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FeSe1-xSx remains one of the most enigmatic systems of Fe-based superconductors. While much is known about the orthorhombic parent compound, FeSe, the tetragonal samples, FeSe1-xSx with x > 0.17, remain relatively unexplored. Here, we provide an in-depth investigation of the electronic states of tetragonal FeSe0.81S0.19, using scanning tunneling microscopy and spectroscopy (STM/S) measurements, supported by angle-resolved photoemission spectroscopy (ARPES) and theoretical modeling. We analyze modulations of the local density of states (LDOS) near and away from Fe vacancy defects separately and identify quasiparticle interference (QPI) signals originating from multiple regions of the Brillouin zone, including the bands at the zone corners. We also observe that QPI signals coexist with a much stronger LDOS modulation for states near the Fermi level whose period is independent of energy. Our measurements further reveal that this strong pattern appears in the STS measurements as short range stripe patterns that are locally two-fold symmetric. Since these stripe patterns coexist with four-fold symmetric QPI around Fe-vacancies, the origin of their local two-fold symmetry must be distinct from that of nematic states in orthorhombic samples. We explore several aspects related to the stripes, such as the role of S and Fe-vacancy defects, and whether they can be explained by QPI. We consider the possibility that the observed stripe patterns may represent incipient charge order correlations, similar to those observed in the cuprates.

Emerging research supports that triclosan (TCS), an antimicrobial agent found in thousands of consumer products, exacerbates colitis and colitis-associated colorectal tumorigenesis in animal models. While the intestinal toxicities of TCS require the presence of gut microbiota, the molecular mechanisms involved have not been defined. Here we show that intestinal commensal microbes mediate metabolic activation of TCS in the colon and drive its gut toxicology. Using a range of in vitro, ex vivo, and in vivo approaches, we identify specific microbial β-glucuronidase (GUS) enzymes involved and pinpoint molecular motifs required to metabolically activate TCS in the gut. Finally, we show that targeted inhibition of bacterial GUS enzymes abolishes the colitis-promoting effects of TCS, supporting an essential role of specific microbial proteins in TCS toxicity. Together, our results define a mechanism by which intestinal microbes contribute to the metabolic activation and gut toxicity of TCS, and highlight the importance of considering the contributions of the gut microbiota in evaluating the toxic potential of environmental chemicals.

Pathogens that persist in environmental reservoirs represent a major and underappreciated risk for humans and animals (1). Bacillus anthracis, the causative agent of anthrax, is an extreme example of environmental [...]

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.

Environmentally mediated indirect pathogen transmission is linked to host movement and foraging in areas where pathogens are maintained in the environment. In the case of anthrax, spores of the causative bacterium Bacillus anthracis are released into the environment following host death and create locally infectious zones (LIZs) around carcass sites; by grazing at LIZs, herbivores are potentially exposed to spores. Here, we used camera traps to assess how ungulate species use carcass sites in southwestern Montana and evaluated how these behaviours may promote indirect anthrax transmission, thus providing, to our knowledge, the first detailed documentation and study of the fine-scale mechanisms underlying foraging-based disease transmission in this ecosystem. We found that carcasses at LIZs significantly increased aboveground biomass of vegetation and concentrations of sodium and phosphorus, potentially making these sites more appealing to grazers. Host behavioural responses to LIZs varied depending on species, sex, season and carcass age; but, overall, our results demonstrated that carcasses or carcass sites serve as an attractant to herbivores in this system. Attraction to LIZs probably represents an increased risk of exposure to B. anthracis and, consequently, increased anthrax transmission rates. Accordingly, continued anthrax surveillance and control strategies are critical in this system.

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)3 oxidation. 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.

Highly functionalized aminocyclopentadienes can be formed through the rearrangement of anions generated from readily prepared 6-silyl-1,2-dihydropyridines by desilylation with fluoride. The scope and generality of the reaction was defined, and diverse transformations were performed on the highly functionalized products. A mechanism and driving force for the rearrangement were identified from experiments and DFT calculations.

Drug-resistant bacteria remain an ever-present danger to patients and patient safety. Understanding whether and how clinicians use recently approved gram-negative antibiotics might help prioritize the patient in future antibiotic development. This study sought to determine use patterns of recently approved gram-negative antibiotics and identify factors associated with their preferential use in patients with gram-negative infections. The study found that despite approval of 7 next-generation gram-negative antibiotics, clinicians still frequently treat resistant gram-negative infections with older, generic antibiotics with suboptimal safety–efficacy profiles. Visual Abstract. Assessing Clinician Utilization of Next-Generation Antibiotics Against Resistant Gram-Negative Infections in U.S. Hospitals: Drug-resistant bacteria remain an ever-present danger to patients and patient safety. Understanding whether and how clinicians use recently approved gram-negative antibiotics might help prioritize the patient in future antibiotic development. This study sought to determine use patterns of recently approved gram-negative antibiotics and identify factors associated with their preferential use in patients with gram-negative infections. The study found that despite approval of 7 next-generation gram-negative antibiotics, clinicians still frequently treat resistant gram-negative infections with older, generic antibiotics with suboptimal safety–efficacy profiles. Background: The U.S. antibiotic market failure has threatened future innovation and supply. Understanding when and why clinicians underutilize recently approved gram-negative antibiotics might help prioritize the patient in future antibiotic development and potential market entry rewards. Objective: To determine use patterns of recently U.S. Food and Drug Administration (FDA)-approved gram-negative antibiotics (ceftazidime–avibactam, ceftolozane–tazobactam, meropenem–vaborbactam, plazomicin, eravacycline, imipenem–relebactam–cilastatin, and cefiderocol) and identify factors associated with their preferential use (over traditional generic agents) in patients with gram-negative infections due to pathogens displaying difficult-to-treat resistance (DTR; that is, resistance to all first-line antibiotics). Design: Retrospective cohort. Setting: 619 U.S. hospitals. Participants: Adult inpatients. Measurements: Quarterly percentage change in antibiotic use was calculated using weighted linear regression. Machine learning selected candidate variables, and mixed models identified factors associated with new (vs. traditional) antibiotic use in DTR infections. Results: Between quarter 1 of 2016 and quarter 2 of 2021, ceftolozane–tazobactam (approved 2014) and ceftazidime–avibactam (2015) predominated new antibiotic usage whereas subsequently approved gram-negative antibiotics saw relatively sluggish uptake. Among gram-negative infection hospitalizations, 0.7% (2551 [2631 episodes] of 362 142) displayed DTR pathogens. Patients were treated exclusively using traditional agents in 1091 of 2631 DTR episodes (41.5%), including "reserve" antibiotics such as polymyxins, aminoglycosides, and tigecycline in 865 of 1091 episodes (79.3%). Patients with bacteremia and chronic diseases had greater adjusted probabilities and those with do-not-resuscitate status, acute liver failure, and Acinetobacter baumannii complex and other nonpseudomonal nonfermenter pathogens had lower adjusted probabilities of receiving newer (vs. traditional) antibiotics for DTR infections, respectively. Availability of susceptibility testing for new antibiotics increased probability of usage. Limitation: Residual confounding. Conclusion: Despite FDA approval of 7 next-generation gram-negative antibiotics between 2014 and 2019, clinicians still frequently treat resistant gram-negative infections with older, generic antibiotics with suboptimal safety–efficacy profiles. Future antibiotics with innovative mechanisms targeting untapped pathogen niches, widely available susceptibility testing, and evidence demonstrating improved outcomes in resistant infections might enhance utilization. Primary Funding Source: U.S. Food and Drug Administration; NIH Intramural Research Program. [ABSTRACT FROM AUTHOR]

Tyrosine kinase domain (TKD) mutations contribute to acquired resistance to FMS-like tyrosine kinase 3 (FLT3) inhibitors used to treat FLT3-mutant acute myeloid leukemia (AML). We report a cocrystal structure of FLT3 with a type I inhibitor, NCGC1481, that retained potent binding and activity against FLT3 TKD and gatekeeper mutations. Relative to the current generation of advanced FLT3 inhibitors, NCGC1481 exhibited superior antileukemic activity against the common, clinically relevant FLT3-mutant AML cells in vitro and in vivo., Introduction Acute myeloid leukemia (AML) is associated with mutations in FMS-like tyrosine kinase 3 (FLT3) in approximately 30% of cases, including internal tandem duplications (ITDs) and point mutations in the [...]

Source Citation: Dulhunty JM, Brett SJ, De Waele JJ, et al; BLING III Study Investigators. Continuous vs intermittent β-lactam antibiotic infusions in critically ill patients with sepsis: the BLING III randomized clinical trial. JAMA. 12 June 2024. [Epub ahead of print.] 38864155 Clinical Impact Ratings: GIM/FP/GP: 5 out of 7 Infectious Disease: 6 out of 7 Critical Care: 7 out of 7 [ABSTRACT FROM AUTHOR]

Source Citation: Abdul-Aziz MH, Hammond NE, Brett SJ, et al. Prolonged vs intermittent infusions of β-lactam antibiotics in adults with sepsis or septic shock: a systematic review and meta-analysis. JAMA. 12 June 2024. [Epub ahead of print.] 38864162 Clinical Impact Ratings: GIM/FP/GP: 6 out of 7 Infectious Disease: 7 out of 7 Critical Care: 6 out of 7 [ABSTRACT FROM AUTHOR]