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The risk of colitis and colorectal cancer increases markedly throughout adult life, endangering the health and lives of elderly individuals. Previous studies have proposed that bacterial translocation and infection are the main risk factors for these diseases. Therefore, in the present study, we aimed to identify the underlying mechanism by focusing on the mucus barrier function and mucin‐type O‐glycosylation. We evaluated alterations in the colon mucus layer in 2‐, 16‐, and 24‐month‐old mice and aged humans. Aged colons showed defective intestinal mucosal barrier and changed mucus properties. The miR‐124‐3p expression level was significantly increased in the aged distal colonic mucosa, which was accompanied by an increase in pathogens and bacterial translocation. Meanwhile, T‐synthase, the rate‐limiting enzyme in O‐glycosylation, displayed an age‐related decline in protein expression. Further experiments indicated that miR‐124‐3p modulated O‐glycosylation by directly targeting T‐synthase. Moreover, young mice overexpressing miR‐124‐3p exhibited abnormal glycosylation, early‐onset, and more severe colitis. These data suggest that miR‐124‐3p predisposes to senile colitis by reducing T‐synthase, and the miR‐124‐3p/T‐synthase/O‐glycans axis plays an essential role in maintaining the physiochemical properties of colonic mucus and intestinal homeostasis. Young colons show intact inner layer and mucin‐type O‐glycosylation, limiting microbiota access to the epithelium. Age‐related alteration in miR‐124‐3p/T‐synthase/O‐glycans axis and reduction in mucus thickness weakened the mucus barrier, leading to abnormal bacterial intrusion and increased susceptibility to senile colitis.

To investigate antiepileptic drugs (AEDs) prescription and pregnancy outcomes in pregnancies with epilepsy in Taiwan between 2004 and 2015. We retrospectively reviewed data from the Taiwanese Registry of Epilepsy and Pregnancy (TREP). The TREP registry is a voluntary prospective cohort registry, which tracks pregnant women with epilepsy and AED prescription throughout pregnancy, delivery, and early childhood development. All TREP pregnancies (n = 318) that had completed questionnaires up until delivery or had had an unsuccessful pregnancy were analyzed. Over 94.7% of women had been prescribed AEDs during pregnancy, with 69.0% and 25.7% having received monotherapy, or polytherapy, respectively. Among live births, 12 (3.9%) reported malformation. Cesarean section rate was reported higher than usual (54.5%). In 2004, 73.3% of AEDs prescribed were 1st generation, with 1st generation prescription rates falling to only 8.3% of total prescribed in 2015. AED polytherapy also fell during the study period (40.0% to 20.0%). Cesarean sections were found to be higher for women over 35 years, who had generalized epilepsy, or had experienced an obstetric complication during pregnancy term. Binary logistic regression revealed that Cesarean section was associated with maternal complications (OR = 5.11, CI 95% = 1.11-23.51, p = 0.036), while malformations were associated with obstetric complication (OR = 20.46, CI 95% = 4.80-87.21, p<0.001). Both AED risk types were not associated with complications or malformations. Our sample provides a unique insight into the women with epilepsy with AED use during pregnancy. Cesarean section rate was observed to be higher than usual, but malformation rates remained low. Results indicate a decrease in both 1st generation AEDs and proportion of patients receiving polytherapy over the study period. Obstetric complications were associated with Cesarean section. Fetal malformations were significantly associated with obstetric complications. AED risk factors were not significantly associated with either complications or malformations.

The β-sheet is one of the common protein secondary structures, and the aberrant aggregation of β-sheets is implicated in various neurodegenerative diseases. Cross-strand interactions are an important determinant of β-sheet stability. Accordingly, both diagonal and lateral cross-strand interactions have been studied. Surprisingly, diagonal cross-strand ion-pairing interactions have yet to be investigated. Herein, we present a systematic study on the effects of charged amino acid side-chain length on a diagonal ion-pairing interaction between carboxylate- and ammonium-containing residues in a β-hairpin. To this end, 2D-NMR was used to investigate the conformation of the peptides. The fraction folded population and the folding free energy were derived from the chemical shift data. The fraction folded population for these peptides with potential diagonal ion pairs was mostly lower compared to the corresponding peptide with a potential lateral ion pair. The diagonal ion-pairing interaction energy was derived using double mutant cycle analysis. The Asp2-Dab9 (Asp: one methylene; Dab: two methylenes) interaction was the most stabilizing (−0.79 ± 0.14 kcal/mol), most likely representing an optimal balance between the entropic penalty to enable the ion-pairing interaction and the number of side-chain conformations that can accommodate the interaction. These results should be useful for designing β-sheet containing molecular entities for various applications.

Background and Objectives: The current study aimed to better understand the changes in respiration that occur with aging in men and women to provide accurate recommendations for breathing exercises to improve health. Materials and Methods: A total of 610 healthy subjects, aged 20 to 59, participated in the study. They performed quiet breathing while wearing two respiration belts (Vernier, Beaverton, OR, USA) at the height of the navel and at the xiphoid process to record abdominal motion (AM) and thoracic motion (TM), respectively. Vital capacity, representing maximal inhalation movement, was measured using a spirometer (Xindonghuateng, Beijing, China). After exclusion, 565 subjects (164 men, aged 41 ± 11; 401 women, aged 42 ± 9) were included for statistical analysis using the Kruskal–Wallis U test and stepwise multiple linear regression. Results: Abdominal motion and its contribution to spontaneous breathing were significantly larger for older men, while the contribution of thoracic motion was smaller for older men. There was no significant difference in thoracic motion between the younger and older men. The differences in women’s respiratory movements among various ages were mild and negligible. The contribution of thoracic motion to spontaneous breathing in women was larger than in men for those of older ages (40–59 years), but not for those of younger ages (20–39 years). Additionally, men’s and women’s vital capacities were less in those of older ages, and the men’s were larger than the women’s. Conclusions: The findings indicate that men’s abdominal contribution to spontaneous breathing increased from 20 to 59 years of age due to increased abdominal motion. Women’s respiratory movements did not change much with aging. The maximal inhalation movement became smaller with aging for men and women. Healthcare professionals should focus on improving thoracic mobility when addressing health concerns about aging.

Background/Aims: Autophagy is an evolutionarily conserved mechanism that affects the survival and functions of vascular smooth muscle cells (VSMCs). We explored the role of microRNAs (miRNAs) in regulating autophagy in VSMCs exposed to high phosphorus (Pi) levels. Methods: VSMCs were isolated from the thoracic aorta of rats and were cultured primarily. Real-time PCR was used to measure the mRNA expression of indicated genes. Western blotting was performed to detect the protein expression of autophagy-related markers. Results: We found that treatment with high Pi levels (1 and 3 mM) activated LC3II expression and promoted autophagic flux in VSMCs. Conversely, treatment with an autophagy inhibitor decreased LC3II expression. Pi stimulation dysregulated the expression of several miRNAs such as miR-18a, miR-21, miR-23a, miR-30b, and miR-31a. However, miR-30b overexpression decreased Pi-induced expression of autophagy-related marker genes such as BECN1, ATG5, and LC3b, whereas miR-30b downregulation increased Pi-induced expression of these genes. In addition, we found that miR-30b directly targeted BECN1. Conclusions: These data suggest that miR-30b plays an important role in the regulation of high Pi level-induced autophagy in VSMCs by targeting BECN1.

Background: Percutaneous vertebroplasty (PVP) is often performed under monitored anesthesia care (MAC) using a combination of propofol and remifentanil. However, the effects of different remifentanil effect-site concentrations (Ce) combined with propofol on perioperative outcomes in this procedure have not been reported. Methods: In this prospective, randomized controlled study, 80 patients scheduled for single-level PVP under MAC were enrolled. Participants were randomly assigned to receive propofol (Ce: 2.0 mcg/mL) combined with either a low (1.0 ng/mL; Group 1) or high (2.0 ng/mL; Group 2) remifentanil Ce. The primary outcome was the incidence of intraoperative patient movement; secondary outcomes included hemodynamic stability, perioperative adverse events, anesthetic consumption, frequency of dose adjustments, postoperative recovery, and anesthesia satisfaction. Results: Group 2 exhibited significantly fewer episodes of patient movement during the procedure and better intraoperative hemodynamic stability. Additionally, fewer upward adjustments in remifentanil infusion were observed in Group 2. Although the total propofol consumption was similar between the groups, Group 2 required a significantly lower propofol Ce to achieve adequate sedation. Surgeon satisfaction with anesthesia was also significantly higher in Group 2. Conclusions: Using a higher remifentanil Ce (2.0 ng/mL) in combination with propofol during PVP under MAC reduces patient movement and improves intraoperative hemodynamic stability without increasing adverse events. This regimen may thereby enhance procedural efficiency and surgeon satisfaction during vertebral interventions.

This study aimed to evaluate the different clinical results and factors associated with cartilage defects in military draftees who underwent different treatments after anterior cruciate ligament (ACL) rupture. Overall, 105 patients who had sustained ACL rupture were military draftees who underwent a conscription examination for physical status assessment from January 2012 to December 2020. Patients were divided into three groups: conservative treatment after ACL rupture, status post-anterior cruciate ligament reconstruction (ACLR), but graft rupture, and status post-ACLR with graft intact. Inter-group comparisons and statistical analyses were performed for age, body mass index (BMI), thigh circumference difference, side-to-side difference in anterior knee translation by KT-2000, meniscus tear, and cartilage defect. Multivariate logistic regression analysis was used to determine the factors associated with cartilage defects. The multivariable regression model showed that BMI (odds ratio OR: 1.303; 95% CI: 1.016–1.672; p = 0.037), thigh circumference difference (OR: 1.403; 95% CI: 1.003–1.084; p = 0.034), tear of lateral meniscus (LM) and medial meniscus (MM) (OR: 13.773; 95% CI: 1.354–140.09; p = 0.027), and graft rupture group (OR: 5.191; 95% CI: 1.388–19.419; p = 0.014) increased the risk of cartilage defects. There was no correlation between cartilage defects and age, KT-2000 difference, tear of LM or MM, or graft intact group. Progression of osteoarthritis was concerned after ACL rupture, and this study identified several factors of post-ACLR graft rupture, greater thigh circumference difference, BMI, and meniscus tear of both LM and MM affecting cartilage defects, which represent early degenerative osteoarthritis changes of the knee. The results of this study should be customized for rehabilitation and military training, especially in military draftees with ACL injuries.

•We present antibiotic-induced membrane thinning of a multi-lamellar thin film sample.•Both penicillin and sulbactam are found positioned outside the model membrane in an aqueous solution.•We demonstrate a hybrid method to study the antibiotic–membrane interaction. Antibiotic drug resistance is a serious issue for the treatment of bacterial infection. Understanding the resistance to antibiotics is a key issue for developing new drugs. We used penicillin and sulbactam as model antibiotics to study their interaction with model membranes. Cholesterol was used to target the membrane for comparison with the well-known insertion model. Lamellar X-ray diffraction (LXD) was used to determine membrane thickness using successive drug-to-lipid molar ratios. The aspiration method for a single giant unilamellar vesicle (GUV) was used to monitor the kinetic binding process of antibiotic–membrane interactions in an aqueous solution. Both penicillin and sulbactam are found positioned outside the model membrane, while cholesterol inserts perpendicularly into the hydrophobic region of the membrane in aqueous solution. This result provides structural insights for understanding the antibiotic–membrane interaction and the mechanism of antibiotics.

Aims: Vascular calcification is a risk factor for causing cardiovascular events and has a high prevalence among chronic kidney disease (CKD) patients. However, the molecular mechanism underlying this pathogenic process is still obscure. Methods: Vascular smooth muscle cells (VSMCs) were induced by a concentration of phosphorus (Pi) of 2.5 m M , and were subjected to cell calcification analyses. The effect of high Pi on the Wnt/β-catenin pathway was measured using a TOP/FOP-Flash reporter assay. The transcriptional regulation of β-catenin on PIT1 (a type III sodium-dependent phosphate cotransporter) was confirmed by promoter reporter and chromatin immunoprecipitation assays. The 5/6 nephrectomized rat was used as an in vivo model and was fed a high Pi diet to induce aortic calcification. Serum levels of phosphate, calcium, creatine, and blood urea nitrogen were measured, and abdominal aortic calcification was examined. Results: High Pi induced VSMC calcification, downregulated expression levels of VSMC markers, and upregulated levels of osteogenic markers. High Pi activated the Wnt/β-catenin pathway and β-catenin activity. β-Catenin was involved in the process of high Pi-induced VSMC calcification. Further investigation revealed that β-catenin transcriptionally regulated Pit1, a necessary player in VSMC osteogenic phenotype change and calcification. The in vivo study showed that β-catenin was involved in rat abdominal aortic calcification induced by high Pi. When knockdown expression of β-catenin in the rat model was investigated, we found that aortic calcification was reduced. Conclusion: These results suggest that β-catenin is an important player in high phosphorus level-induced aortic calcification in CKD.

Dengue virus, a single-stranded positive sense RNA virus, is the most prevalent mosquito-borne pathogen in the world. Like all RNA viruses, it uses conserved structural elements within its genome to control essential replicative steps. A 70 nucleotides stem-loop RNA structure (called SLA) found at the 5'-end of the genome of all flaviviruses, functions as the promoter for viral replication. This highly conserved structure interacts with the viral polymerase NS5 to initiate RNA synthesis. Here we report the NMR structure of a monomeric SLA from Dengue virus serotype 1, assembled to high-resolution from independently folded structural elements. The DENV1 SLA has an L-shape structure, where the top and side helices are coaxially-stacked and the bottom helix is roughly perpendicular to them. Because the sequence is highly conserved among different flavivirus genomes, it is likely that the three-dimensional fold and local structure of SLA are also conserved among flaviviruses and required for efficient replication. This work provides structural insight into the Dengue promoter and provides the foundation for the discovery of new antiviral drugs that target this essential replicative step. Competing Interest Statement The study was supported by NIH grant 1 R35 GM126942. This project has also been funded in part with Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under Contract No. HHSN272201700059C. We acknowledge the use of SAXS Core facility of Center for Cancer Research, National Cancer Institute (NCI) of National Institutes of Health (NIH). The SAXS core resource has been funded in whole or in part with federal funds from NCI under contract 75N91019D00024 and the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. The SAXS data were collected at beamline 12-ID-B of Advanced Photon Source (APS) of Argonne National Laboratory (ANL). We thank Dr. Yu-Xing Wang (NCI) and Dr. Lixin Fan (FNLCR/Leidos) and Dr. Xiaobing Zuo (ANL) for their support. Use of the APS was supported by the U. S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. DE-AC02-06CH11357. The authors declare competing financial interest: G.V. is co-founder of Ithax Pharmaceuticals and Ranar Therapeutics.