [95% CI 0·43-1·92], p=0·80). No serious adverse events were reported.

Interpretation: In patients with mild-to-moderate COVID-19 managed without hospital admission, adding azithromycin to standard care treatment did not reduce the risk of subsequent hospital admission or death. Our findings do not support the use of azithromycin in patients with mild-to-moderate COVID-19.

Funding: National Institute for Health Research Oxford Biomedical Research Centre, University of Oxford and Pfizer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S2213-2600(21)00263-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8270523PMC
July 2021

Multimodal imaging interpreted by graders to detect re-activation of diabetic eye disease in previously treated patients: the EMERALD diagnostic accuracy study.

Health Technol Assess 2021 May;25(32):1-104

Warwick Medical School, University of Warwick, Coventry, UK.

Background: Owing to the increasing prevalence of diabetes, the workload related to diabetic macular oedema and proliferative diabetic retinopathy is rising, making it difficult for hospital eye services to meet demands.

Objective: The objective was to evaluate the diagnostic performance, cost-effectiveness and acceptability of a new pathway using multimodal imaging interpreted by ophthalmic graders to detect reactivation of diabetic macular oedema/proliferative diabetic retinopathy in previously treated patients.

Design: This was a prospective, case-referent, cross-sectional diagnostic study.

Setting: The setting was ophthalmic clinics in 13 NHS hospitals.

Participants: Adults with type 1 or type 2 diabetes with previously successfully treated diabetic macular oedema/proliferative diabetic retinopathy in one/both eyes in whom, at the time of enrolment, diabetic macular oedema/proliferative diabetic retinopathy could be active or inactive.

Methods: For the ophthalmic grader pathway, review of the spectral domain optical coherence tomography scans to detect diabetic macular oedema, and seven-field Early Treatment Diabetic Retinopathy Study/ultra-wide field fundus images to detect proliferative diabetic retinopathy, by trained ophthalmic graders. For the current standard care pathway (reference standard), ophthalmologists examined patients face to face by slit-lamp biomicroscopy for proliferative diabetic retinopathy and, in addition, spectral domain optical coherence tomography imaging for diabetic macular oedema.

Outcome Measures: The primary outcome measure was sensitivity of the ophthalmic grader pathway to detect active diabetic macular oedema/proliferative diabetic retinopathy. The secondary outcomes were specificity, agreement between pathways, cost-consequences, acceptability and the proportion of patients requiring subsequent ophthalmologist assessment, unable to undergo imaging and with inadequate quality images/indeterminate findings. It was assumed for the main analysis that all patients in whom graders diagnosed active disease or were 'unsure' or images were 'ungradable' required examination by an ophthalmologist.

Results: Eligible participants with active and inactive diabetic macular oedema (152 and 120 participants, respectively) and active and inactive proliferative diabetic retinopathy (111 and 170 participants, respectively) were recruited. Under the main analysis, graders had a sensitivity of 97% (142/147) (95% confidence interval 92% to 99%) and specificity of 31% (35/113) (95% confidence interval 23% to 40%) to detect diabetic macular oedema. For proliferative diabetic retinopathy, graders had a similar sensitivity and specificity using seven-field Early Treatment Diabetic Retinopathy Study [sensitivity 85% (87/102), 95% confidence interval 77% to 91%; specificity 48% (77/160), 95% confidence interval 41% to 56%] or ultra-wide field imaging [sensitivity 83% (87/105), 95% confidence interval 75% to 89%; specificity 54% (86/160), 95% confidence interval 46% to 61%]. Participants attending focus groups expressed preference for face-to-face evaluations by ophthalmologists. In the ophthalmologists' absence, patients voiced the need for immediate feedback following grader's assessments, maintaining periodic evaluations by ophthalmologists. Graders and ophthalmologists were supportive of the new pathway. When compared with the reference standard (current standard pathway), the new grader pathway could save £1390 per 100 patients in the review of people with diabetic macular oedema and, depending on the imaging modality used, between £461 and £1189 per 100 patients in the review of people with proliferative diabetic retinopathy.

Conclusions: For people with diabetic macular oedema, the ophthalmic grader pathway appears safe and cost saving. The sensitivity of the new pathway to detect active proliferative diabetic retinopathy was lower, but may still be considered acceptable for patients with proliferative diabetic retinopathy previously treated with laser. Suggestions from focus group discussions should be taken into consideration if the new pathway is introduced to ensure its acceptability to users.

Limitations: Lack of fundus fluorescein angiography to confirm diagnosis of active proliferative diabetic retinopathy.

Future Work: Could refinement of the new pathway increase its sensitivity to detect proliferative diabetic retinopathy? Could artificial intelligence be used for automated reading of images in this previously treated population?

Trial Registration: Current Controlled Trials ISRCTN10856638 and ClinicalTrials.gov NCT03490318.

Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Vol. 25, No. 32. See the NIHR Journals Library website for further project information.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3310/hta25320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8200933PMC
May 2021

Study of Peri-Articular Anaesthetic for Replacement of the Knee (SPAARK): statistical analysis plan for a randomised controlled trial assessing the effectiveness of peri-articular liposomal bupivacaine plus bupivacaine hydrochloride compared with bupivacaine hydrochloride alone.

Trials 2021 May 17;22(1):346. Epub 2021 May 17.

Oxford Clinical Trials Research Unit, Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Windmill Road, Oxford, OX3 7LD, UK.

Background: Up to three quarters of surgical patients receive inadequate pain relief, with 40% of patients reporting severe pain following knee replacement, which may indicate the current pain relief strategies using opiate-based analgesia cannot achieve patient satisfaction. Liposomal bupivacaine is liposome-encapsulated bupivacaine which has been reported to be effective for up to 72 h. The study of Peri-Articular Anaesthetic for Replacement of the Knee (SPAARK) trial has been designed to assess the effectiveness of peri-articular liposomal bupivacaine and bupivacaine hydrochloride compared with peri-articular bupivacaine hydrochloride alone in the management of post-operative pain following knee replacement.

Methods/design: The SPAARK trial is a multi-centre, patient-blinded, randomised controlled trial. The co-primary outcomes are post-operative recovery assessed by global QoR-40 scores at 72 h and cumulative pain VAS score from 6 to 72 h following surgery. Longer-term measures of the co-primary outcomes are collected at 6 weeks and 6 and 12 months post randomisation, together with secondary outcomes, i.e. the Oxford Knee Score, and the American Knee Society Score. Cumulative opiate use and fitness for discharge are measured up to 72 h post-surgery. The analysis approaches for the primary and secondary outcomes are described here, as are the descriptive statistics which will be reported. The full SPAARK protocol has already been published.

Results: The co-primary outcomes will be analysed using multivariate linear regression adjusting for stratification factors and other important prognostic variables, including baseline scores in the case of the QoR-40. The adjusted mean difference between the two groups together with 97.5% confidence intervals will be reported for each of the primary outcomes. Other continuous variables will be assessed using the same method. Binary outcomes will be assessed using chi-squared tests.

Discussion: The paper provides details of the planned statistical analyses for the SPAARK trial and aims to reduce the risk of outcome reporting bias from prior data knowledge. Any changes or deviations from this statistical analysis plan will be described and justified in the final study report.

Trial Registration: ISRCTN54191675 . Registered on 13 November 2017.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13063-021-05293-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8127239PMC
May 2021

Substrate Stiffness and Stretch Regulate Profibrotic Mechanosignaling in Pulmonary Arterial Adventitial Fibroblasts.

Cells 2021 Apr 23;10(5). Epub 2021 Apr 23.

Department of Bioengineering, University of California San Diego, La Jolla, CA 92093-0412, USA.

Pulmonary arterial adventitial fibroblasts (PAAFs) are important regulators of fibrotic vascular remodeling during the progression of pulmonary arterial hypertension (PAH), a disease that currently has no effective anti-fibrotic treatments. We conducted in-vitro experiments in PAAFs cultured on hydrogels attached to custom-made equibiaxial stretchers at 10% stretch and substrate stiffnesses representing the mechanical conditions of mild and severe stages of PAH. The expression of collagens α(1)I and α(1)III and elastin messenger RNAs (, , ) were upregulated by increased stretch and substrate stiffness, while lysyl oxidase-like 1 and α-smooth muscle actin messenger RNAs (, ) were only significantly upregulated when the cells were grown on matrices with an elevated stiffness representative of mild PAH but not on a stiffness representative of severe PAH. Fibronectin messenger RNA () levels were significantly induced by increased substrate stiffness and transiently upregulated by stretch at 4 h, but was not significantly altered by stretch at 24 h. We modified our published computational network model of the signaling pathways that regulate profibrotic gene expression in PAAFs to allow for differential regulation of mechanically-sensitive nodes by stretch and stiffness. When the model was modified so that stiffness activated integrin β, the Macrophage Stimulating 1 or 2 (MST1\2) kinases, angiotensin II (Ang II), transforming growth factor-β (TGF-β), and syndecan-4, and stretch-regulated integrin β, MST1\2, Ang II, and the transient receptor potential (TRP) channel, the model correctly predicted the upregulation of all six genes by increased stiffness and the observed responses to stretch in five out of six genes, although it could not replicate the non-monotonic effects of stiffness on and expression. Blocking Ang II Receptor Type 1 (ATR) with losartan in-vitro uncovered an interaction between the effects of stretch and stiffness and angiotensin-independent activation of expression by stretch in PAAFs grown on 3-kPa matrices. This novel combination of in-vitro and in-silico models of PAAF profibrotic cell signaling in response to altered mechanical conditions may help identify regulators of vascular adventitial remodeling due to changes in stretch and matrix stiffness that occur during the progression of PAH in-vivo.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cells10051000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8146344PMC
April 2021

Evaluation of a New Model of Care for People with Complications of Diabetic Retinopathy: The EMERALD Study.

Ophthalmology 2021 04 31;128(4):561-573. Epub 2020 Oct 31.

Warwick Medical School, University of Warwick, Coventry, United Kingdom.

Purpose: The increasing diabetes prevalence and advent of new treatments for its major visual-threatening complications (diabetic macular edema [DME] and proliferative diabetic retinopathy [PDR]), which require frequent life-long follow-up, have increased hospital demands markedly. Subsequent delays in patient's evaluation and treatment are causing sight loss. Strategies to increase capacity are needed urgently. The retinopathy (EMERALD) study tested diagnostic accuracy, acceptability, and costs of a new health care pathway for people with previously treated DME or PDR.

Design: Prospective, multicenter, case-referent, cross-sectional, diagnostic accuracy study undertaken in 13 hospitals in the United Kingdom.

Participants: Adults with type 1 or 2 diabetes previously successfully treated DME or PDR who, at the time of enrollment, had active or inactive disease.

Methods: A new health care pathway entailing multimodal imaging (spectral-domain OCT for DME, and 7-field Early Treatment Diabetic Retinopathy Study [ETDRS] and ultra-widefield [UWF] fundus images for PDR) interpreted by trained nonmedical staff (ophthalmic graders) to detect reactivation of disease was compared with the current standard care (face-to-face examination by ophthalmologists).

Main Outcome Measures: Primary outcome: sensitivity of the new pathway.

Secondary Outcomes: specificity; agreement between pathways; costs; acceptability; proportions requiring subsequent ophthalmologist assessment, unable to undergo imaging, and with inadequate images or indeterminate findings.

Results: The new pathway showed sensitivity of 97% (95% confidence interval [CI], 92%-99%) and specificity of 31% (95% CI, 23%-40%) to detect DME. For PDR, sensitivity and specificity using 7-field ETDRS images (85% [95% CI, 77%-91%] and 48% [95% CI, 41%-56%], respectively) or UWF images (83% [95% CI, 75%-89%] and 54% [95% CI, 46%-61%], respectively) were comparable. For detection of high-risk PDR, sensitivity and specificity were higher when using UWF images (87% [95% CI, 78%-93%] and 49% [95% CI, 42%-56%], respectively, for UWF versus 80% [95% CI, 69-88%] and 40% [95% CI, 34%-47%], respectively, for 7-field ETDRS images). Participants preferred ophthalmologists' assessments; in their absence, they preferred immediate feedback by graders, maintaining periodic ophthalmologist evaluations. When compared with the current standard of care, the new pathway could save £1390 per 100 DME visits and between £461 and £1189 per 100 PDR visits.

Conclusions: The new pathway has acceptable sensitivity and would release resources. Users' suggestions should guide implementation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ophtha.2020.10.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7980088PMC
April 2021

Quantification of uncertainty in a new network model of pulmonary arterial adventitial fibroblast pro-fibrotic signalling.

Philos Trans A Math Phys Eng Sci 2020 Jun 25;378(2173):20190338. Epub 2020 May 25.

Department of Bioengineering, University of California San Diego, La Jolla, CA 92092, USA.

Here, we present a novel network model of the pulmonary arterial adventitial fibroblast (PAAF) that represents seven signalling pathways, confirmed to be important in pulmonary arterial fibrosis, as 92 reactions and 64 state variables. Without optimizing parameters, the model correctly predicted 80% of 39 results of input-output and inhibition experiments reported in 20 independent papers not used to formulate the original network. Parameter uncertainty quantification (UQ) showed that this measure of model accuracy is robust to changes in input weights and half-maximal activation levels (EC), but is more affected by uncertainty in the Hill coefficient (), which governs the biochemical cooperativity or steepness of the sigmoidal activation function of each state variable. Epistemic uncertainty in model structure, due to the reliance of some network components and interactions on experiments using non-PAAF cell types, suggested that this source of uncertainty had a smaller impact on model accuracy than the alternative of reducing the network to only those interactions reported in PAAFs. UQ highlighted model parameters that can be optimized to improve prediction accuracy and network modules where there is the greatest need for new experiments. This article is part of the theme issue 'Uncertainty quantification in cardiac and cardiovascular modelling and simulation'.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1098/rsta.2019.0338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7287331PMC
June 2020

Quantification of model and data uncertainty in a network analysis of cardiac myocyte mechanosignalling.

Philos Trans A Math Phys Eng Sci 2020 Jun 25;378(2173):20190336. Epub 2020 May 25.

Department of Bioengineering, University of California San Diego, La Jolla, CA 92093, USA.

Cardiac myocytes transduce changes in mechanical loading into cellular responses via interacting cell signalling pathways. We previously reported a logic-based ordinary differential equation model of the myocyte mechanosignalling network that correctly predicts 78% of independent experimental results not used to formulate the original model. Here, we use Monte Carlo and polynomial chaos expansion simulations to examine the effects of uncertainty in parameter values, model logic and experimental validation data on the assessed accuracy of that model. The prediction accuracy of the model was robust to parameter changes over a wide range being least sensitive to uncertainty in time constants and most affected by uncertainty in reaction weights. Quantifying epistemic uncertainty in the reaction logic of the model showed that while replacing 'OR' with 'AND' reactions greatly reduced model accuracy, replacing 'AND' with 'OR' reactions was more likely to maintain or even improve accuracy. Finally, data uncertainty had a modest effect on assessment of model accuracy. This article is part of the theme issue 'Uncertainty quantification in cardiac and cardiovascular modelling and simulation'.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1098/rsta.2019.0336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7287329PMC
June 2020

Syndecan-4 Protects the Heart From the Profibrotic Effects of Thrombin-Cleaved Osteopontin.

J Am Heart Assoc 2020 02 31;9(3):e013518. Epub 2020 Jan 31.

Institute for Experimental Medical Research Oslo University Hospital and University of Oslo Norway.

Background Pressure overload of the heart occurs in patients with hypertension or valvular stenosis and induces cardiac fibrosis because of excessive production of extracellular matrix by activated cardiac fibroblasts. This initially provides essential mechanical support to the heart, but eventually compromises function. Osteopontin is associated with fibrosis; however, the underlying signaling mechanisms are not well understood. Herein, we examine the effect of thrombin-cleaved osteopontin on fibrosis in the heart and explore the role of syndecan-4 in regulating cleavage of osteopontin. Methods and Results Osteopontin was upregulated and cleaved by thrombin in the pressure-overloaded heart of mice subjected to aortic banding. Cleaved osteopontin was higher in plasma from patients with aortic stenosis receiving crystalloid compared with blood cardioplegia, likely because of less heparin-induced inhibition of thrombin. Cleaved osteopontin and the specific osteopontin peptide sequence RGDSLAYGLR that is exposed after thrombin cleavage both induced collagen production in cardiac fibroblasts. Like osteopontin, the heparan sulfate proteoglycan syndecan-4 was upregulated after aortic banding. Consistent with a heparan sulfate binding domain in the osteopontin cleavage site, syndecan-4 was found to bind to osteopontin in left ventricles and cardiac fibroblasts and protected osteopontin from cleavage by thrombin. Shedding of the extracellular part of syndecan-4 was more prominent at later remodeling phases, at which time levels of cleaved osteopontin were increased. Conclusions Thrombin-cleaved osteopontin induces collagen production by cardiac fibroblasts. Syndecan-4 protects osteopontin from cleavage by thrombin, but this protection is lost when syndecan-4 is shed in later phases of remodeling, contributing to progression of cardiac fibrosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/JAHA.119.013518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033859PMC
February 2020

The prevalence of personality disorders in the community: a global systematic review and meta-analysis.

Br J Psychiatry 2020 02;216(2):69-78

Associate Clinical Professor of Forensic Psychiatry, Division of Mental Health and Wellbeing, Warwick Medical School, University of Warwick, UK.

Background: Personality disorders are now internationally recognised as a mental health priority. Nevertheless, there are no systematic reviews examining the global prevalence of personality disorders.

Aims: To calculate the worldwide prevalence of personality disorders and examine whether rates vary between high-income countries and low- and middle-income countries (LMICs).

Method: We systematically searched PsycINFO, MEDLINE, EMBASE and PubMed from January 1980 to May 2018 to identify articles reporting personality disorder prevalence rates in community populations (PROSPERO registration number: CRD42017065094).

Results: A total of 46 studies (from 21 different countries spanning 6 continents) satisfied inclusion criteria. The worldwide pooled prevalence of any personality disorder was 7.8% (95% CI 6.1-9.5). Rates were greater in high-income countries (9.6%, 95% CI 7.9-11.3%) compared with LMICs (4.3%, 95% CI 2.6-6.1%). In univariate meta-regressions, significant heterogeneity was partly attributable to study design (two-stage v. one-stage assessment), county income (high-income countries v. LMICs) and interview administration (clinician v. trained graduate). In multiple meta-regression analysis, study design remained a significant predictor of heterogeneity. Global rates of cluster A, B and C personality disorders were 3.8% (95% CI 3.2, 4.4%), 2.8% (1.6, 3.7%) and 5.0% (4.2, 5.9%).

Conclusions: Personality disorders are prevalent globally. Nevertheless, pooled prevalence rates should be interpreted with caution due to high levels of heterogeneity. More large-scale studies with standardised methodologies are now needed to increase our understanding of population needs and regional variations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1192/bjp.2019.166DOI Listing
February 2020

Genetically encoded sensors of protein hydrodynamics and molecular proximity.

Proc Natl Acad Sci U S A 2015 May 30;112(20):E2569-74. Epub 2015 Apr 30.

Department of Bioengineering, University of California, Berkeley, CA 94720; Lawrence Berkeley National Laboratory, Berkeley, CA 94720;

The specialized light organ of the ponyfish supports the growth of the bioluminescent symbiont Photobacterium leiognathi. The bioluminescence of P. leiognathi is generated within a heteromeric protein complex composed of the bacterial luciferase and a 20-kDa lumazine binding protein (LUMP), which serves as a Förster resonance energy transfer (FRET) acceptor protein, emitting a cyan-colored fluorescence with an unusually long excited state lifetime of 13.6 ns. The long fluorescence lifetime and small mass of LUMP are exploited for the design of highly optimized encoded sensors for quantitative fluorescence anisotropy (FA) measurements of protein hydrodynamics. In particular, large differences in the FA values of the free and target-bound states of LUMP fusions appended with capture sequences of up to 20 kDa are used in quantitative FA imaging and analysis of target proteins. For example, a fusion protein composed of LUMP and a 5-kDa G protein binding domain is used as an FA sensor to quantify the binding of the GTP-bound cell division control protein 42 homolog (Cdc42) (21 kDa) in solution and within Escherichia coli. Additionally, the long fluorescence lifetime and the surface-bound fluorescent cofactor 6,7-dimethyl-8- (1'-dimethyl-ribityl) lumazine in LUMP are utilized in the design of highly optimized FRET probes that use Venus as an acceptor probe. The efficiency of FRET in a zero-length LUMP-Venus fusion is 62% compared to ∼ 31% in a related CFP-Venus fusion. The improved FRET efficiency obtained by using LUMP as a donor probe is used in the design of a FRET-optimized genetically encoded LUMP-Venus substrate for thrombin.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.1424021112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4443326PMC
May 2015

RNA interference of gonadotropin-inhibitory hormone gene induces arousal in songbirds.

PLoS One 2012 18;7(1):e30202. Epub 2012 Jan 18.

Department of Integrative Biology and Helen Wills Neuroscience Institute, University of California, Berkeley, California, United States of America.

Gonadotropin-inhibitory hormone (GnIH) was originally identified in quail as a hypothalamic neuropeptide inhibitor of pituitary gonadotropin synthesis and release. However, GnIH neuronal fibers do not only terminate in the median eminence to control anterior pituitary function but also extend widely in the brain, suggesting it has multiple roles in the regulation of behavior. To identify the role of GnIH neurons in the regulation of behavior, we investigated the effect of RNA interference (RNAi) of the GnIH gene on the behavior of white-crowned sparrows, a highly social songbird species. Administration of small interfering RNA against GnIH precursor mRNA into the third ventricle of male and female birds reduced resting time, spontaneous production of complex vocalizations, and stimulated brief agonistic vocalizations. GnIH RNAi further enhanced song production of short duration in male birds when they were challenged by playbacks of novel male songs. These behaviors resembled those of breeding birds during territorial defense. The overall results suggest that GnIH gene silencing induces arousal. In addition, the activities of male and female birds were negatively correlated with GnIH mRNA expression in the paraventricular nucleus. Density of GnIH neuronal fibers in the ventral tegmental area was decreased by GnIH RNAi treatment in female birds, and the number of gonadotropin-releasing hormone neurons that received close appositions of GnIH neuronal fiber terminals was negatively correlated with the activity of male birds. In summary, GnIH may decrease arousal level resulting in the inhibition of specific motivated behavior such as in reproductive contexts.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0030202PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3261185PMC
July 2012

Gonadotropin-inhibitory hormone identification, cDNA cloning, and distribution in rhesus macaque brain.

J Comp Neurol 2009 Dec;517(6):841-55

Department of Integrative Biology, University of California, Berkeley, CA 94720-3140, USA.

Gonadotropin-inhibitory hormone (GnIH) is a hypothalamic neuropeptide that modulates the reproductive physiology of birds and mammals by inhibiting gonadotropin secretion from the anterior pituitary gland. GnIH can also directly inhibit reproductive behaviors, possibly via action within the brain. Identification of the distribution of GnIH neurons and fibers may provide us with clues to how the brain controls reproductive activities of the animal. Here, we characterized the location and connectivity of GnIH neurons in the rhesus macaque (Macaca mulatta) brain. We determined the macaque GnIH precursor mRNA, and further identified a mature GnIH peptide (SGRNMEVSLVRQVLNLPQRF-NH(2)) by mass spectrometry combined with immunoaffinity purification. The majority of GnIH precursor mRNA-positive and GnIH-immunoreactive (GnIH-ir) cell bodies were localized in the intermediate periventricular nucleus (IPe) in the hypothalamus, as determined by in situ hybridization and immunocytochemistry, respectively. Abundant GnIH-ir fibers were observed in the nucleus of the stria terminalis in the telencephalon; habenular nucleus, paraventricular nucleus of the thalamus, preoptic area, paraventricular nucleus of the hypothalamus, IPe, arcuate nucleus of hypothalamus, median eminence and dorsal hypothalamic area in the diencephalon; medial region of the superior colliculus, central gray substance of the midbrain and dorsal raphe nucleus in the midbrain; and parabrachial nucleus in the pons. GnIH-ir fibers were observed in close proximity to gonadotropin-releasing hormone-I, dopamine, beta-endorphin, and gonadotropin-releasing hormone-II neurons in the preoptic area, IPe, arcuate nucleus of hypothalamus, and central gray substance of midbrain, respectively. GnIH neurons might thus regulate several neural systems in addition to pituitary gonadotropin release.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cne.22191DOI Listing
December 2009

Identification of European starling GnRH-I precursor mRNA and its seasonal regulation.

Gen Comp Endocrinol 2009 Jul 10;162(3):301-6. Epub 2009 Apr 10.

Department of Integrative Biology and Helen Wills Neuroscience Institute, University of California at Berkeley, 3060 Valley Life Sciences Building #3140, Berkeley, CA 94720-3140, USA.

Songbirds show dynamic seasonal changes in their reproductive activities during the year. Gonadotropin-releasing hormone-I (GnRH-I) is critical for the control of reproduction in vertebrates. The molecular mechanisms controlling reproduction are not well understood in songbirds, largely because the GnRH-I precursor polypeptide gene was unknown until now. Here, we report the complete sequence and seasonal regulation of GnRH-I precursor polypeptide mRNA in a songbird, European starling (Sturnus vulgaris). The translated starling GnRH-I precursor polypeptide contained an amino acid sequence that can be processed into chicken GnRH-I peptide (pEHWSYGLQPG-NH(2)). However, the overall homology of GnRH-I precursor polypeptide (including a 23 amino acid signal peptide, the decapeptide hormone and Gly-Lys-Arg cleavage site followed by 55 amino acid GnRH-associated peptide sequences) between starling and chicken was only 58%. GnRH-I mRNA and GnRH-I peptide were observed to be co-localized in the preoptic area of sexually mature birds using in situ hybridization and immunocytochemistry. GnRH-I mRNA exhibited large variance in photosensitive birds, and converged to a high level in photostimulated birds. Subsequently, GnRH-I mRNA decreased to below detectability in most of the photorefractory birds. Changes were also observed in GnRH-I peptide levels, although changes in GnRH-I peptide were not as marked. Our data indicate that GnRH-I mRNA synthesis commences but is variable in photosensitive birds, stabilizes in photostimulated birds, then ceases when birds become photorefractory. Finer-scale investigation into temporal regulation of GnRH-I precursor polypeptide mRNA will provide insight into its regulation by environmental, social and physiological cues.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ygcen.2009.04.001DOI Listing
July 2009
-->