Cell Invasion in Collagen Scaffold Architectures Characterized by Percolation Theory.

The relationship between biological scaffold interconnectivity and cell migration is an important but poorly understood factor in tissue regeneration. Here a scale-independent technique for characterization of collagen scaffold interconnectivity is presented, using a combination of X-ray microcomputed tomography and percolation theory. Confocal microscopy of connective tissue cells reveals this technique as highly relevant for determining the extent of cell invasion.The authors acknowledge financial support from EPSRC, Geistlich Pharma AG and ERC Advanced Grant 320598 3D-E.This is the final version of the article. It first appeared from Wiley at http://dx.doi.org/10.1002/adhm.201500197

The chicken talpid3 gene encodes a novel protein that is essential for hedgehog signaling

Talpid(3) is a classical chicken mutant with abnormal limb patterning and malformations in other regions of the embryo known to depend on Hedgehog signaling. We combined the ease of manipulating chicken embryos with emerging knowledge of the chicken genome to reveal directly the basis of defective Hedgehog signal transduction in talpid(3) embryos and to identify the talpid(3) gene. We show in several regions of the embryo that the talpid(3) phenotype is completely ligand independent and demonstrate for the first time that talpid(3) is absolutely required for the function of both Gli repressor and activator in the intracellular Hedgehog pathway. We map the talpid(3) locus to chromosome 5 and find a frameshift mutation in a KIAA0586 ortholog (ENSGALG00000012025), a gene not previously attributed with any known function. We show a direct causal link between KIAA0586 and the mutant phenotype by rescue experiments. KIAA0586 encodes a novel protein, apparently specific to vertebrates, that localizes to the cytoplasm. We show that Gli3 processing is abnormal in talpid(3) mutant cells but that Gli3 can still translocate to the nucleus. These results suggest that the talpid(3) protein operates in the cytoplasm to regulate the activity of both Gli repressor and activator proteins

Pathways to Coastal Resiliency: The Adaptive Gradients Framework

Current and future climate-related coastal impacts such as catastrophic and repetitive flooding, hurricane intensity, and sea level rise necessitate a new approach to developing and managing coastal infrastructure. Traditional “hard” or “grey” engineering solutions are proving both expensive and inflexible in the face of a rapidly changing coastal environment. Hybrid solutions that incorporate natural, nature-based, structural, and non-structural features may better achieve a broad set of goals such as ecological enhancement, long-term adaptation, and social benefits, but broad consideration and uptake of these approaches has been slow. One barrier to the widespread implementation of hybrid solutions is the lack of a relatively quick but holistic evaluation framework that places these broader environmental and societal goals on equal footing with the more traditional goal of exposure reduction. To respond to this need, the Adaptive Gradients Framework was developed and pilot-tested as a qualitative, flexible, and collaborative process guide for organizations to understand, evaluate, and potentially select more diverse kinds of infrastructural responses. These responses would ideally include natural, nature-based, and regulatory/cultural approaches, as well as hybrid designs combining multiple approaches. It enables rapid expert review of project designs based on eight metrics called “gradients”, which include exposure reduction, cost efficiency, institutional capacity, ecological enhancement, adaptation over time, greenhouse gas reduction, participatory process, and social benefits. The framework was conceptualized and developed in three phases: relevant factors and barriers were collected from practitioners and experts by survey; these factors were ranked by importance and used to develop the initial framework; several case studies were iteratively evaluated using this technique; and the framework was finalized for implementation. The article presents the framework and a pilot test of its application, along with resources that would enable wider application of the framework by practitioners and theorists

Does dissemination extend beyond publication: a survey of a cross section of public funded research in the UK

Background: In the UK, most funding bodies now expect a commitment or effort on the part of grant holders to disseminate the findings of their research. The emphasis is on ensuring that publicly funded research is made available, can be used to support decision making, and ultimately improve the quality and delivery of healthcare provided. In this study, we aimed to describe the dissemination practices and impacts of applied and public health researchers working across the UK.Methods: We conducted a survey of 485 UK-based principal investigators of publicly funded applied and public health research. Participants were contacted by email and invited to complete an online questionnaire via an embedded URL. Gift vouchers were given to all participants who completed the questionnaire. Four reminder emails were sent out to non-respondents at one, two, three, and four weeks; a fifth postal reminder was also undertaken.Results: A total of 243/485 (50%) questionnaires were returned (232 completed, 11 declining to participate). Most researchers recognise the importance of and appear committed to research dissemination. However, most dissemination activity beyond the publishing of academic papers appears to be undertaken an ad hoc fashion. There is some evidence that access to dissemination advice and support may facilitate more policy interactions; though access to such resources is lacking at an institutional level, and advice from funders can be variable. Although a minority of respondents routinely record details about the impact of their research, when asked about impact in relation to specific research projects most were able to provide simple narrative descriptions.Conclusions: Researchers recognise the importance of and appear committed to disseminating the findings of their work. Although researchers are focussed on academic publication, a range of dissemination activities are being applied albeit in an ad hoc fashion. However, what constitutes effective dissemination (in terms of impact and return on investment) remains unclear. Researchers need greater and clearer guidance on how best to plan, resource, and facilitate their dissemination activities

Tracing the wider impacts of biomedical research: A literature search to develop a novel citation categorisation technique

There is an increasing need both to understand the translation of biomedical research into improved healthcare and to assess the range of wider impacts from health research such as improved health policies, health practices and healthcare. Conducting such assessments is complex and new methods are being sought. Our new approach involves several steps. First, we developed a qualitative citation analysis technique to apply to biomedical research in order to assess the contribution that individual papers made to further research. Second, using this method, we then proposed to trace the citations to the original research through a series of generations of citing papers. Third, we aimed eventually to assess the wider impacts of the various generations. This article describes our comprehensive literature search to inform the new technique. We searched various databases, specific bibliometrics journals and the bibliographies of key papers. After excluding irrelevant papers we reviewed those remaining for either general or specific details that could inform development of our new technique. Various characteristics of citations were identified that had been found to predict their importance to the citing paper including the citation’s location; number of citation occasions and whether the author(s) of the cited paper were named within the citing paper. We combined these objective characteristics with subjective approaches also identified from the literature search to develop a citation categorisation technique that would allow us to achieve the first of the steps above, i.e., being able routinely to assess the contribution that individual papers make to further research.Medical Research Council as part of the MRC-NIHR Methodology Research Programme, and Professor Martin Buxton

BlackCAT: A catalogue of stellar-mass black holes in X-ray transients

During the last ~50 years, the population of black hole candidates in X-ray binaries has increased considerably with 59 Galactic objects detected in transient low-mass X-ray binaries, plus a few in persistent systems (including ~5 extragalactic binaries). We collect near-infrared, optical and X-ray information spread over hundreds of references in order to study the population of black holes in X-ray transients as a whole. We present the most updated catalogue of black hole transients, which contains X-ray, optical and near-infrared observations together with their astrometric and dynamical properties. It provides new useful information in both statistical and observational parameters providing a thorough and complete overview of the black hole population in the Milky Way. Analysing the distances and spatial distribution of the observed systems, we estimate a total population of ~1300 Galactic black hole transients. This means that we have already discovered less than ~5% of the total Galactic distribution. The complete version of this catalogue will be continuously updated online and in the Virtual Observatory, including finding charts and data in other wavelengths.Comment: http://www.astro.puc.cl/BlackCAT - Accepted for publication in Astronomy & Astrophysics. 20 pages, 8 figures, 5 Table

HCV co-infection in HIV positive population in British Columbia, Canada

<p>Abstract</p> <p>Background</p> <p>As HIV and hepatitis C (HCV) share some modes of transmission co-infection is not uncommon. This study used a population-based sample of HIV and HCV tested individuals to determine the prevalence of HIV/HCV co-infection, the sequence of virus diagnoses, and demographic and associated risk factors.</p> <p>Methods</p> <p>Positive cases of HIV were linked to the combined laboratory database (of negative and positive HCV antibody results) and HCV reported cases in British Columbia (BC).</p> <p>Results</p> <p>Of 4,598 HIV cases with personal identifiers, 3,219 (70%) were linked to the combined HCV database, 1,700 (53%) of these were anti-HCV positive. HCV was diagnosed first in 52% of co-infected cases (median time to HIV identification 3 1/2 years). HIV and HCV was diagnosed within a two week window in 26% of cases. Among individuals who were diagnosed with HIV infection at baseline, subsequent diagnoses of HCV infection was independently associated with: i) intravenous drug use (IDU) in males and females, Hazard Ratio (HR) = 6.64 (95% CI: 4.86-9.07) and 9.76 (95% CI: 5.76-16.54) respectively; ii) reported Aboriginal ethnicity in females HR = 2.09 (95% CI: 1.34-3.27) and iii) males not identified as men-who-have-sex-with-men (MSM), HR = 2.99 (95% CI: 2.09-4.27).</p> <p>Identification of HCV first compared to HIV first was independently associated with IDU in males and females OR = 2.83 (95% CI: 1.84-4.37) and 2.25 (95% CI: 1.15-4.39) respectively, but not Aboriginal ethnicity or MSM. HIV was identified first in 22%, with median time to HCV identification of 15 months;</p> <p>Conclusion</p> <p>The ability to link BC public health and laboratory HIV and HCV information provided a unique opportunity to explore demographic and risk factors associated with HIV/HCV co-infection. Over half of persons with HIV infection who were tested for HCV were anti-HCV positive; half of these had HCV diagnosed first with HIV identification a median 3.5 years later. This highlights the importance of public health follow-up and harm reduction measures for people identified with HCV to prevent subsequent HIV infection.</p

Striatal neuropeptides enhance selection and rejection of sequential actions

The striatum is the primary input nucleus for the basal ganglia, and receives glutamatergic afferents from the cortex. Under the hypothesis that basal ganglia perform action selection, these cortical afferents encode potential “action requests.” Previous studies have suggested the striatum may utilize a mutually inhibitory network of medium spiny neurons (MSNs) to filter these requests so that only those of high salience are selected. However, the mechanisms enabling the striatum to perform clean, rapid switching between distinct actions that form part of a learned action sequence are still poorly understood. Substance P (SP) and enkephalin are neuropeptides co-released with GABA in MSNs preferentially expressing D1 or D2 dopamine receptors respectively. SP has a facilitatory effect on subsequent glutamatergic inputs to target MSNs, while enkephalin has an inhibitory effect. Blocking the action of SP in the striatum is also known to affect behavioral transitions. We constructed phenomenological models of the effects of SP and enkephalin, and integrated these into a hybrid model of basal ganglia comprising a spiking striatal microcircuit and rate–coded populations representing other major structures. We demonstrated that diffuse neuropeptide connectivity enhanced the selection of unordered action requests, and that for true action sequences, where action semantics define a fixed structure, a patterning of the SP connectivity reflecting this ordering enhanced selection of actions presented in the correct sequential order and suppressed incorrect ordering. We also showed that selective pruning of SP connections allowed context–sensitive inhibition of specific undesirable requests that otherwise interfered with selection of an action group. Our model suggests that the interaction of SP and enkephalin enhances the contrast between selection and rejection of action requests, and that patterned SP connectivity in the striatum allows the “chunking” of actions and improves selection of sequences. Efficient execution of action sequences may therefore result from a combination of ordered cortical inputs and patterned neuropeptide connectivity within striatum

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

Clinical chronobiology: a timely consideration in critical care medicine

A fundamental aspect of human physiology is its cyclical nature over a 24-h period, a feature conserved across most life on Earth. Organisms compartmentalise processes with respect to time in order to promote survival, in a manner that mirrors the rotation of the planet and accompanying diurnal cycles of light and darkness. The influence of circadian rhythms can no longer be overlooked in clinical settings; this review provides intensivists with an up-to-date understanding of the burgeoning field of chronobiology, and suggests ways to incorporate these concepts into daily practice to improve patient outcomes. We outline the function of molecular clocks in remote tissues, which adjust cellular and global physiological function according to the time of day, and the potential clinical advantages to keeping in time with them. We highlight the consequences of "chronopathology", when this harmony is lost, and the risk factors for this condition in critically ill patients. We introduce the concept of "chronofitness" as a new target in the treatment of critical illness: preserving the internal synchronisation of clocks in different tissues, as well as external synchronisation with the environment. We describe methods for monitoring circadian rhythms in a clinical setting, and how this technology may be used for identifying optimal time windows for interventions, or to alert the physician to a critical deterioration of circadian rhythmicity. We suggest a chronobiological approach to critical illness, involving multicomponent strategies to promote chronofitness (chronobundles), and further investment in the development of personalised, time-based treatment for critically ill patients