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Heme oxygenase-like domain-containing oxidases (HDOs) are a rapidly expanding enzyme family that typically use dinuclear metal cofactors instead of heme. FlcD, an HDO from the opportunistic pathogen Pseudomonas aeruginosa, catalyzes the excision of an oxime carbon in the biosynthesis of the copper-containing antibiotic fluopsin C. We show that FlcD is a dioxygenase that catalyzes a four-electron oxidation. Crystal structures of FlcD reveal a mononuclear iron in the active site, which is coordinated by two histidines, one glutamate, and the oxime of the substrate. Enzyme activity, Mössbauer spectroscopy, and electron paramagnetic resonance spectroscopy analyses support the usage of a mononuclear iron cofactor. This cofactor resembles that of mononuclear non-heme iron-dependent enzymes and breaks the paradigm of dinuclear HDO cofactors. This study begins to illuminate the catalytic mechanism of methine excision and indicates convergent evolution of different lineages of mononuclear iron-dependent enzymes.

Nematic phases, in which electrons in a solid spontaneously break rotational symmetry while preserving translational symmetry, exist in several families of unconventional superconductors. Superconductivity mediated by nematic fluctuations is well established theoretically, but it has yet to be unambiguously identified experimentally. One major challenge is that nematicity is often intertwined with other degrees of freedom, such as magnetism and charge order. The FeSe1−xSxfamily of superconductors provides an opportunity to explore this concept, as it features an isolated nematic phase that can be suppressed by sulfur substitution at a quantum critical point where the nematic fluctuations are the largest. Here we determine the momentum structure of the superconducting gap near the centre of the Brillouin zone in FeSe0.81S0.19—close to the quantum critical point—and find that it is anisotropic and nearly nodal. The gap minima occur in a direction that is rotated 45° with respect to the Fe–Fe direction, unlike the usual isotropic gaps due to spin-mediated pairing in other tetragonal Fe-based superconductors. Instead, we find that the gap structure agrees with theoretical predictions for superconductivity mediated by nematic fluctuations, indicating a change in the pairing mechanism across the phase diagram of FeSe1−xSx.

AbstractObjective:Identify risk factors that could increase progression to severe disease and mortality in hospitalized SARS-CoV-2 patients in the Southeast region of the United States.Design, setting, and participants:Multicenter, retrospective cohort including 502 adults hospitalized with laboratory-confirmed COVID-19 between March 1, 2020, and May 8, 2020 within 1 of 15 participating hospitals in 5 health systems across 5 states in the Southeast United States.Methods:The study objectives were to identify risk factors that could increase progression to hospital mortality and severe disease (defined as a composite of intensive care unit admission or requirement of mechanical ventilation) in hospitalized SARS-CoV-2 patients in the Southeast United States.Results:In total, 502 patients were included, and 476 of 502 (95%) had clinically evaluable outcomes. The hospital mortality rate was 16% (76 of 476); 35% (177 of 502) required ICU admission and 18% (91 of 502) required mechanical ventilation. By both univariate and adjusted multivariate analyses, hospital mortality was independently associated with age (adjusted odds ratio [aOR], 2.03 for each decade increase; 95% confidence interval [CI], 1.56-–2.69), male sex (aOR, 2.44; 95% CI, 1.34–4.59), and cardiovascular disease (aOR, 2.16; 95% CI, 1.15–4.09). As with mortality, risk of severe disease was independently associated with age (aOR, 1.17 for each decade increase; 95% CI, 1.00–1.37), male sex (aOR, 2.34; 95% CI, 1.54–3.60), and cardiovascular disease (aOR, 1.77; 95% CI, 1.09–2.85).Conclusions:In an adjusted multivariate analysis, advanced age, male sex, and cardiovascular disease increased risk of severe disease and mortality in patients with COVID-19 in the Southeast United States. In-hospital mortality risk doubled with each subsequent decade of life.

We report a combined photocatalytic and hydrogen atom transfer (HAT) approach for the light-mediated epimerization of readily accessible piperidines to provide the more stable diastereomer with high selectivity. The generality of the transformation was explored for a large variety of di- to tetrasubstituted piperidines with aryl, alkyl, and carboxylic acid derivatives at multiple different sites. Piperidines without substitution on nitrogen as well as N-alkyl and aryl derivatives were effective epimerization substrates. The observed diastereoselectivities correlate with the calculated relative stabilities of the isomers. Demonstration of reaction reversibility, luminescence quenching, deuterium labeling studies, and quantum yield measurements provide information about the mechanism.

We report a photoredox-catalyzed α-amino C–H arylation reaction of highly substituted piperidine derivatives with electron-deficient cyano(hetero)arenes. The scope and limitations of the reaction were explored, with piperidines bearing multiple substitution patterns providing the arylated products in good yields and with high diastereoselectivity. To probe the mechanism of the overall transformation, optical and fluorescent spectroscopic methods were used to investigate the reaction. By employing flash-quench transient absorption spectroscopy, we were able to observe electron transfer processes associated with radical formation beyond the initial excited-state Ir(ppy)3oxidation. Following the rapid and unselective C–H arylation reaction, a slower epimerization occurs to provide the high diastereomer ratio observed for a majority of the products. Several stereoisomerically pure products were resubjected to the reaction conditions, each of which converged to the experimentally observed diastereomer ratios. The observed distribution of diastereomers corresponds to a thermodynamic ratio of isomers based upon their calculated relative energies using density functional theory (DFT).

The origins of π-facial selectivities in the borohydride reduction of endocyclic iminium ions have been elucidated by density functional theory calculations. In reductions of conjugated (“thermodynamic”) iminium ions, the π-facial preference of the hydride attack was found to be due to torsional steering. Attack at the favored π-face leads to a lower-energy “half-chair”-like conformation of the tetrahydropyridine product, whereas attack at the other π-face results in an unfavorable “twist-boat” conformation. In reductions of nonconjugated (“kinetic”) iminium ions, torsional distinction is small between the top- and bottom-face attacks, and the π-facial selectivity of the hydride approach is primarily due to steric hindrance.

Cognitive bias is the tendency to subconsciouslychange ones actions or thought process based on someone else’s comments or behavior. It is important to consider cognitive bias when performing a usability study because it can significantly alter or impair the validity of the results. While cognitive bias cannot always be entirely eliminated, identifying key cognitive biases to which usability study results are particularly susceptible is the first step to mitigating them. Once experimenters are alert to these subtle traps, they can consider approaches that sidestep the biases and greatly improve the accuracy and overall effectiveness of a usability study.

This study examined three methods for retrospectively identifying infection in emergency department (ED) patients: modified objective definitions of infection (MODI) from the CDC/NHSN, physician adjudication determination of infection, and ED treating physician behavior.

Immune stress pathways drive resistance to FLT3 inhibition in FLT3-mutant AML, but a dual inhibitor of FLT3 and IRAK1/4 overcomes this resistance.

Out-of-the-box experience is an important consideration in medical device design that not only impacts the user’s impression of the product, but can also have critical safety implications. This article discusses the basic safety questions to contemplate in a use-related risk analysis pertaining to the out-of-the-box experience, and focuses on how the most critical safety risks can be reduced or eliminated by conducting a usability study related to the out-of-the-box experience.