Activity-Dependent Modulation of Synaptic AMPA Receptor Accumulation

AbstractBoth theoretical and experimental work have suggested that central neurons compensate for changes in excitatory synaptic input in order to maintain a relatively constant output. We report here that inhibition of excitatory synaptic transmission in cultured spinal neurons leads to an increase in mEPSC amplitudes, accompanied by an equivalent increase in the accumulation of AMPA receptors at synapses. Conversely, increasing excitatory synaptic activity leads to a decrease in synaptic AMPA receptors and a decline in mEPSC amplitude. The time course of this synaptic remodeling is slow, similar to the metabolic half-life of neuronal AMPA receptors. Moreover, inhibiting excitatory synaptic transmission significantly prolongs the half-life of the AMPA receptor subunit GluR1, suggesting that synaptic activity modulates the size of the mEPSC by regulating the turnover of postsynaptic AMPA receptors

Long-Term Estrogen Therapy Improves Vascular Function in Male to Female Transsexuals

AbstractObjectives. This study sought to examine the effects of long-term estrogen therapy on vascular function in male to female transsexuals and to compare the findings with those observed in men and premenopausal women.Background. Gender differences in coronary artery disease have largely been attributed to the beneficial effects of estrogen on vascular function and plasma lipids in women. However, the effects of estrogen on the male vasculature have not been widely studied.Methods. We compared the effects of estrogen on vascular function in 14 male to female transsexuals, 14 age-matched men and 15 premenopausal women. Flow-mediated vasodilation and response to nitroglycerin were assessed in the brachial artery using noninvasive ultrasound.Results. Flow-mediated vasodilation was similar in transsexuals and women but greater than that in men ([mean ± SE] 11.5 ± 1.3% and 9.4 ± 1.1% vs. 5.2 ± 1.0% respectively, p < 0.005). Responses to nitroglycerin were also greater in transsexuals and women than in men (21.6 ± 1.7% and 21.0 ± 0.9% vs. 14.5 ± 1.2%, respectively, p = 0.0005). These differences persisted even after adjusting for vessel size. Despite similar total cholesterol levels, transsexuals had high density lipoprotein cholesterol levels similar to those in women and greater than those observed in men (1.76 ± 0.12 and 1.82 ± 0.11 mmol/liter vs. 1.35 ± 0.07 mmol/liter, respectively, p < 0.005). Moreover, triglyceride levels were greater in transsexuals than in men and women, and low density lipoprotein cholesterol (LDL-C) particle size was smaller (25.7 ± 0.2 nm vs. 26.2 ± 0.1 and 26.6 ± 0.1 nm, respectively, p = 0.0001). Serum testosterone (an index of estrogen therapy in transsexuals) was markedly suppressed in transsexuals and similar to that in women. Univariate analysis revealed that there was a strong inverse correlation between serum testosterone and flow-mediated vasodilation (rs= −0.48, p < 0.005). Multivariate analysis revealed that the best combination of predictors of flow-mediated vasodilation was serum testosterone, vessel size and LDL-C (R2= 0.3, p < 0.005).Conclusions. Long-term estrogen therapy appears to improve vascular function in male to female transsexuals and occurs despite higher triglyceride levels and the presence of small, dense LDL-C. The beneficial effects of estrogen are not gender specific or solely mediated through endothelium-derived nitric oxide.(J Am Coll Cardiol 1997;29:1437–44

Cis-effects on gene expression in the human prenatal brain associated with genetic risk for neuropsychiatric disorders

The majority of common risk alleles identified for neuropsychiatric disorders reside in non-coding regions of the genome and are therefore likely to impact gene regulation. However, the genes that are primarily affected and the nature and developmental timing of these effects remain unclear. Given the hypothesised role for early neurodevelopmental processes in these conditions, we here define genetic predictors of gene expression in the human fetal brain with which we perform transcriptome-wide association studies (TWASs) of attention deficit hyperactivity disorder (ADHD), autism spectrum disorder, bipolar disorder, major depressive disorder and schizophrenia. We identify prenatal cis-regulatory effects on 63 genes and 166 individual transcripts associated with genetic risk for these conditions. We observe pleiotropic effects of expression predictors for a number of genes and transcripts, including those of decreased DDHD2 expression in association with risk for schizophrenia and bipolar disorder, increased expression of a ST3GAL3 transcript with risk for schizophrenia and ADHD, and increased expression of an XPNPEP3 transcript with risk for schizophrenia, bipolar disorder and major depression. For the protocadherin alpha cluster genes PCDHA7 and PCDHA8, we find that predictors of low expression are associated with risk for major depressive disorder while those of higher expression are associated with risk for schizophrenia. Our findings support a role for altered gene regulation in the prenatal brain in susceptibility to various neuropsychiatric disorders and prioritize potential risk genes for further neurobiological investigation

Optimising the impact of health services research on the organisation and delivery of health services : a mixed-methods study

The research reported in this issue of the journal was funded by the HSDR programme or one of its preceding programmes as project number 16/52/21.Background The limitations of ‘knowledge transfer’ are increasingly recognised, with growing interest in ‘knowledge co-production in context’. One way of achieving the latter is by ‘embedding’ researchers in health service settings, yet how to deliver such schemes successfully is poorly understood. Objectives The objectives were to examine the nature of ‘embedded knowledge co-production’ and explore how embedded research initiatives can be designed more effectively. Design The study used four linked workstreams. Workstream 1 involved two parallel literature reviews to examine how ‘knowledge co-production’ and ‘embedded research’ are conceptualised, operationalised and discussed. In workstream 2, a scoping review of exisiting or recent ‘embedded researcher’ schemes in UK health settings was carried out. Workstream 3 involved developing four in-depth case studies on such schemes to understand their mechanisms, effectiveness and challenges. In workstream 4, insights from the other workstreams were used to provide recommendations, guidance and templates for the different ways embedded co-production may be framed and specified. The overall goal was to help those interested in developing and using such approaches to understand and address the design choices they face. Setting Embedded research initiatives in UK health settings. Data sources Data were sourced from the following: analysis of the published and grey literature (87 source articles on knowledge co-production, and 47 published reports on extant embedded research initiatives), documentation and interviews with key actors across 45 established embedded research initiatives, in-depth interviews and site observations with 31 participants over 12 months in four intensive case studies, and informal and creative engagement in workshops (n = 2) and with participants in embedded research initiatives who joined various managed discussion forums. Participants The participants were stakeholders and participants in embedded research initiatives. Results The literature reviews from workstream 1 produced practical frameworks for understanding knowledge co-production and embedded research initiatives, which, with the scoping review (workstream 2), informed the identification and articulation of 10 design concerns under three overarching categories: intent (covering outcomes and power dynamics), structures (scale, involvement, proximity and belonging) and processes (the functional activities, skills and expertise required, nature of the relational roles, and the learning mechanisms employed). Current instances of embedded research were diverse across many of these domains. The four case studies (workstream 3) added insights into scheme dynamics and life cycles, deepening understanding of the overarching categories and showing the contingencies experienced in co-producing knowledge. A key finding is that there was often a greater emphasis on embeddedness per se than on co-production, which can be hard to discern. Finally, the engaging and influencing activities running throughout (workstream 4) allowed these research-rooted insights to be translated into practical tools and resources, evidenced by peer-reviewed publications, for those interested in exploring and developing the approach. Conclusions Embedded research has a strong underpinning rationale, and more is becoming known about its design and management challenges. The tools and resources developed in this project provide a coherent evidence-informed framework for designing, operationalising and managing such schemes. It cannot yet be said with clarity that the potential benefits of embedded research are always deliverable, nor what the cost would be. Future work With the means to describe and categorise different types of embedded research initiatives, more evaluative work is now needed to examine the relative merits and costs of different designs. Funding This project was funded by the National Institute for Health Research (NIHR) Health and Social Care Delivery Research programme and will be published in full in Health and Social Care Delivery Research; Vol. 10, No. 3. See the NIHR Journals Library website for further project information.Publisher PDFPeer reviewe

Cost-Effectiveness of Health Care Interventions to Address Intimate Partner Violence: What Do We Know and What Else Should We Look for?

Intimate partner violence (IPV) creates a substantial burden of disease and significant costs to families, communities, and governments. Building the evidence for effective interventions to reduce violence and its sequelae requires increased use of economic evaluation to inform policy through the analysis of costs and potential savings of interventions. The authors review existing economic evaluations and present case studies of current research from the United Kingdom and Australia to illustrate the strengths and limitations of two approaches to generating economic evidence: economic evaluation alongside randomized controlled trials and economic modeling. Economic evaluation should always be considered in the design of IPV intervention research

The use of nanovibration to discover specific and potent bioactive metabolites that stimulate osteogenic differentiation in mesenchymal stem cells

Bioactive metabolites have wide-ranging biological activities and are a potential source of future research and therapeutic tools. Here, we use nanovibrational stimulation to induce osteogenic differentiation of mesenchymal stem cells, in the absence of off-target, nonosteogenic differentiation. We show that this differentiation method, which does not rely on the addition of exogenous growth factors to culture media, provides an artifact-free approach to identifying bioactive metabolites that specifically and potently induce osteogenesis. We first identify a highly specific metabolite, cholesterol sulfate, an endogenous steroid. Next, a screen of other small molecules with a similar steroid scaffold identified fludrocortisone acetate with both specific and highly potent osteogenic-inducing activity. Further, we implicate cytoskeletal contractility as a measure of osteogenic potency and cell stiffness as a measure of specificity. These findings demonstrate that physical principles can be used to identify bioactive metabolites and then enable optimization of metabolite potency can be optimized by examining structure-function relationships

Using a stair horizontal-vertical illusion to increase foot clearance over an inconsistently taller stair-riser

Introduction: Stair falls can be caused by inconsistent stair dimensions. During ascent, inconsistently taller stair risers lead to reduced foot clearances as the inconsistency goes unnoticed. A stair horizontal-vertical illusion increases perceived riser heights and foot clearance and could offset reduced foot clearances over inconsistently taller risers, though this might impact other stair safety measures. Method: Twelve participants (age: 22 (3) years) ascended a seven-step staircase under three conditions: i) all steps consistent in riser height (consistent), ii) a 1cm increase in step 5 riser height (inconsistent) and iii) a 1cm increase in step 5 riser height, superimposed with a stair horizontal-vertical illusion (illusion). Vertical foot clearance, foot overhang, and margins of stability were assessed over step 4, 5 and 6. Perceived riser height due to the illusion was determined through a computer perception test. A One-Way Repeated Measures ANOVA compared biomechanical variables between conditions. A One Sample t test compared perceived riser height to the true height. Results: Over the inconsistent step 5, foot clearance reduced by 0.8cm compared to consistent. Illusion increased foot clearance by 1.1cm and decreased foot overhang by 4% compared to inconsistent. On step 4 the illusion led to more anterior instability compared to inconsistent. Illusion and inconsistent led to more mediolateral stability compared to consistent. The illusion increased perceived riser height by 12%. Discussion: Foot clearance reductions over inconsistently taller risers can be offset by a stair horizontal-vertical illusion. Additional benefits included a safer foot overhang and unaffected stability over the inconsistent riser. Changes to step 4 stability might have resulted from leaning forward to look at the step 5 illusion. The stair horizontal-vertical illusion could be a practical solution for inconsistently taller stair risers, where a rebuild is usually the only solution

On the dynamics of planetesimals embedded in turbulent protoplanetary discs with dead zones

(abridged) Accretion in protoplanetary discs is thought to be driven by [...] turbulence via the magnetorotational instability (MRI). Recent work has shown that a planetesimal swarm embedded in a fully turbulent disc is subject to strong excitation of the velocity dispersion, leading to collisional destruction of bodies with radii R_p < 100 km. Significant diffusion of planetesimal semimajor axes also arises, leading to large-scale spreading of the planetesimal population throughout the inner regions of the protoplanetary disc, in apparent contradiction of constraints provided by the distribution of asteroids within the asteroid belt. In this paper, we examine the dynamics of planetesimals embedded in vertically stratified turbulent discs, with and without dead zones. Our main aims are to examine the turbulent excitation of the velocity dispersion, and the radial diffusion, of planetesimals in these discs. We employ three dimensional MHD simulations [...], along with an equilibrium chemistry model [...] We find that planetesimals in fully turbulent discs develop large random velocities that will lead to collisional destruction/erosion for bodies with sizes below 100 km, and undergo radial diffusion on a scale \sim 2.5 au over a 5 Myr disc life time. But planetesimals in a dead zone experience a much reduced excitation of their random velocities, and equilibrium velocity dispersions lie between the disruption thresholds for weak and strong aggregates for sizes R_p < 100 km. We also find that radial diffusion occurs over a much reduced length scale \sim 0.25 au over the disc life time, this being consistent with solar system constraints. We conclude that planetesimal growth via mutual collisions between smaller bodies cannot occur in a fully turbulent disc. By contrast, a dead zone may provide a safe haven in which km-sized planetesimals can avoid mutual destruction through collisions.Comment: 18 pages, 13 figures, 3 tables, MNRAS in press, minor corrections to match the published versio

Identifying the science and technology dimensions of emerging public policy issues through horizon scanning

Public policy requires public support, which in turn implies a need to enable the public not just to understand policy but also to be engaged in its development. Where complex science and technology issues are involved in policy making, this takes time, so it is important to identify emerging issues of this type and prepare engagement plans. In our horizon scanning exercise, we used a modified Delphi technique [1]. A wide group of people with interests in the science and policy interface (drawn from policy makers, policy adviser, practitioners, the private sector and academics) elicited a long list of emergent policy issues in which science and technology would feature strongly and which would also necessitate public engagement as policies are developed. This was then refined to a short list of top priorities for policy makers. Thirty issues were identified within broad areas of business and technology; energy and environment; government, politics and education; health, healthcare, population and aging; information, communication, infrastructure and transport; and public safety and national security.Public policy requires public support, which in turn implies a need to enable the public not just to understand policy but also to be engaged in its development. Where complex science and technology issues are involved in policy making, this takes time, so it is important to identify emerging issues of this type and prepare engagement plans. In our horizon scanning exercise, we used a modified Delphi technique [1]. A wide group of people with interests in the science and policy interface (drawn from policy makers, policy adviser, practitioners, the private sector and academics) elicited a long list of emergent policy issues in which science and technology would feature strongly and which would also necessitate public engagement as policies are developed. This was then refined to a short list of top priorities for policy makers. Thirty issues were identified within broad areas of business and technology; energy and environment; government, politics and education; health, healthcare, population and aging; information, communication, infrastructure and transport; and public safety and national security