Rational design peptide inhibitors of Cyclophilin D as a potential treatment for acute pancreatitis.

Cyclophilin D (CypD) is a mitochondrial matrix peptidyl prolidase that regulates the mitochondrial permeability transition pore. Inhibition of CypD was suggested as a therapeutic strategy for acute pancreatitis. Peptide inhibitors emerged as novel binding ligand for blocking receptor activity. In this study, we present our computational approach for designing peptide inhibitors of CypD. The 3-D structure of random peptides were built, and docked into the active center of CypD using Rosetta script integrated FlexPepDock module. The peptide displayed the lowest binding energy against CypD was further selected for virtual iterative mutation based on virtual mutagenesis and molecular docking. Finally, the top 5 peptides with the lowest binding energy was selected for validating their affinity against CypD using inhibitory assay. We showed 4 out of the selected 5 peptides were capable for blocking the activity of CypD, while WACLQ display the strongest affinity against CypD, which reached 0.28 mM. The binding mechanism between WACLQ and CypD was characterized using molecular dynamics simulation. Here, we proved our approach can be a robust method for screening peptide inhibitors.

Subdural evacuating port system with subdural thrombolysis for the treatment of chronic subdural hematoma in patients older than 80 years.

Objective: The subdural evacuating port system (SEPS) is a minimally invasive approach that can be performed under local anesthesia for the treatment of chronic subdural hematoma (CSDH). Subdural thrombolysis has been described as an exhaustive drainage strategy and found to be safe and effective for improving drainage. We aim to analyze the effectiveness of SEPS with subdural thrombolysis in patients older than 80 years. Method: Consecutive patients aged ≥80 years old who presented with symptomatic CSDH and underwent SEPS followed by subdural thrombolysis between January 2014 and February 2021 were retrospectively studied. Outcome measures included complications, mortality, recurrence, and modified Rankin Scale (mRS) scores at discharge and 3 months. Results: In total, 52 patients with CSDH in 57 hemispheres were operated on, with a mean age of 83.9 ± 3.3 years, and 40 (76.9%) patients were men. The preexisting medical comorbidities were observed in 39 patients (75.0%). Postoperative complications occurred in nine patients (17.3%), with two having significant complications (3.8%). The complications observed included pneumonia (11.5%), acute epidural hematoma (3.8%), and ischemic stroke (3.8%). One patient experienced contralateral malignant middle cerebral artery infarction and died of subsequent severe herniation, contributing to a perioperative mortality rate of 1.9%. Discharge and 3 months of favorable outcomes (mRS score 0-3) were achieved in 86.5% and 92.3% of patients, respectively. CSDH recurrence was observed in five patients (9.6%), and repeat SEPS was performed. Conclusion: As an exhaustive drainage strategy, SEPS followed by thrombolysis is safe and effective with excellent outcomes among elderly patients. It is a technically easy and less invasive procedure with similar complications, mortality, and recurrence rates compared with burr-hole drainage in the literature.

Therapeutic plasma exchange in patients with sepsis: Secondary analysis of a cluster-randomized controlled trial.

INTRODUCTION: Sepsis is life-threatening organ dysfunction caused by infection-related inflammatory response. Therapeutic plasma exchange (TPE) can remove inflammatory mediators and benefit patients in different disease settings. However, no solid evidence showed the efficacy and safety of TPE in sepsis. METHODS: This study was a secondary analysis of a randomized controlled trial. Critically ill patients with sepsis were divided into two groups according to whether treated with TPE. The primary outcome was the delta Sequential Organ Failure Assessment (SOFA) score from days 1 to 7. Secondary outcomes included new-onset organ failure, intensive care unit (ICU)-free and alive days to day 28, and 28-day mortality. Propensity score-matched (PSM) analysis was applied to control confounders. Analysis of covariance (ANCOVA) and logistic regression were used to assess the association between TPE and selected outcomes. RESULTS: Among the 2772 critically ill patients enrolled in the trial, 742 patients with sepsis were selected and 22 patients received TPE were matched with 22 control patients. No significant difference was found in the delta SOFA score and 28-day mortality between TPE group and control group. The ICU-free and alive days in the TPE group were significantly shorter than the control group. CONCLUSIONS: TPE may be not associated with improvement of organ failure and mortality in critically ill patients with sepsis and may be associated with a prolonged ICU stay.

A multigroup structural equation modeling analysis of students' perception, motivation, and performance in computational thinking.

Students' perceptions of learning are important predictors of their learning motivation and academic performance. Examining perceptions of learning has meaningful implications for instruction practices, while it has been largely neglected in the research of computational thinking (CT). To contribute to the development of CT education, we explored the influence of students' perceptions on their motivation and performance in CT acquisition and examined the gender difference in the structural model using a multigroup structural equation modeling (SEM) analysis. Two hundred and eighty-five students from a Chinese urban high school were recruited for the study. The analysis revealed that students' perceptions of CT positively influenced their CT performance and learning motivation, and some motivational constructs, namely self-efficacy and learning goal orientation (LGO), also positively influenced their CT performance. Furthermore, in the male student group, perceptions of CT exhibited significant correlations with both self-efficacy and LGO. However, no significant correlation was found in the female student group. Implications for research and teaching practice in CT education are presented herein.

Azithromycin "ghost peak": A solution degradation product of azithromycin via leaching from borosilicate glass volumetric flasks and vials.

An interference peak was found while detecting related substances of azithromycin. It is impressive that the degradation peak occurred at about 70 min in the next injection of the test solution (4 mg/mL or higher). Once the degradation peak was observed, it would keep growing. By using a strategy that Q-TOF high resolution mass spectrometry with mechanism-based stress studies, followed by preparative subsequent structure characterization by 1D and 2D NMR, the unknown peak was identified as azithromycin hydrogen borate. It apparently results from azithromycin and residual boron leaching out of the inner surface of the glass volumetric flasks and vials used in the sample preparation. By simulating the above chemical process, boric acid and azithromycin were dissolved in the same extraction diluent and a big interference peak occurred. It was found that boron-free flasks and vials, such as PMP or PP flasks and PTFE or PP vials could be used for the detection of azithromycin related substances to avoid the production of azithromycin hydrogen borate.

Circular RNA expression profile in human primary multiple intracranial aneurysm.

Primary multiple intracranial aneurysm (MIA) is a vascular disease that frequently leads to fatal vascular rupture and subarachnoid hemorrhage. However, the epigenetic regulation associated with MIA has remained largely elusive. Circular RNAs (circRNAs) serve important roles in cardiovascular diseases; however, their association with MIA has remained to be investigated. The present study initially aimed to explore novel mechanisms of MIA through examining circRNA expression profiles. Comprehensive circRNA expression profiles were detected by RNA sequencing (RNA-Seq) in human peripheral blood mononuclear cells. The RNA-Seq results were validated by reverse transcription-quantitative PCR. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses suggested the functions of these circRNAs. A competing endogenous RNA network was constructed to reveal the circRNA-microRNA-mRNA relationship. Among the 3,328 differentially expressed circRNAs between the MIA and matched control groups, 60 exhibited significant expression changes (|log2 fold change|≥2; P<0.05). Among these 60 circRNAs, 20 were upregulated, while the other 40 were downregulated. A number of downregulated circRNAs were involved in inflammation. The most significant KEGG pathway was 'leukocyte transendothelial migration'. The circRNAs Homo sapiens (hsa)_circ_0135895, hsa_circ_0000682 and hsa_circ_0000690, which were also associated with the above-mentioned pathway, were indicated to be able to regulate protein tyrosine kinase 2, protein kinase Cß and integrin subunit αL, respectively. To the best of our knowledge, the present study was the first to perform a circRNA sequencing analysis of MIA. The results specifically predicted the regulatory role of circRNAs in the pathogenesis of MIA. 'Leukocyte transendothelial migration' may be critical for the pathogenesis of MIA.

The squaramide-catalyzed asymmetric Michael/cyclization tandem reaction for the synthesis of chiral trifluoromethylated hydroxyimino tetrahydrobenzofuranones.

An enantioselective synthesis of trifluoromethylated hydroxyimino tetrahydrobenzofuranones has been developed. 1,3-Dicarbonyl carbocyclic compounds react with ß-CF3-ß-disubstituted nitroalkenes in the presence of a chiral squaramide catalyst, providing efficient access to diverse hydroxyimino tetrahydrobenzofuranones featuring a trifluoromethyl group at the C3-position of an all-carbon quaternary stereocenter with good yields (up to 81%) and enantioselectivities (up to 89% ee).

Prevention of hyperglycemia-induced myocardial apoptosis by gene silencing of Toll-like receptor-4.

BACKGROUND: Apoptosis is an early event involved in cardiomyopathy associated with diabetes mellitus. Toll-like receptor (TLR) signaling triggers cell apoptosis through multiple mechanisms. Up-regulation of TLR4 expression has been shown in diabetic mice. This study aimed to delineate the role of TLR4 in myocardial apoptosis, and to block this process through gene silencing of TLR4 in the myocardia of diabetic mice. METHODS: Diabetes was induced in C57/BL6 mice by the injection of streptozotocin. Diabetic mice were treated with 50 µg of TLR4 siRNA or scrambled siRNA as control. Myocardial apoptosis was determined by TUNEL assay. RESULTS: After 7 days of hyperglycemia, the level of TLR4 mRNA in myocardial tissue was significantly elevated. Treatment of TLR4 siRNA knocked down gene expression as well as diminished its elevation in diabetic mice. Apoptosis was evident in cardiac tissues of diabetic mice as detected by a TUNEL assay. In contrast, treatment with TLR4 siRNA minimized apoptosis in myocardial tissues. Mechanistically, caspase-3 activation was significantly inhibited in mice that were treated with TLR4 siRNA, but not in mice treated with control siRNA. Additionally, gene silencing of TLR4 resulted in suppression of apoptotic cascades, such as Fas and caspase-3 gene expression. TLR4 deficiency resulted in inhibition of reactive oxygen species (ROS) production and NADPH oxidase activity, suggesting suppression of hyperglycemia-induced apoptosis by TLR4 is associated with attenuation of oxidative stress to the cardiomyocytes. CONCLUSIONS: In summary, we present novel evidence that TLR4 plays a critical role in cardiac apoptosis. This is the first demonstration of the prevention of cardiac apoptosis in diabetic mice through silencing of the TLR4 gene.