The prevalence of obesity in both adults and children is increasing rapidly. Obesity in children is independently associated with arterial endothelial dysfunction and wall thickening, key early ...events in atherogenesis that precede plaque formation.
To evaluate the reversibility of obesity-related arterial dysfunction and carotid intima-media thickening by dietary and/or exercise intervention programs, 82 overweight children (body mass index, 25+/-3), 9 to 12 years of age, were randomly assigned to dietary modification only or diet plus a supervised structured exercise program for 6 weeks and subsequently for 1 year. The prospectively defined primary end points were ultrasound-derived arterial endothelial function (endothelium-dependent dilation) of the brachial artery and intima-media thickness of common carotid artery. At 6 weeks, both interventions were associated with decreased waist-hip ratio (P<0.02) and cholesterol level (P<0.05) as well as improved arterial endothelial function. Diet and exercise together were associated with a significantly greater improvement in endothelial function than diet alone (P=0.01). At 1 year, there was significantly less thickening of the carotid wall (P<0.001) as well as persistent improvements in body fat content and lipid profiles in the group continuing an exercise program. Vascular function was significantly better in those children continuing exercise (n=22) compared with children who withdrew from the exercise program (n=19) (P<0.05).
Obesity-related vascular dysfunction in otherwise healthy young children is partially reversible with diet alone or particularly diet combined with exercise training at 6 weeks, with sustained improvements at 1 year in those persisting with diet plus regular exercise.
With more than 900,000 confirmed cases worldwide and nearly 50,000 deaths during the first 3 months of 2020, the coronavirus disease 2019 (COVID-19) pandemic has emerged as an unprecedented health ...care crisis. The spread of COVID-19 has been heterogeneous, resulting in some regions having sporadic transmission and relatively few hospitalized patients with COVID-19 and others having community transmission that has led to overwhelming numbers of severe cases. For these regions, health care delivery has been disrupted and compromised by critical resource constraints in diagnostic testing, hospital beds, ventilators, and health care workers who have fallen ill to the virus exacerbated by shortages of personal protective equipment. Although mild cases mimic common upper respiratory viral infections, respiratory dysfunction becomes the principal source of morbidity and mortality as the disease advances. Thoracic imaging with chest radiography and CT are key tools for pulmonary disease diagnosis and management, but their role in the management of COVID-19 has not been considered within the multivariable context of the severity of respiratory disease, pretest probability, risk factors for disease progression, and critical resource constraints. To address this deficit, a multidisciplinary panel comprised principally of radiologists and pulmonologists from 10 countries with experience managing patients with COVID-19 across a spectrum of health care environments evaluated the utility of imaging within three scenarios representing varying risk factors, community conditions, and resource constraints. Fourteen key questions, corresponding to 11 decision points within the three scenarios and three additional clinical situations, were rated by the panel based on the anticipated value of the information that thoracic imaging would be expected to provide. The results were aggregated, resulting in five main and three additional recommendations intended to guide medical practitioners in the use of chest radiography and CT in the management of COVID-19.
Histone variants, present in various cell types and tissues, are known to exhibit different functions. For example, histone H3.3 and H2A.Z are both involved in gene expression regulation, whereas ...H2A.X is a specific variant that responds to DNA double-strand breaks. In this study, we characterized H4G, a novel hominidae-specific histone H4 variant. We found that H4G is expressed in a variety of human cell lines and exhibit tumor-stage dependent overexpression in tissues from breast cancer patients. We found that H4G localized primarily to the nucleoli of the cell nucleus. This localization was controlled by the interaction of the alpha-helix 3 of the histone fold motif with a histone chaperone, nucleophosmin 1. In addition, we found that modulating H4G expression affects rRNA expression levels, protein synthesis rates and cell-cycle progression. Our data suggest that H4G expression alters nucleolar chromatin in a way that enhances rDNA transcription in breast cancer tissues.
19F-NMR has proved to be a valuable tool in fragment-based drug discovery. Its applications include screening libraries of fluorinated fragments, assessing competition among elaborated fragments and ...identifying the binding poses of promising hits. By observing fluorine in both the ligand and the target protein, useful information can be obtained on not only the binding pose but also the dynamics of ligand-protein interactions. These applications of 19F-NMR will be illustrated in this review with studies from our fragment-based drug discovery campaigns against protein targets in parasitic and infectious diseases.
Predicting the rate of nonfacilitated permeation of solutes across lipid bilayers is important to drug design, toxicology, and signaling. These rates can be estimated using molecular dynamics ...simulations combined with the inhomogeneous solubility-diffusion model, which requires calculation of the potential of mean force and position-dependent diffusivity of the solute along the transmembrane axis. In this paper, we assess the efficiency and accuracy of several methods for the calculation of the permeability of a model DMPC bilayer to urea, benzoic acid, and codeine. We compare umbrella sampling, replica exchange umbrella sampling, adaptive biasing force, and multiple-walker adaptive biasing force for the calculation of the transmembrane PMF. No definitive advantage for any of these methods in their ability to predict the membrane permeability coefficient P m was found, provided that a sufficiently long equilibration is performed. For diffusivities, a Bayesian inference method was compared to a generalized Langevin method, both being sensitive to chosen parameters and the slow relaxation of membrane defects. Agreement within 1.5 log units of the computed P m with experiment is found for all permeants and methods. Remaining discrepancies can likely be attributed to limitations of the force field as well as slowly relaxing collective movements within the lipid environment. Numerical calculations based on model profiles show that P m can be reliably estimated from only a few data points, leading to recommendations for calculating P m from simulations.
Abstract
We present the survey design, implementation, and outlook for COSMOS-Web, a 255 hr treasury program conducted by the James Webb Space Telescope in its first cycle of observations. COSMOS-Web ...is a contiguous 0.54 deg
2
NIRCam imaging survey in four filters (F115W, F150W, F277W, and F444W) that will reach 5
σ
point-source depths ranging ∼27.5–28.2 mag. In parallel, we will obtain 0.19 deg
2
of MIRI imaging in one filter (F770W) reaching 5
σ
point-source depths of ∼25.3–26.0 mag. COSMOS-Web will build on the rich heritage of multiwavelength observations and data products available in the COSMOS field. The design of COSMOS-Web is motivated by three primary science goals: (1) to discover thousands of galaxies in the Epoch of Reionization (6 ≲
z
≲ 11) and map reionization’s spatial distribution, environments, and drivers on scales sufficiently large to mitigate cosmic variance, (2) to identify hundreds of rare quiescent galaxies at
z
> 4 and place constraints on the formation of the universe’s most-massive galaxies (
M
⋆
> 10
10
M
⊙
), and (3) directly measure the evolution of the stellar-mass-to-halo-mass relation using weak gravitational lensing out to
z
∼ 2.5 and measure its variance with galaxies’ star formation histories and morphologies. In addition, we anticipate COSMOS-Web’s legacy value to reach far beyond these scientific goals, touching many other areas of astrophysics, such as the identification of the first direct collapse black hole candidates, ultracool subdwarf stars in the Galactic halo, and possibly the identification of
z
> 10 pair-instability supernovae. In this paper we provide an overview of the survey’s key measurements, specifications, goals, and prospects for new discovery.
Background Survivors of intracerebral hemorrhage (ICH) are at high risk for recurrent stroke, which is associated with blood pressure control. Because most recurrent stroke events occur within 12 to ...18 months of the index ICH, rapid blood pressure control is likely to be crucial. We investigated the frequency and prognostic impact of uncontrolled short-term hypertension after ICH. Methods and Results We analyzed data from Massachusetts General Hospital (n=1305) and the University of Hong Kong (n=523). We classified hypertension as controlled, undertreated, or treatment resistant at 3 months after ICH and determined the following: (1) the risk factors for uncontrolled hypertension and (2) whether hypertension control at 3 months is associated with stroke recurrence and mortality. We followed 1828 survivors of ICH for a median of 46.2 months. Only 9 of 234 (4%) recurrent strokes occurred before 3 months after ICH. At 3 months, 713 participants (39%) had controlled hypertension, 755 (41%) had undertreated hypertension, and 360 (20%) had treatment-resistant hypertension. Black, Hispanic, and Asian race/ethnicity and higher blood pressure at time of ICH increased the risk of uncontrolled hypertension at 3 months (all
<0.05). Uncontrolled hypertension at 3 months was associated with recurrent stroke and mortality during long-term follow-up (all
<0.05). Conclusions Among survivors of ICH, >60% had uncontrolled hypertension at 3 months, with undertreatment accounting for the majority of cases. The 3-month blood pressure measurements were associated with higher recurrent stroke risk and mortality. Black, Hispanic, and Asian survivors of ICH and those presenting with severe acute hypertensive response were at highest risk for uncontrolled hypertension.
By examining the state of operations management (OM) research from 1980 to 2015 and by considering three new industry trends, we propose new OM research directions in socially and environmentally ...responsible value chains that fundamentally expand existing OM research in three dimensions: (a)
contexts
(emerging and developing economies); (b)
objectives
(economic, environmental, and social responsibility); and (c)
stakeholders
(producers, consumers, shareholders, for-profit/nonprofit/social enterprises, governments, and nongovernmental organizations). In this paper, we describe some examples of this new research direction that are intended to stimulate more exciting OM research, to contribute to the economic and social well-being of both developing and developed economies.
This paper was accepted by Teck-Hua Ho, operations management.
This study examines the deep convection populations and mesoscale convective systems (MCSs) simulated in the DYAMOND (DYnamics of the atmospheric general circulation modeled on non‐hydrostatic ...domains) winter project. A storm tracking algorithm is applied to six DYAMOND simulations and a global high‐resolution satellite cloud and precipitation data set for comparison. The simulated frequencies of tropical deep convection and organized convective systems vary widely among models and regions, although robust MCSs are generally underestimated. The diurnal cycles of MCS initiation and mature stages are well simulated, but the amplitudes are exaggerated over land. Most models capture the observed MCS lifetime, cloud shield area, rainfall volume and movement speed. However, cloud‐top height and convective rainfall intensity are consistently overestimated, and stratiform rainfall area and amount are consistently underestimated. Possible causes for the model differences compared to observations and implications for future model developments are discussed.
Plain Language Summary
A new class of high‐resolution global atmosphere models is emerging for Earth system modeling. These new models can directly simulate convective storm systems and hold promises to improve the simulation of hydrological extremes such as flood‐producing rainfall and how they may change in future climate. This study assesses the fidelity of simulated convective storms from six global models against high‐resolution satellite observations. We find that the models simulate widely different frequency of convective storms in the tropics, but many do not produce storms that grow as large as observed. Several important aspects of observed storms such as the diurnal cycle, land‐ocean contrast, and storm rainfall amount are reasonably captured by the models; however, precipitation intensity is consistently overestimated and the storm rainfall area is too small. We further discussed potential causes for the model differences with observations and future model development needs.
Key Points
Deep convective clouds and mesoscale convective systems are tracked in global convection‐permitting simulations and satellite observations
Models produce a diverse range of tropical deep convective systems and MCS frequencies and their proportions in key climate regions
Models reasonably simulate tropical MCS diurnal cycle and some MCS characteristics, but overestimate MCS precipitation intensity
The cytoplasmic pattern recognition receptor RIG-I is activated by viral RNA and induces type I IFN responses to control viral replication. The cellular dsRNA binding protein PACT can also activate ...RIG-I. To counteract innate antiviral responses, some viruses, including Ebola virus (EBOV), encode proteins that antagonize RIG-I signaling. Here, we show that EBOV VP35 inhibits PACT-induced RIG-I ATPase activity in a dose-dependent manner. The interaction of PACT with RIG-I is disrupted by wild-type VP35, but not by VP35 mutants that are unable to bind PACT. In addition, PACT-VP35 interaction impairs the association between VP35 and the viral polymerase, thereby diminishing viral RNA synthesis and modulating EBOV replication. PACT-deficient cells are defective in IFN induction and are insensitive to VP35 function. These data support a model in which the VP35-PACT interaction is mutually antagonistic and plays a fundamental role in determining the outcome of EBOV infection.
•Ebola virus VP35 disrupts RIG-I-PACT interaction to block PACT-mediated RIG-I activation•PACT binding requires VP35 IID region and correlates with RIG-I inhibition•VP35-PACT interaction inhibits viral RNA synthesis•PACT-deficient cells are insensitive to VP35 function
PDF
