Rapid Formation of Intramolecular Disulfide Bridges using Light: An Efficient Method to Control the Conformation and Function of Bioactive Peptides.

Disulfide bonds are widely found in natural peptides and play a pivotal role in stabilizing their secondary structures, which are highly associated with their biological functions. Herein, we introduce a light-mediated strategy to effectively control the formation of disulfides. Our strategy is based on 2-nitroveratryl (oNv), a widely used photolabile motif, which serves both as a photocaging group and an oxidant (after photolysis). We demonstrated that irradiation of oNv-caged thiols with UV light could release free thiols that are rapidly oxidized by locally released byproduct nitrosoarene, leading to a "break-to-bond" fashion. This strategy is highlighted by the in situ restoration of the antimicrobial peptide tachyplesin I (TPI) from its external disulfide-caged analogue TPI-1. TPI-1 exhibits a distorted structure and a diminished function. However, upon irradiation, the ß-hairpin structure and membrane activity of TPI were largely restored via rapid intramolecular disulfide formation. Our study proposes a powerful method to regulate the conformation and function of peptides in a spatiotemporal manner, which has significant potential for the design of disulfide-centered light-responsive systems.

A new role for host annexin A2 in establishing bacterial adhesion to vascular endothelial cells: lines of evidence from atomic force microscopy and an in vivo study.

Understanding bacterial adhesion is challenging and critical to our understanding of the initial stages of the pathogenesis of endovascular bacterial infections. The vascular endothelial cell (EC) is the main target of Rickettsia, an obligately intracellular bacterium that causes serious systemic disease in humans and animals. But the mechanism(s) underlying bacterial adherence to ECs under shear stress from flowing blood prior to activation are unknown for any bacteria. Although host surface annexin a2 (ANXA2) has been identified to participate in efficient bacterial invasion of epithelial cells, direct evidence is lacking in the field of bacterial infections of ECs. In the present study, we employ a novel, anatomically based, in vivo quantitative bacterial-adhesion-to-vascular-EC system, combined with atomic force microscopy (AFM), to examine the role of endothelial luminal surface ANXA2 during rickettsial adherence to ECs. We also examined whether ANXA2 antibody affected binding of Staphylococcus aureus to ECs. We found that deletion of ANXA2 impeded rickettsial attachment to the ECs in vitro and blocked rickettsial adherence to the blood vessel luminal surface in vivo. The AFM studies established that EC surface ANXA2 acts as an adherence receptor for rickettsiae, and that rickettsial adhesin OmpB is the associated bacterial ligand. Furthermore, pretreatment of ECs with anti-ANXA2 antibody reduced EC surface-associated S. aureus. We conclude that the endothelial surface ANXA2 plays an important role in initiating pathogen-host interactions, ultimately leading to bacterial anchoring on the vascular luminal surface.

Oxidative Alkane C-H Alkoxycarbonylation.

Directly utilizing a chemical feedstock to construct valuable compounds is an attractive prospect in organic synthesis. In particular, the combination of C(sp(3) )-H activation and oxidative carbonylation involving alkanes and CO gas is a promising and efficient method to synthesize carbonyl derivatives. However, due to the high C-H bond dissociation energy and low polarity of unactivated alkanes, the carbonylation of unactivated C(sp(3) )-H bonds still remains a great challenge. In this work, we introduce a palladium-catalyzed radical oxidative alkoxycarbonylation of alkanes to prepare numerous alkyl carboxylates. Various alkanes and alcohols were compatible, generating the desired products in up to 94 % yield. Remarkably, ethane, a constituent of natural gas, could be employed as a substrate under the standard reaction conditions. Preliminary mechanistic studies revealed a probable palladium-catalyzed radical process.

Electrochemical oxidative radical cascade cyclization of dienes and diselenides towards the synthesis of seleno-benzazepines.

Selenium-containing compounds are important scaffolds owing to their value in medicinal chemistry, biochemistry and material chemistry. Herein, we report an electrochemical approach to access seleno-benzazepines through an oxidative radical cascade cyclization of dienes with diselenides under metal-free, external oxidant-free and base-free conditions. In a simple undivided cell, various dienes and diselenides were suitable for this transformation, generating the desired products in up to 84% yields. This method provides a green and convenient route for the synthesis of valuable selenium-containing seven-membered N-heterocycles from simple starting materials.

Framework to Guide Health Professions Faculty Towards Increased Scholarship: Recommendations from the ASAHP Research, Discovery & Innovation Committee.

The Research, Discovery, and Innovation Publications (RDI-P) Task Force met from October 2020 to March 2022 to discuss ways in which the Association of Schools Advancing Health Professions (ASAHP) can help to guide institutional leaders to assign faculty effort and resources to enable success with the scholarship mission. The purpose of this White Paper is to propose a guiding framework for institutional leaders to determine their faculty's individual or team scholarly goals, assign appropriate percent efforts (funded/unfunded), and guide an overall faculty mix that balances required teaching loads with scholarly activities. The Task Force identified seven modifiable factors that can influence workload allocation for scholarship: 1. Limited range of the spectrum for effort distribution; 2. Matching expectations with reality; 3. Clinical training undervalued as adequate prep for translational or implementation research; 4. Limited support for mentorship availability; 5. Richer collaborations needed; 6. Finding resources and matching them to individual faculty needs; and 7. Further time for training needed. We then provide a set of recommendations to address the seven issues described. Finally, we describe four foci of scholarly activity (evidence-based educator; evidence-based clinical application; evidence-based collaborator; and evidence-based principal leader) with which a leader can develop strategies to align faculty interests and growth opportunities towards advancing scholarship.

Electrochemical Oxidative Cross-Coupling of Enaminones and Thiophenols to Construct C-S Bonds.

An electrochemical oxidative C(sp2)-H sulfuration has been developed. Various enaminones and thiophenols were compatible, generating the desired alkenyl sulfur compounds in up to 87 % yield. This transformation proceeded smoothly under mild reaction conditions without external oxidant and transition-metal catalyst. Remarkably, thiophenols selectively coupled with enamines when substrates had other alkenyl groups. In addition, the desired products could be further transformed into a series of α-sulfur isoxazoles, which are a kind of useful heterocycles in materials and bioactive molecules.

Copper-catalyzed selective radical-radical cross-coupling for C-S bond formation: an access to α-alkylthionitriles.

A new protocol for C-S bond formation was developed by selective cross-coupling between a thiyl radical and an isobutyronitrile radical. Using this strategy, a series of valuable α-alkylthionitrile derivatives were synthesized from basic starting materials. Preliminary mechanistic investigation was performed by EPR and XAFS, revealing that the transient thiyl radical could be stabilized by a copper catalyst to a persistent one. Therefore, on the basis of the persistent radical effect, selective radical-radical cross-coupling between the thiyl radical and the isobutyronitrile radical was achieved successfully in this work.

Palladium/Copper-Catalyzed Oxidative Coupling of Arylboronic Acids with Isocyanides: Selective Routes to Amides and Diaryl Ketones.

An efficient and alternative oxidative cross-coupling strategy starting from arylboronic acids and isocyanides for the selective synthesis of amides and diaryl ketones with palladium/copper catalysis is developed. Various substituted benzamides and benzophenones could be obtained in good yields. The reaction represents an efficient and alternative strategy for the synthesis of carbonyl compounds.

Speech tasks and interrater reliability in perceptual voice evaluation.

OBJECTIVE/HYPOTHESIS: The optimal selection of speech task is essential for more reliable perceptual ratings and a better understanding of the perceptual qualities of pathologic voices. Nevertheless, researchers have rarely explored this issue using the GRBAS scale. This study investigates the effect of speech task selection on interrater reliability during perceptual voice assessment. STUDY DESIGN: Experimental study. METHODS: Sixty subjects, 39 dysphonic subjects and 21 normal controls, performed 13 speech tasks including three 5-second sustained vowel sounds (/ɑ/, /i/, and /u/) each at three pitch levels (high, habitual, and low), maximum phonation of the vowel /ɑ/, pitch glide, counting from 1 to 10, and oral reading of the Rainbow Passage. A group of 18 graduate students in speech-language pathology served as perceptual judges and rated the dysphonic severity for the speech samples based on three parameters in the GRBAS scale-Grade, Roughness, and Breathiness. The formalism of the AC1 statistic proposed by Gwet was applied to determine relative reliability between the speech tasks and the raters. RESULTS: The counting task and sustained vowel /ɑ/ in high, habitual, and low registers exhibited the most reproducibility and consequently the highest reliability statistic. CONCLUSIONS: The counting task and sustained /ɑ/ phonation are the optimal tasks for perceptual voice judgment in regard to interrater reliability. Future perceptional studies may benefit from this finding to determine the relationship between speech task selection and the validity of any given perceptual rating system in terms of sensitivity and specificity.

Efficacy of intensive phonatory-respiratory treatment (LSVT) for presbyphonia: two case reports.

OBJECTIVES: Research evidence has shown that neither traditional voice therapy nor surgery was efficacious in managing age-related dysphonia, specifically for more severe cases with pronounced fold atrophy or larger glottal gaps. The purpose of this study was to examine the efficacy of intensive respiratory-phonatory treatment (Lee Silverman voice treatment [LSVT]) for glottal incompetence associated with presbyphonia. STUDY DESIGN: Nonrandomized prospective study. METHODS: Two subjects with age-related vocal fold bowing received 4 weeks of the LSVT. Strobolaryngoscopic examination, phonatory function measurement, acoustical analyses, and perceptual judgments of voice were obtained at baseline and 2 weeks posttreatment. Additional acoustic measures of phonatory function, including vocal intensity, maximum phonation time, and pitch range, were also obtained during 16 treatment sessions. RESULTS: Both subjects exhibited significant improvements in glottal closure, phonatory function, acoustic features, and perceptual ratings of voice after treatment. Significant changes of phonatory function measures were noticed relatively early and remained steady throughout the course of treatment. CONCLUSIONS: These findings provide solid evidence that speakers with age-related vocal fold bowing and dysphonia may improve glottal competence and related vocal function with neither laryngeal trauma nor maladaptive laryngeal hyperfunction after the LSVT.