Search

Abstract Background An increasing number of older patients require emergency abdominal surgery for acute abdomen. They are susceptible to surgical stress and lose their independence in performing daily activities. Laparoscopic surgery is associated with faster recovery, less postoperative pain, and shorter hospital stay. However, few studies have examined the relationship between laparoscopic surgery and physical functional decline. Thus, we aimed to examine the relationship between changes in physical function and the surgical procedure. Methods In this was a single-center, retrospective cohort study, we enrolled patients who were aged ≥ 65 years and underwent emergency abdominal surgery for acute abdomen between January 1, 2019, and December 31, 2021. We assessed their activities of daily living using the Barthel Index. Functional decline was defined as a decrease of ≥ 20 points in Barthel Index at 28 days postoperatively, compared with the preoperative value. We evaluated an association between functional decline and surgical procedures among older patients, using multiple logistic regression analysis. Results During the study period, 852 patients underwent emergency abdominal surgery. Among these, 280 patients were eligible for the analysis. Among them, 94 underwent laparoscopic surgery, while 186 underwent open surgery. Patients who underwent laparoscopic surgery showed a less functional decline at 28 days postoperatively (6 vs. 49, p

Protein-protein interactions (PPIs) play a crucial role in most biological processes and are important targets in the development of therapeutic agents. However, small molecule drug discovery that targets PPIs remains very challenging. Targeting hot spot residues is considered the best option for inhibiting such interactions, but there are few examples of how knowledge of hot spots can be used in high throughput screening to find hit compounds. A substrate adaptor protein for a ubiquitin ligase complex, Kelch-like ECH-associated protein 1 (Keap1), negatively modulates the expression of genes involved in cellular protection against oxidative stress. Here, we focused on three arginine hot spot residues in the Keap1 substrate binding pocket (Arg380, Arg415, and Arg483), and screened the carboxylic acid library owned by Japan Tobacco Inc. for compounds that interact with the arginine residues in differential scanning fluorescence assays. Furthermore, we identified several small molecule compounds that specifically bind to the Keap1 Kelch domain hot spots by comparing binding to alanine mutant proteins (R380A, R415A, and R483A) with binding to the wild-type protein using surface plasmon resonance (SPR) screening. These compounds inhibited the protein-protein interaction between the Keap1 Kelch domain and the nuclear factor erythroid 2-related factor 2 (Nrf2) peptide, and the ubiquitination of Nrf2 catalyzed by the Cul3/RINGBox 1 E3 ligase. In addition, the binding mode of one compound (Compound 4) was determined by X-ray crystallography after validation of binding by isothermal titration calorimetry, native mass spectrometry, and nuclear magnetic resonance. Compound 4 had favorable thermodynamic properties, and noncovalently bound to Keap1 with a stoichiometry of 1:1. Our results suggest that Compound 4 could potentially be developed into effective therapeutic or preventive agents for a variety of diseases and conditions such as oxidative stress response, inflammation, and carcinogenesis. We believe that the use of a set of complementary biophysical techniques including the SPR assay with single alanine mutant of hot spots provides opportunities to identify hit compounds for developing inhibitors of PPIs.

Abstract Background Older individuals increasingly require emergency abdominal surgeries. They are susceptible to surgical stress and loss of independence in performing daily activities. We hypothesized that the psoas muscle volume would be significantly associated with postoperative functional decline (FD) in older patients undergoing emergency abdominal surgery and aimed to evaluate the use of the psoas muscle volume on computed tomography (CT) scans. Methods A retrospective, single-center study of patients aged ≥ 65 years who had undergone emergency abdominal surgery between January 2019 and June 2021 was performed. We assessed patients’ activities of daily living using the Barthel Index. FD was defined as a ≥ 5-point decrease between preoperative and 28-day postoperative values. The psoas muscle volume was measured by CT, which was used for diagnosis, and normalized by height to calculate total psoas muscle index (TPI). We evaluated associations between FD and TPI using receiver operating characteristics (ROC) analysis and multiple logistic regression analysis. Results Of 238 eligible patients, 71 (29.8%) had clinical postoperative FD. Compared to the non-FD group, the FD group was significantly older and had a higher proportion of females, higher Charlson Comorbidity Index, lower body mass index, higher American Society of Anesthesiology score, lower serum albumin level, and lower TPI. ROC analyses revealed that TPI had the highest area under the curve (0.802; 95% confidence interval [CI], 0.75–0.86). A multivariable logistic regression model revealed that low TPI was an independent predictor of postoperative FD (odds ratio, 0.14; 95% CI, 0.06–0.32). Conclusions TPI can predict postoperative FD due to emergency abdominal surgery. Identification of patients who are at high risk of FD before surgery may be useful for enhancing the regionalized system of care for emergency general surgery.

A panel of nanobodies are presented that can detect the spike proteins of five SARS-CoV-2 variants of concern and structural analyses show that one clone targets conserved epitopes on the receptor-binding domain and contacts the N-terminal domain.