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Proteins and ligands sample a conformational ensemble that governs molecular recognition, activity, and dissociation. In structure-based drug design, access to this conformational ensemble is critical to understand the balance between entropy and enthalpy in lead optimization. However, ligand conformational heterogeneity is currently severely underreported in crystal structures in the Protein Data Bank, owing in part to a lack of automated and unbiased procedures to model an ensemble of protein-ligand states into X-ray data. Here, we designed a computational method, qFit-ligand , to automatically resolve conformationally averaged ligand heterogeneity in crystal structures, and applied it to a large set of protein receptor-ligand complexes. We found that up to 29 % of a dataset of protein crystal structures bound with drug-like molecules present evidence of unmodeled, averaged, relatively isoenergetic conformations in ligand-receptor interactions. In many retrospective cases, these alternate conformations were adventitiously exploited to guide compound design, resulting in improved potency or selectivity. Combining qFit-ligand with high-throughput screening or multi-temperature crystallography could therefore augment the structure-based drug design toolbox.

An outbreak of pneumonia of unknown etiology in Wuhan, China, was reported to the World Health Organization on December 31, 2019 (1). Researchers determined that the illness, later known as [...]

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in late 2019, and the outbreak rapidly evolved into the current coronavirus disease pandemic. SARS-CoV-2 is a respiratory virus that causes symptoms similar to those caused by influenza A and B viruses. On July 2, 2020, the US Food and Drug Administration granted emergency use authorization for in vitro diagnostic use of the Influenza SARS-CoV-2 Multiplex Assay. This assay detects influenza A virus at 102.0, influenza B virus at 102.2, and SARS-CoV-2 at 100.3 50% tissue culture or egg infectious dose, or as few as 5 RNA copies/reaction. The simultaneous detection and differentiation of these 3 major pathogens increases overall testing capacity, conserves resources, identifies co-infections, and enables efficient surveillance of influenza viruses and SARS-CoV-2.

Results of kinetic experiments and quantum chemical computations on a series of platinum-promoted polycyclization reactions are described. Analyses of these results reveal a reactivity model that reaches beyond the energetics of the cascade itself, incorporating an ensemble of pre-cyclization conformations of the platinum-alkene reactant complex, only a subset of which are productive for bi- (or larger) cyclization and lead to products. Similarities and differences between this scenario, including reaction coordinates for polycyclization, for platinum- and enzyme-promoted polycyclization reactions are highlighted.

X-ray emission spectroscopy is emerging as an important complement to x-ray absorption fine structure spectroscopy, providing a characterization of the occupied electronic density of states local to the species of interest. Here, we present details of the design and performance of a compact x-ray emission spectrometer that uses a dispersive refocusing Rowland (DRR) circle geometry to achieve excellent performance for the 2-2.5 keV range, i.e., especially for the K-edge emission from sulfur and phosphorous. The DRR approach allows high energy resolution even for unfocused x-ray sources. This property enables high count rates in laboratory studies, approaching those of insertion-device beamlines at third-generation synchrotrons, despite use of only a low-powered, conventional x-ray tube. The spectrometer, whose overall scale is set by use of a 10-cm diameter Rowland circle and a new small-pixel complementary metal-oxide-semiconductor x-ray camera, is easily portable to synchrotron or x-ray free electron laser beamlines. Photometrics from measurements at the Advanced Light Source show excellent overall instrumental efficiency. In addition, the compact size of this instrument lends itself to future multiplexing to gain large factors in net collection efficiency or its implementation in controlled gas gloveboxes either in the lab or in an endstation.

α,β-Unsaturated acylammonium salts are useful dienophiles enabling highly enantioselective and stereodivergent Diels-Alder-initiated organocascades with furan-based dienes. Complex polycyclic systems can thus be obtained from readily prepared dienes, commodity acid chlorides, and a chiral isothiourea organocatalyst under mild conditions. We describe the use of furan-based dienes bearing pendant sulfonamides leading to the generation of oxa-bridged, trans-fused tricyclic γ-lactams. This process constitutes the first highly enantio- and diastereoselective, organocatalytic Diels-Alder cycloadditions with these typically problematic dienes due to their reversibility. Computational studies suggest that the high diastereoselectivity with these furan dienes may be due to a reversible Diels-Alder cycloaddition for the endo adducts. In addition, the utility of this methodology is demonstrated through a concise approach to a core structure with similarity to the natural product isatisine A and a nonpeptidyl ghrelin-receptor inverse agonist.

Chiral α,β-unsaturated acylammonium salts are novel dienophiles enabling enantioselective Diels-Alder-lactonization (DAL) organocascades leading to cis- and trans-fused, bicyclic γ- and δ-lactones from readily prepared dienes, commodity acid chlorides, and a chiral isothiourea organocatalyst under mild conditions. We describe extensions of stereodivergent DAL organocascades to other racemic dienes bearing pendant secondary and tertiary alcohols, and application to a formal synthesis of (+)-dihydrocompactin is described. A combined experimental and computational investigation of unsaturated acylammonium salt formation and the entire DAL organocascade pathway provide a rationalization of the effect of Brønsted base additives and enabled a controllable, diastereodivergent DAL process leading to a full complement of possible stereoisomeric products. Evaluation of free energy and enthalpy barriers in conjunction with experimentally observed temperature effects revealed that the DAL is a rare case of an entropy-controlled diastereoselective process. NMR analysis of diene alcohol-Brønsted base interactions and computational studies provide a plausible explanation of observed stabilization of exo transition-state structures through hydrogen-bonding effects.

Abstract Background The Patient Protection and Affordable Care Act of 2010, commonly referred to as the Affordable Care Act (ACA), was created to increase access to primary care, improve quality of care, and decrease healthcare costs. A key provision in the law that mandated expansion of state Medicaid programme changed when states were given the option to voluntarily expand Medicaid. Our study sought to measure the impact of ACA Medicaid expansion on preventable hospitalization (PH) rates, a measure of access to primary care. Methods We performed an interrupted time series analysis of quarterly hospitalization rates across eight states from 2012 to 2015. Segmented regression analysis was utilized to determine the impact of policy reform on PH rates. Results The Affordable Care Act’s Medicaid expansion led to decreased rates of PH (improved access to care); however, the finding was not significant (coefficient estimate: −0.0059, CI −0.0225, 0.0107, p = 0.4856). Healthcare system characteristics, such as Medicaid spending per enrollee and Medicaid income eligibility, were associated with a significant decrease in rates of PH (improved access to care). However, the Medicaid-to-Medicare fee index (physician reimbursement) and states with a Democratic state legislature had a significant increase in rates of PH (poor access to care). Conclusion Health policy reform and healthcare delivery characteristics impact access to care. Researchers should continue evaluating such policy changes across more states over longer periods of time. Researchers should translate these findings into cost analysis for state policy-makers to make better-informed decisions for their constituents. Contribution to knowledge Ambulatory care-sensitive conditions are a feasible method for evaluating policy and measuring access to primary care. Policy alone cannot improve access to care. Other factors (trust, communication, policy-makers’ motivations and objectives, etc.) must be addressed to improve access.

Semiconductor quantum dots (QDs) are efficient organic photoredox catalysts due to their high extinction coefficients and easily tunable band edge potentials. Despite the majority of the surface being covered by ligands, our understanding of the effect of the ligand shell on organic photocatalysis is limited to steric effects. We hypothesize that we can increase the activity of QD photocatalysts by designing a ligand shell with targeted electronic properties, namely, redox-mediating ligands. Herein, we functionalize our QDs with hole-mediating ferrocene (Fc) derivative ligands and perform a reaction where the slow step is hole transfer from QD to substrate. Surprisingly, we find that a hole-shuttling Fc inhibits catalysis, but confers much greater stability to the catalyst by preventing a build-up of destructive holes. We also find that dynamically bound Fc ligands can promote catalysis by surface exchange and creation of a more permeable ligand shell. Finally, we find that trapping the electron on a ligand dramatically increases the rate of reaction. These results have major implications for understanding the rate-limiting processes for charge transfer from QDs and the role of the ligand shell in modulating it. [ABSTRACT FROM AUTHOR]

A series of computational laboratory experiments aimed at teaching students principles of rational drug design are described and evaluated. These experiments range from an introduction to viewing protein-ligand complexes to optimizing geometries of potential drugs with quantum chemistry and automated docking. Student feedback indicates that such a course increased their appreciation for the roles of chemists in the drug discovery-development process.

We demonstrate that active site ensembles on transition metal phosphides tune the selectivity of the nitrate reduction reaction. Using Ni2P nanocrystals as a case study, we report a mechanism involving competitive co-adsorption of H* and NOx* intermediates. A near 100% faradaic efficiency for nitrate reduction over hydrogen evolution is observed at −0.4 V, while NH3 selectivity is maximized at −0.2 V vs. RHE. [ABSTRACT FROM AUTHOR]

CdS quantum dots (QDs) are widely employed as photocatalysts for reactions such as hydrogen evolution, and their degradation under aerobic aqueous conditions is well understood. However, despite evidence of aggregation and precipitation of CdS QD photocatalysts under anaerobic conditions, catalyst speciation and degradation under such conditions are underexplored. In this work, we demonstrate that during a reductive dehalogenation reaction, CdS QDs undergo surface ligand etching, which leads to a loss of colloidal stability and the formation of microcrystalline cadmium metal deposits. We hypothesize that this results from the accumulation of electrons on the QD surface. In addition, we demonstrate mild surface sulfur oxidation and the formation of an ammonium salt byproduct of a commonly used hole quencher. This work adds to our atomic-level understanding of the reactions occurring at the QD surface during photocatalysis, so that we can design more stable and efficient photocatalysts for organic synthesis. [ABSTRACT FROM AUTHOR]

Organophosphate hydrolysis is important for degrading environmentally harmful compounds and recovering phosphate ions in biological molecules. CeO2 nanoparticles have been well-studied for dephosphorylation via hydrolysis owing to the accessible and tunable distribution of Ce3+ and Ce4+ ions. However, there remains uncertainty in the literature regarding which surface defect properties direct catalytic activity, such as the Ce3+/Ce4+ distribution, oxygen vacancies, faceting, and dopants, and to what degree they contribute to efficient hydrolysis. Trivalent (M3+) dopants serve as a tool for manipulating defects, including the concentration of Ce3+ and oxygen vacancies, thereby influencing the hydrolytic activity of CeO2. Herein, trivalent metal ions (M = Y3+, Cr3+, In3+, and Gd3+) were employed to modulate the active sites on the CeO2 nanoparticle surface, and their effects on organophosphate hydrolysis were investigated. M-doped CeO2 nanoparticles were synthesized via hydrothermal methods, followed by annealing to remove ligands and prime the nanocrystal surface for catalysis. Catalytic performance was evaluated using dimethyl-p-nitrophenyl phosphate (DMNP) as a model organophosphate substrate, with degradation monitored over time using ultraviolet–visible (UV–vis) absorption spectroscopy. Powder X-ray diffraction (PXRD), X-ray photoelectron spectroscopy (XPS), and Raman spectroscopy revealed successful doping of CeO2 in all cases, albeit with distinctive characteristics demonstrating how M3+ dopants affect catalysis. We show that CeO2 exhibits high sensitivity to dopants that generate Ce3+ ions, oxygen vacancy defects, and lattice strain. Consequently, achieving high catalytic efficiency within CeO2 requires a balanced active site ensemble, wherein defects are maintained at optimal concentrations and distributions on the nanocrystal surface. [ABSTRACT FROM AUTHOR]

Older adults' wellbeing during the transition into an assisted living facility (ALF) is not well understood and may influence their wellbeing. The Mueller Assessment of Transition (MAT) was created to measure the impact of transition on older adults' wellbeing. Early developmental testing of the MAT revealed a hypothesized model with two constructs (adjustment strategies and constraints to wellbeing). Therefore, the purpose of this study was to confirm the factor structure of the MAT with a representative sample of older adults transitioning into ALFs. In a nationwide sample, 108 older adult participants completed the MAT to measure wellbeing when relocating into ALFs. Confirmatory factor analysis (CFA) assessed the structural validity of the MAT. Internal consistency was evaluated, and chi-square tests of association for regional differences in MAT scores were also conducted. The CFA produced strong fit indices to confirm the hypothesized 2-factor (constraints to wellbeing and adjustment strategies) model of the MAT. Cronbach's alpha for the internal consistency was 0.784 and chi-square test indicated no significant regional differences. The MAT was established as a valid and reliable standardized assessment. Implications for using the MAT as a tool to measure older adults' wellbeing and future research are discussed. [ABSTRACT FROM AUTHOR]

The article focuses on investigating whether bottlenose dolphins' circulating factors offer protection against age-related endothelial dysfunction, drawing from their unique physiological adaptations. Topics include the impact of serum from bottlenose dolphins on endothelial function in mice, comparative vascular physiology in dolphins versus humans, and the potential for future studies to explore underlying mechanisms of endothelial protection through a multi-omics approach.

The Thelon Basin is temporally and spatially related to the Athabasca Basin in Saskatchewan, Canada, which hosts the highest-grade unconformity-related uranium deposits in the world. Several uranium deposits occur within the Aberdeen sub-basin of the Thelon Basin, and it has been suggested that they may also be unconformity-related deposits. However, the genesis of the deposits is still debated and the age of the uranium mineralization event remains loosely constrained. In this study, we use secondary ion mass spectrometry to measure three sulphur (S) isotopes in pyrite from the Kiggavik deposit to constrain the sources of sulphur. We use this information to determine whether these sulphides, if dated by the Re--Os method, would provide a better constraint on the timing of uranium mineralization. The Kiggavik deposit comprises three zones (Main, Centre, and East) that formed from ~200 [degrees]C fluids at ~1600 Ma. Non-hydrothermal pyrite and galena from all three zones have a wide range of [delta][.sup.34]S values, from-41.2[per thousand] to+37.4[per thousand]. The A[.sup.33]S values (>0[per thousand]) indicate recycling of mass independent fractionation sulphur, suggesting that pyrite from the Kiggavik deposit derived sulphur from the Neoarchean metagraywacke host rock. The preservation of these anomalous [DELTA][.sup.33]S values suggests that the pyrite formed from low-temperature processes rather than hydrothermal processes. Low-temperature, high-latitude fluids may have been involved in the formation of the pyrite because some of these sulphides are also associated with uranium minerals that are devoid of Pb and contain corroded calcite. Based on these data, Re--Os geochronology of these sulphides would not yield an age that would constrain the timing of hydrothermal uranium mineralization. Key words: Thelon Basin, Kiggavik, uranium mineralization, sulphur isotopes, secondary ion mass spectrometry (SIMS), isotope geochemistry. Le bassin de Thelon est associé dans le temps et l'espace au bassin d'Athabasca en Saskatchewan (Canada), qui est l'hôte des gisements d'uranium associés àune discordance les plus riches du monde. Plusieurs gisements uranifères sont présents dans le sous-bassin d'Aberdeen du bassin de Thelon, et il a été suggéré qu'il pourrait s'agir de gisements associés à des discordances. La formation de ces gisements fait toujours débat, et l'âge de l'épisode de minéralisation uranifère n'est qu'approximativement établi. Dans la présente étude, nous utilisons la spectrométrie de masse d'ions secondaires pour mesurer trois isotopes du soufre (S) dans de la pyrite du gisement de Kiggavik pour déterminer les sources du soufre. Nous utilisons cette information pour établir si la datation de ces sulfures par la méthode Re--Os permettrait de mieux délimiter le moment de la minéralisation uranifère. Le gisement de Kiggavik comprend trois zones (principale, centrale et est) qui ont été formées par des fluides à ~200 [degrees]C vers 1600 Ma. De la pyrite et de la galène non hydrothermales provenant des trois zones définissent de grandes fourchettes de valeurs de [delta][.sup.34]S allant de -41, 2[per thousand] à +37,4[per thousand]. Les valeurs de [DELTA][.sup.33]S (>0[per thousand]) témoignent du recyclage de soufre issu du fractionnement indépendant de la masse, ce qui indiquerait que la pyrite du gisement de Kiggavik comprend du soufre provenant du métagrauwacke néoarchéen encaissant. La préservation de ces valeurs anormales de [DELTA][.sup.33]S donne à penser que la pyrite s'est formée par des processus de basse température plutôt que des processus hydrothermaux. Des fluides de haute latitude et de basse température pourraient être intervenus dans la formation de la pyrite puisque certains de ces sulfures sont aussi associés à des minéraux d'uranium exempts de Pb et contiennent de la calcite corrodée. À la lumière de ces données, la géochronologie Re--Os de ces sulfures ne donnerait pas un âge qui délimiterait le moment de la minéralisation uranifère hydrothermale. [Traduit par la Rédaction] Mots-clés: bassin de Thelon, Kiggavik, minéralisation uranifère, isotopes du soufre, la spectrométrie de masse d'ions secondaires (SIMS), géochimie isotopique., Introduction Mining of Proterozoic unconformity-related uranium deposits produces ~30% of the world's uranium (OECD 2018). They are generally high-grade and medium tonnage deposits (Lambert et al. 2005) that are associated [...]