348 research outputs found

    Ucma/GRP inhibits phosphate-induced vascular smooth muscle cell calcification via SMAD-dependent BMP signalling

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    Vascular calcification (VC) is the process of deposition of calcium phosphate crystals in the blood vessel wall, with a central role for vascular smooth muscle cells (VSMCs). VC is highly prevalent in chronic kidney disease (CKD) patients and thought, in part, to be induced by phosphate imbalance. The molecular mechanisms that regulate VC are not fully known. Here we propose a novel role for the mineralisation regulator Ucma/GRP (Upper zone of growth plate and Cartilage Matrix Associated protein/Gla Rich Protein) in phosphate-induced VSMC calcification. We show that Ucma/GRP is present in calcified atherosclerotic plaques and highly expressed in calcifying VSMCs in vitro. VSMCs from Ucma/GRP(-/-) mice showed increased mineralisation and expression of osteo/chondrogenic markers (BMP-2, Runx2, beta-catenin, p-SMAD1/5/8, ALP, OCN), and decreased expression of mineralisation inhibitor MGP, suggesting that Ucma/GRP is an inhibitor of mineralisation. Using BMP signalling inhibitor noggin and SMAD1/5/8 signalling inhibitor dorsomorphin we showed that Ucma/GRP is involved in inhibiting the BMP-2-SMAD1/5/8 osteo/chondrogenic signalling pathway in VSMCs treated with elevated phosphate concentrations. Additionally, we showed for the first time evidence of a direct interaction between Ucma/GRP and BMP-2. These results demonstrate an important role of Ucma/GRP in regulating osteo/chondrogenic differentiation and phosphate-induced mineralisation of VSMCs.NWO ZonMw [MKMD 40-42600-98-13007]; FCT [SFRH/BPD/70277/2010]info:eu-repo/semantics/publishedVersio

    TRY plant trait database - enhanced coverage and open access

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    Plant traits-the morphological, anatomical, physiological, biochemical and phenological characteristics of plants-determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait-based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits-almost complete coverage for 'plant growth form'. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait-environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives

    Moral Distress Amongst American Physician Trainees Regarding Futile Treatments at the End of Life: A Qualitative Study.

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    BACKGROUND: Ethical challenges are common in end of life care; the uncertainty of prognosis and the ethically permissible boundaries of treatment create confusion and conflict about the balance between benefits and burdens experienced by patients. OBJECTIVE: We asked physician trainees in internal medicine how they reacted and responded to ethical challenges arising in the context of perceived futile treatments at the end of life and how these challenges contribute to moral distress. DESIGN: Semi-structured in-depth qualitative interviews. PARTICIPANTS: Twenty-two internal medicine residents and fellows across three American academic medical centers. APPROACH: This study uses systematic qualitative methods of data gathering, analysis and interpretation. KEY RESULTS: Physician trainees experienced significant moral distress when they felt obligated to provide treatments at or near the end of life that they believed to be futile. Some trainees developed detached and dehumanizing attitudes towards patients as a coping mechanism, which may contribute to a loss of empathy. Successful coping strategies included formal and informal conversations with colleagues and superiors about the emotional and ethical challenges of providing care at the end of life. CONCLUSIONS: Moral distress amongst physician trainees may occur when they feel obligated to provide treatments at the end of life that they believe to be futile or harmful.This study was funded by the Health Resources and Service Administration T32 HP10025-20 Training Grant, the Gates Cambridge Scholarship, Society of General Internal Medicine Founders Grant, and the Ho-Chiang Palliative Care Research Fellowship at the Johns Hopkins School of Medicine.This is the author accepted manuscript. The final version is available from Springer via http://dx.doi.org/10.1007/s11606-015-3505-

    Molecular psychiatry of zebrafish

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    Due to their well-characterized neural development and high genetic homology to mammals, zebrafish (Danio rerio) have emerged as a powerful model organism in the field of biological psychiatry. Here, we discuss the molecular psychiatry of zebrafish, and its implications for translational neuroscience research and modeling central nervous system (CNS) disorders. In particular, we outline recent genetic and technological developments allowing for in vivo examinations, high-throughput screening and whole-brain analyses in larval and adult zebrafish. We also summarize the application of these molecular techniques to the understanding of neuropsychiatric disease, outlining the potential of zebrafish for modeling complex brain disorders, including attention-deficit/hyperactivity disorder (ADHD), aggression, post-traumatic stress and substance abuse. Critically evaluating the advantages and limitations of larval and adult fish tests, we suggest that zebrafish models become a rapidly emerging new field in modern molecular psychiatry research

    A multiple timepoint pre-post evaluation of a ‘sexual respect’ dvd to improve competence in discussing sex with patients with disability

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    Sexual problems are common after chronic illnesses and disability, yet research indicates that this is a neglected area in healthcare services. Evaluation studies provide evidence of the effectiveness of education in enhancing professionals’ knowledge, skills, and comfort in addressing patients’ sexual concerns. However, there are limited evaluations aimed at improving ability to discuss sexuality when working with people with disabilities. The overall aim of this study was to evaluate a ‘Sexual Respect’ DVD as an intervention to improve competence in addressing ‘sexuality and disability’. A mixed methods design was used with both quantitative and qualitative components. Nursing students’ self-report ratings of knowledge, confidence, comfort and willingness (to discuss sexuality) levels were collected across four time points: baseline, pre-intervention, post-intervention, and follow-up. Data were analysed using one-way repeated measures ANOVAs with post hoc comparisons. Open-ended qualitative comments relating to the barriers and facilitators to discussing sexuality were analysed using content analysis and subsequent frequency analysis. Reported barriers included lack of knowledge about sex¬uality and disability issues, the patient’s level of disability, and waiting for the patient to raise sexuality issues first. Facilitators included education/training, written information, and if the patient raised it first. Overall, the DVD intervention had a significant and positive impact on nursing students’ self-reported knowledge, confidence, comfort and willingness levels. The findings are discussed in relation to the PLISSIT model, which emphasises the importance of a proactive approach to addressing sexuality issues

    Multi-messenger observations of a binary neutron star merger

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    On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

    Reaction mechanism for the replacement of calcite by dolomite and siderite: Implications for geochemistry, microstructure and porosity evolution during hydrothermal mineralisation

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    Carbonate reactions are common in mineral deposits due to CO2-rich mineralising fluids. This study presents the first in-depth, integrated analysis of microstructure and microchemistry of fluid-mediated carbonate reaction textures at hydrothermal conditions. In doing so, we describe the mechanisms by which carbonate phases replace one another, and the implications for the evolution of geochemistry, rock microstructures and porosity. The sample from the 1.95 Moz Junction gold deposit, Western Australia, contains calcite derived from carbonation of a metamorphic amphibole—plagioclase assemblage that has further altered to siderite and dolomite. The calcite is porous and contains iron-rich calcite blebs interpreted to have resulted from fluid-mediated replacement of compositionally heterogeneous amphiboles. The siderite is polycrystalline but nucleates topotactically on the calcite. As a result, the boundaries between adjacent grains are low-angle boundaries (<10°), which are geometrically similar to those formed by crystal–plastic deformation and recovery. Growth zoning within individual siderite grains shows that the low-angle boundaries are growth features and not due to deformation. Low-angle boundaries develop due to the propagation of defects at grain faces and zone boundaries and by impingement of grains that nucleated with small misorientations relative to each other during grain growth.The cores of siderite grains are aligned with the twin planes in the parent calcite crystal showing that the reactant Fe entered the crystal along the twin boundaries. Dolomite grains, many of which appear to in-fill space generated by the siderite replacement, also show alignment of cores along the calcite twin planes, suggesting that they did not grow into space but replaced the calcite. Where dolomite is seen directly replacing calcite, it nucleates on the Fe-rich calcite due to the increased compatibility of the Fe-bearing calcite lattice relative to the pure calcite. Both reactions are interpreted as fluid-mediated replacement reactions which use the crystallography and elemental chemistry of the calcite. Experiments of fluid-mediated replacement reactions show that they proceed much faster than diffusion-based reactions. This is important when considering the rates of reactions relative to fluid flow in mineralising systems

    Endoscopic diagnosis of acute intestinal GVHD following allogeneic hematopoietic SCT: a retrospective analysis in 175 patients

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    Diagnosis of acute intestinal GVHD (aGVHD) following allogeneic hematopoietic cell transplantation is based on clinical symptoms and histological lesions. This retrospective analysis aimed to validate the ‘Freiburg Criteria' for the endoscopic grading of intestinal aGVHD. Grade 1: no clear-cut criteria; grade 2: spotted erythema; grade 3: aphthous lesions; and grade 4: confluent defects, ulcers, denudation of the mucosa. Having excluded patients with infectious diarrhea, we evaluated 175 consecutive patients between January 2001 and June 2009. Setting a cutoff between grade 1 (no change in therapy) and grade 2 (intensification of immunosuppression), macroscopy had a sensitivity of 89.2% (95% confidence interval (CI): 80.4–94.9%), a specificity of 79.4% (95% CI: 69.6–87.1%), a positive-predictive value of 79.6% (95% CI: 70.0–87.2%) and a negative-predictive value of 89.0% (95% CI: 80.2–94.9%). In all, 20% of patients with aGVHD in the lower gastrointestinal tract (GIT) had lesions only in the terminal ileum. In all patients with aGVHD ⩾2 of the upper GIT, typical lesions were also found in the lower GIT. Ileo-colonoscopy showed the highest diagnostic yield for aGVHD. In conclusion, the ‘Freiburg Criteria' for macroscopic diagnosis of intestinal aGVHD provide high accuracy for identifying aGVHD ⩾2

    Prokayrotic Ubiquitin-Like Protein (Pup) Proteome of Mycobacterium tuberculosis

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    Prokaryotic ubiquitin-like protein (Pup) in Mycobacterium tuberculosis (Mtb) is the first known post-translational small protein modifier in prokaryotes, and targets several proteins for degradation by a bacterial proteasome in a manner akin to ubiquitin (Ub) mediated proteolysis in eukaryotes. To determine the extent of pupylation in Mtb, we used tandem affinity purification to identify its “pupylome”. Mass spectrometry identified 55 out of 604 purified proteins with confirmed pupylation sites. Forty-four proteins, including those with and without identified pupylation sites, were tested as substrates of proteolysis in Mtb. Under steady state conditions, the majority of the test proteins did not accumulate in degradation mutants, suggesting not all targets of pupylation are necessarily substrates of the proteasome under steady state conditions. Four proteins implicated in Mtb pathogenesis, Icl (isocitrate lyase), Ino1 (inositol-1-phosphate synthase), MtrA (Mtb response regulator A) and PhoP (phosphate response regulator P), showed altered levels in degradation defective Mtb. Icl, Ino1 and MtrA accumulated in Mtb degradation mutants, suggesting these proteins are targeted to the proteasome. Unexpectedly, PhoP was present in wild type Mtb but undetectable in the degradation mutants. Taken together, these data demonstrate that pupylation regulates numerous proteins in Mtb and may not always lead to degradation
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