Carbon is the fourth-most prevalent element in the Universe and essential for all known life. In the elemental form it is found in multiple allotropes, including graphite, diamond and fullerenes, and ...it has long been predicted that even more structures can exist at pressures greater than those at Earth's core
. Several phases have been predicted to exist in the multi-terapascal regime, which is important for accurate modelling of the interiors of carbon-rich exoplanets
. By compressing solid carbon to 2 terapascals (20 million atmospheres; more than five times the pressure at Earth's core) using ramp-shaped laser pulses and simultaneously measuring nanosecond-duration time-resolved X-ray diffraction, we found that solid carbon retains the diamond structure far beyond its regime of predicted stability. The results confirm predictions that the strength of the tetrahedral molecular orbital bonds in diamond persists under enormous pressure, resulting in large energy barriers that hinder conversion to more-stable high-pressure allotropes
, just as graphite formation from metastable diamond is kinetically hindered at atmospheric pressure. This work nearly doubles the highest pressure at which X-ray diffraction has been recorded on any material.
A coupled system of wind, wind wave, and coastal circulation models has been implemented for southern Louisiana and Mississippi to simulate riverine flows, tides, wind waves, and hurricane storm ...surge in the region. The system combines the NOAA Hurricane Research Division Wind Analysis System (H*WIND) and the Interactive Objective Kinematic Analysis (IOKA) kinematic wind analyses, the Wave Model (WAM) offshore and Steady-State Irregular Wave (STWAVE) nearshore wind wave models, and the Advanced Circulation (ADCIRC) basin to channel-scale unstructured grid circulation model. The system emphasizes a high-resolution (down to 50 m) representation of the geometry, bathymetry, and topography; nonlinear coupling of all processes including wind wave radiation stress-induced set up; and objective specification of frictional parameters based on land-cover databases and commonly used parameters. Riverine flows and tides are validated for no storm conditions, while winds, wind waves, hydrographs, and high water marks are validated for Hurricanes Katrina and Rita.
Hurricanes Katrina and Rita were powerful storms that impacted southern Louisiana and Mississippi during the 2005 hurricane season. In Part I, the authors describe and validate a high-resolution ...coupled riverine flow, tide, wind, wave, and storm surge model for this region. Herein, the model is used to examine the evolution of these hurricanes in more detail. Synoptic histories show how storm tracks, winds, and waves interacted with the topography, the protruding Mississippi River delta, east-west shorelines, manmade structures, and low-lying marshes to develop and propagate storm surge. Perturbations of the model, in which the waves are not included, show the proportional importance of the wave radiation stress gradient induced setup.
Determining the mechanisms by which genes are switched on and off during development is a key aim of current biomedical research. Gene transcription has been widely observed to occur in a ...discontinuous fashion, with short bursts of activity interspersed with periods of inactivity. It is currently not known if or how this dynamic behaviour changes as mammalian cells differentiate. To investigate this, using an on-microscope analysis, we monitored mouse α-globin transcription in live cells throughout erythropoiesis. We find that changes in the overall levels of α-globin transcription are most closely associated with changes in the fraction of time a gene spends in the active transcriptional state. We identify differences in the patterns of transcriptional bursting throughout differentiation, with maximal transcriptional activity occurring in the mid-phase of differentiation. Early in differentiation, we observe increased fluctuation in transcriptional activity whereas at the peak of gene expression, in early erythroblasts, transcription is relatively stable. Later during differentiation as α-globin expression declines, we again observe more variability in transcription within individual cells. We propose that the observed changes in transcriptional behaviour may reflect changes in the stability of active transcriptional compartments as gene expression is regulated during differentiation.
In the past decade, interest by the general public in the use of herbal dietary supplements has risen exponentially. As throughout history, individuals are now turning to the use of ʺnaturalʺ ...therapies for the prevention, treatment and cure of almost every ailment and aging malady imaginable...often without substantial proof of safety or efficacy. One of the most popular herbal supplements is Ginkgo biloba extract, taken for its perceived ʺmemory enhancingʺ properties. Given the inordinate popularity, growing use, and substantial number of pharmaceutical products containing G. biloba, coupled with demands for product safety and ʺhard evidence,ʺ science has followed this trend closely with an ever-expanding body of pharmacological and clinical data on such preparations. Claims that standardized G. biloba extract (EGb 761) can modulate the cellular environment of an organism under both physiological and stress conditions may be attributed to its multivalent or totipotent properties, and can now be substantiated by the availability of modern molecular techniques. As opposed to pharmacologically manufactured or synthetic drugs, which provide a single target for a single receptor as the mechanism of action, EGb 761 is able to up- or down-regulate signaling pathways, gene transcription, cellular metabolism, etc., and thus assist in the regulation of the general physiological status of the cell and/or organism in response to stressors posed by both intracellular and extracellular conditions. Presumably, this is one of the biggest advantages of using natural products for the prevention and treatment of infirmity, as well as the maintenance of health in an organism.
Significance Genome sequencing of a multidrug-resistant clinical isolate of Salmonella Typhimurium from a patient that failed ciprofloxacin therapy revealed a mutation in the efflux pump gene, acrB . ...Computational modelling revealed that the G288D substitution changed the binding of drugs to the distal binding pocket of AcrB. The mutation was recreated in an unrelated Salmonella strain and also in Escherichia coli ; in both species the efflux of ciprofloxacin was increased by the mutation, explaining its resistant phenotype. This is the first time a substitution within an efflux pump protein has been shown to cause drug resistance. Importantly, the finding that one amino acid change can cause resistance to some drugs, but susceptibility to others, informs those developing new antibiotics.
The incidence of multidrug-resistant bacterial infections is increasing globally and the need to understand the underlying mechanisms is paramount to discover new therapeutics. The efflux pumps of Gram-negative bacteria have a broad substrate range and transport antibiotics out of the bacterium, conferring intrinsic multidrug resistance (MDR). The genomes of pre- and posttherapy MDR clinical isolates of Salmonella Typhimurium from a patient that failed antibacterial therapy and died were sequenced. In the posttherapy isolate we identified a novel G288D substitution in AcrB, the resistance-nodulation division transporter in the AcrAB-TolC tripartite MDR efflux pump system. Computational structural analysis suggested that G288D in AcrB heavily affects the structure, dynamics, and hydration properties of the distal binding pocket altering specificity for antibacterial drugs. Consistent with this hypothesis, recreation of the mutation in standard Escherichia coli and Salmonella strains showed that G288D AcrB altered substrate specificity, conferring decreased susceptibility to the fluoroquinolone antibiotic ciprofloxacin by increased efflux. At the same time, the substitution increased susceptibility to other drugs by decreased efflux. Information about drug transport is vital for the discovery of new antibacterials; the finding that one amino acid change can cause resistance to some drugs, while conferring increased susceptibility to others, could provide a basis for new drug development and treatment strategies.
During wound healing, the distribution, availability, and signaling of growth factors (GFs) are orchestrated by their binding to extracellular matrix components in the wound microenvironment. ...Extracellular matrix proteins have been shown to modulate angiogenesis and promote wound healing through GF binding. The hemostatic protein von Willebrand factor (VWF) released by endothelial cells (ECs) in plasma and in the subendothelial matrix has been shown to regulate angiogenesis; this function is relevant to patients in whom VWF deficiency or dysfunction is associated with vascular malformations. Here, we show that VWF deficiency in mice causes delayed wound healing accompanied by decreased angiogenesis and decreased amounts of angiogenic GFs in the wound. We show that in vitro VWF binds to several GFs, including vascular endothelial growth factor-A (VEGF-A) isoforms and platelet-derived growth factor-BB (PDGF-BB), mainly through the heparin-binding domain (HBD) within the VWF A1 domain. VWF also binds to VEGF-A and fibroblast growth factor-2 (FGF-2) in human plasma and colocalizes with VEGF-A in ECs. Incorporation of the VWF A1 HBD into fibrin matrices enables sequestration and slow release of incorporated GFs. In vivo, VWF A1 HBD-functionalized fibrin matrices increased angiogenesis and GF retention in VWF-deficient mice. Treatment of chronic skin wounds in diabetic mice with VEGF-A165 and PDGF-BB incorporated within VWF A1 HBD-functionalized fibrin matrices accelerated wound healing, with increased angiogenesis and smooth muscle cell proliferation. Therefore, the VWF A1 HBD can function as a GF reservoir, leading to effective angiogenesis and tissue regeneration.
•VWF heparin-binding domain binds to GFs.•VWF heparin-binding domain enhances angiogenesis in wound healing in collaboration with GFs.
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The association between type 2 diabetes (T2D) and the development of cardiac arrhythmias and conduction disturbances has not been extensively studied. Arrhythmia was defined as atrial fibrillation ...and flutter (AF/AFl), ventricular tachycardia (VT) and ventricular fibrillation (VF), and conduction abnormality as sinus node disease (SND), atrioventricular (AV) block or pacemaker implantation, and intraventricular conduction blocks (IVCB). Incidence rates and Cox regression were used to compare outcomes, and to assess optimal levels for cardiometabolic risk factors and risk associated with multifactorial risk factor control (i.e., HbA1c, LDL-C, systolic blood pressure (SBP), BMI and eGFR), between patients with versus without T2D. The analyses included data from 617,000 patients with T2D and 2,303,391 matched controls. Patients with diabetes and the general population demonstrated a gradual increase in rates for cardiac conduction abnormalities and virtually all age-groups for AF/AFI showed increased incidence during follow-up. For patients with versus without T2D, risks for cardiac arrhythmias were higher, including for AF/AFl (HR 1.17, 95% CI 1.16-1.18), the composite of SND, AV-block or pacemaker implantation (HR 1.40, 95% CI 1.37-1.43), IVCB (HR 1.23, 95% CI 1.18-1.28) and VT/VF (HR 1.08, 95% CI 1.04-1.13). For patients with T2D who had selected cardiometabolic risk factors within target ranges, compared with controls, risk of arrythmia and conduction abnormalities for T2D vs not were: AF/AFl (HR 1.09, 95% CI 1.05-1.14), the composite of SND, AV-block or pacemaker implantation (HR 1.06, 95% CI 0.94-1.18), IVCB (HR 0.80, 95% CI 0.60-0.98), and for VT/VF (HR 0.97, 95% CI 0.80-1.17). Cox models showed a linear risk increase for SBP and BMI, while eGFR showed a U-shaped association. Individuals with T2D had a higher risk of arrhythmias and conduction abnormalities than controls, but excess risk associated with T2D was virtually not evident among patients with T2D with all risk factors within target range. BMI, SBP and eGFR displayed significant associations with outcomes among patients with T2D.
The quest to develop materials that enable the manufacture of dimensionally ultra-stable structures for critical-dimension components in spacecraft has led to much research over many decades and the ...evolution of carbon fibre reinforced polymer materials. This has resulted in structural designs that feature a near-zero coefficient of thermal expansion. However, the dimensional instabilities that result from moisture ingression and release remain the fundamental vulnerability of the matrix, which restricts many applications. Here, we address this challenge by developing a space-qualifiable physical surface barrier that blends within the mechanical properties of the composite, thus becoming part of the composite itself. The resulting enhanced composite features mechanical integrity and a strength that is superior to the underlying composite, while remaining impervious to moisture and outgassing. We demonstrate production capability for a model-sized component for the Sentinel-5 mission and demonstrate such capability for future European Space Agency (ESA) and National Aeronautics and Space Administration (NASA) programmes such as Copernicus Extension, Earth Explorer and Science Cosmic Visions.
Abstract
Hurricane Gustav (2008) made landfall in southern Louisiana on 1 September 2008 with its eye never closer than 75 km to New Orleans, but its waves and storm surge threatened to flood the ...city. Easterly tropical-storm-strength winds impacted the region east of the Mississippi River for 12–15 h, allowing for early surge to develop up to 3.5 m there and enter the river and the city’s navigation canals. During landfall, winds shifted from easterly to southerly, resulting in late surge development and propagation over more than 70 km of marshes on the river’s west bank, over more than 40 km of Caernarvon marsh on the east bank, and into Lake Pontchartrain to the north. Wind waves with estimated significant heights of 15 m developed in the deep Gulf of Mexico but were reduced in size once they reached the continental shelf. The barrier islands further dissipated the waves, and locally generated seas existed behind these effective breaking zones.
The hardening and innovative deployment of gauges since Hurricane Katrina (2005) resulted in a wealth of measured data for Gustav. A total of 39 wind wave time histories, 362 water level time histories, and 82 high water marks were available to describe the event. Computational models—including a structured-mesh deepwater wave model (WAM) and a nearshore steady-state wave (STWAVE) model, as well as an unstructured-mesh “simulating waves nearshore” (SWAN) wave model and an advanced circulation (ADCIRC) model—resolve the region with unprecedented levels of detail, with an unstructured mesh spacing of 100–200 m in the wave-breaking zones and 20–50 m in the small-scale channels. Data-assimilated winds were applied using NOAA’s Hurricane Research Division Wind Analysis System (H*Wind) and Interactive Objective Kinematic Analysis (IOKA) procedures. Wave and surge computations from these models are validated comprehensively at the measurement locations ranging from the deep Gulf of Mexico and along the coast to the rivers and floodplains of southern Louisiana and are described and quantified within the context of the evolution of the storm.
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