Spectroscopy of Nine Cataclysmic Variable Stars

We present optical spectroscopy of nine cataclysmic binary stars, mostly dwarf novae, obtained primarily to determine orbital periods Porb. The stars and their periods are LX And, 0.1509743(5) d; CZ Aql, 0.2005(6) d; LU Cam, 0.1499686(4) d; GZ Cnc, 0.0881(4) d; V632 Cyg, 0.06377(8) d; V1006 Cyg, 0.09903(9) d; BF Eri, 0.2708804(4) d; BI Ori, 0.1915(5) d; and FO Per, for which Porb is either 0.1467(4) or 0.1719(5) d. Several of the stars proved to be especially interesting. In BF Eri, we detect the absorption spectrum of a secondary star of spectral type K3 +- 1 subclass, which leads to a distance estimate of approximately 1 kpc. However, BF Eri has a large proper motion (100 mas/yr), and we have a preliminary parallax measurement that confirms the large proper motion and yields only an upper limit for the parallax. BF Eri's space velocity is evidently large, and it appears to belong to the halo population. In CZ Aql, the emission lines have strong wings that move with large velocity amplitude, suggesting a magnetically-channeled accretion flow. The orbital period of V1006 Cyg places it squarely within the 2- to 3-hour "gap" in the distribution of cataclysmic binary orbital periods.Comment: 31 pages, 5 postscript and one PNG figure. Accepted for PAS

Information-sharing with respite care services for older adults:a qualitative exploration of carers’ experiences

This study was financially supported by the Queen’s Nursing Institute Scotland (QNIS Project ELCRI01), Edinburgh, Scotland.Respite services play an important role in supporting older adults and their carers. When an older person is unable to fully represent themselves, provision of respite care relies on effective information-sharing between carers and respite staff. This study aimed to explore, from carers’ perspectives, the scope, quality and fit of information-sharing between carers, older people and respite services. An explorative, cross-sectional qualitative study involving a purposive sample of 24 carers, recruited via carer support groups and community groups in voluntary organisations, was undertaken in North East Scotland. Data were collected from August 2013 to September 2014, with participants taking part in a focus group or individual interview. Data were analysed systematically using the Framework Approach. The multiple accounts elicited from carers identified how barriers and facilitators to information-sharing with respite services changed over time across three temporal phases: ‘Reaching a point’, ‘Trying it out’ and ‘Settled in’. Proactive information-sharing about accessibility and eligibility for respite care, and assessment of carers’ needs in their own right, were initially important; as carers and older people moved on to try services out, time and space to develop mutual understandings and negotiate care arrangements came to the fore; then, once shared expectations had been established, carers’ chief concerns were around continuity of care and maintaining good interpersonal relationships. The three temporal phases also impacted on which modes of information-sharing were available to, and worked best for, carers as well as on carers’ perceptions of how information and communication technologies should be utilised. This study highlights the need for respite staff to take proactive, flexible approaches to working with carers and to make ongoing efforts to engage with carers, and older people, throughout the months and years of them utilising respite services. Information and communication technologies have potential to enhance information-sharing but traditional approaches will remain important.PostprintPeer reviewe

Immunohistochemical Characterization of Procaspase-3 Overexpression as a Druggable Target With PAC-1, a Procaspase-3 Activator, in Canine and Human Brain Cancers

Gliomas and meningiomas are the most common brain neoplasms affecting both humans and canines, and identifying druggable targets conserved across multiple brain cancer histologies and comparative species could broadly improve treatment outcomes. While satisfactory cure rates for low grade, non-invasive brain cancers are achievable with conventional therapies including surgery and radiation, the management of non-resectable or recurrent brain tumors remains problematic and necessitates the discovery of novel therapies that could be accelerated through a comparative approach, such as the inclusion of pet dogs with naturally-occurring brain cancers. Evidence supports procaspase-3 as a druggable brain cancer target with PAC-1, a pro-apoptotic, small molecule activator of procaspase-3 that crosses the blood-brain barrier. Procaspase-3 is frequently overexpressed in malignantly transformed tissues and provides a preferential target for inducing cancer cell apoptosis. While preliminary evidence supports procaspase-3 as a viable target in preclinical models, with PAC-1 demonstrating activity in rodent models and dogs with spontaneous brain tumors, the broader applicability of procaspase-3 as a target in human brain cancers, as well as the comparability of procaspase-3 expressions between differing species, requires further investigation. As such, a large-scale validation of procaspase-3 as a druggable target was undertaken across 651 human and canine brain tumors. Relative to normal brain tissues, procaspase-3 was overexpressed in histologically diverse cancerous brain tissues, supporting procaspase-3 as a broad and conserved therapeutic target. Additionally, procaspase-3 expressing glioma and meningioma cell lines were sensitive to the apoptotic effects of PAC-1 at biologically relevant exposures achievable in cancer patients. Importantly, the clinical relevance of procaspase-3 as a potential prognostic variable was demonstrated in human astrocytomas of variable histologic grades and associated clinical outcomes, whereby tumoral procaspase-3 expression was negatively correlated with survival; findings which suggest that PAC-1 might provide the greatest benefit for patients with the most guarded prognoses

Defining sustainable transport in rural tourism: experiences from the New Forest

Transport policy agendas have long sought to bring about more sustainable transport at tourism destinations. While there are examples of successes, it remains unclear what inroads have been made towards creating a sustainable transport future. Policy directions have evolved over a number of years and in many tourism destination contexts it is far from clear what a desirable transport future looks like. When translated to implementation, the aims of initiatives can be unclear and baseline measures inconsistent, making success difficult to judge. This paper analyses how sustainable travel has been implemented in practice at a destination level. The focus is rural tourism and data are derived from a specific case, the New Forest National Park, UK, where a wide range of transport initiatives have been implemented since the Park’s designation in 2005. The study adopts a social practice theory perspective. Data are derived from a visitor survey, interviews and observations. It finds there is scope to improve sustainable transport provision at destinations through understanding visitor practices, but limited scope to influence meanings associated with visitor travel and travel skills. Policy meets the needs of some visitors more than others

An Experimental and Computational Study of the Effect of ActA Polarity on the Speed of Listeria monocytogenes Actin-based Motility

Listeria monocytogenes is a pathogenic bacterium that moves within infected cells and spreads directly between cells by harnessing the cell's dendritic actin machinery. This motility is dependent on expression of a single bacterial surface protein, ActA, a constitutively active Arp2,3 activator, and has been widely studied as a biochemical and biophysical model system for actin-based motility. Dendritic actin network dynamics are important for cell processes including eukaryotic cell motility, cytokinesis, and endocytosis. Here we experimentally altered the degree of ActA polarity on a population of bacteria and made use of an ActA-RFP fusion to determine the relationship between ActA distribution and speed of bacterial motion. We found a positive linear relationship for both ActA intensity and polarity with speed. We explored the underlying mechanisms of this dependence with two distinctly different quantitative models: a detailed agent-based model in which each actin filament and branched network is explicitly simulated, and a three-state continuum model that describes a simplified relationship between bacterial speed and barbed-end actin populations. In silico bacterial motility required a cooperative restraining mechanism to reconstitute our observed speed-polarity relationship, suggesting that kinetic friction between actin filaments and the bacterial surface, a restraining force previously neglected in motility models, is important in determining the effect of ActA polarity on bacterial motility. The continuum model was less restrictive, requiring only a filament number-dependent restraining mechanism to reproduce our experimental observations. However, seemingly rational assumptions in the continuum model, e.g. an average propulsive force per filament, were invalidated by further analysis with the agent-based model. We found that the average contribution to motility from side-interacting filaments was actually a function of the ActA distribution. This ActA-dependence would be difficult to intuit but emerges naturally from the nanoscale interactions in the agent-based representation

Reliance on habits at the expense of goal-directed control following dopamine precursor depletion

Rationale Dopamine is well known to play an important role in learning and motivation. Recent animal studies have implicated dopamine in the reinforcement of stimulus-response habits, as well as in flexible, goal-directed action. However, the role of dopamine in human action control is still not well understood. Objectives We present the first investigation of the effect of reducing dopamine function in healthy volunteers on the balance between habitual and goal-directed action control. Methods The dietary intervention of acute dietary phenylalanine and tyrosine depletion (APTD) was adopted to study the effects of reduced global dopamine function on action control. Participants were randomly assigned to either the APTD or placebo group (ns = 14) to allow for a between-subjects comparison of performance on a novel three-stage experimental paradigm. In the initial learning phase, participants learned to respond to different stimuli in order to gain rewarding outcomes. Subsequently, an outcome-devaluation test and a slips-of-action test were conducted to assess whether participants were able to flexibly adjust their behaviour to changes in the desirability of the outcomes. Results APTD did not prevent stimulus-response learning, nor did we find evidence for impaired response-outcome learning in the subsequent outcome-devaluation test. However, when goal-directed and habitual systems competed for control in the slips-of-action test, APTD tipped the balance towards habitual control. These findings were restricted to female volunteers. Conclusions We provide direct evidence that the balance between goal-directed and habitual control in humans is dopamine dependent. The results are discussed in light of gender differences in dopamine function and psychopathologies

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Stromal transcriptional profiles reveal hierarchies of anatomical site, serum response and disease and identify disease specific pathways

Synovial fibroblasts in persistent inflammatory arthritis have been suggested to have parallels with cancer growth and wound healing, both of which involve a stereotypical serum response programme. We tested the hypothesis that a serum response programme can be used to classify diseased tissues, and investigated the serum response programme in fibroblasts from multiple anatomical sites and two diseases. To test our hypothesis we utilized a bioinformatics approach to explore a publicly available microarray dataset including rheumatoid arthritis (RA), osteoarthritis (OA) and normal synovial tissue, then extended those findings in a new microarray dataset representing matched synovial, bone marrow and skin fibroblasts cultured from RA and OA patients undergoing arthroplasty. The classical fibroblast serum response programme discretely classified RA, OA and normal synovial tissues. Analysis of low and high serum treated fibroblast microarray data revealed a hierarchy of control, with anatomical site the most powerful classifier followed by response to serum and then disease. In contrast to skin and bone marrow fibroblasts, exposure of synovial fibroblasts to serum led to convergence of RA and OA expression profiles. Pathway analysis revealed three inter-linked gene networks characterising OA synovial fibroblasts: Cell remodelling through insulin-like growth factors, differentiation and angiogenesis through -3 integrin, and regulation of apoptosis through CD44. We have demonstrated that Fibroblast serum response signatures define disease at the tissue level, and that an OA specific, serum dependent repression of genes involved in cell adhesion, extracellular matrix remodelling and apoptosis is a critical discriminator between cultured OA and RA synovial fibroblasts

Variable responses of individual species to tropical forest degradation

The functional stability of ecosystems depends greatly on interspecific differences in responses to environmental perturbation. However, responses to perturbation are not necessarily invariant among populations of the same species, so intraspecific variation in responses might also contribute. Such inter-population response diversity has recently been shown to occur spatially across species ranges, but we lack estimates of the extent to which individual populations across an entire community might have perturbation responses that vary through time. We assess this using 524 taxa that have been repeatedly surveyed for the effects of tropical forest logging at a focal landscape in Sabah, Malaysia. Just 39 % of taxa – all with non-significant responses to forest degradation – had invariant responses. All other taxa (61 %) showed significantly different responses to the same forest degradation gradient across surveys, with 6 % of taxa responding to forest degradation in opposite directions across multiple surveys. Individual surveys had low power (< 80 %) to determine the correct direction of response to forest degradation for one-fifth of all taxa. Recurrent rounds of logging disturbance increased the prevalence of intra-population response diversity, while uncontrollable environmental variation and/or turnover of intraspecific phenotypes generated variable responses in at least 44 % of taxa. Our results show that the responses of individual species to local environmental perturbations are remarkably flexible, likely providing an unrealised boost to the stability of disturbed habitats such as logged tropical forests

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery