375 research outputs found
Towards Automated Benchmarking of Atomistic Forcefields: Neat Liquid Densities and Static Dielectric Constants from the ThermoML Data Archive
Atomistic molecular simulations are a powerful way to make quantitative
predictions, but the accuracy of these predictions depends entirely on the
quality of the forcefield employed. While experimental measurements of
fundamental physical properties offer a straightforward approach for evaluating
forcefield quality, the bulk of this information has been tied up in formats
that are not machine-readable. Compiling benchmark datasets of physical
properties from non-machine-readable sources require substantial human effort
and is prone to accumulation of human errors, hindering the development of
reproducible benchmarks of forcefield accuracy. Here, we examine the
feasibility of benchmarking atomistic forcefields against the NIST ThermoML
data archive of physicochemical measurements, which aggregates thousands of
experimental measurements in a portable, machine-readable, self-annotating
format. As a proof of concept, we present a detailed benchmark of the
generalized Amber small molecule forcefield (GAFF) using the AM1-BCC charge
model against measurements (specifically bulk liquid densities and static
dielectric constants at ambient pressure) automatically extracted from the
archive, and discuss the extent of available data. The results of this
benchmark highlight a general problem with fixed-charge forcefields in the
representation low dielectric environments such as those seen in binding
cavities or biological membranes
Supplementary guidance: listening to staff: Autumn 2017
Kinases play a critical
role in cellular signaling and are dysregulated
in a number of diseases, such as cancer, diabetes, and neurodegeneration.
Therapeutics targeting kinases currently account for roughly 50% of
cancer drug discovery efforts. The ability to explore human kinase
biochemistry and biophysics in the laboratory is essential to designing
selective inhibitors and studying drug resistance. Bacterial expression
systems are superior to insect or mammalian cells in terms of simplicity
and cost effectiveness but have historically struggled with human
kinase expression. Following the discovery that phosphatase coexpression
produced high yields of Src and Abl kinase domains in bacteria, we
have generated a library of 52 His-tagged human kinase domain constructs
that express above 2 μg/mL of culture in an automated bacterial
expression system utilizing phosphatase coexpression (YopH for Tyr
kinases and lambda for Ser/Thr kinases). Here, we report a structural
bioinformatics approach to identifying kinase domain constructs previously
expressed in bacteria and likely to express well in our protocol,
experiments demonstrating our simple construct selection strategy
selects constructs with good expression yields in a test of 84 potential
kinase domain boundaries for Abl, and yields from a high-throughput
expression screen of 96 human kinase constructs. Using a fluorescence-based
thermostability assay and a fluorescent ATP-competitive inhibitor,
we show that the highest-expressing kinases are folded and have well-formed
ATP binding sites. We also demonstrate that these constructs can enable
characterization of clinical mutations by expressing a panel of 48
Src and 46 Abl mutations. The wild-type kinase construct library is
available publicly via Addgene
Acute exacerbation of idiopathic pulmonary fibrosis: International survey and call for harmonisation.
AIM
Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is an often deadly complication of IPF. No focused international guidelines for the management of AE-IPF exist. The aim of this international survey was to assess the global variability in prevention, diagnostic and treatment strategies for AE-IPF.
MATERIAL AND METHODS
Pulmonologists with ILD expertise were invited to participate in a survey designed by an international expert panel.
RESULTS
509 pulmonologists from 66 countries responded. Significant geographical variability in approaches to manage AE-IPF was found. Common preventive measures included antifibrotic drugs and vaccination. Diagnostic differences were most pronounced regarding use of KL-6 and viral testing, while HRCT, BNP and D-Dimer are generally applied. High dose steroids are widely administered (94%); the use of other immunosuppressant and treatment strategies is highly variable. Very few (4%) responders never use immunosuppression. Antifibrotic treatments are initiated during AE-IPF by 67%. Invasive ventilation or extracorporeal membrane oxygenation are mainly used as a bridge to transplantation. Most physicians educate patients comprehensively on the severity of AE-IPF (82%) and consider palliative care (64%).
CONCLUSION
Approaches to the prevention, diagnosis and treatment of AE-IPF vary worldwide. Global trials and guidelines to improve the prognosis of AE-IPF are needed
Hazard characterization of Alternaria toxins to identify data gaps and improve risk assessment for human health
Fungi of the genus Alternaria are ubiquitous plant pathogens and saprophytes which are able to grow under varying temperature and moisture conditions as well as on a large range of substrates. A spectrum of structurally diverse secondary metabolites with toxic potential has been identified, but occurrence and relative proportion of the different metabolites in complex mixtures depend on strain, substrate, and growth conditions. This review compiles the available knowledge on hazard identification and characterization of Alternaria toxins. Alternariol (AOH), its monomethylether AME and the perylene quinones altertoxin I (ATX-I), ATX-II, ATX-III, alterperylenol (ALP), and stemphyltoxin III (STTX-III) showed in vitro genotoxic and mutagenic properties. Of all identified Alternaria toxins, the epoxide-bearing analogs ATX-II, ATX-III, and STTX-III show the highest cytotoxic, genotoxic, and mutagenic potential in vitro. Under hormone-sensitive conditions, AOH and AME act as moderate xenoestrogens, but in silico modeling predicts further Alternaria toxins as potential estrogenic factors. Recent studies indicate also an immunosuppressive role of AOH and ATX-II; however, no data are available for the majority of Alternaria toxins. Overall, hazard characterization of Alternaria toxins focused, so far, primarily on the commercially available dibenzo-α-pyrones AOH and AME and tenuazonic acid (TeA). Limited data sets are available for altersetin (ALS), altenuene (ALT), and tentoxin (TEN). The occurrence and toxicological relevance of perylene quinone-based Alternaria toxins still remain to be fully elucidated. We identified data gaps on hazard identification and characterization crucial to improve risk assessment of Alternaria mycotoxins for consumers and occupationally exposed workers.The European Partnership for the Assessment of Risks from Chemicals has received funding from the European Union’s Horizon Europe research and innovation program under Grant Agreement No 101057014 and has received co-funding of the authors’ institutions. Views and opinions expressed are, however, those of the author(s) only and do not necessarily reflect those of the European Union or the Health and Digital Executive Agency. Neither the European Union nor the granting authority can be held responsible for them.info:eu-repo/semantics/publishedVersio
Photochemically-produced SO in the atmosphere of WASP-39b
Photochemistry is a fundamental process of planetary atmospheres that
regulates the atmospheric composition and stability. However, no unambiguous
photochemical products have been detected in exoplanet atmospheres to date.
Recent observations from the JWST Transiting Exoplanet Early Release Science
Program found a spectral absorption feature at 4.05 m arising from SO
in the atmosphere of WASP-39b. WASP-39b is a 1.27-Jupiter-radii, Saturn-mass
(0.28 M) gas giant exoplanet orbiting a Sun-like star with an equilibrium
temperature of 1100 K. The most plausible way of generating SO in
such an atmosphere is through photochemical processes. Here we show that the
SO distribution computed by a suite of photochemical models robustly
explains the 4.05 m spectral feature identified by JWST transmission
observations with NIRSpec PRISM (2.7) and G395H (4.5). SO
is produced by successive oxidation of sulphur radicals freed when hydrogen
sulphide (HS) is destroyed. The sensitivity of the SO feature to the
enrichment of the atmosphere by heavy elements (metallicity) suggests that it
can be used as a tracer of atmospheric properties, with WASP-39b exhibiting an
inferred metallicity of 10 solar. We further point out that
SO also shows observable features at ultraviolet and thermal infrared
wavelengths not available from the existing observations.Comment: 39 pages, 14 figures, accepted to be published in Natur
Photochemically produced SO2 in the atmosphere of WASP-39b
Photochemistry is a fundamental process of planetary atmospheres that regulates the atmospheric composition and stability1. However, no unambiguous photochemical products have been detected in exoplanet atmospheres so far. Recent observations from the JWST Transiting Exoplanet Community Early Release Science Program2,3 found a spectral absorption feature at 4.05 μm arising from sulfur dioxide (SO2) in the atmosphere of WASP-39b. WASP-39b is a 1.27-Jupiter-radii, Saturn-mass (0.28 MJ) gas giant exoplanet orbiting a Sun-like star with an equilibrium temperature of around 1,100 K (ref. 4). The most plausible way of generating SO2 in such an atmosphere is through photochemical processes5,6. Here we show that the SO2 distribution computed by a suite of photochemical models robustly explains the 4.05-μm spectral feature identified by JWST transmission observations7 with NIRSpec PRISM (2.7σ)8 and G395H (4.5σ)9. SO2 is produced by successive oxidation of sulfur radicals freed when hydrogen sulfide (H2S) is destroyed. The sensitivity of the SO2 feature to the enrichment of the atmosphere by heavy elements (metallicity) suggests that it can be used as a tracer of atmospheric properties, with WASP-39b exhibiting an inferred metallicity of about 10× solar. We further point out that SO2 also shows observable features at ultraviolet and thermal infrared wavelengths not available from the existing observations
Behavioral responses of terrestrial mammals to COVID-19 lockdowns
COVID-19 lockdowns in early 2020 reduced human mobility, providing an opportunity to disentangle its effects on animals from those of landscape modifications. Using GPS data, we compared movements and road avoidance of 2300 terrestrial mammals (43 species) during the lockdowns to the same period in 2019. Individual responses were variable with no change in average movements or road avoidance behavior, likely due to variable lockdown conditions. However, under strict lockdowns 10-day 95th percentile displacements increased by 73%, suggesting increased landscape permeability. Animals' 1-hour 95th percentile displacements declined by 12% and animals were 36% closer to roads in areas of high human footprint, indicating reduced avoidance during lockdowns. Overall, lockdowns rapidly altered some spatial behaviors, highlighting variable but substantial impacts of human mobility on wildlife worldwide.acceptedVersio
Penilaian Kinerja Keuangan Koperasi di Kabupaten Pelalawan
This paper describe development and financial performance of cooperative in District Pelalawan among 2007 - 2008. Studies on primary and secondary cooperative in 12 sub-districts. Method in this stady use performance measuring of productivity, efficiency, growth, liquidity, and solvability of cooperative. Productivity of cooperative in Pelalawan was highly but efficiency still low. Profit and income were highly, even liquidity of cooperative very high, and solvability was good
Differential cross section measurements for the production of a W boson in association with jets in proton–proton collisions at √s = 7 TeV
Measurements are reported of differential cross sections for the production of a W boson, which decays into a muon and a neutrino, in association with jets, as a function of several variables, including the transverse momenta (pT) and pseudorapidities of the four leading jets, the scalar sum of jet transverse momenta (HT), and the difference in azimuthal angle between the directions of each jet and the muon. The data sample of pp collisions at a centre-of-mass energy of 7 TeV was collected with the CMS detector at the LHC and corresponds to an integrated luminosity of 5.0 fb[superscript −1]. The measured cross sections are compared to predictions from Monte Carlo generators, MadGraph + pythia and sherpa, and to next-to-leading-order calculations from BlackHat + sherpa. The differential cross sections are found to be in agreement with the predictions, apart from the pT distributions of the leading jets at high pT values, the distributions of the HT at high-HT and low jet multiplicity, and the distribution of the difference in azimuthal angle between the leading jet and the muon at low values.United States. Dept. of EnergyNational Science Foundation (U.S.)Alfred P. Sloan Foundatio
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