Abstract
The relationships between the onset of tropical deep convection, column water vapor (CWV), and other measures of conditional instability are analyzed with 2 yr of data from the DOE ...Atmospheric Radiation Measurement (ARM) Mobile Facility in Manacapuru, Brazil, as part of the Green Ocean Amazon (GOAmazon) campaign, and with 3.5 yr of CWV derived from global positioning system meteorology at a nearby site in Manaus, Brazil. Important features seen previously in observations over tropical oceans—precipitation conditionally averaged by CWV exhibiting a sharp pickup at high CWV, and the overall shape of the CWV distribution for both precipitating and nonprecipitating points—are also found for this tropical continental region. The relationship between rainfall and CWV reflects the impact of lower-free-tropospheric moisture variability on convection. Specifically, CWV over land, as over ocean, is a proxy for the effect of free-tropospheric moisture on conditional instability as indicated by entraining plume calculations from GOAmazon data. Given sufficient mixing in the lower troposphere, higher CWV generally results in greater plume buoyancies through a deep convective layer. Although sensitivity of buoyancy to other controls in the Amazon is suggested, such as boundary layer and microphysical processes, the CWV dependence is consistent with the observed precipitation onset. Overall, leading aspects of the relationship between CWV and the transition to deep convection in the Amazon have close parallels over tropical oceans. The relationship is robust to averaging on time and space scales appropriate for convective physics but is strongly smoothed for averages greater than 3 h or 2.5°.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Recent research suggests that heat exposure may increase the risk of traumatic injuries. Published heat-related epidemiological studies have relied upon exposure data from individual weather ...stations.
To evaluate the association between heat exposure and traumatic injuries in outdoor agricultural workers exposed to ambient heat and internal heat generated by physical activity using modeled ambient exposure data.
A case-crossover study using time-stratified referent selection among 12,213 outdoor agricultural workers with new Washington State Fund workers' compensation traumatic injury claims between 2000 and 2012 was conducted. Maximum daily Humidex exposures, derived from modeled meteorological data, were assigned to latitudes and longitudes of injury locations on injury and referent dates. Conditional logistic regression was used to estimate odds ratios of injury for a priori daily maximum Humidex categories.
The mean of within-stratum (injury day and corresponding referent days) standard deviations of daily maximum Humidex was 4.8. The traumatic injury odds ratio was 1.14 (95% confidence interval 1.06, 1.22), 1.15 (95% confidence interval 1.06, 1.25), and 1.10 (95% confidence interval 1.01, 1.20) for daily maximum Humidex of 25-29, 30-33, and ≥34, respectively, compared to < 25, adjusted for self-reported duration of employment. Stronger associations were observed during cherry harvest duties in the June and July time period, compared to all duties over the entire study period.
Agricultural workers laboring in warm conditions are at risk for heat-related traumatic injuries. Combined heat-related illness and injury prevention efforts should be considered in high-risk populations exposed to warm ambient conditions in the setting of physical exertion.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
BACKGROUND
Intracranial pressure (ICP) is a clinically important variable after severe traumatic brain injury (TBI) and has been monitored, along with clinical outcome, for over 25 yr in ...Addenbrooke's hospital, Cambridge, United Kingdom. This time period has also seen changes in management strategies with the implementation of protocolled specialist neurocritical care, expansion of neuromonitoring techniques, and adjustments of clinical treatment targets.
OBJECTIVE
To describe the changes in intracranial monitoring variables over the past 25 yr.
METHODS
Data from 1146 TBI patients requiring ICP monitoring were analyzed. Monitored variables included ICP, cerebral perfusion pressure (CPP), and the cerebral pressure reactivity index (PRx). Data were stratified into 5-yr epochs spanning the 25 yr from 1992 to 2017.
RESULTS
CPP increased sharply with specialist neurocritical care management (P < 0.0001) (introduction of a specific TBI management algorithm) before stabilizing from 2000 onwards. ICP decreased significantly over the 25 yr of monitoring from an average of 19 to 12 mmHg (P < 0.0001) but PRx remained unchanged. The mean number of ICP plateau waves and the number of patients developing refractory intracranial hypertension both decreased significantly. Mortality did not significantly change in the cohort (22%).
CONCLUSION
We demonstrate the evolving trends in neurophysiological monitoring over the past 25 yr from a single, academic neurocritical care unit. ICP and CPP were responsive to the introduction of an ICP/CPP protocol while PRx has remained unchanged.
Graphical Abstract
Graphical Abstract
Self-assembled nanofibers are ubiquitous in nature and serve as inspiration for the design of supramolecular hydrogels. A multicomponent approach offers the possibility of enhancing the tunability ...and functionality of this class of materials. We report on the synergistic multicomponent self-assembly involving a peptide amphiphile (PA) and a 1,3:2,4-dibenzylidene-d-sorbitol (DBS) gelator to generate hydrogels with tunable nanoscale morphology, improved stiffness, enhanced self-healing, and stability to enzymatic degradation. Using induced circular dichroism of Thioflavin T (ThT), electron microscopy, small-angle neutron scattering, and molecular dynamics approaches, we confirm that the PA undergoes self-sorting, while the DBS gelator acts as an additive modifier for the PA nanofibers. The supramolecular interactions between the PA and DBS gelators result in improved bulk properties and cytocompatibility of the two-component hydrogels as compared to those of the single-component systems. The tunable mechanical properties, self-healing ability, resistance to proteolysis, and biocompatibility of the hydrogels suggest future opportunities for the hydrogels as scaffolds for tissue engineering and drug delivery vehicles.
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IJS, KILJ, NUK, PNG, UL, UM
Xenotransplantation research has made considerable progress in recent years, largely through the increasing availability of pigs with multiple genetic modifications, effective immunosuppressive ...therapy, and anti‐inflammatory therapy to protect pig tissues from the primate immune and inflammatory responses and correct molecular incompatibilities. Further study is required regarding identification and investigation of physiological incompatibilities.
Although the exact cause remains uncertain, we and others have observed relatively rapid growth of kidney xenografts after transplantation into nonhuman primates (NHPs). There has also been some evidence of growth, or at least ventricular hypertrophy, of the pig heart after orthotopic transplantation into NHPs. Rapid growth could be problematic, particularly with regard to the heart within the relatively restricted confines of the chest.
It has been suggested that the problem of rapid growth of the pig organ after transplantation could be resolved by growth hormone receptor (GHR) gene knockout in the pig. The GHR, although most well‐known for regulating growth, has many other biological functions, including regulating metabolism and controlling physiological processes. Genetically modified GHRKO pigs have recently become available. We provide data on their growth compared to comparable pigs that do not include GHRKO, and we have reviewed the literature regarding the effect of GHRKO, and its relevance to xenotransplantation.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Pancreatic cancer is one of the most deadly cancers affecting the Western world. Because the disease is highly metastatic and difficult to diagnosis until late stages, the 5-y survival rate is around ...5%. The identification of molecular cancer drivers is critical for furthering our understanding of the disease and development of improved diagnostic tools and therapeutics. We have conducted a mutagenic screen using Sleeping Beauty (SB) in mice to identify new candidate cancer genes in pancreatic cancer. By combining SB with an oncogenic Kras allele, we observed highly metastatic pancreatic adenocarcinomas. Using two independent statistical methods to identify loci commonly mutated by SB in these tumors, we identified 681 loci that comprise 543 candidate cancer genes (CCGs); 75 of these CCGs, including Mll3 and Ptk2, have known mutations in human pancreatic cancer. We identified point mutations in human pancreatic patient samples for another 11 CCGs, including Acvr2a and Map2k4. Importantly, 10% of the CCGs are involved in chromatin remodeling, including Arid4b, Kdm6a, and Nsd3, and all SB tumors have at least one mutated gene involved in this process; 20 CCGs, including Ctnnd1, Fbxo11, and Vgll4, are also significantly associated with poor patient survival. SB mutagenesis provides a rich resource of mutations in potential cancer drivers for cross-comparative analyses with ongoing sequencing efforts in human pancreatic adenocarcinoma.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Scleroderma is an autoimmune disease with a characteristic vascular pathology. The vasculopathy associated with scleroderma is one of the major contributors to the clinical manifestations of the ...disease.
We used immunohistochemical and mRNA in situ hybridization techniques to characterize this vasculopathy and showed with morphometry that scleroderma has true capillary rarefaction. We compared skin biopsies from 23 scleroderma patients and 24 normal controls and 7 scleroderma patients who had undergone high dose immunosuppressive therapy followed by autologous hematopoietic cell transplant. Along with the loss of capillaries there was a dramatic change in endothelial phenotype in the residual vessels. The molecules defining this phenotype are: vascular endothelial cadherin, a supposedly universal endothelial marker required for tube formation (lost in the scleroderma tissue), antiangiogenic interferon alpha (overexpressed in the scleroderma dermis) and RGS5, a signaling molecule whose expression coincides with the end of branching morphogenesis during development and tumor angiogenesis (also overexpressed in scleroderma skin. Following high dose immunosuppressive therapy, patients experienced clinical improvement and 5 of the 7 patients with scleroderma had increased capillary counts. It was also observed in the same 5 patients, that the interferon alpha and vascular endothelial cadherin had returned to normal as other clinical signs in the skin regressed, and in all 7 patients, RGS5 had returned to normal.
These data provide the first objective evidence for loss of vessels in scleroderma and show that this phenomenon is reversible. Coordinate changes in expression of three molecules already implicated in angiogenesis or anti-angiogenesis suggest that control of expression of these three molecules may be the underlying mechanism for at least the vascular component of this disease. Since rarefaction has been little studied, these data may have implications for other diseases characterized by loss of capillaries including hypertension, congestive heart failure and scar formation.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Convective processes in the atmosphere over the Maritime Continent and their diurnal cycles have important repercussions for the circulations in the tropics and beyond. In this work, we ...present a new dataset of precipitable water vapor (PWV) obtained from the Sumatran GPS Array (SuGAr), a dense network of GPS stations principally for examining seismic and tectonic activity along the western coast of Sumatra and several offshore islands. The data provide an opportunity to examine the characteristics of convection over the area in greater detail than before. In particular, our results show that the diurnal cycle of PWV on Sumatra has a single late afternoon peak, while that offshore has both a midday and a nocturnal peak. The SuGAr data are in good agreement with GPS radio occultation data from the Constellation Observing System for Meteorology, Ionosphere, and Climate (COSMIC) mission, as well as with imaging spectrometer data from the Ozone Measuring Instrument (OMI). A comparison between SuGAr and the NASA Water Vapor Project (NVAP), however, shows significant differences, most likely due to discrepancies in the temporal and spatial resolutions. To further understand the diurnal cycle contained in the SuGAr data, we explore the impact of the Madden–Julian oscillation (MJO) on the diurnal cycle with the aid of the Weather Research and Forecasting (WRF) Model. Results show that the daily mean and the amplitude of the diurnal cycle appear smaller during the suppressed phase relative to the developing/active MJO phase. Furthermore, the evening/nighttime peaks of PWV offshore appear later during the suppressed phase of the MJO compared to the active phase.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Aging reduces skeletal muscle mass and strength, but the underlying molecular mechanisms remain elusive. Here, we used mouse models to investigate molecular mechanisms of age-related skeletal muscle ...weakness and atrophy as well as new potential interventions for these conditions. We identified two small molecules that significantly reduce age-related deficits in skeletal muscle strength, quality, and mass: ursolic acid (a pentacyclic triterpenoid found in apples) and tomatidine (a steroidal alkaloid derived from green tomatoes). Because small molecule inhibitors can sometimes provide mechanistic insight into disease processes, we used ursolic acid and tomatidine to investigate the pathogenesis of age-related muscle weakness and atrophy. We found that ursolic acid and tomatidine generate hundreds of small positive and negative changes in mRNA levels in aged skeletal muscle, and the mRNA expression signatures of the two compounds are remarkably similar. Interestingly, a subset of the mRNAs repressed by ursolic acid and tomatidine in aged muscle are positively regulated by activating transcription factor 4 (ATF4). Based on this finding, we investigated ATF4 as a potential mediator of age-related muscle weakness and atrophy. We found that a targeted reduction in skeletal muscle ATF4 expression reduces age-related deficits in skeletal muscle strength, quality, and mass, similar to ursolic acid and tomatidine. These results elucidate ATF4 as a critical mediator of age-related muscle weakness and atrophy. In addition, these results identify ursolic acid and tomatidine as potential agents and/or lead compounds for reducing ATF4 activity, weakness, and atrophy in aged skeletal muscle.
Background: Aging reduces skeletal muscle strength and mass.
Results: The transcription factor ATF4 is required for age-related muscle weakness and atrophy, and the small molecules ursolic acid and tomatidine reduce ATF4 activity, weakness, and atrophy in aged skeletal muscle.
Conclusion: ATF4 is an essential mediator of muscle aging.
Significance: These results identify new strategies for reducing weakness and muscle loss during aging.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
Planets orbiting M-dwarf stars are prime targets in the search for rocky exoplanet atmospheres. The small size of M dwarfs renders their planets exceptional targets for transmission ...spectroscopy, facilitating atmospheric characterization. However, it remains unknown whether their host stars’ highly variable extreme-UV radiation environments allow atmospheres to persist. With JWST, we have begun to determine whether or not the most favorable rocky worlds orbiting M dwarfs have detectable atmospheres. Here, we present a 2.8–5.2
μ
m JWST NIRSpec/G395H transmission spectrum of the warm (700 K, 40.3× Earth’s insolation) super-Earth GJ 486b (1.3
R
⊕
and 3.0
M
⊕
). The measured spectrum from our two transits of GJ 486b deviates from a flat line at 2.2
σ
− 3.3
σ
, based on three independent reductions. Through a combination of forward and retrieval models, we determine that GJ 486b either has a water-rich atmosphere (with the most stringent constraint on the retrieved water abundance of H
2
O > 10% to 2
σ
) or the transmission spectrum is contaminated by water present in cool unocculted starspots. We also find that the measured stellar spectrum is best fit by a stellar model with cool starspots and hot faculae. While both retrieval scenarios provide equal quality fits (
χ
ν
2
=
1.0
) to our NIRSpec/G395H observations, shorter wavelength observations can break this degeneracy and reveal if GJ 486b sustains a water-rich atmosphere.
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