Abstract The accuracy of statistically downscaled (SD) general circulation model (GCM) simulations of monthly surface climate for historical conditions (1950–2005) was assessed for the conterminous ...United States (CONUS). The SD monthly precipitation (PPT) and temperature (TAVE) from 95 GCMs from phases 3 and 5 of the Coupled Model Intercomparison Project (CMIP3 and CMIP5) were used as inputs to a monthly water balance model (MWBM). Distributions of MWBM input (PPT and TAVE) and output runoff (RUN) variables derived from gridded station data (GSD) and historical SD climate were compared using the Kolmogorov–Smirnov (KS) test For all three variables considered, the KS test results showed that variables simulated using CMIP5 generally are more reliable than those derived from CMIP3, likely due to improvements in PPT simulations. At most locations across the CONUS, the largest differences between GSD and SD PPT and RUN occurred in the lowest part of the distributions (i.e., low-flow RUN and low-magnitude PPT). Results indicate that for the majority of the CONUS, there are downscaled GCMs that can reliably simulate historical climatic conditions. But, in some geographic locations, none of the SD GCMs replicated historical conditions for two of the three variables (PPT and RUN) based on the KS test, with a significance level of 0.05. In these locations, improved GCM simulations of PPT are needed to more reliably estimate components of the hydrologic cycle. Simple metrics and statistical tests, such as those described here, can provide an initial set of criteria to help simplify GCM selection.
Resonance assignment of human LARP4A La module Cruz-Gallardo, Isabel; Martino, Luigi; Trotta, Roberta ...
Biomolecular NMR assignments,
04/2019, Letnik:
13, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Human LARP4A belongs to a superfamily of RNA binding proteins called La-related proteins (LARPs). Whilst being a positive regulator of protein synthesis and a promoter of mRNA stability, LARP4A also ...controls cell morphology and motility in human breast and prostate cancer cells. All LARPs share a characteristic RNA binding unit named the La–module, which despite a high level of primary structure conservation exhibits a great versatility in RNA target selection. Human LARP4A La–module is the most divergent compared with other LARPs and its RNA recognition properties have only recently started to be revealed. Given the key role of LARP4A protein in cancer cell biology, we have initiated a complete NMR characterisation of its La-module and here we report the assignment of
1
H,
15
N and
13
C resonances resulting from our studies.
PDZ domains are highly abundant protein–protein interaction modules commonly found in multidomain scaffold proteins. The PDZ1 domain of MAGI-1, a protein present at cellular tight junctions that ...contains six PDZ domains, is targeted by the E6 oncoprotein of the high-risk human papilloma virus. Thermodynamic and dynamic studies using complementary isothermal titration calorimetry and nuclear magnetic resonance (NMR) 15N heteronuclear relaxation measurements were conducted at different temperatures to decipher the molecular mechanism of this interaction. Binding of E6 peptides to the MAGI-1 PDZ1 domain is accompanied by an unusually large and negative change in heat capacity (ΔCp ) that is attributed to a disorder-to-order transition of the C-terminal extension of the PDZ1 domain upon E6 binding. Analysis of temperature-dependent thermodynamic parameters and 15N NMR relaxation data of a PDZ1 mutant in which this disorder-to-order transition was abolished allows the unusual thermodynamic signature of E6 binding to be correlated to local folding of the PDZ1 C-terminal extension. Comparison of the exchange contributions observed for wild-type and mutant proteins explains how variation in the solvent-exposed area may compensate for the loss of conformational entropy and further designates a distinct set of a few residues that mediate this local folding phenomena.
ChEMBL is a large-scale, open-access drug discovery resource containing bioactivity information primarily extracted from scientific literature. A substantial dataset of more than 135,000 in vivo ...assays has been collated as a key resource of animal models for translational medicine within drug discovery. To improve the utility of the in vivo data, an extensive data curation task has been undertaken that allows the assays to be grouped by animal disease model or phenotypic endpoint. The dataset contains previously unavailable information about compounds or drugs tested in animal models and, in conjunction with assay data on protein targets or cell- or tissue- based systems, allows the investigation of the effects of compounds at differing levels of biological complexity. Equally, it enables researchers to identify compounds that have been investigated for a group of disease-, pharmacology- or toxicity-relevant assays.
Abstract
Human soluble epoxide hydrolase (hsEH) is an enzyme responsible for the inactivation of bioactive epoxy fatty acids, and its inhibition is emerging as a promising therapeutical strategy to ...target hypertension, cardiovascular disease, pain and insulin sensitivity. Here, we uncover the molecular bases of hsEH inhibition mediated by the endogenous 15-deoxy-Δ
12,14
-Prostaglandin J
2
(15d-PGJ
2
). Our data reveal a dual inhibitory mechanism, whereby hsEH can be inhibited by reversible docking of 15d-PGJ
2
in the catalytic pocket, as well as by covalent locking of the same compound onto cysteine residues C423 and C522, remote to the active site. Biophysical characterisations allied with in silico investigations indicate that the covalent modification of the reactive cysteines may be part of a hitherto undiscovered allosteric regulatory mechanism of the enzyme. This study provides insights into the molecular modes of inhibition of hsEH epoxy-hydrolytic activity and paves the way for the development of new allosteric inhibitors.
Steven J Thomas and colleagues think that recent changes in dental care provision have led to increased numbers of hospital admissions for dental abscess, and they suggest that access to routine and ...emergency dental care needs to be reviewed
Fluorescent tags are commonly used for imaging of proteins and peptides during biological events; however, the large size of dyes can disrupt protein structure and function, and typically require the ...use of a chemical spacer. Herein, we report the synthesis of a new class of fluorescent unnatural -amino acid, containing carbazole side-chains designed to mimic
l
-tryptophan and thus, readily incorporated into peptides. The amino acids were constructed using a Negishi cross-coupling reaction as the key step and exhibited strong fluorescent emission, with high quantum yields in both organic solvents and water. Compatible with solid phase peptide synthesis, the carbazole amino acids were used to replace tryptophan in a -hairpin model peptide and shown to be a close structural mimic with retention of conformation. They were also found to be effective fluorescent molecular reporters for biological events. Incorporation into a proline-rich ligand of the WW domain protein demonstrated that the fluorescent properties of a carbazole amino acid could be used to measure the proteinprotein binding interaction of this important biological signalling process.
Unnatural -amino acids bearing carbazole side-chains have been shown to be effective structural mimics of tryptophan in peptides and valuable fluorescent probes for the analysis of proteinprotein interactions.
SummaryBackground & aimsUrinary sodium concentration is a commonly used marker for extracellular fluid depletion which is often associated with dehydration. A point of care test for urinary sodium ...may reduce delays in clinical decision making by offering more timely guidance leading to improved salt and fluid management. We compared laboratory assessed urinary sodium with a potential point of care measure of urinary chloride in a variety of in- and outpatient specialities, to explore its use as an indicator of low urine sodium.MethodsUrinary chloride concentrations were estimated using a Quantab titrator stick in samples from patients that had been sent for urinary sodium assays. We validated the results of this titrator stick with laboratory-assessed sodium concentrations by deriving correlation coefficients between these methods and using limits of agreement testing. We determined the optimal titrator stick cut-point for identifying low urinary sodium (urinary sodium <20 mmol/L) by maximising the product of the sensitivity and specificity. This level of urinary sodium was used to mirror the British Society of Gastroenterology guidance on short bowel patients Nightingale and Woodward, 2006.ResultsWe obtained laboratory urinary sodium concentration and Quantab stick chloride measures on 127 samples. Twenty three percent had a urinary sodium below 20 mmol/L so were regarded as biochemically dehydrated. A threshold of <4.3 on the Quantab scale had a positive predictive value for low sodium of 56% (95%CI 40%–71%) and a negative predictive value of 94% (95%CI 87%–98%).ConclusionsThese data suggest that the Quantab stick could be used as a point of care test to aid fluid and salt management decisions in an outpatient setting. Further work to explore the use of the titrator stick in specific patient populations at risk of salt and water depletion is justified.
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