Structure-Guided Discovery of a Potent Inhibitor of the Ferric Citrate Binding Protein FecB in Vibrio Bacteria.

Infections caused by Gram-negative bacteria present a significant risk to human health worldwide. Novel strategies are needed to deal with the challenge caused by drug-resistant bacteria. Here, we report a new approach to combat infections by targeting iron-binding proteins to suppress bacterial growth. We investigated the function of the conserved periplasmic binding protein FecB from Vibrio alginolyticus. FecB was known to play a crucial role in the bacterial growth and to relate with biofilm formation. We then solved the crystal structures and elucidated the binding mechanism of FecB with ferric ion chelated by citrate. The results indicated that FecB binds weakly to one citrate molecule and strongly to the Fe3+-(citrate)2 complex. Based on these results, a structure-based virtual screening approach was conducted against FecB to identify small molecules that block ferric-citrate uptake. Further evaluations in vivo and in vitro demonstrated that salvianolic acid C significantly suppressed bacterial growth, indicating that targeting bacterial nutrient absorption is a promising strategy for identifying potential antibacterial drugs.

Associations between soft drinks intake and primary dysmenorrhea among Chinese undergraduate female students.

Primary dysmenorrhea (PD) is a common global health concern. However, limited studies explored the association between soft drinks intake and PD among female undergraduates in China. To determine the association between soft drinks (carbonated soft drinks, etc.) as well coffee intake and the incidence/severity of PD among female undergraduates in China. We performed a cross-sectional study among 1809 female undergraduates in China from September 29, 2020 to October 22, 2020. The demographic information and menstrual information of the participants were collected by a self-administrated questionnaire. Chi-square test, ANOVA test, and logistic regression test were used to investigate the association between soft drinks intake and the incidence/severity of PD. We also conducted stratification analysis among different locations (rural or urban). The prevalence of PD was 47.1% (n = 852). There were 221 (25.9%) participants suffered from severe pain. In the participants with PD, the OR of carbonated soft drinks intake was 1.244 (95% CI 1.010-1.533). Among the participants with PD from rural areas, the OR of carbonated soft drinks intake was 1.402 (95% CI 1.045-1.881), compared with the non-carbonated soft drink group. In the participants with moderate and severe PD, the OR of coffee intake was 0.451 (95% CI 0.228-0.892), compared with the non-coffee-drinking group. There was a significant association between carbonated soft drinks intake frequency and the severity of PD (P < 0.05). Our study showed that carbonated soft drinks intake is a risk factor for PD, especially in participants from rural areas. Coffee intake is a protective factor for the severity of PD. Periodical awareness programs about adverse effects of excessive soft drink consumption should be introduced to reduce the prevalence and exacerbation of PD. Coffee intake might be helpful to relieve the severity of PD.

Disparities in COVID-19 vaccine uptake, attitudes, and experiences between food system and non-food system essential workers.

The COVID-19 pandemic has disproportionately affected the health of food system (FS) essential workers compared with other essential and non-essential workers. Even greater disparity exists for workers in certain FS work settings and for certain FS worker subpopulations. We analyzed essential worker respondents (n = 151,789) in May-November 2021 data from the National Immunization Survey Adult COVID Module (NIS-ACM) to assess and characterize COVID-19 vaccination uptake (≥1 dose) and intent (reachable, reluctant), attitudes about COVID-19 and the vaccine, and experiences and difficulties getting the vaccine. We compared rates, overall and by certain characteristics, between workers of the same group, and between FS (n = 17,414) and non-food system (NFS) worker groups (n = 134,375), to determine if differences exist. FS worker groups were classified as "agriculture, forestry, fishing, or hunting" (AFFH; n = 2,730); "food manufacturing facility" (FMF; n = 3,495); and "food and beverage store" (FBS; n = 11,189). Compared with NFS workers, significantly lower percentages of FS workers reported ≥1 dose of COVID-19 vaccine or vaccine requirements at work or school, but overall vaccine experiences and difficulties among vaccinated FS workers were statistically similar to NFS workers. When we examined intent regarding COVID-19 vaccination among unvaccinated FS workers compared with NFS counterparts, we found a higher percentage of FMF and FBS workers were reachable whereas a higher percentage of AFFH workers were reluctant about vaccination, with differences by sociodemographic characteristics. Overall, results showed differences in uptake, intent, and attitudes between worker groups and by some sociodemographic characteristics. The findings reflect the diversity of FS workers and underscore the importance of collecting occupational data to assess health inequalities and of tailoring efforts to worker groups to improve confidence and uptake of vaccinations for infectious diseases such as COVID-19. The findings can inform future research, adult infectious disease interventions, and emergency management planning.

The Role of ICG-Guided Fluorescent Mode in Boosting the Learning Curve of Laparoscopic Cholecystectomy.

Background: The most common therapy for gallstones is laparoscopic cholecystectomy (LC). How to help young residents avoid bile duct injuries (BDI) during surgery and grasp LC seems to be a paradox. Methods: We retrospectively reviewed 145 cases of LC operated by two residents under indocyanine green (ICG)-guided mode or normal LC procedures to illustrate the role of ICG mode in boosting the LC learning curve. The clinic data were analyzed by logistic regression, receiver operator curve tests, Cumulative Sum (CUSUM), and Risk-Adjusted Cumulative Sum (RA-CUSUM) analysis. Results: The operation failure rate is similar. However, operation time under ICG mode is shorter than that under normal mode. The peak at the 49th case represented the normal resident's complete mastery of the surgery, while the peak point of ICG mode appeared at the 36th case in the fitting curve. The most significant cumulative risk (peak point) of operation failure of LC was at the 35th case in ICG LC mode, while it appeared in the 49th in normal LC mode. Conclusions: Owing to the advantage of real-time imaging and the stable success rate of cholangiography, ICG-guided LC helps residents shorten the operation time, boost the learning curve, and manage to control the operation failure rate.

Evaluation of Latent Tuberculosis Infection Using the ESAT6-CFP10 Skin Test Among International Freshmen With Diverse Skin Tones at a University - Nanjing City, Jiangsu Province, China, September 2023.

Introduction: Newer skin tests, including the ESAT6-CFP10 (EC) skin test, were recommended for diagnosing Mycobacterium tuberculosis (M. tb) infection. However, no data exist assessing the diagnostic performance of the EC skin test among foreign students with different skin tones. Methods: A cohort study at Nanjing Medical University screened incoming foreign freshmen. The EC skin test was used to assess for M. tb infection, and results were read at 24, 48, 72, and 96-hours post-administration. Results: Among 96 participants, M. tb infection rates at 24, 48, 72, and 96-hours post-injection were 3.13%, 7.29%, 13.54%, and 9.38%, respectively. While infection rates were lower among individuals with darker skin tones, the difference was not statistically significant (P=0.186), and variations were consistent across different measurement times. Trajectory analysis revealed 5.3% in the continuous-increasing group, 86.5% in the low-stable group, and 5.2% in the elevated-decreasing group. Notably, participants in the elevated-decreasing group had lighter skin tones, with trajectory patterns consistent across different skin colors. Discussion: The EC skin test is safe, and redness diameter is a more reliable indicator than induration. Results should be collected within 48 to 72 hours, with verification at 72 hours crucial if initial results are negative. Importantly, skin color does not affect EC skin test outcomes.

USP22 promotes gefitinib resistance and inhibits ferroptosis in non-small cell lung cancer by deubiquitination of MDM2.

BACKGROUND: The emergence of chemoresistance markedly compromised the treatment efficiency of human cancer, including non-small cell lung cancer (NSCLC). In the present study, we aimed to explore the effects of ubiquitin-specific peptidase 22 (USP22) and murine double minute 2 (MDM2) in gefitinib resistance in NSCLC. METHODS: Immunohistochemistry (IHC) assay, quantitative real-time polymerase chain reaction (qRT-PCR) assay and western blot assay were carried out to determine the expression of USP22 and MDM2. Transwell assay and flow cytometry analysis were performed to evaluate cell migration and apoptosis. Cell Counting Kit-8 (CCK-8) assay was employed to assess gefitinib resistance. The phenomenon of ferroptosis was estimated by related commercial kits. The oxidized C11-BODIPY fluorescence intensity by C11-BODIPY staining. The relation between USP22 and MDM2 was analyzed by ubiquitination assay and co-immunoprecipitation (Co-IP) assay. RESULTS: USP22 was abnormally upregulated in NSCLC tissues and cells, and USP22 silencing markedly repressed NSCLC cell migration and facilitated apoptosis and ferroptosis. Moreover, our results indicated that ferroptosis could enhance the suppressive effect of gefitinib on NSCLC cells. Besides, USP22 overexpression enhanced gefitinib resistance and ferroptosis protection in NSCLC cells. Mechanically, USP22 stabilized MDM2 and regulated MDM2 expression through deubiquitination of MDM2. MDM2 deficiency partially restored the effects of USP22 on gefitinib resistance and ferroptosis in NSCLC cells. Of note, we validated the promotional effect of USP22 on gefitinib resistance in NSCLC in vivo through establishing the murine xenograft model. CONCLUSION: USP22/MDM2 promoted gefitinib resistance and inhibited ferroptosis in NSCLC, which might offer a novel strategy for overcoming gefitinib resistance in NSCLC.

Associations between blood nickel and lung function in young Chinese: An observational study combining epidemiology and metabolomics.

Prior research has explored the relationship between occupational exposure to nickel and lung function. Nonetheless, there is limited research examining the correlation between blood nickel levels and lung function among young adults in the general population. The metabolomic changes associated with nickel exposure have not been well elucidated. On August 23, 2019, we enrolled 257 undergraduate participants from the Chinese Undergraduates Cohort to undergo measurements of blood nickel levels and lung function. The follow-up study was conducted in May 2021. A linear mixed-effects model was employed to assess the relationship between blood nickel levels and lung function. We also conducted stratified analyses by home address. In addition, in order to explore the biological mechanism of lung function damage caused by nickel exposure, we performed metabolomic analyses of baseline serum samples (N = 251). Both analysis of variance and mixed linear effect models were utilized to assess the impact of blood nickel exposure on metabolism. Our findings from cross-sectional and cohort analyses revealed a significant association between blood nickel levels and decreased forced expiratory volume in the first second (FEV1) and forced vital capacity (FVC) among young adults in the general population. Furthermore, we found stronger associations in urban areas. In metabolomics analysis, a total of nine metabolites were significantly changed under blood nickel exposure. The changed metabolites were mainly enriched in six pathways including carbohydrate, amino acid, and cofactor vitamin metabolism. These metabolic pathways involve inflammation and oxidative stress, indicating that high concentrations of nickel exposure can cause inflammation and oxidative stress by disrupting the above metabolism of the body.

Description of Short-Range Interactions of Carbon-Based Materials with a Combined AIREBO and ZBL Potential.

An accurate description of short-range interactions among atoms is crucial for simulating irradiation effects in applications related to ion modification techniques. A smooth integration of the Ziegler-Biersack-Littmark (ZBL) potential with the adaptive intermolecular reactive empirical bond-order (AIREBO) potential was achieved to accurately describe the short-range interactions for carbon-based materials. The influence of the ZBL connection on potential energy, force, and various AIREBO components, including reactive empirical bond-order (REBO), Lennard-Jones (LJ), and the torsional component, was examined with configurations of the dimer structure, tetrahedron structure, and monolayer graphene. The REBO component is primarily responsible for the repulsive force, while the LJ component is mainly active in long-range interactions. It is shown that under certain conditions, the torsional energy can lead to a strong repulsive force at short range. Molecular dynamics simulations were performed to study the collision process in configurations of the C-C dimer and bulk graphite. Cascade collisions in graphite with kinetic energies of 1 keV and 10 keV for primary knock-on atoms showed that the short-range description can greatly impact the number of generated defects and their morphology.

A patient-derived cell model for malignant transformation in IDH-mutant glioma.

Malignant transformation (MT) is commonly seen in IDH-mutant gliomas. There has been a growing research interest in revealing its underlying mechanisms and intervening prior to MT at the early stages of the transforming process. Here we established a unique pair of matched 3D cell models: 403L, derived from a low-grade glioma (LGG), and 403H, derived from a high-grade glioma (HGG), by utilizing IDH-mutant astrocytoma samples from the same patient when the tumor was diagnosed as WHO grade 2 (tumor mutational burden (TMB) of 3.96/Mb) and later as grade 4 (TMB of 70.07/Mb), respectively. Both cell models were authenticated to a patient's sample retaining endogenous expression of IDH1 R132H. DNA methylation profiles of the parental tumors referred to LGG and HGG IDH-mutant glioma clusters. The immunopositivity of SOX2, NESTIN, GFAP, OLIG2, and beta 3-Tubulin suggested the multilineage potential of both models. 403H was more prompt to cell invasion and developed infiltrative HGG in vivo. The differentially expressed genes (DEGs) from the RNA sequencing analysis revealed the tumor invasion and aggressiveness related genes exclusively upregulated in the 403H model. Pathway analysis showcased an enrichment of genes associated with epithelial-mesenchymal transition (EMT) and Notch signaling pathways in 403H and 403L, respectively. Mass spectrometry-based targeted metabolomics and hyperpolarized (HP) 1-13C pyruvate in-cell NMR analyses demonstrated significant alterations in the TCA cycle and fatty acid metabolism. Citrate, glutamine, and 2-HG levels were significantly higher in 403H. To our knowledge, this is the first report describing the development of a matched pair of 3D patient-derived cell models representative of MT and temozolomide (TMZ)-induced hypermutator phenotype (HMP) in IDH-mutant glioma, providing insights into genetic and metabolic changes during MT/HMP. This novel in vitro model allows further investigation of the mechanisms of MT at the cellular level.

Novel 4-chlorophenoxyacetate dioxygenase-mediated phenoxyalkanoic acid herbicides initial catabolism in Cupriavidus sp. DL-D2.

Microbial metabolism is an important driving force for the elimination of 4-chlorophenoxyacetic acid residues in the environment. The α-Ketoglutarate-dependent dioxygenase (TfdA) or 2,4-D oxygenase (CadAB) catalyzes the cleavage of the aryl ether bond of 4-chlorophenoxyacetic acid to 4-chlorophenol, which is one of the important pathways for the initial metabolism of 4-chlorophenoxyacetic acid by microorganisms. However, strain Cupriavidus sp. DL-D2 could utilize 4-chlorophenoxyacetic acid but not 4-chlorophenol for growth. This scarcely studied degradation pathway may involve novel enzymes that has not yet been characterized. Here, a gene cluster (designated cpd) responsible for the catabolism of 4-chlorophenoxyacetic acid in strain DL-D2 was cloned and identified, and the dioxygenase CpdA/CpdB responsible for the initial degradation of 4-chlorophenoxyacetic acid was successfully expressed, which could catalyze the conversion of 4-chlorphenoxyacetic acid to 4-chlorocatechol. Then, an aromatic cleavage enzyme CpdC further converts 4-chlorocatechol into 3-chloromuconate. The results of substrate degradation experiments showed that CpdA/CpdB could also degrade 3-chlorophenoxyacetic acid and phenoxyacetic acid, and homologous cpd gene clusters were widely discovered in microbial genomes. Our findings revealed a novel degradation mechanism of 4-chlorophenoxyacetic acid at the molecular level.

Quantitative assessment methods and qualitative evaluation system for the complementary characteristics of multi-energy.

Assessing and analyzing the complementary characteristics of renewable energy (RE) is crucial for designing, operating, and optimizing multi-energy complementary systems (MECSs). However, unified and precise quantitative descriptions of the complementary and stability characteristics among various energy outputs in MECSs have lacked attention and research. Here, this study innovatively proposed a mathematical model for the multi-energy complementarity index (MECI), which considers the complementarity rates of multiple energy outputs during zero and non-zero output periods, and a mathematical model for the multi-energy volatility index (MEVI), which accounts for fluctuation thresholds and the overall volatility of output processes. An evaluation system for multi-energy complementarity characteristics qualitative analysis has been established. The natural output processes of RE at three MECSs in China were applied in the case calculations and verification. Results show that the hydropower rated discharge (Qrating) has a significant negative correlation with MECI, with the MECI decreasing by an average of 0.0046 for every 5 m³/s increase in Qrating. The relationship between the Qrating and MEVI shows an overall negative correlation with local fluctuations. Notably, The MECI of the BeiPan River MECSs exhibits significant seasonal characteristics, with the MEVI in summer (0.378) and autumn (0.395) higher than those in spring (0.132) and winter (0.160), closely related to the natural seasonal variations of the three energy sources: water, wind, and solar. We believe that the study can assist in evaluating and making decisions on the multi-energy complementarity characteristics of RE bases in the future, making a significant contribution to achieving dual carbon goals.

Transcriptional activation of SIRT5 by FOXA1 reprograms glycolysis to facilitate the malignant progression of diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most common diagnosed subtype of lymphoma with high invasiveness and heterogeneity. Glycolysis is involved in regulating DLBCL progression. We aimed to explore the role of forkhead box protein A1 (FOXA1) in DLBCL and the mechanisms related to sirtuine5 (SIRT5) and glycolysis. FOXA1 expression in DLBCL cells was analyzed. Then, the proliferation and apoptosis of DLBCL cells were detected using Cell Counting Kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EDU) staining and flow cytometry analysis following FOXA1 or SIRT5 knockdown. The glycolysis was assessed by measuring extracellular acidification rate (ECAR), glucose consumption and lactate secretion. Immunoblotting was employed to examine the expression of apoptosis- and glycolysis-related proteins. Additionally, luciferase reporter assay and chromatin immunoprecipitation (ChIP) assay were conducted to test the combination of FOXA1 to SIRT5 promotor region. Subsequently, SIRT5 expression was upregulated to conduct rescue assays. Finally, the effects of FOXA1 downregulation on the growth and glycolysis in OCI-ly7 tumor-bearing mice were examined. As a result, FOXA1 was upregulated in DLBCL cells and FOXA1 or SIRT5 knockdown inhibited the proliferation, accelerated the apoptosis and suppressed glycolysis reprograming in DLBCL cells. Importantly, FOXA1 could transcriptionally activate SIRT5 expression in DLBCL cells. Besides, SIRT5 overexpression counteracted the effects of FOXA1 deficiency on the proliferation, apoptosis and glycolysis reprogramming in DLBCL cells. Furthermore, FOXA1 knockdown inhibited the tumor growth, suppressed the glycolysis reprogramming and downregulated SIRT5 expression in vivo. In summary, FOXA1 could transcriptionally activate SIRT5 to reprogram glycolysis, thereby facilitating the malignant progression of DLBCL.

Real-world effectiveness and safety of recombinant human endostatin plus PD-1 inhibitors and chemotherapy as first-line treatment for EGFR/ALK-negative, advanced or metastatic non-small cell lung cancer.

BACKGROUND: This study aimed to evaluate the effectiveness and safety of recombinant human endostatin (Rh-endostatin) plus programmed cell death 1 (PD-1) inhibitors and chemotherapy as first-line treatment for advanced or metastatic non-small cell lung cancer (NSCLC) in a real-world setting. METHODS: This was a retrospective study on patients with EGFR/ALK-negative, advanced or metastatic NSCLC. Patients received Rh-endostatin plus PD-1 inhibitors and chemotherapy every three weeks for 4 to 6 cycles. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. RESULTS: A total of 68 patients were included in this retrospective analysis. As of data cutoff (December 13, 2022), the median follow-up of 21.4 months (interquartile range [IQR], 8.3-44.4 months). The median PFS and OS was 22.0 (95% confidence interval [CI]: 16.6-27.4) and 31.0 months (95% CI: 23.4-not evaluable [NE]), respectively. The ORR was 72.06% (95% CI: 59.85-82.27%), and DCR was 95.59% (95% CI: 87.64-99.08%). Patients with stage IIIB/IIIC NSCLC had significantly longer median PFS (23.4 vs. 13.2 months), longer median OS (not reached vs. 18.0 months), and higher ORR (89.2% vs. 51.6%) than those with stage IV NSCLC (all p ≤ 0.001). The ORR was higher in patients with high PD-L1 expression (tumor proportion score [TPS] ≥ 50%) than in those with low PD-L1 expression or positive PD-L1 expression (75% vs. 50%, p = 0.025). All patients experienced treatment-related adverse events (TRAEs), and ≥ grade 3 TRAEs occurred in 16 (23.53%) patients. CONCLUSIONS: Rh-endostatin combined with PD-1 inhibitors plus chemotherapy as first-line treatment yielded favorable effectiveness with a manageable profile in patients with advanced or metastatic NSCLC, representing a promising treatment modality.

Bromodomain-containing protein 4 knockdown promotes neuronal ferroptosis in a mouse model of subarachnoid hemorrhage.

Neuronal cell death is a common outcome of multiple pathophysiological processes and a key factor in neurological dysfunction after subarachnoid hemorrhage. Neuronal ferroptosis in particular plays an important role in early brain injury. Bromodomain-containing protein 4, a member of the bromo and extraterminal domain family of proteins, participated in multiple cell death pathways, but the mechanisms by which it regulates ferroptosis remain unclear. The primary aim of this study was to investigate how bromodomain-containing protein 4 affects neuronal ferroptosis following subarachnoid hemorrhage in vivo and in vitro. Our findings revealed that endogenous bromodomain-containing protein 4 co-localized with neurons, and its expression was decreased 48 hours after subarachnoid hemorrhage of the cerebral cortex in vivo. In addition, ferroptosis-related pathways were activated in vivo and in vitro after subarachnoid hemorrhage. Targeted inhibition of bromodomain-containing protein 4 in neurons increased lipid peroxidation and intracellular ferrous iron accumulation via ferritinophagy and ultimately led to neuronal ferroptosis. Using cleavage under targets and tagmentation analysis, we found that bromodomain-containing protein 4 enrichment in the Raf-1 promoter region decreased following oxyhemoglobin stimulation in vitro. Furthermore, treating bromodomain-containing protein 4-knockdown HT-22 cell lines with GW5074, a Raf-1 inhibitor, exacerbated neuronal ferroptosis by suppressing the Raf-1/ERK1/2 signaling pathway. Moreover, targeted inhibition of neuronal bromodomain-containing protein 4 exacerbated early and long-term neurological function deficits after subarachnoid hemorrhage. Our findings suggest that bromodomain-containing protein 4 may have neuroprotective effects after subarachnoid hemorrhage, and that inhibiting ferroptosis could help treat subarachnoid hemorrhage.

Eight new dammarane-type triterpenoid saponins from Gynostemma pentaphyllum.

Phytochemical investigation of Gynostemma pentaphyllum led to the purification of five novel dammarane-type triterpene isolates, gypenosides B1 - B5 (1-5). Their structures were determined through comprehensive 1D and 2D NMR spectroscopic analyses and HRESIMS data. Of note, 1-3 are inseparable mixtures of epimers due to their unstable nature, and a total of eight dammarane-type triterpene saponins were identified. Additionally, the protective activities of these new compounds against PC12 cell injury induced by hypoxia were evaluated.

Preoperative CT Measurements and Computer-assisted Design in Auricular Reconstruction for Microtia.

OBJECTIVE: To evaluate the utility of 3-dimensional computed tomography (3D CT) reconstruction in rib cartilages harvest and auricular reconstruction. METHODS: This was a retrospective study of 105 patients with microtia who underwent auricular reconstruction in our department, including 53 controls. All patients underwent chest CT scans and 52 patients in the CT group underwent rib cartilage reconstruction simultaneously. All patients' sex, age, height, and body weight were reviewed. Preoperative CT measurements included the length and width of the sixth, seventh, eighth, and ninth rib cartilages. Operative measurements included the number, amount, length and width of the costal cartilages harvested, operation time, and the amount of bleeding. RESULTS: There was no significant difference in the preoperative and operative measurements of the seventh rib. The mean age, height, and weight of the 3D CT group were significantly less than the control group. Compared with the control group, the costicartilage taken in the 3D CT group was significantly shorter in length, but there was no significant difference in the number of ribs taken. The operation time of the 3D CT group was less than the control group. CONCLUSIONS: Reconstructive 3D CT provides vivid and accurate data of costochondral volume, and is valuable for surgical timing and cartilage sculpting. With the aid of the 3D CT measurements, surgeons can make an individualized surgical planning. Unnecessary harvest of rib cartilage and surgical time are avoided by having a throughout plan before operation.

Geniposide modulates GSK3ß to inhibit Th17 differentiation and mitigate endothelial damage in intracranial aneurysm.

Intracranial aneurysm (IA) is a common cerebrovascular disease. Immune system disorders and endothelial dysfunction are essential mechanisms of its pathogenesis. This study aims to explore the therapeutic effect and mechanism of Geniposide (Gen) on IA, which has a protective impact on endothelial cells and cardiovascular and cerebrovascular diseases. IA mouse models were administered intraperitoneal injections of geniposide for 2 weeks following elastase injection into the right basal ganglia of the brain for intervention. The efficacy of Gen in treating IA was evaluated through pathological testing and transcriptome sequencing analysis of Willis ring vascular tissue. The primary mechanism of action was linked to the expression of GSK3ß in Th17 cells. The percentage of splenic Th17 cell differentiation in IA mice was significantly inhibited by Gen. GSK3ß/STAT3, and other pathway protein expression levels were also significantly inhibited by Gen. Additionally, TNF-α and IL-23 cytokine contents were significantly downregulated after Gen treatment. These results indicated that Gen significantly inhibited the percentage of Th17 cell differentiation, an effect that was reversed upon overexpression of the GSK3B gene. Furthermore, Gen-treated, Th17 differentiation-inducing cell-conditioned medium significantly up-regulated the expression of tight junction proteins ZO-1, Occludin, and Claudin-5 in murine aortic endothelial cells. Administering the GSK3ß inhibitor Tideglusib to IA mice alleviated the severity of IA disease pathology and up-regulated aortic tight junction protein expression. In conclusion, Gen inhibits Th17 cell differentiation through GSK3ß, which reduces endothelial cell injury and up-regulates tight junction protein expression.

Splicing of Helix Framework in Modified Nagata Method Stage I for Auricle Reconstruction in Patients With Insufficient 8th Rib Cartilage.

BACKGROUND: The 8th rib cartilage was sometimes insufficient to construct a complete external helix in ear reconstruction for microtia. The aim of this study was to investigate the splicing technique of 8th rib cartilage in modified Nagata method stage I. METHODS: Between September 2022 and May 2023, 231 consecutive patients with microtia underwent auricular reconstruction with modified Nagata method stage I. Thirty-four patients with insufficient 8th rib cartilage were screened out by three-dimensional (3D) computed tomography preoperatively, who were included in the study prospectively. The 8th rib was spliced to create the external helix when fabricating the ear framework in the stage I surgery for the 34 patients. The median duration of follow-up was 12.1 months (8-15 months). RESULTS: There were no perioperative complications in our study. During follow-up, all patients had satisfying outcomes, with no inward collapse, displacement, or absorption of the spliced external helix. The splicing point was not obvious. CONCLUSIONS: It was safe and effective to splice the 8th rib cartilage for external helix of the cartilage framework in ear reconstruction for microtia.