Discovery of an ultramassive pulsating white dwarf

We announce the discovery of the most massive pulsating hydrogen-atmosphere (DA) white dwarf (WD) ever discovered, GD 518. Model atmosphere fits to the optical spectrum of this star show it is a 12,030 +/- 210 K WD with a log(g) = 9.08 +/- 0.06, which corresponds to a mass of 1.20 +/- 0.03 Msun. Stellar evolution models indicate that the progenitor of such a high-mass WD endured a stable carbon-burning phase, producing an oxygen-neon-core WD. The discovery of pulsations in GD 518 thus offers the first opportunity to probe the interior of a WD with a possible oxygen-neon core. Such a massive WD should also be significantly crystallized at this temperature. The star exhibits multi-periodic luminosity variations at timescales ranging from roughly 425-595 s and amplitudes up to 0.7%, consistent in period and amplitude with the observed variability of typical ZZ Ceti stars, which exhibit non-radial g-mode pulsations driven by a hydrogen partial ionization zone. Successfully unraveling both the total mass and core composition of GD 518 provides a unique opportunity to investigate intermediate-mass stellar evolution, and can possibly place an upper limit to the mass of a carbon-oxygen-core WD, which in turn constrains SNe Ia progenitor systems.Comment: 5 pages, 3 figures, Astrophysical Journal Letters, 771, L2 (2013

Three-year follow-up and event rates in the international REduction of Atherothrombosis for Continued Health Registry

To determine 3-year event rates in outpatients with vascular disease enrolled in the REduction of Atherothrombosis for Continued Health (REACH) Registry. Methods and results REACH enrolled 67 888 outpatients with atherothrombosis [ established coronary artery disease (CAD), cerebrovascutar disease, or peripheral arterial disease (PAD)], or with at least three atherothrombotic risk factors, from 44 countries . Among the 55 499 patients at baseline with symptomatic disease, 39 675 were eligible for 3-year follow-up, and 32 247 had data available (81% retention rate). Among the symptomatic patients at 3 years, 92% were taking an antithrombotic agent, 91% an anti hypertensive, and 76% were on Upid- lowering therapy. For myocardial infarction (Ml)/ stroke/vascutar death, 1 - and 3-year event rates for all patients were 4.2 and 11.0%, respectively. Event rates (MI/ stroke/vascutar death) were significantly higher for patients with symptomatic disease vs. those with risk factors only at 1 year (4.7 vs. 2.3%, P < 0.001) and at 3 years (12.0 vs. 6.0%, P < 0.001). One and 3-year rates of MI /stroke/vascular cleath/ rehospitatization were 14.4 and 28.4 %, respectively, for patients with symptomatic disease. Rehospitalization for a vascular event other than Mi/ stroke/ vascular death was common at 3 years (19.0% overall; 33.6% for PAD ; 23.0% for CAD). For patients with symptomatic vascular disease in one vascular bed vs. multiple vascular beds, 3-year event rates for MI/stroke/ vascular death/ rehospitalization were 25.5 vs. 40.5% (P < 0.001). Conclusion Despite contemporary therapy, outpatients with symptomatic atherothrombotic vascular disease experience high rates of recurrent vascular events and rehospitalizations

Genetic aetiologies for childhood speech disorder: Novel pathways co-expressed during brain development

Childhood apraxia of speech (CAS), the prototypic severe childhood speech disorder, is characterized by motor programming and planning deficits. Genetic factors make substantive contributions to CAS aetiology, with a monogenic pathogenic variant identified in a third of cases, implicating around 20 single genes to date. Here we aimed to identify molecular causation in 70 unrelated probands ascertained with CAS. We performed trio genome sequencing. Our bioinformatic analysis examined single nucleotide, indel, copy number, structural and short tandem repeat variants. We prioritised appropriate variants arising de novo or inherited that were expected to be damaging based on in silico predictions. We identified high confidence variants in 18/70 (26%) probands, almost doubling the current number of candidate genes for CAS. Three of the 18 variants affected SETBP1, SETD1A and DDX3X, thus confirming their roles in CAS, while the remaining 15 occurred in genes not previously associated with this disorder. Fifteen variants arose de novo and three were inherited. We provide further novel insights into the biology of child speech disorder, highlighting the roles of chromatin organization and gene regulation in CAS, and confirm that genes involved in CAS are co-expressed during brain development. Our findings confirm a diagnostic yield comparable to, or even higher, than other neurodevelopmental disorders with substantial de novo variant burden. Data also support the increasingly recognised overlaps between genes conferring risk for a range of neurodevelopmental disorders. Understanding the aetiological basis of CAS is critical to end the diagnostic odyssey and ensure affected individuals are poised for precision medicine trials

On the temperature dependence of organic reactivity, nitrogen oxides, ozone production, and the impact of emission controls in San Joaquin Valley, California

The San Joaquin Valley (SJV) experiences some of the worst ozone air quality in the US, frequently exceeding the California 8 h standard of 70.4 ppb. To improve our understanding of trends in the number of ozone violations in the SJV, we analyze observed relationships between organic reactivity, nitrogen oxides (NO[subscript x]), and daily maximum temperature in the southern SJV using measurements made as part of California at the Nexus of Air Quality and Climate Change in 2010 (CalNex-SJV). We find the daytime speciated organic reactivity with respect to OH during CalNex-SJV has a temperature-independent portion with molecules typically associated with motor vehicles being the major component. At high temperatures, characteristic of days with high ozone, the largest portion of the total organic reactivity increases exponentially with temperature and is dominated by small, oxygenated organics and molecules that are unidentified. We use this simple temperature classification to consider changes in organic emissions over the last and next decade. With the CalNex-SJV observations as constraints, we examine the sensitivity of ozone production (PO[subscript 3]) to future NO[subscript x] and organic reactivity controls. We find that PO[subscript 3] is NO[subscript x]-limited at all temperatures on weekends and on weekdays when daily maximum temperatures are greater than 29 °C. As a consequence, NO[subscript x] reductions are the most effective control option for reducing the frequency of future ozone violations in the southern SJV.California Environmental Protection Agency. Air Resources Board (Contract CARB 08-316)United States. National Aeronautics and Space Administration (Grant NNX10AR36G

Orexin-1 Receptor Co-Localizes with Pancreatic Hormones in Islet Cells and Modulates the Outcome of Streptozotocin-Induced Diabetes Mellitus

Recent studies have shown that orexins play a critical role in the regulation of sleep/wake states, feeding behaviour, and reward processes. The exocrine and endocrine pancreas are involved in the regulation of food metabolism and energy balance. This function is deranged in diabetes mellitus. This study examined the pattern of distribution of orexin-1 receptor (OX1R) in the endocrine cells of the pancreas of normal and diabetic Wistar (a model of type 1 diabetes), Goto-Kakizaki (GK, a model of type 2 diabetes) rats and in orexin-deficient (OX−/−) and wild type mice. Diabetes mellitus (DM) was induced in Wistar rats and mice by streptozotocin (STZ). At different time points (12 h, 24 h, 4 weeks, 8 months and 15 months) after the induction of DM, pancreatic fragments of normal and diabetic rats were processed for immunohistochemistry and Western blotting. OX1R-immunoreactive nerves were observed in the pancreas of normal and diabetic Wistar rats. OX1R was also discernible in the pancreatic islets of normal and diabetic Wistar and GK rats, and wild type mice. OX1R co-localized with insulin (INS) and glucagon (GLU) in the pancreas of Wistar and GK rats. The number of OX1R-positive cells in the islets increased markedly (p<0.0001) after the onset of DM. The increase in the number of OX1R-positive cells is associated with a high degree of co-localization with GLU. The number of GLU- positive cells expressing OX1R was significantly (p<0.0001) higher after the onset of DM. The tissue level of OX1R protein increased with the duration of DM especially in type 1 diabetes where it co-localized with cleaved caspase 3 in islet cells. In comparison to STZ-treated wild type mice, STZ-treated OX−/− animals exhibited reduced hyperglycemia and handled glucose more efficiently in glucose tolerance test. The findings suggest an important role for the OX-OX1R pathway in STZ-induced experimental diabetes

Cystic Fibrosis: A New Target for 4-Imidazo[2,1-b]thiazole-1,4-dihydropyridines

The pharmacology of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel has attracted significant interest in recent years with the aim to search for rational new therapies for diseases caused by CFTR malfunction. Mutations that abolish the function of CFTR cause the life-threatening genetic disease cystic fibrosis (CF). The most common cause of CF is the deletion of phenylalanine 508 (ΔF508) in the CFTR chloride channel. Felodipine, nifedipine, and other antihypertensive 1,4-dihydropyridines (1,4-DHPs) that block L-type Ca(2+) channels are also effective potentiators of CFTR gating, able to correct the defective activity of ΔF508 and other CFTR mutants ( Mol. Pharmacol. 2005 , 68 , 1736 ). For this purpose, we evaluated the ability of the previously and newly synthesized 4-imidazo[2,1-b]thiazoles-1,4-dihydropyridines without vascular activity and inotropic and/or chronotropic cardiac effects ( J. Med. Chem. 2008 , 51 , 1592 ) to enhance the activity of ΔF508-CFTR. Our studies indicate compounds 17, 18, 20, 21, 38, and 39 as 1,4-DHPs with an interesting profile of activity

2020 American College of Rheumatology Guideline for the Management of Gout

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/155484/1/art41247.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/155484/2/art41247_am.pd