Discovery of Isojacareubin as a covalent inhibitor of SARS‐CoV‐2 main protease using structural and experimental approaches

alexandrossfakianakis shared this article with you from Inoreader Discovery of Isojacareubin as a covalent inhibitor of SARS‐CoV‐2 main protease using structural and experimental approaches via Journal of Medical Virology Abstract The ongoing pandemic with the emergence of immune evasion potential and particularly the current omicron sub variants intensified the situation further. Although vaccine are available but the immune evasion capabilities of the recent variants demand further efficient therapeutic choices to control the SARS-CoV-2 pandemic. Hence, considering the necessity of the small molecule inhibitor we target the main protease (3CLpro) which is an appealing target for the development of anti-viral drugs against the SARS-CoV-2. High-throughput molecular in silico screening of South African natural compounds database (SANCDB) reported as Isojacareubin and Glabranin the potential inhibitors for main protease. The calculated docking scores were reported to be -8.47 kcal/mol and -8.03 kcal/mol respectively. Moreover, the structural-dynamic assessment reported that Isojacareubin in complex with 3CLpro exhibit more stable dynamic behaviour than Glabranin. Inhibition assay indicated that Isojacareubin could inhibit SARS-CoV-2 3CLpro in a time- and dose-dependent manner, with IC50 values of 16.00±1.35 μM (60-min incubation). Next, the covalent binding sites of Isojacareubin on SARS-CoV-2 3CLpro was identified by biomass spectrometry which reported that Isojacareubin can covalently bind to thiols or Cysteine through Michael addition. To evaluate the inactivation potency of Isojacareubin, the inactivation kinetics was further investigated. The inactivation kinetic curves were plotted according to various concentrations with gradient-ascending incubation times. The K I value of Isojacareubin was determined as 30.71 μM, while the K inact value was calculated as 0.054 min-1. These results suggest that Isojacareubin is a covalent inhibitor of SARS-CoV-2 3CLpro. This article is protected by copyright. All rights reserved. View on Web

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α‐KG Up‐regulates Autophagic Activity in Peri‐implant Environment and Enhances Dental Implant Osseointegration in Osteoporotic Mice

alexandrossfakianakis shared this article with you from Inoreader α‐KG Up‐regulates Autophagic Activity in Peri‐implant Environment and Enhances Dental Implant Osseointegration in Osteoporotic Mice via Journal of Clinical Periodontology Abstract Aim The osseointegration of dental implants is impaired among patients with osteoporosis, leading to significantly higher failure rate. This study set out to investigate the potential effects of alpha-ketoglutarate (α-KG) on implant osseointegration in an osteoporotic mouse model. Material and Methods Female C57BL/6 mice received ovariectomy and bilateral first maxillary molars extraction at the age of seven weeks. Dental implants were inserted eight weeks after tooth extraction. In one of the groups, α-KG was administered via drinking water throughout the experiment period. Specimens were collected on post-implant day (PID) 3, 7, 14, and 21 for micro-CT, histological and immunohistochemical analyses. At the same time, bone marrow-derived mesenchymal stem cells (BMMSCs) treated with α-KG were interrogated for osteogenic differentiation, autophagic activity, and apoptosis. Results α-KG supplement in drinking water resulted in enhanced dental implant osseointegration in ovariectomized mice, with upregulated osteogenic and autophagic activity and downregulated osteoclast differentiation and cell apoptosis. α-KG treated BMMSCs demonstrated enhanced activity in proliferation, survival, colony formation, osteogenic differentiation, as well as autophagic activity. Conclusions Systemic α-KG supplement effectively prevents the failure of dental implant osseointegration in mice under an osteoporotic state. This article is protected by copyright. All rights reserved. View on Web

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Longitudinal Trends in 30-Day Mortality Between Multi-Site and Single-Site Surgeons

alexandrossfakianakis shared this article with you from Inoreader Longitudinal Trends in 30-Day Mortality Between Multi-Site and Single-Site Surgeons via Annals of Surgery - Most Popular Articles Background: Quality leaders are concerned that creation of multi-hospital health systems may lead to surgeons traveling to and from distant hospitals and thus to more fragmented surgical care and worse outcomes for their patients. Despite this concern, little empirical data exist on outcomes of multi-site versus single-site surgeons. Methods: Using national Medicare data, we assessed trends in the number of multi-site vs. single-site surgeons from 2011 to 2016. We performed a multivariable regression analysis to compare overall 30-day mortality differences, stratified by system and rural status, and examined trends over time. Results: The number of multi-site surgeons and the percentage of multi-site surgeons per hospital decreased over time (24.2%–19.0%; 44.3%–41.8%). Overall, multi-site surgeons had lower 30-day mortality than single-site surgeons (2.24% vs 2.50%, P View on Web

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A high prevalence of neutrophil‐specific antibodies in ELANE‐mutated severe congenital neutropenia

alexandrossfakianakis shared this article with you from Inoreader A high prevalence of neutrophil‐specific antibodies in ELANE‐mutated severe congenital neutropenia via Pediatric Blood & Cancer Abstract An assay for neutrophil-specific antibodies is frequently used in the workup of chronic severe neutropenia and is suggestive of autoimmune, or sporadically alloimmune neutropenia, rather than severe congenital neutropenia (SCN). We analyzed a neutropenia consortium database for the outcomes of antibody testing initiated before receiving genetic diagnosis in Polish SCN cohort. Test results, performed in a single reference laboratory, were available for 14 patients with ELANE-mutated SCN or cyclic neutropenia, and were frequently positive (36%). We note that the trigger for genetic studies in severe neutropenia should not be affected by antibody-positivity and should be clinically driven. View on Web

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