ORCID Profile
0000-0001-7790-9261
Current Organisation
The University of Edinburgh
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Publisher: Wiley
Date: 22-09-2020
DOI: 10.1111/JNE.12903
Publisher: Public Library of Science (PLoS)
Date: 12-2011
Publisher: Springer Science and Business Media LLC
Date: 15-03-2018
Abstract: A major endeavor of systems biology is the construction of graphical and computational models of biological pathways as a means to better understand their structure and function. Here, we present a protocol for a biologist-friendly graphical modeling scheme that facilitates the construction of detailed network diagrams, summarizing the components of a biological pathway (such as proteins and biochemicals) and illustrating how they interact. These diagrams can then be used to simulate activity flow through a pathway, thereby modeling its dynamic behavior. The protocol is ided into four sections: (i) assembly of network diagrams using the modified Edinburgh Pathway Notation (mEPN) scheme and yEd network editing software with pathway information obtained from published literature and databases of molecular interaction data (ii) parameterization of the pathway model within yEd through the placement of 'tokens' on the basis of the known or imputed amount or activity of a component (iii) model testing through visualization and quantitative analysis of the movement of tokens through the pathway, using the network analysis tool Graphia Professional and (iv) optimization of model parameterization and experimentation. This is the first modeling approach that combines a sophisticated notation scheme for depicting biological events at the molecular level with a Petri net-based flow simulation algorithm and a powerful visualization engine with which to observe the dynamics of the system being modeled. Unlike many mathematical approaches to modeling pathways, it does not require the construction of a series of equations or rate constants for model parameterization. Depending on a model's complexity and the availability of information, its construction can take days to months, and, with refinement, possibly years. However, once assembled and parameterized, a simulation run, even on a large model, typically takes only seconds. Models constructed using this approach provide a means of knowledge management, information exchange and, through the computation simulation of their dynamic activity, generation and testing of hypotheses, as well as prediction of a system's behavior when perturbed.
Publisher: Bioscientifica
Date: 05-2021
DOI: 10.1530/REP-20-0629
Abstract: The epididymis is an androgen-responsive organ, whose structure and functions are modulated by the coordination between androgen and epididymal cues. Highly regulated molecular interaction within the epididymis is required to support viable sperm development necessary for subsequent fertilization. In the present study, we extended our earlier findings on a promising epididymal protein, quiescin sulfhydryl oxidase 2 (QSOX2), and demonstrated a positive correlation between testosterone and QSOX2 protein synthesis through the use of loss- and restore-of-function animal models. Moreover, based on transcriptomic analyses and 2D culture system, we determined that an additional polarized effect of glutamate is indispensable for the regulatory action of testosterone on QSOX2 synthesis. In conclusion, we propose noncanonical testosterone signaling supports epididymal QSOX2 protein synthesis, providing a novel perspective on the regulation of sperm maturation within the epididymis.
Publisher: Springer New York
Date: 2016
DOI: 10.1007/978-1-4939-3724-0_14
Abstract: Conditional gene targeting has revolutionized molecular genetic analysis of nuclear receptor proteins, however development and analysis of such conditional knockouts is far from simple, with many caveats and pitfalls waiting to snare the novice or unprepared. In this chapter, we describe our experience of generating and analyzing mouse models with conditional ablation of the androgen receptor (AR) from tissues of the reproductive system and other organs. The guidance, suggestions, and protocols outlined in the chapter provide the key starting point for analyses of conditional-ARKO mice, completing them as described provides an excellent framework for further focussed project-specific analyses, and applies equally well to analysis of reproductive tissues from any mouse model generated through conditional gene targeting.
Publisher: Elsevier BV
Date: 08-2015
DOI: 10.1016/J.BEEM.2015.04.006
Abstract: Androgens such as testosterone are steroid hormones essential for normal male reproductive development and function. Mutations of androgen receptors (AR) are often found in patients with disorders of male reproductive development, and milder mutations may be responsible for some cases of male infertility. Androgens exert their action through AR and its signalling in the testis is essential for spermatogenesis. AR is not expressed in the developing germ cell lineage so is thought to exert its effects through testicular Sertoli and peri-tubular myoid (PTM) cells. AR signalling in spermatogenesis has been investigated in rodent models where testosterone levels are chemically supressed or models with transgenic disruption of AR. These models have pinpointed the steps of spermatogenesis that require AR signalling, specifically maintenance of spermatogonial numbers, blood-testis barrier integrity, completion of meiosis, adhesion of spermatids and spermiation, together these studies detail the essential nature of androgens in the promotion of male fertility.
Publisher: Cold Spring Harbor Laboratory
Date: 04-04-2016
DOI: 10.1101/047043
Abstract: In silico modelling of biological pathways is a major endeavour of systems biology. Here we present a methodology for construction of pathway models from the literature and other sources using a biologist-friendly graphical modelling system. The pathway notation scheme, called mEPN, is based on the principles of the process diagrams and Petri nets, and facilitates both the graphical representation of complex systems as well as dynamic simulation of their activity. The protocol is ided into four sections: 1) assembly of the pathway in the yEd software package using the mEPN scheme, 2) conversion of the pathway into a computable format, 3) pathway visualisation and in silico simulation using the BioLayout Express 3D software, 4) optimisation of model parameterisation. This method allows reconstruction of any metabolic, signalling and transcriptional pathway as a means of knowledge management, as well as supporting the systems level modelling of their dynamic activity.
Publisher: Springer Science and Business Media LLC
Date: 18-07-2019
DOI: 10.1038/S41598-019-46049-3
Abstract: Androgens are known to be an essential regulator of male health. Androgen receptor (AR) is widely expressed throughout the adrenal cortex, yet the wider role for androgen signalling in the adrenal remains underexplored. To investigate AR-dependent and AR-independent androgen signalling in the adrenal, we used a novel mouse model with a specific ablation of androgen receptor in the adrenal cortex with or without reduction of circulating androgen levels by castration. Our results describe AR expression in the human and mouse adrenal and highlight that the mouse is a viable model to investigate androgen signalling in the adrenal cortex. We show androgen signalling via AR is required for X-zone regression during puberty. Furthermore, cortex measurements define differences in X-zone morphology depending on whether circulating androgens or AR have been removed. We show androgens promote both cortical cell differentiation and apoptosis but are dispensable for the formation of the definitive cortex. Additionally, investigation of aged mice with AR ablation reveals severe cortex disruption, spindle cell hyperplasia and X-zone expansion. The data described herein demonstrates AR-signalling is required to facilitate X-zone regression, cell clearance and to protect against adrenal degeneration during ageing.
Publisher: Wiley
Date: 10-06-2021
DOI: 10.1111/ANDR.13040
Abstract: Circulating prolactin concentration in rodents and humans is sexually dimorphic. Oestrogens are a well‐characterised stimulator of prolactin release. Circulating prolactin fluctuates throughout the menstrual/oestrous cycle of females in response to oestrogen levels, but remains continually low in males. We have previously identified androgens as an inhibitor of prolactin release through characterisation of males of a mouse line with a conditional pituitary androgen receptor knockout (PARKO) which have an increase in circulating prolactin, but unchanged lactotroph number. In the present study, we aimed to specify the cell type that androgens act on to repress prolactin release. PARKO, lactotroph‐specific, Pit1 lineage‐specific and neural‐specific conditional androgen receptor knockout male mice were investigated using prolactin ELISA, pituitary electron microscopy, immunohistochemistry and qRT‐PCR. Lactotroph‐specific, Pit1 lineage‐specific and neural‐specific conditional AR knockouts did not duplicate the high circulating prolactin seen in the PARKO line. Using electron microscopy to examine ultrastructure, we showed that pituitary androgen receptor knockout male mice develop lactotrophs that resemble those seen in female mice. Castrated PARKO males have significantly reduced circulating prolactin compared to intact males. When expression of selected oestrogen‐regulated anterior pituitary genes was examined, there were no differences in expression level between controls and knockouts. The cell type that androgens act on to repress prolactin release is not the lactotroph, cells in the Pit1‐lineage, or the dopaminergic neurons in the hypothalamus. PARKO males develop a female‐specific lactotroph ultrastructure that this is likely to contribute to the increase in circulating prolactin. Castrated PARKO males have significantly reduced circulating prolactin compared to intact males, which suggests that removal of both circulating oestrogens and androgens reduces the stimulation of pituitary prolactin release. Further investigation is needed into prolactin regulation by changes in androgen‐oestrogen balance, which is involved sexual dimorphism of development and diseases including hyperprolactinemia.
Publisher: The Endocrine Society
Date: 22-12-2010
DOI: 10.1210/EN.2010-0928
Abstract: The epididymis plays an essential role in male fertility, and disruption of epididymal function can lead to obstructive azoospermia. Formation and function of the epididymis is androgen-dependent. The androgen receptor (AR) is expressed in both the stromal and epithelial compartments of the epididymis, and androgen action mediated via stromal cells is vital for its normal development and function. However the impact of epithelial specific AR-dependent signaling in the epididymis remains underexplored. To address this, we used conditional gene-targeting in mice to selectively ablate AR from the caput epididymal epithelium, and characterized the resulting phenotype at multiple postnatal ages. Caput epithelium androgen receptor knock-out mice have normal serum testosterone concentrations at day (d) 21 and d100, but do not develop an epididymal initial segment. The remaining caput epithelium displays a significant decrease in epithelial cell height from d11 and lumen diameter from d21 and disruption of the smooth muscle layer of the caput epididymis at d100. From d21, caput epithelium androgen receptor knock-out mice accumulate cell debris, proteinaceous material, and, at later ages, spermatozoa in their efferent ducts, which prevents normal passage of spermatozoa from the testis into the cauda epididymis resulting in infertility when tested at d100. This efferent duct obstruction leads to fluid back-pressure and disruption of the seminiferous epithelium of the adult testis. We conclude that epithelial AR signaling is essential for postnatal development and function of the epididymal epithelium and that disruption of this signaling can contribute to obstructive azoospermia.
Publisher: Springer Science and Business Media LLC
Date: 24-04-2018
Publisher: Proceedings of the National Academy of Sciences
Date: 21-04-2014
Abstract: Men are defined by androgens (testosterone), which drive fetal masculinization (male development) and puberty and maintain masculinity in adulthood, including sex drive, erectile function, and fertility. Moreover, Western cardiometabolic diseases are all associated with lowered testosterone levels in men. Therefore, influences on testosterone levels in adulthood have pervasive importance for masculinity and health. Our study shows, for the first time, to our knowledge, that testosterone levels during fetal masculinization can (re)program adult testosterone levels through effects on stem cells, which develop into adult Leydig cells (the source of testosterone) after puberty. These stem cells are present in fetal testes of humans and animals, and using the latter, we show how these cells are reprogrammed to affect adult testosterone levels.
Publisher: The Company of Biologists
Date: 15-05-2014
DOI: 10.1242/DEV.107029
Abstract: Sertoli cells (SCs) regulate testicular fate in the differentiating gonad and are the main regulators of spermatogenesis in the adult testis however, their role during the intervening period of testis development, in particular during adult Leydig cell (ALC) differentiation and function, remains largely unknown. To examine SC function during fetal and prepubertal development we generated two transgenic mouse models that permit controlled, cell-specific ablation of SCs in pre- and postnatal life. Results show that SCs are required: (1) to maintain the differentiated phenotype of peritubular myoid cells (PTMCs) in prepubertal life (2) to maintain the ALC progenitor population in the postnatal testis and (3) for development of normal ALC numbers. Furthermore, our data show that fetal LCs function independently from SC, germ cell or PTMC support in the prepubertal testis. Together, these findings reveal that SCs remain essential regulators of testis development long after the period of sex determination. These findings have significant implications for our understanding of male reproductive disorders and wider androgen-related conditions affecting male health.
Publisher: Springer Science and Business Media LLC
Date: 03-2019
DOI: 10.1038/S41598-019-39867-Y
Abstract: The hypothalamic-pituitary-adrenal (HPA) axis regulates responses to internal and external stressors. Many patients diagnosed with conditions such as depression or anxiety also have hyperactivity of the HPA axis. Hyper-stimulation of the HPA axis results in sustained elevated levels of glucocorticoids which impair neuronal function and can ultimately result in a psychiatric disorder. Studies investigating Glucocorticoid Receptor (GR/NR3C1) in the brain have primarily focused on the forebrain, however in recent years, the hindbrain has become a region of interest for research into the development of anxiety and depression, though the role of GR signalling in the hindbrain remains poorly characterised. To determine the role of glucocorticoid signalling in the hindbrain we have developed a novel mouse model that specifically ablates hindbrain GR to ascertain its role in behaviour, HPA-axis regulation and adrenal structure. Our study highlights that ablation of GR in the hindbrain results in excessive barbering, obsessive compulsive digging and lack of cage exploration. These mice also develop kyphosis, elevated circulating corticosterone and severe adrenal cortex disruption. Together, this data demonstrates a role for hindbrain GR signalling in regulating stress-related behaviour and identifies a novel mouse model to allow further investigation into the pathways impacting stress and anxiety.
Publisher: Springer Science and Business Media LLC
Date: 21-08-2017
DOI: 10.1038/S41598-017-09016-4
Abstract: The tamoxifen-inducible Cre system is a popular transgenic method for controlling the induction of recombination by Cre at a specific time and in a specific cell type. However, tamoxifen is not an inert inducer of recombination, but an established endocrine disruptor with mixed agonist/antagonist activity acting via endogenous estrogen receptors. Such potentially confounding effects should be controlled for, but % of publications that have used tamoxifen to generate conditional knockouts have not reported even the minimum appropriate controls. To highlight the importance of this issue, the present study investigated the long-term impacts of different doses of a single systemic tamoxifen injection on the testis and the wider endocrine system. We found that a single dose of tamoxifen less than 10% of the mean dose used for recombination induction, caused adverse effects to the testis and to the reproductive endocrine system that persisted long-term. These data raise significant concerns about the widespread use of tamoxifen induction of recombination, and highlight the importance of including appropriate controls in all pathophysiological studies using this means of induction.
Publisher: Wiley
Date: 19-01-2015
DOI: 10.1111/AJI.12363
Abstract: Previous studies demonstrated a strong association between low androgen levels and reduced capacity to mount an inflammatory response. However, the mechanisms underlying these observations are largely not understood. Generation of CD4+CD25+Foxp3+ regulatory T cells in Leydig cell-conditioned media was determined by flow cytometry and ELISA. Influence of testosterone on cytokine response was measured in LPS-stimulated testicular macrophages, Sertoli and peritubular cells. Leydig cell-conditioned media dose-dependently stimulated expression of transcription factor Foxp3 and secretion of IL-10 in splenic CD4+ T cells, an effect abolished by addition of the anti-androgen flutamide. In isolated Sertoli and peritubular cells, testosterone pre-treatment suppressed the LPS-induced inflammatory response on TNF-α mRNA expression, while no effect was evident in testicular macrophages (TM). Androgens can influence the immune system under normal conditions by the generation and functional differentiation of regulatory T cells and in testicular inflammation by direct effect on Sertoli and peritubular cells.
Publisher: Springer Science and Business Media LLC
Date: 09-01-2012
Publisher: Springer Science and Business Media LLC
Date: 17-04-2019
Publisher: Public Library of Science (PLoS)
Date: 23-03-2015
Publisher: Public Library of Science (PLoS)
Date: 03-01-2014
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Laura O'Hara.