Characterization of the Temporomandibular Joint of Southern Sea Otters (Enhydra lutris nereis).

The structure-function relationship of the temporomandibular joint (TMJ) of southern sea otter has largely not been described. This study aims to describe the histological, biochemical, and biomechanical features of the TMJ disk in the southern sea otter. The TMJ disks from fresh cadaver heads of southern sea otter adult males (n = 8) and females (n = 8) acquired from strandings were examined. Following macroscopical evaluation, the TMJs were investigated for their histological, mechanical, and biochemical properties. We found that the sea otter TMJ disks are, in general, similar to other carnivores. Macroscopically, the TMJ disk was highly congruent, and the mandibular head was encased tightly by the mandibular fossa with a thin disk separating the joint into two compartments. Histologically, the articular surfaces were lined with dense fibrous connective tissue that gradually transitioned into one to two cell thick layer of hyaline-like cartilage. The disk fibers were aligned primarily in the rostrocaudal direction and had occasional lacuna with chondrocyte-like cells. The disk was composed primarily of collagen type 1. Biochemical analysis indicates sulfated glycosaminoglycan content lower than other mammals, but significantly higher in male sea otters than female sea otters. Finally, mechanical analysis demonstrated a disk that was not only stronger and stiffer in the rostrocaudal direction than the mediolateral direction but also significantly stronger and stiffer in females than males. We conclude that the congruent design of the TMJ, thin disk, biochemical content, and mechanical properties all reflect a structure-function relationship within the TMJ disk that is likely designed for the sea otter's hard diet and continuous food intake

Calpeptin is a potent cathepsin inhibitor and drug candidate for SARS-CoV-2 infections

Several drug screening campaigns identified Calpeptin as a drug candidate against SARS-CoV-2. Initially reported to target the viral main protease (Mpro), its moderate activity in Mpro inhibition assays hints at a second target. Indeed, we show that Calpeptin is an extremely potent cysteine cathepsin inhibitor, a finding additionally supported by X-ray crystallography. Cell infection assays proved Calpeptin’s efficacy against SARS-CoV-2. Treatment of SARS-CoV-2-infected Golden Syrian hamsters with sulfonated Calpeptin at a dose of 1 mg/kg body weight reduces the viral load in the trachea. Despite a higher risk of side effects, an intrinsic advantage in targeting host proteins is their mutational stability in contrast to highly mutable viral targets. Here we show that the inhibition of cathepsins, a protein family of the host organism, by calpeptin is a promising approach for the treatment of SARS-CoV-2 and potentially other viral infections

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Characterization of the Temporomandibular Joint of Southern Sea Otters (Enhydra lutris nereis).

The structure-function relationship of the temporomandibular joint (TMJ) of southern sea otter has largely not been described. This study aims to describe the histological, biochemical, and biomechanical features of the TMJ disk in the southern sea otter. The TMJ disks from fresh cadaver heads of southern sea otter adult males (n = 8) and females (n = 8) acquired from strandings were examined. Following macroscopical evaluation, the TMJs were investigated for their histological, mechanical, and biochemical properties. We found that the sea otter TMJ disks are, in general, similar to other carnivores. Macroscopically, the TMJ disk was highly congruent, and the mandibular head was encased tightly by the mandibular fossa with a thin disk separating the joint into two compartments. Histologically, the articular surfaces were lined with dense fibrous connective tissue that gradually transitioned into one to two cell thick layer of hyaline-like cartilage. The disk fibers were aligned primarily in the rostrocaudal direction and had occasional lacuna with chondrocyte-like cells. The disk was composed primarily of collagen type 1. Biochemical analysis indicates sulfated glycosaminoglycan content lower than other mammals, but significantly higher in male sea otters than female sea otters. Finally, mechanical analysis demonstrated a disk that was not only stronger and stiffer in the rostrocaudal direction than the mediolateral direction but also significantly stronger and stiffer in females than males. We conclude that the congruent design of the TMJ, thin disk, biochemical content, and mechanical properties all reflect a structure-function relationship within the TMJ disk that is likely designed for the sea otter's hard diet and continuous food intake

Calpeptin is a potent cathepsin inhibitor and drug candidate for SARS-CoV-2 infections

Several drug screening campaigns identified Calpeptin as a drug candidate against SARS-CoV-2. Initially reported to target the viral main protease (M$^{\mathrm{pro}}$), its moderate activity in M$^{\mathrm{pro}}$ inhibition assays hints at a second target. Indeed, we show that Calpeptin is an extremely potent cysteine cathepsin inhibitor, a finding additionally supported by X-ray crystallography. Cell infection assays proved Calpeptin’s efficacy against SARS-CoV-2. Treatment of SARS-CoV-2-infected Golden Syrian hamsters with sulfonated Calpeptin at a dose of 1 mg/kg body weight reduces the viral load in the trachea. Despite a higher risk of side effects, an intrinsic advantage in targeting host proteins is their mutational stability in contrast to highly mutable viral targets. Here we show that the inhibition of cathepsins, a protein family of the host organism, by calpeptin is a promising approach for the treatment of SARS-CoV-2 and potentially other viral infections

SARS-CoV-2 papain-like protease PLpro in complex with natural compounds reveal allosteric sites for antiviral drug design

SARS-CoV-2 papain-like protease (PLpro) covers multiple functions. Beside the cysteine-protease activity, PLpro has the additional and vital function of removing ubiquitin and ISG15 (Interferon-stimulated gene 15) from host-cell proteins to aid coronaviruses in evading the host’s innate immune responses. We established a high-throughput X-ray screening to identify inhibitors by elucidating the native PLpro structure refined to 1.42 Å and performing co-crystallization utilizing a diverse library of selected natural compounds. We identified three phenolic compounds as potential inhibitors. Crystal structures of PLpro inhibitor complexes, obtained to resolutions between 1.7-1.9 Å, show that all three compounds bind at the ISG15/Ub-S2 allosteric binding site, preventing the essential ISG15-PLpro molecular interactions. All compounds demonstrate clear inhibition in a deISGylation assay, two exhibit distinct antiviral activity and one inhibited a cytopathic effect in a non-cytotoxic concentration range. These results highlight the druggability of the rarely explored ISG15/Ub-S2 PLpro allosteric binding site to identify new and effective antiviral compounds. Importantly, in the context of increasing PLpro mutations in the evolving new variants of SARS-CoV-2, the natural compounds we identified may also reinstate the antiviral immune response processes of the host that are down-regulated in COVID-19 infections

Antiviral activity of natural phenolic compounds in complex at an allosteric site of SARS-CoV-2 papain-like protease

SARS-CoV-2 papain-like protease (PLpro) covers multiple functions. Beside the cysteine-protease activity, facilitating cleavage of the viral polypeptide chain, PLpro has the additional and vital function of removing ubiquitin and ISG15 (Interferon-stimulated gene 15) from host-cell proteins to support coronaviruses in evading the host’s innate immune responses. We identified three phenolic compounds bound to PLpro, preventing essential molecular interactions to ISG15 by screening a natural compound library. The compounds identified by X-ray screening and complexed to PLpro demonstrate clear inhibition of PLpro in a deISGylation activity assay. Two compounds exhibit distinct antiviral activity in Vero cell line assays and one inhibited a cytopathic effect in non-cytotoxic concentration ranges. In the context of increasing PLpro mutations in the evolving new variants of SARS-CoV-2, the natural compounds we identified may also reinstate the antiviral immune response processes of the host that are down-regulated in COVID-19 infections