Centrosome dysfunction associated with somatic expression of the synaptonemal complex protein TEX12

The synaptonemal complex (SC) is a supramolecular protein scaffold that mediates chromosome synapsis and facilitates crossing over during meiosis. In mammals, SC proteins are generally assumed to have no other function. Here, we show that SC protein TEX12 also localises to centrosomes during meiosis independently of chromosome synapsis. In somatic cells, ectopically expressed TEX12 similarly localises to centrosomes, where it is associated with centrosome amplification, a pathology correlated with cancer development. Indeed, TEX12 is identified as a cancer-testis antigen and proliferation of some cancer cells is TEX12-dependent. Moreover, somatic expression of TEX12 is aberrantly activated via retinoic acid signalling, which is commonly disregulated in cancer. Structure-function analysis reveals that phosphorylation of TEX12 on tyrosine 48 is important for centrosome amplification but not for recruitment of TEX12 to centrosomes. We conclude that TEX12 normally localises to meiotic centrosomes, but its misexpression in somatic cells can contribute to pathological amplification and dysfunction of centrosomes in cancers

Supporting Shared Decision-Making for Older People with Multiple Health and Social Care Needs: a Protocol for a Realist Synthesis to Inform Integrated Care Models

Introduction: Including the patient or user perspective is a central organising principle of integrated care. Moreover, there is increasing recognition of the importance of strengthening relationships among patients, carers and practitioners, particularly for individuals receiving substantial health and care support, such as those with long-term or multiple conditions. The overall aims of this synthesis are to provide a context-relevant understanding of how models to facilitate shared decision-making (SDM) might work for older people with multiple health and care needs, and how they might be applied to integrated care models. Methods and analysis: The synthesis draws on the principles of realist inquiry, to explain how, in what contexts and for whom, interventions that aim to strengthen SDM among older patients, carers and practitioners are effective. We will use an iterative, stakeholder-driven, three-phase approach. Phase 1: development of programme theory/theories that will be tested through a first scoping of the literature and consultation with key stakeholder groups; phase 2: systematic searches of the evidence to test and develop the theories identified in phase 1; phase 3: validation of programme theory/theories with a purposive sample of participants from phase 1. The synthesis will draw on prevailing theories such as candidacy, self-efficacy, personalisation and coproduction. Ethics and dissemination: Ethics approval for the stakeholder interviews was obtained from the University of Hertfordshire ECDA (Ethics Committee with Delegated Authority), reference number HSK/SF/UH/02387. The propositions arising from this review will be used to develop recommendations about how to tailor SDM interventions to older people with complex health and social care needs in an integrated care setting

Supporting Shared Decision-Making for Older People with Multiple Health and Social Care Needs: a Protocol for a Realist Synthesis to Inform Integrated Care Models

Introduction: Including the patient or user perspective is a central organising principle of integrated care. Moreover, there is increasing recognition of the importance of strengthening relationships among patients, carers and practitioners, particularly for individuals receiving substantial health and care support, such as those with long-term or multiple conditions. The overall aims of this synthesis are to provide a context-relevant understanding of how models to facilitate shared decision-making (SDM) might work for older people with multiple health and care needs, and how they might be applied to integrated care models. Methods and analysis: The synthesis draws on the principles of realist inquiry, to explain how, in what contexts and for whom, interventions that aim to strengthen SDM among older patients, carers and practitioners are effective. We will use an iterative, stakeholder-driven, three-phase approach. Phase 1: development of programme theory/theories that will be tested through a first scoping of the literature and consultation with key stakeholder groups; phase 2: systematic searches of the evidence to test and develop the theories identified in phase 1; phase 3: validation of programme theory/theories with a purposive sample of participants from phase 1. The synthesis will draw on prevailing theories such as candidacy, self-efficacy, personalisation and coproduction. Ethics and dissemination: Ethics approval for the stakeholder interviews was obtained from the University of Hertfordshire ECDA (Ethics Committee with Delegated Authority), reference number HSK/SF/UH/02387. The propositions arising from this review will be used to develop recommendations about how to tailor SDM interventions to older people with complex health and social care needs in an integrated care setting

High redshift X-ray cooling-core cluster associated with the luminous radio loud quasar 3C186

We present the first results from a new, deep (200ks) Chandra observation of the X-ray luminous galaxy cluster surrounding the powerful (L ~10^47 erg/s), high-redshift (z=1.067), compact-steep-spectrum radio-loud quasar 3C186. The diffuse X-ray emission from the cluster has a roughly ellipsoidal shape and extends out to radii of at least ~60 arcsec (~500 kpc). The centroid of the diffuse X-ray emission is offset by 0.68(+/-0.11) arcsec (5.5+/-0.9 kpc) from the position of the quasar. We measure a cluster mass within the radius at which the mean enclosed density is 2500 times the critical density, r_2500=283(+18/-13)kpc, of 1.02 (+0.21/-0.14)x10^14 M_sun. The gas mass fraction within this radius is f_gas=0.129(+0.015/-0.016). This value is consistent with measurements at lower redshifts and implies minimal evolution in the f_gas(z) relation for hot, massive clusters at 0<z<1.1. The measured metal abundance of 0.42(+0.08/-0.07) Solar is consistent with the abundance observed in other massive, high redshift clusters. The spatially-resolved temperature profile for the cluster shows a drop in temperature, from kT~8 keV to kT~3 keV, in its central regions that is characteristic of cooling core clusters. This is the first spectroscopic identification of a cooling core cluster at z>1. We measure cooling times for the X-ray emitting gas at radii of 50 kpc and 25 kpc of 1.7(+/-0.2)x10^9 years and 7.5(+/-2.6)x 10^8 years, as well as a nominal cooling rate (in the absence of heating) of 400(+/-190)M_sun/year within the central 100 kpc. In principle, the cooling gas can supply enough fuel to support the growth of the supermassive black hole and to power the luminous quasar. The radiative power of the quasar exceeds by a factor of 10 the kinematic power of the central radio source, suggesting that radiative heating may be important at intermittent intervals in cluster cores.Comment: 15 pages, 9 figures, ApJ in pres

Managing for healthy white pine ecosystems in the United States to reduce the impacts of white pine blister rust

Gerald W. Williams Collectio

Deep Chandra X-ray Imaging of a Nearby Radio Galaxy 4C+29.30: X-ray/Radio Connection

We report results from our deep Chandra X-ray observations of a nearby radio galaxy, 4C+29.30 (z=0.0647). The Chandra image resolves structures on sub-arcsec to arcsec scales, revealing complex X-ray morphology and detecting the main radio features: the nucleus, a jet, hotspots, and lobes. The nucleus is absorbed (N(H)=3.95 (+0.27/-0.33)x10^23 atoms/cm^2) with an unabsorbed luminosity of L(2-10 keV) ~ (5.08 +/-0.52) 10^43 erg/s characteristic of Type 2 AGN. Regions of soft (<2 keV) X-ray emission that trace the hot interstellar medium (ISM) are correlated with radio structures along the main radio axis indicating a strong relation between the two. The X-ray emission beyond the radio source correlates with the morphology of optical line-emitting regions. We measured the ISM temperature in several regions across the galaxy to be kT ~ 0.5 with slightly higher temperatures (of a few keV) in the center and in the vicinity of the radio hotspots. Assuming these regions were heated by weak shocks driven by the expanding radio source, we estimated the corresponding Mach number of 1.6 in the southern regions. The thermal pressure of the X-ray emitting gas in the outermost regions suggest the hot ISM is slightly under-pressured with respect to the cold optical-line emitting gas and radio-emitting plasma, which both seem to be in a rough pressure equilibrium. We conclude that 4C+29.30 displays a complex view of interactions between the jet-driven radio outflow and host galaxy environment, signaling feedback processes closely associated with the central active nucleus.Comment: ApJ in pres

Are there valid proxy measures of clinical behaviour?

Background: Accurate measures of health professionals' clinical practice are critically important to guide health policy decisions, as well as for professional self-evaluation and for research-based investigation of clinical practice and process of care. It is often not feasible or ethical to measure behaviour through direct observation, and rigorous behavioural measures are difficult and costly to use. The aim of this review was to identify the current evidence relating to the relationships between proxy measures and direct measures of clinical behaviour. In particular, the accuracy of medical record review, clinician self-reported and patient-reported behaviour was assessed relative to directly observed behaviour. Methods: We searched: PsycINFO; MEDLINE; EMBASE; CINAHL; Cochrane Central Register of Controlled Trials; science/social science citation index; Current contents (social & behavioural med/clinical med); ISI conference proceedings; and Index to Theses. Inclusion criteria: empirical, quantitative studies; and examining clinical behaviours. An independent, direct measure of behaviour (by standardised patient, other trained observer or by video/audio recording) was considered the 'gold standard' for comparison. Proxy measures of behaviour included: retrospective self-report; patient-report; or chart-review. All titles, abstracts, and full text articles retrieved by electronic searching were screened for inclusion and abstracted independently by two reviewers. Disagreements were resolved by discussion with a third reviewer where necessary. Results: Fifteen reports originating from 11 studies met the inclusion criteria. The method of direct measurement was by standardised patient in six reports, trained observer in three reports, and audio/video recording in six reports. Multiple proxy measures of behaviour were compared in five of 15 reports. Only four of 15 reports used appropriate statistical methods to compare measures. Some direct measures failed to meet our validity criteria. The accuracy of patient report and chart review as proxy measures varied considerably across a wide range of clinical actions. The evidence for clinician self-report was inconclusive. Conclusion: Valid measures of clinical behaviour are of fundamental importance to accurately identify gaps in care delivery, improve quality of care, and ultimately to improve patient care. However, the evidence base for three commonly used proxy measures of clinicians' behaviour is very limited. Further research is needed to better establish the methods of development, application, and analysis for a range of both direct and proxy measures of behaviour

Silent progression in disease activity-free relapsing multiple sclerosis.

ObjectiveRates of worsening and evolution to secondary progressive multiple sclerosis (MS) may be substantially lower in actively treated patients compared to natural history studies from the pretreatment era. Nonetheless, in our recently reported prospective cohort, more than half of patients with relapsing MS accumulated significant new disability by the 10th year of follow-up. Notably, "no evidence of disease activity" at 2 years did not predict long-term stability. Here, we determined to what extent clinical relapses and radiographic evidence of disease activity contribute to long-term disability accumulation.MethodsDisability progression was defined as an increase in Expanded Disability Status Scale (EDSS) of 1.5, 1.0, or 0.5 (or greater) from baseline EDSS = 0, 1.0-5.0, and 5.5 or higher, respectively, assessed from baseline to year 5 (±1 year) and sustained to year 10 (±1 year). Longitudinal analysis of relative brain volume loss used a linear mixed model with sex, age, disease duration, and HLA-DRB1*15:01 as covariates.ResultsRelapses were associated with a transient increase in disability over 1-year intervals (p = 0.012) but not with confirmed disability progression (p = 0.551). Relative brain volume declined at a greater rate among individuals with disability progression compared to those who remained stable (p &lt; 0.05).InterpretationLong-term worsening is common in relapsing MS patients, is largely independent of relapse activity, and is associated with accelerated brain atrophy. We propose the term silent progression to describe the insidious disability that accrues in many patients who satisfy traditional criteria for relapsing-remitting MS. Ann Neurol 2019;85:653-666

γ-Butyrobetaine Is A Proatherogenic Intermediate in Gut Microbial Metabolism of L-Carnitine to TMAO

L-carnitine, a nutrient in red meat, was recently reported to accelerate atherosclerosis via a metaorganismal pathway involving gut microbial trimethylamine (TMA) formation and host hepatic conversion into trimethylamine-N-oxide (TMAO). Herein, we show that following L-carnitine ingestion, γ-butyrobetaine (γBB) is produced as an intermediary metabolite by gut microbes at a site anatomically proximal to and at a rate ∼1,000-fold higher than the formation of TMA. Moreover, we show that γBB is the major gut microbial metabolite formed from dietary L-carnitine in mice, is converted into TMA and TMAO in a gut microbiota-dependent manner (like dietary L-carnitine), and accelerates atherosclerosis. Gut microbial composition and functional metabolic studies reveal that distinct taxa are associated with the production of γBB or TMA/TMAO from dietary L-carnitine. Moreover, despite their close structural similarity, chronic dietary exposure to L-carnitine or γBB promotes development of functionally distinct microbial communities optimized for the metabolism of L-carnitine or γBB, respectively

Gut Microbial Metabolite TMAO Enhances Platelet Hyperreactivity and Thrombosis Risk

Normal platelet function is critical to blood hemostasis and maintenance of a closed circulatory system. Heightened platelet reactivity, however, is associated with cardiometabolic diseases and enhanced potential for thrombotic events. We now show gut microbes, through generation of trimethylamine N-oxide (TMAO), directly contribute to platelet hyperreactivity and enhanced thrombosis potential. Plasma TMAO levels in subjects (n \u3e 4,000) independently predicted incident (3 years) thrombosis (heart attack, stroke) risk. Direct exposure of platelets to TMAO enhanced sub-maximal stimulus-dependent platelet activation from multiple agonists through augmented Ca2+ release from intracellular stores. Animal model studies employing dietary choline or TMAO, germ-free mice, and microbial transplantation collectively confirm a role for gut microbiota and TMAO in modulating platelet hyperresponsiveness and thrombosis potential and identify microbial taxa associated with plasma TMAO and thrombosis potential. Collectively, the present results reveal a previously unrecognized mechanistic link between specific dietary nutrients, gut microbes, platelet function, and thrombosis risk