Synthesis of atropisomeric phosphino-triazoles and their corresponding gold(i) complexes

The synthesis of atropisomeric phoshino-triazoles is disclosed. It was found that the introduction of a phosphine functionality onto the 5-position of a 1,2,3-triazole ring could be highly restrictive towards the rotation around a triazole-aryl bond. VT NMR and chiral HPLC studies demonstrated that rotation was restricted even at high temperatures. Gold(I) chloride complexes of single-enantiomer phosphines were prepared and again demonstrated to be conformationally stable

Semiclassical Stability of the Extreme Reissner-Nordstrom Black Hole

The stress-energy tensor of a free quantized scalar field is calculated in the extreme Reissner-Nordstr\"{o}m black hole spacetime in the zero temperature vacuum state. The stress-energy appears to be regular on the event horizon, contrary to the suggestion provided by two-dimensional calculations. An analytic calculation on the event horizon for a thermal state shows that if the temperature is nonzero then the stress-energy diverges strongly there.Comment: 10 pages, REVTeX, 4 figures in separate uuencoded compressed fil

Thermal divergences on the event horizons of two-dimensional black holes

The expectation value of the stress-energy tensor \langleT_{\mu\nu}\rangle of a free conformally invariant scalar field is computed in a general static two-dimensional black hole spacetime when the field is in either a zero temperature vacuum state or a thermal state at a nonzero temperature. It is found that for every static two-dimensional black hole the stress-energy diverges strongly on the event horizon unless the field is in a state at the natural black hole temperature which is defined by the surface gravity of the event horizon. This implies that both extreme and nonextreme two-dimensional black holes can only be in equilibrium with radiation at the natural black hole temperature.Comment: 13 pages, REVTe

Design of 280 GHz feedhorn-coupled TES arrays for the balloon-borne polarimeter SPIDER

We describe 280 GHz bolometric detector arrays that instrument the balloon-borne polarimeter SPIDER. A primary science goal of SPIDER is to measure the large-scale B-mode polarization of the cosmic microwave background in search of the cosmic-inflation, gravitational-wave signature. 280 GHz channels aid this science goal by constraining the level of B-mode contamination from galactic dust emission. We present the focal plane unit design, which consists of a 16$\times$16 array of conical, corrugated feedhorns coupled to a monolithic detector array fabricated on a 150 mm diameter silicon wafer. Detector arrays are capable of polarimetric sensing via waveguide probe-coupling to a multiplexed array of transition-edge-sensor (TES) bolometers. The SPIDER receiver has three focal plane units at 280 GHz, which in total contains 765 spatial pixels and 1,530 polarization sensitive bolometers. By fabrication and measurement of single feedhorns, we demonstrate 14.7$^{\circ}$ FHWM Gaussian-shaped beams with $<$1% ellipticity in a 30% fractional bandwidth centered at 280 GHz. We present electromagnetic simulations of the detection circuit, which show 94% band-averaged, single-polarization coupling efficiency, 3% reflection and 3% radiative loss. Lastly, we demonstrate a low thermal conductance bolometer, which is well-described by a simple TES model and exhibits an electrical noise equivalent power (NEP) = 2.6 $\times$ 10$^{-17}$ W/$\sqrt{\mathrm{Hz}}$, consistent with the phonon noise prediction.Comment: Proceedings of SPIE Astronomical Telescopes + Instrumentation 201

Lowering β-Amyloid Levels Rescues Learning and Memory in a Down Syndrome Mouse Model

β-amyloid levels are elevated in Down syndrome (DS) patients throughout life and are believed to cause Alzheimer's disease (AD) in adult members of this population. However, it is not known if β-amyloid contributes to intellectual disability in younger individuals. We used a γ-secretase inhibitor to lower β-amyloid levels in young mice that model DS. This treatment corrected learning deficits characteristic of these mice, suggesting that β-amyloid-lowering therapies might improve cognitive function in young DS patients

The Atacama Cosmology Telescope: Mitigating the impact of extragalactic foregrounds for the DR6 CMB lensing analysis

We investigate the impact and mitigation of extragalactic foregrounds for the CMB lensing power spectrum analysis of Atacama Cosmology Telescope (ACT) data release 6 (DR6) data. Two independent microwave sky simulations are used to test a range of mitigation strategies. We demonstrate that finding and then subtracting point sources, finding and then subtracting models of clusters, and using a profile bias-hardened lensing estimator, together reduce the fractional biases to well below statistical uncertainties, with the inferred lensing amplitude, $A_{\mathrm{lens}}$, biased by less than $0.2\sigma$. We also show that another method where a model for the cosmic infrared background (CIB) contribution is deprojected and high frequency data from Planck is included has similar performance. Other frequency-cleaned options do not perform as well, incurring either a large noise cost, or resulting in biased recovery of the lensing spectrum. In addition to these simulation-based tests, we also present null tests performed on the ACT DR6 data which test for sensitivity of our lensing spectrum estimation to differences in foreground levels between the two ACT frequencies used, while nulling the CMB lensing signal. These tests pass whether the nulling is performed at the map or bandpower level. The CIB-deprojected measurement performed on the DR6 data is consistent with our baseline measurement, implying contamination from the CIB is unlikely to significantly bias the DR6 lensing spectrum. This collection of tests gives confidence that the ACT DR6 lensing measurements and cosmological constraints presented in companion papers to this work are robust to extragalactic foregrounds.Comment: Companion paper to Qu et al and Madhavacheril et a

The rationale and design of the antihypertensives and vascular, endothelial, and cognitive function (AVEC) trial in elderly hypertensives with early cognitive impairment: Role of the renin angiotensin system inhibition

<p>Abstract</p> <p>Background</p> <p>Prior evidence suggests that the renin angiotensin system and antihypertensives that inhibit this system play a role in cognitive, central vascular, and endothelial function. Our objective is to conduct a double-blind randomized controlled clinical trial, the antihypertensives and vascular, endothelial, and cognitive function (AVEC), to compare 1 year treatment of 3 antihypertensives (lisinopril, candesartan, or hydrochlorothiazide) in their effect on memory and executive function, cerebral blood flow, and central endothelial function of seniors with hypertension and early objective evidence of executive or memory impairments.</p> <p>Methods/Design</p> <p>The overall experimental design of the AVEC trial is a 3-arm double blind randomized controlled clinical trial. A total of 100 community eligible individuals (60 years or older) with hypertension and early cognitive impairment are being recruited from the greater Boston area and randomized to lisinopril, candesartan, or hydrochlorothiazide ("active control") for 12 months. The goal of the intervention is to achieve blood pressure control defined as SBP < 140 mm Hg and DBP < 90 mm Hg. Additional antihypertensives are added to achieve this goal if needed. Eligible participants are those with hypertension, defined as a blood pressure 140/90 mm Hg or greater, early cognitive impairment without dementia defined (10 or less out of 15 on the executive clock draw test or 1 standard deviation below the mean on the immediate memory subtest of the repeatable battery for the assessment of neuropsychological status and Mini-Mental-Status-exam >20 and without clinical diagnosis of dementia or Alzheimer's disease). Individuals who are currently receiving antihypertensives are eligible to participate if the participants and the primary care providers are willing to taper their antihypertensives. Participants undergo cognitive assessment, measurements of cerebral blood flow using Transcranial Doppler, and central endothelial function by measuring changes in cerebral blood flow in response to changes in end tidal carbon dioxide at baseline (off antihypertensives), 6, and 12 months. Our outcomes are change in cognitive function score (executive and memory), cerebral blood flow, and carbon dioxide cerebral vasoreactivity.</p> <p>Discussion</p> <p>The AVEC trial is the first study to explore impact of antihypertensives in those who are showing early evidence of cognitive difficulties that did not reach the threshold of dementia. Success of this trial will offer new therapeutic application of antihypertensives that inhibit the renin angiotensin system and new insights in the role of this system in aging.</p> <p>Trial Registration</p> <p>Clinicaltrials.gov NCT00605072</p

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.