Elite Social Movements and the State: A Case Study of the Committee on the Present Danger

http://deepblue.lib.umich.edu/bitstream/2027.42/51183/1/416.pd

A Bayesian approach for energy-based estimation of acoustic aberrations in high intensity focused ultrasound treatment

High intensity focused ultrasound is a non-invasive method for treatment of diseased tissue that uses a beam of ultrasound to generate heat within a small volume. A common challenge in application of this technique is that heterogeneity of the biological medium can defocus the ultrasound beam. Here we reduce the problem of refocusing the beam to the inverse problem of estimating the acoustic aberration due to the biological tissue from acoustic radiative force imaging data. We solve this inverse problem using a Bayesian framework with a hierarchical prior and solve the inverse problem using a Metropolis-within-Gibbs algorithm. The framework is tested using both synthetic and experimental datasets. We demonstrate that our approach has the ability to estimate the aberrations using small datasets, as little as 32 sonication tests, which can lead to significant speedup in the treatment process. Furthermore, our approach is compatible with a wide range of sonication tests and can be applied to other energy-based measurement techniques

Ruprecht 147: The oldest nearby open cluster as a new benchmark for stellar astrophysics

Ruprecht 147 is a hitherto unappreciated open cluster that holds great promise as a standard in fundamental stellar astrophysics. We have conducted a radial velocity survey of astrometric candidates with Lick, Palomar, and MMT observatories and have identified over 100 members, including 5 blue stragglers, 11 red giants, and 5 double-lined spectroscopic binaries (SB2s). We estimate the cluster metallicity from spectroscopic analysis, using Spectroscopy Made Easy (SME), and find it to be [M/H] = +0.07 \pm 0.03. We have obtained deep CFHT/MegaCam g'r'i' photometry and fit Padova isochrones to the (g' - i') and 2MASS (J - K) CMDs using the \tau^2 maximum-likelihood procedure of Naylor (2009), and an alternative method using 2D cross-correlations developed in this work. We find best fits for isochrones at age t = 2.5 \pm 0.25 Gyr, m - M = 7.35 \pm 0.1, and A_V = 0.25 \pm 0.05, with additional uncertainty from the unresolved binary population and possibility of differential extinction across this large cluster. The inferred age is heavily dependent by our choice of stellar evolution model: fitting Dartmouth and PARSEC models yield age parameters of 3 Gyr and 3.25 Gyr respectively. At approximately 300 pc and 3 Gyr, Ruprecht 147 is by far the oldest nearby star cluster.Comment: 31 pages, 21 figures, 6 tables. Comments welcom

A Bayesian Approach for Energy-Based Estimation of Acoustic Aberrations in High Intensity Focused Ultrasound Treatment

High intensity focused ultrasound is a non-invasive method for treatment of diseased tissue that uses a beam of ultrasound to generate heat within a small volume. A common challenge in application of this technique is that heterogeneity of the biological medium can defocus the ultrasound beam. Here we reduce the problem of refocusing the beam to the inverse problem of estimating the acoustic aberration due to the biological tissue from acoustic radiative force imaging data. We solve this inverse problem using a Bayesian framework with a hierarchical prior and solve the inverse problem using a Metropolis-within-Gibbs algorithm. The framework is tested using both synthetic and experimental datasets. We demonstrate that our approach has the ability to estimate the aberrations using small datasets, as little as 32 sonication tests, which can lead to significant speedup in the treatment process. Furthermore, our approach is compatible with a wide range of sonication tests and can be applied to other energy-based measurement techniques

In vitro antiviral activity of SCH446211 (SCH6), a novel inhibitor of the hepatitis C virus NS3 serine protease

Background: Current hepatitis C virus (HCV) therapies may cure ∼60% of infections. They are often contraindicated or poorly tolerated, underscoring the need for safer and more effective drugs. A novel, α-ketoamide-derived, substrate-based inhibitor of the HCV serine protease (SCH446211) was developed. Compared with earlier reported inhibitors of similar chemical class, it has a P1′-P2′ extension which provides extended interaction with the protease active site. The aim of this study was to evaluate the in vitro antiviral activity of SCH446211. Methods: Binding constant of SCH446211 to HCV NS3 protease was measured with the chromogenic substrate in vitro cleavage assay. Cell-based activity of SCH446211 was evaluated in replicon cells, which are Huh-7 hepatoma cells stably transfected with a subgenomic HCV RNA as reported previously. After 72 h of incubation with SCH446211, viral transcription and protein expression were measured by real-time RT-PCR (TaqMan), quantitative in situ hybridization, immunoblot and indirect immunofluorescence. Results: The binding constant of SCH446211 to HCV NS3 protease was 3.8 ± 0.4 nM. HCV replication and protein expression were inhibited by SCH446211 in replicon cells as consistently shown by four techniques. In particular, based on quantitative real-time RT-PCR measurements, the IC50 and IC90 of SCH446211 were estimated to be 40 ± 20 and 100 ± 20 nM (n = 17), respectively. Long-term culture of replicon cells with SCH446211 reduced replicon RNA to <0.1 copy per cell. SCH446211 did not show cellular toxicity at concentrations up to 50 μM. Conclusions: SCH446211 is a potent inhibitor of HCV protease in vitro. Its extended interaction with the HCV NS3 protease active site is associated with potent in vitro antiviral activity. This observation is potentially a useful guide for development of future potent inhibitors against HCV NS3 proteas

Key steps in the structure-based optimization of the hepatitis C virus NS3/4A protease inhibitor SCH503034

Crystal structures of protease/inhibitor complexes guided optimization of the buried nonpolar surface area thereby maximizing hydrophobic binding. The resulting potent tripeptide inhibitor is in clinical trials

Cardiovascular disease, chronic kidney disease, and diabetes mortality burden of cardiometabolic risk factors from 1980 to 2010: A comparative risk assessment

Background: High blood pressure, blood glucose, serum cholesterol, and BMI are risk factors for cardiovascular diseases and some of these factors also increase the risk of chronic kidney disease and diabetes. We estimated mortality from cardiovascular diseases, chronic kidney disease, and diabetes that was attributable to these four cardiometabolic risk factors for all countries and regions from 1980 to 2010. Methods: We used data for exposure to risk factors by country, age group, and sex from pooled analyses of population-based health surveys. We obtained relative risks for the effects of risk factors on cause-specific mortality from meta-analyses of large prospective studies. We calculated the population attributable fractions for each risk factor alone, and for the combination of all risk factors, accounting for multicausality and for mediation of the effects of BMI by the other three risks. We calculated attributable deaths by multiplying the cause-specific population attributable fractions by the number of disease-specific deaths. We obtained cause-specific mortality from the Global Burden of Diseases, Injuries, and Risk Factors 2010 Study. We propagated the uncertainties of all the inputs to the final estimates. Findings: In 2010, high blood pressure was the leading risk factor for deaths due to cardiovascular diseases, chronic kidney disease, and diabetes in every region, causing more than 40% of worldwide deaths from these diseases; high BMI and glucose were each responsible for about 15% of deaths, and high cholesterol for more than 10%. After accounting for multicausality, 63% (10·8 million deaths, 95% CI 10·1-11·5) of deaths from these diseases in 2010 were attributable to the combined effect of these four metabolic risk factors, compared with 67% (7·1 million deaths, 6·6-7·6) in 1980. The mortality burden of high BMI and glucose nearly doubled from 1980 to 2010. At the country level, age-standardised death rates from these diseases attributable to the combined effects of these four risk factors surpassed 925 deaths per 100 000 for men in Belarus, Kazakhstan, and Mongolia, but were less than 130 deaths per 100 000 for women and less than 200 for men in some high-income countries including Australia, Canada, France, Japan, the Netherlands, Singapore, South Korea, and Spain. Interpretation: The salient features of the cardiometabolic disease and risk factor epidemic at the beginning of the 21st century are high blood pressure and an increasing effect of obesity and diabetes. The mortality burden of cardiometabolic risk factors has shifted from high-income to low-income and middle-income countries. Lowering cardiometabolic risks through dietary, behavioural, and pharmacological interventions should be a part of the global response to non-communicable diseases. Funding: UK Medical Research Council, US National Institutes of Health. © 2014 Elsevier Ltd

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality