Nonsteroidal anti-inflammatory drugs (NSAIDs) and nucleotide analog GS-441524 conjugates with potent in vivo efficacy against coronaviruses.

Coronaviruses (CoVs) infect a broad range of hosts, including humans and various animals, with a tendency to cross the species barrier, causing severe harm to human society and fostering the need for effective anti-coronaviral drugs. GS-441524 is a broad-spectrum antiviral nucleoside with potent anti-CoVs activities. However, its application is limited by poor oral bioavailability. Herein, we designed and synthesized several conjugates via covalently binding NSAIDs to 5'-OH of GS-441524 through ester bonds. The ibuprofen conjugate, ATV041, exhibited potent in vitro anti-coronaviral efficacy against four zoonotic coronaviruses in the alpha- and beta-genera. Oral-dosed ATV041 resulted in favorable bioavailability and rapid tissue distribution of GS-441524 and ibuprofen. In MHV-A59 infected mice, ATV041 dose-dependently decreased viral RNA replication and significantly reduced the proinflammatory cytokines in the liver and the lung at 3 dpi. As a result, the MHV-A59-induced lung and liver inflammatory injury was significantly alleviated. Taken together, this work provides a novel drug conjugate strategy to improve oral PK and offers a potent anti-coronaviral lead compound for further studies.

A meta-analysis of proactive personality and career success: The mediating effects of task performance and organizational citizenship behavior.

This study aims to reveal the impact of proactive personality on career success (i.e., subjective career success, salary, and promotion) and the sequential mediation effect of organizational citizenship behavior (OCB) and task performance on the relationship. Utilizing meta-analytic structural equation modeling (MASEM) technology sampling 101,131 employees from multiple organizations and industries, which deeply decreased sampling error, the results indicated slightly different findings of proactive personality and three types of career success. Specifically, in relation to salary, OCB and task performance independently transmit the effects of proactive personality to subjective career success, but they sequentially mediate this link as well. In regard to subjective career success and promotion, OCB (but not task performance) mediates the relationship between proactive personality and promotion. OCB and task performance sequentially mediate these links. We discussed findings cautiously and purpose future research directions.

Can SpRY recognize any PAM in human cells?

The application of clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated proteins (Cas) can be limited due to a lack of compatible protospacer adjacent motif (PAM) sequences in the DNA regions of interest. Recently, SpRY, a variant of Streptococcus pyogenes Cas9 (SpCas9), was reported, which nearly completely fulfils the PAM requirement. Meanwhile, PAMs for SpRY have not been well addressed. In our previous study, we developed the PAM Definition by Observable Sequence Excision (PAM-DOSE) and green fluorescent protein (GFP)|-reporter systems to study PAMs in human cells. Herein, we endeavored to identify the PAMs of SpRY with these two methods. The results indicated that 5'-NRN-3', 5'-NTA-3', and 5'-NCK-3' could be considered as canonical PAMs. 5'-NCA-3' and 5'-NTK-3' may serve as non-priority PAMs. At the same time, PAM of 5'-NYC-3' is not recommended for human cells. These findings provide further insights into the application of SpRY for human genome editing.

A patient with severe congenital neutropenia harbors a missense ELANE mutation due to paternal germline mosaicism.

BACKGROUND: Clinical and genetic characteristics of ELANE mutation of a 3-year-old male who had a severe congenital neutropenia (SCN) were examined. We then investigated whether CRISPR/Cas9-mediated gene editing could correct the mutation. PROCEDURE: The proband underwent extensive clinical assessments, such as exome sequencing and bioinformatics analysis, so that pathogenic genes could be identified. Sanger sequencing was also utilized for confirmation. The cell line, 293-ELANE, harboring ELANE mutation was generated, and the mutation was then corrected by CRISPR/Cas9-mediated homology-directed repair (HDR). RESULTS: The ELANE gene test in the proband unveiled a heterozygous de novo missense mutation: c. 248T > A (p.V83D), which was not detected in his asymptomatic parents who had provided peripheral blood samples. We found that 46.01% of his father's sperm cells had the same mutation. These results demonstrate that the proband inherited the ELANE mutation from his father, who had an average neutrophil count but had a germline mosaicism. The highest repair efficiency of CRISPR/Cas9-mediated HDR for 293-ELANE is 4.43%. CONCLUSIONS: We identified a missense mutation (p.V83D) in ELANE that causes SCN. This is the first report on paternal semen mosaicism of an ELANE mutation. Our study paves the way for preimplantation genetic diagnosis (PGD) based on ELANE mutation prevention and clinical treatment of congenital disabilities.

Humble leadership and its outcomes: A meta-analysis.

The importance of humble leadership has garnered attention from both researchers and practitioners. Unfortunately, despite the accumulation of recent findings on the effects of leader humility, a quantitative review remains scant. In addressing this void, this study is among the first to conduct a meta-analytic review of humble leadership and its outcomes. Eighty-four correlations (N = 16,534) from 53 independent studies are synthesized. The authors found that: (a) humble leadership is positively related to affective commitment (ρ = 0.56), affective trust (ρ = 0.62), creativity (ρ = 0.39), engagement (ρ = 0.40), leader-member exchange (LMX) (ρ = 0.58), job satisfaction (ρ = 0.51), organizational identification (ρ = 0.48), psychological empowerment (ρ = 0.33), self-efficacy (ρ = 0.24), task performance (ρ = 0.33), and voice (ρ = 0.34); and that (b) humble leadership contributes a significant incremental variance beyond transformational, servant, and ethical leadership in several crucial criterion variables, providing solid evidence for the construct's uniqueness. However, humble leadership does not explain incremental variance in some criterion variables, indicating that future studies should control for the influence of some positive leadership (e.g., transformational and servant leadership). Age, gender, study design, country, and year partially moderate the correlations of interest. We discuss our findings with caution and propose future research directions.

Thioether-Directed NiH-Catalyzed Remote γ-C(sp3)-H Hydroamidation of Alkenes by 1,4,2-Dioxazol-5-ones.

A NiH-catalyzed thioether-directed cyclometalation strategy is developed to enable remote methylene C-H bond amidation of unactivated alkenes. Due to the preference for five-membered nickelacycle formation, the chain-walking isomerization initiated by the NiH insertion to an alkene can be terminated at the γ-methylene site remote from the alkene moiety. By employing 2,9-dibutyl-1,10-phenanthroline (L4) as the ligand and dioxazolones as the reagent, the amidation occurs at the γ-C(sp3)-H bonds to afford the amide products in up to 90% yield (>40 examples) with remarkable regioselectivity (up to 24:1 rr).

Design and Synthesis of Chiral oxa-Spirocyclic Ligands for Ir-Catalyzed Direct Asymmetric Reduction of Bringmann's Lactones with Molecular H2.

We herein present a facile and column-free synthetic route toward a structurally unique oxa-spirocyclic diphenol, termed as O-SPINOL. Features of the synthesis include the construction of the all-carbon quaternary center at an early stage, a key double intramolecular SNAr step to introduce the spirocycles and the feasibility of operating on >100 g scale. Both enantiomers of O-SPINOL can be easily accessed through optical resolution with l-proline by control of the solvent. The chiral tridentate ligand O-SpiroPAP derived from O-SPINOL has been successfully synthesized and applied in the iridium-catalyzed asymmetric hydrogenation of bridged biaryl lactones under mild reaction conditions, providing valuable and enantioenriched axially chiral molecules in excellent yields and enantioselectivities (up to 99% yield and >99% ee). This method represents a rare example of constructing axially chiral molecules by direct reduction of esters with H2.