322 research outputs found

    Mapping interactions with the chaperone network reveals factors that protect against tau aggregation.

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    A network of molecular chaperones is known to bind proteins ('clients') and balance their folding, function and turnover. However, it is often unclear which chaperones are critical for selective recognition of individual clients. It is also not clear why these key chaperones might fail in protein-aggregation diseases. Here, we utilized human microtubule-associated protein tau (MAPT or tau) as a model client to survey interactions between ~30 purified chaperones and ~20 disease-associated tau variants (~600 combinations). From this large-scale analysis, we identified human DnaJA2 as an unexpected, but potent, inhibitor of tau aggregation. DnaJA2 levels were correlated with tau pathology in human brains, supporting the idea that it is an important regulator of tau homeostasis. Of note, we found that some disease-associated tau variants were relatively immune to interactions with chaperones, suggesting a model in which avoiding physical recognition by chaperone networks may contribute to disease

    Differential livelihood adaptation to social-ecological change in coastal Bangladesh

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    Social-ecological changes, brought about by the rapid growth of the aquaculture industry and the increased occurrence of climatic stressors, have significantly affected the livelihoods of coastal communities in Asian mega-deltas. This paper explores the livelihood adaptation responses of households of different wealth classes, the heterogeneous adaptation opportunities, barriers and limits (OBLs) faced by these households and the dynamic ways in which these factors interact to enhance or impede adaptive capacities. A mixed methods approach was used to collect empirical evidence from two villages in coastal Bangladesh. Findings reveal that households’ adaptive capacities largely depend on their wealth status, which not only determine their availability of productive resources, but also empower them to navigate social-ecological change in desirable ways. Households operate within a shared response space, which is shaped by the broader socio-economic and political landscape, as well as their previous decisions that can lock them in to particular pathways. While an adaptive response may be effective for one social group, it may cause negative externalities that can undermine the adaptation options and outcomes of another group. Adaptation OBLs interact in complex ways; the extent to which these OBLs affect different households depend on the specific livelihood activities being considered and the differential values and interests they hold. To ensure more equitable and environmentally sustainable livelihoods in future, policies and programs should aim to expand households’ adaptation space by accounting for the heterogeneous needs and complex interdependencies between response processes of different groups

    Pattern recognition receptors as potential therapeutic targets in inflammatory rheumatic disease

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    The pattern recognition receptors of the innate immune system are part of the first line of defence against pathogens. However, they also have the ability to respond to danger signals that are frequently elevated during tissue damage and at sites of inflammation. Inadvertent activation of pattern recognition receptors has been proposed to contribute to the pathogenesis of many conditions including inflammatory rheumatic diseases. Prolonged inflammation most often results in pain and damage to tissues. In particular, the Toll-like receptors and nucleotide-binding oligomerisation domain-like receptors that form inflammasomes have been postulated as key contributors to the inflammation observed in rheumatoid arthritis, osteoarthritis, gout and systemic lupus erythematosus. As such, there is increasing interest in targeting these receptors for therapeutic treatment in the clinic. Here the role of pattern recognition receptors in the pathogenesis of these diseases is discussed, with an update on the development of interventions to modulate the activity of these potential therapeutic targets

    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

    Comparing United States and Canadian population exposures from National Biomonitoring Surveys: Bisphenol A intake as a case study

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    The Centers for Disease Control and Prevention provides biomonitoring data in the United States as part of the National Health and Nutrition Examination Survey (NHANES). Recently, Statistics Canada initiated a similar survey — the Canadian Health Measures Survey (CHMS). Comparison of US and Canadian biomonitoring data can generate hypotheses regarding human exposures from environmental media and consumer products. To ensure that such comparisons are scientifically meaningful, it is essential to first evaluate aspects of the surveys' methods that can impact comparability of data. We examined CHMS and NHANES methodologies, using bisphenol A (BPA) as a case study, to evaluate whether survey differences exist that would hinder our ability to compare chemical concentrations between countries. We explored methods associated with participant selection, urine sampling, and analytical methods. BPA intakes were also estimated to address body weight differences between countries. Differences in survey methods were identified but are unlikely to have substantial impacts on inter-survey comparisons of BPA intakes. BPA intakes for both countries are below health-based guidance values set by the US, Canada and the European Food Safety Authority. We recommend that before comparing biomonitoring data between surveys, a thorough review of methodologic aspects that might impact biomonitoring results be conducted

    Modelling the population effectiveness of the national seasonal influenza vaccination programme in Scotland : the impact of targeting all individuals aged 65 years and over Flu Vaccination Programme Effectiveness

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    Background: For the last 17 years, the UK has employed a routine influenza vaccination programme with the aim of reducing the spread of seasonal influenza. In mid-2000, the programme moved from a purely risk-based approach to a risk and age group targeted approach with all those aged 65+ years being included. To date, there has been no assessment of the population effectiveness of this age targeted policy in Scotland. Objectives: Statistical modelling techniques were used to determine what impact the routine vaccination of those aged 65+ years has had on influenza related morbidity and mortality in Scotland. Methods: Two Poisson regression models were developed using weekly counts of all-cause mortality, cause specific mortality and emergency hospitalisations for the period 1981 – 2012, one using week-in-year and the other using temperature to capture the seasonal variability in mortality/hospitalisations. These models were used to determine the number of excess deaths/hospitalisations associated with the introduction of the local risk and age-based vaccination programme in 2000. Results: Routinely vaccinating those aged 65+ years is associated with a reduction in excess allcause mortality, cardiovascular and COPD related mortality and COPD related hospitalisations. Our analysis suggests that using the week-in-year model, on average, 732 (95%CI 66 – 1,398) deaths from all-causes, 248 (95%CI 10 – 486) cardiovascular related deaths, 123 (95%CI 28 – 218) COPD related deaths, and 425 (95%CI 258 – 592) COPD related hospitalisations have been prevented each flu season among the those aged 65+. Similar results were found using the temperature model. There was no evidence to suggest that the change in policy was associated with reductions in influenza/pneumonia related mortality or influenza/cardiovascular related hospitalisations. Conclusions: Routinely vaccinating those aged 65+ years appears to have reduced influenza related morbidity and mortality in Scotland. With the childhood vaccination programme well underway, these data provide an importance benchmark which can be used to accurately assess the impact of this new seasonal influenza vaccination programme

    Androgen receptor expression predicts breast cancer survival: the role of genetic and epigenetic events

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    Background: Breast cancer outcome, including response to therapy, risk of metastasis and survival, is difficult to predict using currently available methods, highlighting the urgent need for more informative biomarkers. Androgen receptor (AR) has been implicated in breast carcinogenesis however its potential to be an informative biomarker has yet to be fully explored. In this study, AR protein levels were determined in a cohort of 73 Grade III invasive breast ductal adenocarcinomas
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