Androgen receptor signalling in Vascular Endothelial cells is dispensable for spermatogenesis and male fertility

<p>Abstract</p> <p>Background</p> <p>Androgen signalling is essential both for male development and function of the male reproductive system in adulthood. Within the adult testis, Germ cells (GC) do not express androgen receptor (AR) suggesting androgen-mediated promotion of spermatogenesis must act via AR-expressing somatic cell-types. Several recent studies have exploited the Cre/lox system of conditional gene-targeting to ablate AR function from key somatic cell-types in order to establish the cell-specific role of AR in promotion of male fertility. In this study, we have used a similar approach to specifically ablate AR-signalling from Vascular Endothelial (VE) cells, with a view to defining the significance of androgen signalling within this cell-type on spermatogenesis.</p> <p>Findings</p> <p>AR expression in VE cells of the testicular vasculature was confirmed using an antibody against AR. A Cre-inducible fluorescent reporter line was used to empirically establish the utility of a mouse line expressing Cre Recombinase driven by the Tie2-Promoter, for targeting VE cells. Immunofluorescent detection revealed expression of YFP (and therefore Cre Recombinase function) limited to VE cells and an interstitial population of cells, believed to be macrophages, that did not express AR. Mating of Tie2-Cre males to females carrying a floxed AR gene produced Vascular Endothelial Androgen Receptor Knockout (VEARKO) mice and littermate controls. Ablation of AR from all VE cells was confirmed; however, no significant differences in bodyweight or reproductive tissue weights could be detected in VEARKO animals and spermatogenesis and fertility was unaffected.</p> <p>Conclusions</p> <p>We demonstrate the successful generation and empirical validation of a cell-specific knockout of AR from VE cells, and conclude that AR expression in VE cells is not essential for spermatogenesis or male fertility.</p

The global field of multi-family offices: An institutionalist perspective

We apply the notion of the organisational field to internationally operating multi-family offices. These organisations specialise on the preservation of enterprising and geographically dispersed families’ fortunes. They provide their services across generations and countries. Based on secondary data of Bloomberg’s Top 50 Family Offices, we show that they constitute a global organisational field that comprises two clusters of homogeneity. Clients may decide between two different configurations of activities, depending on their preferences regarding asset management, resource management, family management, and service architecture. The findings also reveal that multi-family offices make relatively similar value propositions all over the world. The distinctiveness of the clusters within the field is not driven by the embeddedness of the multi-family offices in different national environments or their various degrees of international experience. Rather, it is weakly affected by two out of four possible value propositions, namely the exclusiveness and the transparency of services

Why is it so hard to enact responsible change?: Scientists need to work more closely with other social groups to implement sustainable innovation

This is the final version. Available on open access from EMBO Press via the DOI in this record. Biotechnology and Biological Sciences Research Council (BBSRC)UK Research and Innovation | Engineering and Physical Sciences Research Council (EPSRC)Wellcome Trus

Memory consolidation in the cerebellar cortex

Several forms of learning, including classical conditioning of the eyeblink, depend upon the cerebellum. In examining mechanisms of eyeblink conditioning in rabbits, reversible inactivations of the control circuitry have begun to dissociate aspects of cerebellar cortical and nuclear function in memory consolidation. It was previously shown that post-training cerebellar cortical, but not nuclear, inactivations with the GABA(A) agonist muscimol prevented consolidation but these findings left open the question as to how final memory storage was partitioned across cortical and nuclear levels. Memory consolidation might be essentially cortical and directly disturbed by actions of the muscimol, or it might be nuclear, and sensitive to the raised excitability of the nuclear neurons following the loss of cortical inhibition. To resolve this question, we simultaneously inactivated cerebellar cortical lobule HVI and the anterior interpositus nucleus of rabbits during the post-training period, so protecting the nuclei from disinhibitory effects of cortical inactivation. Consolidation was impaired by these simultaneous inactivations. Because direct application of muscimol to the nuclei alone has no impact upon consolidation, we can conclude that post-training, consolidation processes and memory storage for eyeblink conditioning have critical cerebellar cortical components. The findings are consistent with a recent model that suggests the distribution of learning-related plasticity across cortical and nuclear levels is task-dependent. There can be transfer to nuclear or brainstem levels for control of high-frequency responses but learning with lower frequency response components, such as in eyeblink conditioning, remains mainly dependent upon cortical memory storage

The 'At-risk mental state' for psychosis in adolescents : clinical presentation, transition and remission.

Despite increased efforts over the last decade to prospectively identify individuals at ultra-high risk of developing a psychotic illness, limited attention has been specifically directed towards adolescent populations (<18 years). In order to evaluate how those under 18 fulfilling the operationalised criteria for an At-Risk Mental State (ARMS) present and fare over time, we conducted an observational study. Participants (N = 30) generally reported a high degree of functional disability and frequent and distressing perceptual disturbance, mainly in the form of auditory hallucinations. Seventy percent (21/30) were found to fulfil the criteria for a co-morbid ICD-10 listed mental health disorder, with mood (affective; 13/30) disorders being most prevalent. Overall transition rates to psychosis were low at 24 months follow-up (2/28; 7.1 %) whilst many participants demonstrated a significant reduction in psychotic-like symptoms. The generalisation of these findings may be limited due to the small sample size and require replication in a larger sample

A pragmatic randomised controlled trial of the Welsh National Exercise Referral Scheme: protocol for trial and integrated economic and process evaluation

Background: The benefits to health of a physically active lifestyle are well established and there is evidence that a sedentary lifestyle plays a significant role in the onset and progression of chronic disease. Despite a recognised need for effective public health interventions encouraging sedentary people with a medical condition to become more active, there are few rigorous evaluations of their effectiveness. Following NICE guidance, the Welsh national exercise referral scheme was implemented within the context of a pragmatic randomised controlled trial. Methods/Design: The randomised controlled trial, with nested economic and process evaluations, recruited 2,104 inactive men and women aged 16+ with coronary heart disease (CHD) risk factors and/or mild to moderate depression, anxiety or stress. Participants were recruited from 12 local health boards in Wales and referred directly by health professionals working in a range of health care settings. Consenting participants were randomised to either a 16 week tailored exercise programme run by qualified exercise professionals at community sports centres (intervention), or received an information booklet on physical activity (control). A range of validated measures assessing physical activity, mental health, psycho-social processes and health economics were administered at 6 and 12 months, with the primary 12 month outcome measure being 7 day Physical Activity Recall. The process evaluation explored factors determining the effectiveness or otherwise of the scheme, whilst the economic evaluation determined the relative cost-effectiveness of the scheme in terms of public spending. Discussion: Evaluation of such a large scale national public health intervention presents methodological challenges in terms of trial design and implementation. This study was facilitated by early collaboration with social research and policy colleagues to develop a rigorous design which included an innovative approach to patient referral and trial recruitment, a comprehensive process evaluation examining intervention delivery and an integrated economic evaluation. This will allow a unique insight into the feasibility, effectiveness and cost effectiveness of a national exercise referral scheme for participants with CHD risk factors or mild to moderate anxiety, depression, or stress and provides a potential model for future policy evaluations. Trial registration: Current Controlled Trials ISRCTN4768044

Midlands Cadences: Narrative Voices in the Work of Alan Sillitoe

This paper will examine excerpts from a range of Alan Sillitoe’s prose fiction, most notably Saturday Night and Sunday Morning (1958) and short stories from the collection The Loneliness of the Long-Distance Runner (1958), via a comparative exploration of the texts’ representations of Midlands English demotic. Both texts enact Bakhtin’s notion of novelistic dialogism and find much expressive capital in the tension between discourses: between the oral and the written. Indeed, it could be argued that much of Sillitoe’s work functions as a direct challenge to dominant notions of the literary. The narrative discourse attempts to trace a link between the quotidian experience of the Midlands English working classes represented and the demotic language which they speak. His technique also explores the link between language and sensibility; i.e. verbal articulacy need not be a limit to expression of a character’s distinctive identity. In contrast to the more radical techniques of novelists like James Kelman and Irvine Welsh, all instances of phonetically-rendered demotic remain imprisoned by what Joyce called ‘perverted commas’ – as direct speech. However, the diegetic narrative discourse itself is redolent of registers rooted in 1950s English working class life. The texts also contain different methods of representing their protagonists’ consciousness through their own idiolect. In Saturday Night and Sunday Morning, this is evidenced by the use of the second person ‘you’. It functions simultaneously as a representation of Seaton’s consciousness in the oral register which he might choose to articulate it, and as a dialogic ‘sideways glance’ at the reader and assumed shared experience. The second is more redolent of internal monologue, using the first-person form (as seen in the homodiegetic narration of the second novel); crucially, though, it remains in Standard English, if explicitly orientated towards oral register. Sillitoe’s is a novelistic discourse which refuses to normalise itself to accord with the conventions of classic realism, and as such prefigures the ambitions of many contemporary writers who incline their narrative voices towards the oral – asserting the right of a character’s dialect/idiolect to be the principal register of the narrative. The paper will demonstrate this thesis through the ideas of Bakhtin, and through an analytical taxonomy derived from literary stylistics. It aims to propose a model which can be used to analyse and explore any fiction which has been labelled as ‘working class’, and asserts that such an approach leads to a more principled characterisation of working class fiction (based on its use of language) than current literary-critical discussions based simply on cultural/social context and biography

Circulating CD133+CD34+ progenitor cells inversely correlate with soluble ICAM-1 in early ischemic stroke patients

<p>Abstract</p> <p>Background and Purpose</p> <p>Both endothelial progenitor cells (EPC) and markers of neuroinflammation are candidate biomarkers for stroke severity and outcome prediction. A relationship between EPC and neuroinflammatory markers in early stroke is not fully elucidated. The objectives were to investigate correlations between EPC and neuroinflammation markers (adhesion molecules ICAM-1, VCAM-1, E-selectin, tumor necrosis factor (TNF)-α, interleukin (IL)-6, endothelin (ET)-1, markers of tissue injury (matrix metalloproteinases (MMP)-9 and tissue inhibitor of matrix metalloproteinases (TIMP)-1) in early stroke patients.</p> <p>Methods</p> <p>We prospectively recruited symptomatic patients with ischemic cerebrovascular disease. We assessed stroke severity by using of acute (diffusion-weighted imaging (DWI) and final lesion volumes (fluid attenuated inversion recovery (FLAIR). We measured serum soluble ICAM-1, VCAM-1, E-selectin, MMP-9, TIMP-1 and plasma TNF-α, IL-6, ET-1 by ELISA, and quantified EPC in mononuclear fraction of peripheral blood on days 1 and 3 in 17 patients (mean(SD) age 62(14), with admission National Institutes of Health Stroke Scale (NIHSS) 10(8)) selected from 175 patients with imaging confirmed ischemic stroke. Non-parametric statistics, univariate and multivariate analysis were used.</p> <p>Results</p> <p>Only ICAM-1 inversely correlated with EPC subset CD133+CD34+ on day 1 (Spearman r = -0.6, p < 0.01) and on day 3 (r = -0.967, p < 0.001). This correlation remained significant after adjustment for age and NIHSS (beta -0.992, p < 0.004), for glucose and systolic blood pressure (beta -0.86, p < 0.005), and for white blood cells and hematocrit (beta -1.057, p < 0.0001) on day 3. MMP-9 (r = 0.509, p < 0.04) and MMP-9/TIMP-1 (r = 0.59, p < 0.013) on day 1 correlated with acute lesion volume. Both IL-6 (r = 0.624, p < 0.01) and MMP-9/TIMP-1 (r = 0.56, p < 0.02) correlated with admission NIHSS.</p> <p>Conclusion</p> <p>Our study showed that high ICAM-1 is associated with low CD133+CD34+subset of EPC. Biomarkers of neuroinflammation may predict tissue injury and stroke severity in early ischemia.</p

Planet formation in Binaries

Spurred by the discovery of numerous exoplanets in multiple systems, binaries have become in recent years one of the main topics in planet formation research. Numerous studies have investigated to what extent the presence of a stellar companion can affect the planet formation process. Such studies have implications that can reach beyond the sole context of binaries, as they allow to test certain aspects of the planet formation scenario by submitting them to extreme environments. We review here the current understanding on this complex problem. We show in particular how each of the different stages of the planet-formation process is affected differently by binary perturbations. We focus especially on the intermediate stage of kilometre-sized planetesimal accretion, which has proven to be the most sensitive to binarity and for which the presence of some exoplanets observed in tight binaries is difficult to explain by in-situ formation following the "standard" planet-formation scenario. Some tentative solutions to this apparent paradox are presented. The last part of our review presents a thorough description of the problem of planet habitability, for which the binary environment creates a complex situation because of the presence of two irradation sources of varying distance.Comment: Review chapter to appear in "Planetary Exploration and Science: Recent Advances and Applications", eds. S. Jin, N. Haghighipour, W.-H. Ip, Springer (v2, numerous typos corrected

Valuing biodiversity and ecosystem services: a useful way to manage and conserve marine resources?

Valuation of biodiversity and ecosystem services (ES) is widely recognized as a useful, though often controversial, approach to conservation and management. However, its use in the marine environment, hence evidence of its efficacy, lags behind that in terrestrial ecosystems. This largely reflects key challenges to marine conservation and management such as the practical difficulties in studying the ocean, complex governance issues and the historically-rooted separation of biodiversity conservation and resource management. Given these challenges together with the accelerating loss of marine biodiversity (and threats to the ES that this biodiversity supports), we ask whether valuation efforts for marine ecosystems are appropriate and effective. We compare three contrasting systems: the tropical Pacific, Southern Ocean and UK coastal seas. In doing so, we reveal a diversity in valuation approaches with different rates of progress and success. We also find a tendency to focus on specific ES (often the harvested species) rather than biodiversity. In light of our findings, we present a new conceptual view of valuation that should ideally be considered in decision-making. Accounting for the critical relationships between biodiversity and ES, together with an understanding of ecosystem structure and functioning, will enable the wider implications of marine conservation and management decisions to be evaluated. We recommend embedding valuation within existing management structures, rather than treating it as an alternative or additional mechanism. However, we caution that its uptake and efficacy will be compromised without the ability to develop and share best practice across regions