Differential activation of six galanin receptors by the spexin peptide in yellowtail kingfish (Seriola lalandi).

Spexin (SPX1) is a novel neuropeptide composed of 14 amino acids and well conserved across vertebrates, and it has been implicated in various physiological functions via galanin receptor 2 (GALR2) and GALR3. However, the detailed signaling pathways mediating its actions in target cells are still largely unknown. Accordingly, we addressed this issue in the present study using yellowtail kingfish as a model. SPX1 significantly increased CRE-luc activity in COS-7 cells expressing its cognate receptors GALR2a and GALR2b, and this stimulatory effect was attenuated by two inhibitors of the PKA pathway. Similarly, an evident induction of SRE-luc activity was observed when COS-7 cells transfected with GALR1b, GALR2a, GALR2b, GALR type 1, or GALR type 2 were challenged with SPX1, and two blockers of the PKC pathway suppressed this stimulatory action. Moreover, SPX1 markedly elevated NFAT-RE-luc activity in COS-7 cells expressing GALR1a, GALR2a, or GALR2b, and this promotion was inhibited by two antagonists of the Ca2+ route. Overall, our results have revealed that activation of six yellowtail kingfish galanin receptors by the SPX1 peptide may occur with different downstream signaling events, which could account for its pleotropic functions.

Causal Relationship Between Gastroesophageal Reflux Disease and the Risk of Chronic Rhinosinusitis: Insights from Multivariable and Mediation Mendelian Randomization Analysis.

Background: Previous studies have shown an association between chronic rhinosinusitis (CRS) and gastroesophageal reflux disease (GERD). However, the findings of these studies are controversial, and evaluating this association could help in the treatment of CRS. Thus, we aimed to clarify the relationship between GERD and CRS. Methods: We conducted a Mendelian randomization (MR) study. Pooled data on CRS, GERD, and their associated risk factors were extracted from large genome-wide association studies. Independent single-nucleotide polymorphisms were rigorously screened as instrumental variables. Causal associations between GERD and CRS were assessed, and mediation analyses were performed using multivariate and 2-step MR. Asthma served as a mediator because of its association with both CRS and GERD. Sensitivity tests were also performed. Results: MR analysis showed that genetically predicted GERD was associated with an increased risk of CRS (P < .001). Multivariate MR analysis showed that the effect of GERD on CRS was relatively independent. Mediation analysis showed that asthma mediated the association with a mediation effect of 21.07% (95% CI, 2.70%-40.18%). Sensitivity analyses did not reveal any significant effects of pleiotropy and heterogeneity. Conclusions: We found a causal relationship between genetically predicted GERD and an increase in the risk of CRS. As a mediator, asthma contributed to the effect of GERD on CRS. This study provides high-quality causal evidence for the prevention of CRS.

The two-component sensor factor envZ influences antibiotic resistance and virulence in the evolutionary dynamics of multidrug-resistant Salmonella enteritidis causing multisite invasive infections.

OBJECTIVES: To assess the impact of mutations in the two-component sensor envZ on antibiotic resistance and virulence in the evolutionary dynamics of MDR Salmonella enteritidis (S. enteritidis). METHODS: Five S. enteritidis isolates obtained from a patient with multisite invasive infections were analysed. Analysis of antibiotic resistance genes, virulence genes and SNP was performed through WGS. RNA sequencing, quantitative RT-PCR, virulence testing in a Galleria mellonella (G. mellonella) infection model and in vitro cell experiments were used to examine the effects of envZ mutations. RESULTS: WGS revealed identical resistance and virulence genes on an IncFIB(S)/IncFII(S)/IncX1 fusion plasmid in all strains. The faecal strains harboured envZ mutations, reducing outer membrane protein ompD and ompF transcriptional level. Virulence testing demonstrated elevated virulence in envZ mutant strains. In vitro experiments revealed increased adhesion, invasion and phagocytosis resistance in envZ mutants, along with reduced biofilm formation and growth rates. CONCLUSIONS: These findings highlight novel genetic locations on envZ influencing antibiotic resistance and virulence in clinical S. enteritidis strains. envZ mutations impact antibiotic resistance by down-regulating ompD and ompF expression and enhance virulence, contributing to multisite infections with increased fitness costs.

Association Between the Aggregate Index of Systemic Inflammation and Clinical Outcomes in Patients with Acute Myocardial Infarction: A Retrospective Study.

Purpose: The Aggregate Index of Systemic Inflammation (AISI) has emerged as a novel marker for inflammation and prognosis, but its role in patients with acute myocardial infarction has not been studied. Therefore, this study aimed to investigate the impact of different AISI levels on the clinical outcomes of patients with acute myocardial infarction. Patients and Methods: This study was a retrospective study, including 1044 patients with acute myocardial infarction (AMI) who were treated at the Fujian Medical University Affiliated Union Hospital, China from May 2017 to December 2022. The patients were divided into high and low AISI groups based on the median value (Q1 Group, ≤ 416.15, n=522; Q2 Group, ≥ 416.16, n=522), and the differences in baseline characteristics and clinical outcomes between the two groups were analyzed. The primary outcome included major adverse cardiovascular and cerebrovascular events (MACCEs), while the secondary outcomes included contrast-induced nephropathy (CIN) risk and all-cause rehospitalization rate. Results: The findings of the single-factor analysis suggest that a significant association between high AISI levels and the occurrence of MACCEs in AMI patients. After adjusting for confounding factors, the results indicated that compared to Q1, patients in the Q2 group had a higher risk of all-cause mortality [adjusted odds ratio (aOR) 4.64; 95% CI 1.37-15.72; p=0.032], new-onset atrial fibrillation (aOR 1.75; 95% CI 1.02-3.00; p=0.047), and CIN (aOR 1.75; 95% CI 1.02-3.01; p=0.043), with all differences being statistically significant. Conclusion: In the population of AMI patients, an elevated AISI level is significantly associated with an increased risk of cardiovascular death and can serve as an early marker for adverse prognosis.

Efficacy and safety of 4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1, 2-benzothiazin-3-carboxamide 1,1-dioxide, a rapid-acting meloxicam formulation, for analgesia after orthopaedic surgery under general anaesthesia: a randomized controlled trial.

BACKGROUND: Postoperative pain management is one of the most challenging treatments after orthopaedic surgery, and improved medical treatment options are urgently needed. This study aimed to evaluate the efficacy and safety of 4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1, 2-benzothiazin-3-carboxamide 1,1-dioxide (QP001) for moderate to severe pain following orthopaedic surgery. METHODS: This randomized clinical trial enlisted patients experiencing moderate to severe pain following orthopaedic surgery in 20 hospitals in China. We allocated randomly 132 participants to receive 30 mg QP001 and 66 participants to receive 0.9% saline pre-surgery. The primary efficacy outcome was the total morphine consumption within 24 h. RESULTS: The total morphine consumption in the QP001 group, versus placebo group, was significantly lower over the following 24 h [12.53 (10.51) vs. 26.13 (13.98), P < 0.001]. The total morphine consumption in the QP001 group, versus placebo group, was also significantly decreased over the following 48 h (P < 0.001). The QP001 group, versus placebo, showed a significant decrease in the effective pressing times of the analgesic pump, morphine relief analgesia ratio over the 24 h and 48 h periods and the area under the curve for pain intensity-time as well as a significant prolonged in the time of first pressing the analgesic pump and the time of first morphine rescue analgesia (P < 0.001). The QP001 groups, versus placebo, show no significant difference in adverse events, but the incidence of adverse drug reactions decreased (59.4% vs. 75.8%, P = 0.023). CONCLUSION: QP001 provides analgesia and reduces opioid consumption in patients with moderate to severe pain after orthopaedic surgery, with a favorable safety profile.

Development and validation of a predictive model for assessing the risk of follicular carcinoma in thyroid nodules identified as suspicious by intraoperative frozen section.

Introduction: Follicular thyroid carcinoma (FTC) is the second most common thyroid malignancy and is characterized by a higher risk of distant metastasis compared to papillary thyroid cancer. Intraoperative frozen section (IOFS) diagnosis of FTC is challenging due to its limited sensitivity and accuracy, leading to uncertainty in intraoperative surgical decision-making. In response, we developed a predictive model to assess the risk of follicular carcinoma in thyroid nodules identified as suspicious for follicular neoplasm by IOFS. Methods: This model was derived from preoperative clinical and ultrasound data of 493 patients who underwent thyroid surgery at Ningbo Medical Center Lihuili Hospital. It identified five significant predictors of follicular carcinoma: nodule size, thyroglobulin (Tg) level, hypoechogenicity, lobulated or irregular margins, and thick halo. Results: The model demonstrated robust discrimination and calibration, with an area under the curve (AUC) of 0.83 (95% CI: 0.77-0.90) in the training set and 0.78 (95% CI: 0.68-0.88) in the validation set. In addition, it achieved a sensitivity of 81.63% (95% CI: 69.39-91.84) and 68.00% (95% CI: 48.00--4.00), a specificity of 77.42% (95% CI: 72.18-82.66) and 72.51% (95% CI: 65.50-78.96), an accuracy of 78.1% (95% CI: 73.4-82.4) and 71.9% (95% CI: 65.3-78.6), a positive predictive value (PPV) of 41. 67% (95% CI: 35.65-48.84) and 26.79% (95% CI: 19.40-34.33), respectively, and a negative predictive value (NPV) of 95.61% (95% CI: 92.86-97.99) and 94.07% (95% CI: 90.44-97.08) in the training and validation sets, respectively. Conclusion: The model can accurately rule out FTC in low-risk nodules, thereby providing surgeons with a practical tool to determine the necessary extent of surgical intervention for nodules flagged as suspicious by IOFS.

Artificial photosynthetic system for diluted CO2 reduction in gas-solid phase.

Rational design of robust photocatalytic systems to direct capture and in-situ convert diluted CO2 from flue gas is a promising but challenging way to achieve carbon neutrality. Here, we report a new type of host-guest photocatalysts by integrating CO2-enriching ionic liquids and photoactive metal-organic frameworks PCN-250-Fe2M (M = Fe, Co, Ni, Zn, Mn) for artificial photosynthetic diluted CO2 reduction in gas-solid phase. As a result, [Emim]BF4(39.3 wt%)@PCN-250-Fe2Co exhibits a record high CO2-to-CO reduction rate of 313.34 µmol g-1 h-1 under pure CO2 atmosphere and 153.42 µmol g-1 h-1 under diluted CO2 (15%) with about 100% selectivity. In scaled-up experiments with 1.0 g catalyst and natural sunlight irradiation, the concentration of pure and diluted CO2 (15%) could be significantly decreased to below 85% and 10%, respectively, indicating its industrial application potential. Further experiments and theoretical calculations reveal that ionic liquids not only benefit CO2 enrichment, but also form synergistic effect with Co2+ sites in PCN-250-Fe2Co, resulting in a significant reduction in Gibbs energy barrier during the rate-determining step of CO2-to-CO conversion.

Modified blepharoplasty combined with autologous fat transplantation into the orbital septum for the correction of dermatochalasis and sunken eyelids.

BACKGROUND: Periorbital aging typically manifests with dermatochalasis and depression of the upper eyelid. While blepharoplasty is a popular choice for addressing upper eyelid skin laxity, it is not effective for treating sunken eyelids. This study introduces an innovative approach for periorbital rejuvenation by simultaneously addressing dermatochalasis and sunken upper eyelids in aging Asian women. METHOD: This study involved 45 patients with upper eyelid dermatochalasis accompanied by moderate to severe depression. Sub-brow blepharoplasty was performed in conjunction with upper eyelid granular fat grafting in the orbital septum for these patients. Preoperative measurements of the depth and volume of the upper eyelid depressions were taken, and surgical outcomes were assessed at 3 and 6 months postoperatively using the Global Aesthetic Improvement Scale (GAIS) score and the Antera 3D camera. RESULT: The average depth of the upper eyelid depression before surgery was 6.501 ± 1.473 mm, and the average volume was 0.579 ± 0.144 cm3. Significant improvements in both the depth and volume of the depressions were observed at 3 and 6 months after surgery compared to preoperative measurements. The GAIS scores were also improved and postoperative outcomes were deemed satisfactory. CONCLUSION: For patients with dermatochalasis accompanied by moderate to severe upper eyelid depression, standard blepharoplasty alone is insufficient to correct the sunken eyelid. This novel technique, which combines autologous granular fat injection into the orbital septum with blepharoplasty, effectively addresses periorbital aging, enhancing facial rejuvenation.

ctDNA SNORD3F Hypermethylation is a Prognostic Indicator in EGFR-TKI-Treated Advanced Non-Small Cell Lung Cancer.

Purpose: DNA methylation plays a regulatory role in the oncogenesis and tumor progression and is valuable in the diagnosis and prognosis of cancer. While circulating tumor DNA (ctDNA) is widely used in the detection of oncogenic mutations and the guidance of treatment in advanced non-small cell lung cancer (NSCLC), studies of ctDNA methylation remains insufficient. We aim to investigate the methylation profiles of ctDNA in patients with advanced NSCLC undergoing EGFR-tyrosine kinase inhibitor (EGFR-TKI) therapy and to discover novel biomarkers with predictive or prognostic value. Patients and Methods: We recruited 49 patients with EGFR-mutated advanced NSCLC undergoing EGFR-TKI as first-line treatment. Utilizing next-generation sequencing, we examined the somatic mutations and methylation signatures within the tumor-associated genomic regions of ctDNA from pre-treatment blood. Subsequently, we explored the association of these molecular features with the patients' response to therapy and their progression-free survival (PFS). Results: Genomic mutation profiling revealed no significant association of PFS or best overall response (BOR) and ctDNA status. Evaluation of ctDNA methylation showed a negative correlation between the methylation of small nucleolar RNA (snoRNA) genes and PFS (R=-0.31, P=0.043). Furthermore, high-level methylation of SNORD3F was associated with poorer PFS (mPFS 346d vs 243d, HR 0.49, 95% CI 0.24-0.93, P=0.029). Conclusion: Our study explored the prognostic value of ctDNA methylation in patients with advanced NSCLC undergoing targeted therapies and first revealed the predictive role of SNORD3F.

Lightweight TiVNb medium-entropy alloy with weak strength dependence on temperature.

Herein, a TiVNb medium-entropy alloy was prepared via vacuum arc melting. The alloy maintained a body-centred cubic (BCC)-dominant phase following an annealing treatment at 1300 °C for 12 h. Although its structure was coarsened due to grain growth during annealing, the alloy developed a few Ti-rich nanobands and showed an increase in dislocations, resulting in its hardness increasing from 241.7 to 341.1 HV and strength increasing by tens of MPa relative to that of the as-melt TiVNb alloy. The tensile strength of the coarsened alloy reached 647 MPa at room temperature and 405 MPa at 800 °C. Further, the compressive yield strength reached 438 MPa at 800 °C, under which condition the alloy exhibited fewer cracks. Rapid softening was observed at 1200 °C, reducing the yield strength to ∼50 MPa. The coarsened TiVNb alloy showed weak dependence of its strength on temperature.

Exosomes from hypoxic urine-derived stem cells facilitate healing of diabetic wound by targeting SERPINE1 through miR-486-5p.

Vascular pathologies and injuries are important factors for the delayed wound healing in diabetes. Previous studies have demonstrated that hypoxic environments could induce formation of new blood vessels by regulating intercellular communication and cellular behaviors. In this study, we have enhanced the angiogenic potential of exosomes by subjecting urine-derived stem cells (USCs) to hypoxic preconditioning. To prolong the retention of exosomes at the wound site, we have also engineered a novel dECM hydrogel termed SISMA, which was modified from porcine small intestinal submucosa (SIS). For its rapid and controllable gelation kinetics, excellent biocompatibility, and exosome release capability, the SISMA hydrogel has proven to be a reliable delivery vehicle for exosomes. The hypoxia-induced exosomes-loaded hydrogel has promoted endothelial cell proliferation, migration, and tube formation. More importantly, as evidenced by significant in vivo vascular regeneration in the early stages post-injury, it has facilitated tissue repair. This may because miR-486-5p in H-exo inhibit SERPINE1 activity in endothelial cell. Additionally, miRNA sequencing analysis suggested that the underlying mechanism for enhanced angiogenesis may be associated with the activation of classical HIF-1α signaling pathway. In summary, our study has presented a novel non-invasive, cell-free therapeutic approach for accelerating diabetes wound healing and development of a practical and efficient exosomes delivery platform.

Isolation, identification, and technological characteristics analysis of yeast strains from Pyracantha fortuneana fruits fermentation liquid.

Pyracantha fortuneana (P. fortuneana), as a medicinal and edible plant resource, is rich in nutrients. In order to screen the high quality yeast used in Firebone fruit wine, 12 strains of yeast were isolated and purified from P. fortuneana fermentation broth by traditional pure culture method. They were identified by molecular biology as Pichia kudriavzevii (P. kudriavzevii) and Saccharomyces cerevisiae (S. cerevisiae), respectively. Strain HJ-2 could grow normally at 30℃, alcohol content 15%, SO2 mass concentration 360 mg/L, pH 3.2, sucrose mass concentration 400 g/L and glucose mass concentration 250 g/L. Strain HJ-6 could grow normally at 30℃, alcohol content 3%, SO2 concentration 360 mg/L, pH 3.2, sucrose concentration 250 g/L, glucose concentration 300 g/L. Based on the technological characteristics of fruit wine, S. cerevisiae HJ-2 has the potential of brewing P. fortuneana fruit wine. P. kudriavzevii HJ-6 has a low tolerance to ethanol and is suitable for the production of fermented beverages such as low-alcohol wine or beer.

Potential of observing the diameter of the optic nerve sheath using computed tomography in diagnosing high intracranial pressure in patients with spontaneous CSF rhinorrhea.

KEY POINTS: Spontaneous cerebrospinal fluid rhinorrhea (sCSFR) is often accompanied by an increase in intracranial pressure (ICP). The widening of optic nerve sheath diameter (ONSD) is an indicator of increased ICP. Using CT to measure ONSD is a simple and noninvasive auxiliary method for determining high ICP in sCSFR patients.

Machine learning model to predict early recurrence in patients with perihilar cholangiocarcinoma planned treatment with curative resection: a multicenter study.

BACKGROUND: Early recurrence is the leading cause of death for patients with perihilar cholangiocarcinoma (pCCA) after surgery. Identifying high-risk patients preoperatively is important. This study aimed to construct a preoperative prediction model for the early recurrence of patients with pCCA to facilitate planned treatment with curative resection. METHODS: This study ultimately enrolled 400 patients with pCCA after curative resection in 5 hospitals between 2013 and 2019. They were randomly divided into training (n = 300) and testing groups (n = 100) at a ratio of 3:1. Associated variables were identified via least absolute shrinkage and selection operator (LASSO) regression. Four machine learning models were constructed: support vector machine, random forest (RF), logistic regression, and K-nearest neighbors. The predictive ability of the models was evaluated via receiving operating characteristic (ROC) curves, precision-recall curve (PRC) curves, and decision curve analysis. Kaplan-Meier (K-M) survival curves were drawn for the high-/low-risk population. RESULTS: Five factors: carbohydrate antigen 19-9, tumor size, total bilirubin, hepatic artery invasion, and portal vein invasion, were selected by LASSO regression. In both the training and testing groups, the ROC curve (area under the curve: 0.983 vs 0.952) and the PRC (0.981 vs 0.939) showed that RF was the best. The cutoff value for distinguishing high- and low-risk patients was 0.51. K-M survival curves revealed that in both groups, there was a significant difference in RFS between high- and low-risk patients (P < .001). CONCLUSION: This study used preoperative variables from a large, multicenter database to construct a machine learning model that could effectively predict the early recurrence of pCCA in patients to facilitate planned treatment with curative resection and help clinicians make better treatment decisions.

Stress triggers irritable bowel syndrome with diarrhea through a spermidine-mediated decline in type I interferon.

Irritable bowel syndrome with diarrhea (IBS-D) is a common and chronic gastrointestinal disorder that is characterized by abdominal discomfort and occasional diarrhea. The pathogenesis of IBS-D is thought to be related to a combination of factors, including psychological stress, abnormal muscle contractions, and inflammation and disorder of the gut microbiome. However, there is still a lack of comprehensive analysis of the logical regulatory correlation among these factors. In this study, we found that stress induced hyperproduction of xanthine and altered the abundance and metabolic characteristics of Lactobacillus murinus in the gut. Lactobacillus murinus-derived spermidine suppressed the basal expression of type I interferon (IFN)-α in plasmacytoid dendritic cells by inhibiting the K63-linked polyubiquitination of TRAF3. The reduction in IFN-α unrestricted the contractile function of colonic smooth muscle cells, resulting in an increase in bowel movement. Our findings provided a theoretical basis for the pathological mechanism of, and new drug targets for, stress-exposed IBS-D.

Burden of biliary tract carcinoma in China (1990-2021): Findings from the 2021 Global Burden of Disease Study.

Biliary tract carcinoma (BTC) is a group of malignant tumors that originate in the digestive system and occurs with a high incidence in China. Few consistent and comparable assessments of BTC disease burden have been conducted at national or subnational levels, and little is known about the demographic, temporal, and geographic patterns of epidemiological characteristics and disease burden of BTC in China. The incidence, mortality, disability-adjusted life-years (DALYs), years of life lost (YLLs) due to premature death and years lived with disability (YLDs) of BTC were comprehensively examined by age, sex, and calendar year in the Chinese population, using the methodological framework and analytical strategies used for the 2021 Global Burden of Disease study. All-age incidence increased from 17,077 to 51,720 between 1990 and 2021, and the age-standardized incidence rate rose by 13.62%; all-age deaths increased from 17,251 to 37,833, but the age-standardized mortality rate fell by nearly one-fifth. The DALYs rose by 89.57% while the age-standardized DALY rate fell by 23.24%. Variations of the tendencies in BTC burden were found between sexes and age groups. Data for each provincial region indicate that coastal eastern provincial regions have higher incidence and YLD levels, whereas northern provincial regions have higher mortality, DALY, and YLL levels. The proportions of DALYs attributable to high body mass index (BMI) illustrate the growing attribution obesity has made, and high BMI usually puts more burden on northern provincial regions. These results provide evidence to support precise, targeted, and customed public health strategies aimed at enhancing biliary tract health among the Chinese population.

Anatomical study and clinical outcomes of endoscopic transoral surgery for benign salivary gland tumors in the parapharyngeal space.

The existing literature provides little insight into the efficacy of transoral endoscopy in exposing benign tumors originating from salivary glands in the parapharyngeal space at the parotid gland base and resecting part of the deep lobe with a safe margin. This study aims to investigate the efficacy of the endoscopic transoral approach for the visualization and resection of such tumors. Through transoral endoscopic cadaveric dissections and surgical procedures, we examined the anatomical structures of the parapharyngeal space and the deep lobe of the parotid gland, identifying key anatomical landmarks. We conducted a retrospective analysis of 19 patients with benign salivary gland-derived tumors in the parapharyngeal space who underwent transoral endoscopic resection. Intraoperative visualization of the tumor pedicle and the deep lobe of the parotid gland was successfully achieved in all cases, allowing for resection with safe margins. During a median follow-up period of 54.0 months, imaging revealed no signs of recurrence. Endoscopic transoral approach provides effective visualization of the deep lobe of the parotid gland and the medial portion of the parotid bed from the parapharyngeal space. Benign tumors of salivary gland-derived in this area can be well exposed and safely resected with adequate margins.

New finding based on Comparative Toxicogenomics Database: Hepatic YY1 mediates drug-induced liver injury.

BACKGROUND: YY1 plays a crucial part in the onset and progression of numerous liver diseases, yet the significant contribution of YY1 to drug-induced liver injury (DILI) appears to have been underestimated by researchers. PURPOSE: To reveal the underlying role of YY1 in DILI. METHOD: The compounds that interact with YY1 were queried in the Comparative Toxicogenomics Database (CTD), with the majority found to be hepatotoxic, which includes certain widely used drugs. Molecular docking and SPR characterized the robust binding of hepatotoxic compounds to YY1. The duty of YY1 in DILI was investigated in Diosbulbin B (DIOB), a recently identified hepatotoxic compound that tightly associates with YY1, and further validated on ANIT, LCA, APAP, and CDDP. Transcriptomic analysis disclosed the underlying mechanisms involved in DIOB-induced liver injury. RT-qPCR, immunohistochemistry, immunofluorescence, western blotting, and cellular transfection techniques were employed to validate the specific mechanism. RESULTS: Among the 94 compounds affecting YY1 expression in the CTD, 59 compounds exhibited hepatotoxicity, showing close interactions with YY1 and almost consistent binding sites by molecular docking. The SPR validated the tough binding of several hepatotoxic compounds to YY1, including five FDA-approved hepatotoxic drugs. Mechanistically, the involvement of YY1 in DILI was uncovered through the cholestasis lens, mice hepatic YY1 was up-regulated by hepatotoxic DIOB and transcriptionally inhibited FXR and its downstream BSEP and MRP2 expression, initiating early in cholestatic liver injury and persisting to drive the progression of cholestasis. ANIT and LCA-induced model of cholestasis provided evidence for the hypothesis that YY1 frequently mediates drug induced cholestasis (DIC). APAP and CDDP indicated that YY1 may also be involved in hepatocellular and mixed type DILI. CONCLUSION: YY1 widely mediated the development of DIC and also might be engaged in other types of DILI. YY1 presented a common target for hepatotoxic medications and the targeting of liver YY1 for drug development may offer a novel approach for managing DILI.

Does green transportation affect carbon emission efficiency? Evidence from a quasi-experimental study in China.

The establishment of a low-carbon transportation system (LCTS) holds prominent importance in advancing modern transportation development and achieving green growth. Employing the LCTS pilot policy as a shock to green transportation construction in China, we investigate its influence on carbon emission efficiency (CEE) using urban panel data from 2006 to 2021. Results based on difference-in-differences (DID) show that LCTS contributes to increasing CEE following such a pilot policy. This finding still holds after we perform a propensity score matching DID method, double machine learning, instrumental variable method, heterogeneous treatment effect, and other robustness checks. Meanwhile, the mediation analysis shows that the increased CEE can be accounted for by spurring green innovation activities. Moreover, the moderation outcomes reveal that FinTech exerts a positive moderating influence on the increased impacts of LCTS on CEE. Heterogeneity analysis shows that LCTS's impact on CEE varies by region and development level. Overall, our research stresses the importance of green transportation construction in shaping CEE, which has significant practical and theoretical implications for scholars and policymakers.

Tertiary lymphoid structures' pattern and prognostic value in primary adenocarcinoma of jejunum and ileum.

To date, there have been no reports on tertiary lymphoid structures (TLS) in primary adenocarcinoma of jejunum and ileum. In this study, we employed digital pathology image analysis software to classify and quantify TLS, and evaluated the maturity of TLS using immunohistochemistry. Molecular genetics and immunotherapy biomarker detection were performed using next-generation sequencing technology, such as tumor mutational burden (TMB) and microsatellite instability (MSI). The aim of this study was to investigate the presence, location, maturity, association with immunotherapy biomarkers, and prognostic value of TLS in primary adenocarcinoma of jejunum and ileum. Compared to secondary follicle-like TLS (SFL-TLS), intra-tumoral TLS (IT-TLS) were more likely to manifest as early TLS (E-TLS) (P = 0.007). Compared to IT-TLS, SFL-TLS had a higher propensity to occur at the invasive margin (IM) (P = 0.032) and showed a trend towards being more prevalent at the tumor periphery (P = 0.057). In terms of immunotherapy biomarkers, there was a higher trend of IM-TLS density in PD-L1(22C3) score CPS < 1 group compared to PD-L1(22C3) score CPS ≥ 1 group (P = 0.071). TMB-H was significantly associated with MSI-H (P = 0.040). Univariate survival analysis demonstrated a correlation between high SFL-TLS group and prolonged disease free survival (DFS) (P = 0.047). There was also a trend towards prolonged DFS in the E-TLS-high group compared to the E-TLS-low group (P = 0.069). The peri-tumoral TLS (PT-TLS)-high group showed a trend of prolonged overall survival (OS) compared to the PT-TLS-low group (P = 0.090). In conclusion, the majority of TLS were located at the invasive margin and tumor periphery, predominantly consisting of mature TLS, while IT-TLS were mainly immature. Notably, TMB was closely associated with MSI and PD-L1, indicating potential predictive value for immunotherapy in primary adenocarcinoma of jejunum and ileum.