HAP1 facilitates effects of mutant huntingtin on inositol 1,4,5-trisphosphate-induced Ca2+ release in primary culture of striatal medium spiny neurons

Huntington's disease is caused by polyglutamine expansion (exp) in huntingtin (Htt). Htt-associated protein-1 (HAP1) was the first identified Htt-binding partner. The type 1 inositol (1,4,5)-trisphosphate receptor (InsP3R1) is an intracellular Ca2+ release channel that plays an important role in neuronal function. Recently, we identified a InsP3R1-HAP1A-Htt ternary complex in the brain and demonstrated that Httexp, but not normal Htt, activates InsP3R1 in bilayers and facilitates InsP3R1-mediated intracellular Ca2+ release in medium spiny striatal neurons [MSN; T.-S. Tang et al. (2003) Neuron, 39, 227-239]. Here we took advantage of mice with targeted disruption of both HAP1 alleles (HAP1 -/-) to investigate the role of HAP1 in functional interactions between Htt and InsP3R1. We determined that: (i) HAP1 is expressed in the MSN; (ii) HAP1A facilitates functional effects of Htt and Htt(exp) on InsP3R1 in planar lipid bilayers; (iii) HAP1 is required for changes in MSN basal Ca2+ levels resulting from Htt or Htt(exp) overexpression; (iv) HAP1 facilitates potentiation of InsP3R1-mediated Ca2+ release by Htt(exp) in mouse MSN. Our present results indicate that HAP1 plays an important role in functional interactions between Htt and InsP3R1

Prediction of cardiovascular events in rheumatoid arthritis using risk age calculations: Evaluation of concordance across risk age models

Background: In younger individuals, low absolute risk of cardiovascular disease (CVD) may conceal an increased risk age and relative risk of CVD. Calculation of risk age is proposed as an adjuvant to absolute CVD risk estimation in European guidelines. We aimed to compare the discriminative ability of available risk age models in prediction of CVD in rheumatoid arthritis (RA). Secondly, we also evaluated the performance of risk age models in subgroups based on RA disease characteristics. Methods: RA patients aged 30-70 years were included from an international consortium named A Trans-Atlantic Cardiovascular Consortium for Rheumatoid Arthritis (ATACC-RA). Prior CVD and diabetes mellitus were exclusion criteria. The discriminatory ability of specific risk age models was evaluated using c-statistics and their standard errors after calculating time until fatal or non-fatal CVD or last follow-up. Results: A total of 1974 patients were included in the main analyses, and 144 events were observed during follow-up, the median follow-up being 5.0 years. The risk age models gave highly correlated results, demonstrating R 2 values ranging from 0.87 to 0.97. However, risk age estimations differed > 5 years in 15-32% of patients. C-statistics ranged 0.68-0.72 with standard errors of approximately 0.03. Despite certain RA characteristics being associated with low c-indices, standard errors were high. Restricting analysis to European RA patients yielded similar results. Conclusions: The cardiovascular risk age and vascular age models have comparable performance in predicting CVD in RA patients. The influence of RA disease characteristics on the predictive ability of these prediction models remains inconclusive. © 2020 The Author(s)

An international audit of the management of dyslipidaemia and hypertension in patients with rheumatoid arthritis: results from 19 countries

AIMS: To assess differences in estimated cardiovascular disease (CVD) risk among rheumatoid arthritis (RA) patients from different world regions and to evaluate the management and goal attainment of lipids and blood pressure (BP). METHODS AND RESULTS: The survey of CVD risk factors in patients with RA was conducted in 14 503 patients from 19 countries during 2014-19. The treatment goal for BP was <140/90 mmHg. CVD risk prediction and lipid goals were according to the 2016 European guidelines. Overall, 21% had a very high estimated risk of CVD, ranging from 5% in Mexico, 15% in Asia, 19% in Northern Europe, to 31% in Central and Eastern Europe and 30% in North America. Of the 52% with indication for lipid-lowering treatment (LLT), 44% were using LLT. The lipid goal attainment was 45% and 18% in the high and very high risk groups, respectively. Use of statins in monotherapy was 24%, while 1% used statins in combination with other LLT. Sixty-two per cent had hypertension and approximately half of these patients were at BP goal. The majority of the patients used antihypertensive treatment in monotherapy (24%), while 10% and 5% as a two- or three-drug combination. CONCLUSION: We revealed considerable geographical differences in estimated CVD risk and preventive treatment. Low goal attainment for LLT was observed, and only half the patients obtained BP goal. Despite a high focus on the increased CVD risk in RA patients over the last decade, there is still substantial potential for improvement in CVD preventive measures

The miniJPAS survey: a preview of the Universe in 56 colours

International audienceThe Javalambre-Physics of the Accelerating Universe Astrophysical Survey (J-PAS) will soon start to scan thousands of square degrees of the northern extragalactic sky with a unique set of $56$ optical filters from a dedicated $2.55$m telescope, JST, at the Javalambre Astrophysical Observatory. Before the arrival of the final instrument (a 1.2 Gpixels, 4.2deg$^2$ field-of-view camera), the JST was equipped with an interim camera (JPAS-Pathfinder), composed of one CCD with a 0.3deg$^2$ field-of-view and resolution of 0.23 arcsec pixel$^{-1}$. To demonstrate the scientific potential of J-PAS, with the JPAS-Pathfinder camera we carried out a survey on the AEGIS field (along the Extended Groth Strip), dubbed miniJPAS. We observed a total of $\sim 1$ deg$^2$, with the $56$ J-PAS filters, which include $54$ narrow band (NB, $\rm{FWHM} \sim 145$Angstrom) and two broader filters extending to the UV and the near-infrared, complemented by the $u,g,r,i$ SDSS broad band (BB) filters. In this paper we present the miniJPAS data set, the details of the catalogues and data access, and illustrate the scientific potential of our multi-band data. The data surpass the target depths originally planned for J-PAS, reaching $\rm{mag}_{\rm {AB}}$ between $\sim 22$ and $23.5$ for the NB filters and up to $24$ for the BB filters ($5\sigma$ in a $3$~arcsec aperture). The miniJPAS primary catalogue contains more than $64,000$ sources extracted in the $r$ detection band with forced photometry in all other bands. We estimate the catalogue to be complete up to $r=23.6$ for point-like sources and up to $r=22.7$ for extended sources. Photometric redshifts reach subpercent precision for all sources up to $r=22.5$, and a precision of $\sim 0.3$% for about half of the sample. (Abridged

The miniJPAS survey: A preview of the Universe in 56 colors

International audienceThe Javalambre-Physics of the Accelerating Universe Astrophysical Survey (J-PAS) will scan thousands of square degrees of the northern sky with a unique set of 56 filters using the dedicated 2.55 m Javalambre Survey Telescope (JST) at the Javalambre Astrophysical Observatory. Prior to the installation of the main camera (4.2 deg2 field-of-view with 1.2 Gpixels), the JST was equipped with the JPAS-Pathfinder, a one CCD camera with a 0.3 deg2 field-of-view and plate scale of 0.23 arcsec pixel−1. To demonstrate the scientific potential of J-PAS, the JPAS-Pathfinder camera was used to perform miniJPAS, a ∼1 deg2 survey of the AEGIS field (along the Extended Groth Strip). The field was observed with the 56 J-PAS filters, which include 54 narrow band (FWHM ∼ 145 Å) and two broader filters extending to the UV and the near-infrared, complemented by the u, g, r, i SDSS broad band filters. In this miniJPAS survey overview paper, we present the miniJPAS data set (images and catalogs), as we highlight key aspects and applications of these unique spectro-photometric data and describe how to access the public data products. The data parameters reach depths of magAB ≃ 22−23.5 in the 54 narrow band filters and up to 24 in the broader filters (5σ in a 3″ aperture). The miniJPAS primary catalog contains more than 64 000 sources detected in the r band and with matched photometry in all other bands. This catalog is 99% complete at r = 23.6 (r = 22.7) mag for point-like (extended) sources. We show that our photometric redshifts have an accuracy better than 1% for all sources up to r = 22.5, and a precision of ≤0.3% for a subset consisting of about half of the sample. On this basis, we outline several scientific applications of our data, including the study of spatially-resolved stellar populations of nearby galaxies, the analysis of the large scale structure up to z ∼ 0.9, and the detection of large numbers of clusters and groups. Sub-percent redshift precision can also be reached for quasars, allowing for the study of the large-scale structure to be pushed to z > 2. The miniJPAS survey demonstrates the capability of the J-PAS filter system to accurately characterize a broad variety of sources and paves the way for the upcoming arrival of J-PAS, which will multiply this data by three orders of magnitude.Key words: surveys / techniques: photometric / astronomical databases: miscellaneous / stars: general / galaxies: general / cosmology: observations⋆ miniJPAS data and associated value added catalogs are publicly available http://archive.cefca.es/catalogues/minijpas-pdr20191

Vorapaxar in the secondary prevention of atherothrombotic events

Item does not contain fulltextBACKGROUND: Thrombin potently activates platelets through the protease-activated receptor PAR-1. Vorapaxar is a novel antiplatelet agent that selectively inhibits the cellular actions of thrombin through antagonism of PAR-1. METHODS: We randomly assigned 26,449 patients who had a history of myocardial infarction, ischemic stroke, or peripheral arterial disease to receive vorapaxar (2.5 mg daily) or matching placebo and followed them for a median of 30 months. The primary efficacy end point was the composite of death from cardiovascular causes, myocardial infarction, or stroke. After 2 years, the data and safety monitoring board recommended discontinuation of the study treatment in patients with a history of stroke owing to the risk of intracranial hemorrhage. RESULTS: At 3 years, the primary end point had occurred in 1028 patients (9.3%) in the vorapaxar group and in 1176 patients (10.5%) in the placebo group (hazard ratio for the vorapaxar group, 0.87; 95% confidence interval [CI], 0.80 to 0.94; P<0.001). Cardiovascular death, myocardial infarction, stroke, or recurrent ischemia leading to revascularization occurred in 1259 patients (11.2%) in the vorapaxar group and 1417 patients (12.4%) in the placebo group (hazard ratio, 0.88; 95% CI, 0.82 to 0.95; P=0.001). Moderate or severe bleeding occurred in 4.2% of patients who received vorapaxar and 2.5% of those who received placebo (hazard ratio, 1.66; 95% CI, 1.43 to 1.93; P<0.001). There was an increase in the rate of intracranial hemorrhage in the vorapaxar group (1.0%, vs. 0.5% in the placebo group; P<0.001). CONCLUSIONS: Inhibition of PAR-1 with vorapaxar reduced the risk of cardiovascular death or ischemic events in patients with stable atherosclerosis who were receiving standard therapy. However, it increased the risk of moderate or severe bleeding, including intracranial hemorrhage. (Funded by Merck; TRA 2P-TIMI 50 ClinicalTrials.gov number, NCT00526474.)