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A series of quinoxalinone-1,2,3-triazole derivatives have been synthesized and tested for antifungal activity against phytopathogenic fungus through mycelial growth inhibition in vitro, spore germination inhibition in vitro and control effect in vivo. The results showed that the pharmacophore quinoxalinone and 1,2,3-triazole displayed promising antifungal activity. The EC50 value against C. gloeosporioides of 6a-1 was 1.17 μg/mL and the compound 6c-1 showed the good bioactivity against C. fragariae Brooks and P. oryzae Cav., displaying EC50 values of 5.56, 4.62 μg/mL, respectively. The inhibitory of spore germination by 6a-1 was performed with EC50 value of 1.91 μg/mL. In addition, the in vivo bioassay indicated that 6a-1 possessed effective control against Pepper Anthrax Disease in protective treatment. For given activity data of target compounds, structure-activity relationship (SAR) study was operated, hoping for optimizing the target structure to find lead compound with higher activity.

Abstract Early patterning of DNA methylation (DNAm) may play an important role in later disease development. To better understand intergenerational epigenetic inheritance, we investigated the correlation between DNAm in blood in mother-newborn and in father-newborn pairs in the Isle of Wight (IoW) birth cohort. For parent-newborn pairs (n = 48), offspring DNAm was measured in cord blood and the parent’s DNAm in whole blood. Mothers’ DNAm was analyzed at birth (Guthrie card), age 18, early and late pregnancy respectively, and fathers’ DNAm was measured during the mother’s pregnancy. Linear regressions were applied to assess the intergenerational correlation of parental DNAm with that of offspring. Among various pairs of mother-newborn and father-newborn DNAm, the pairs where the mothers’ DNAm was measured at age 18 years exhibited the highest number of CpGs with significant intergenerational correlation in DNAm, with 1829 CpGs (0.54%) of the 338,526 CpGs studied (FDR

Abstract Background An increasing number of clinical studies have begun to explore combination strategies with immune checkpoint inhibitors, aiming to present new opportunities for overcoming anti-PD-1 treatment resistance in gastric cancer. Unfortunately, the exploration of certain immune checkpoint inhibitor combination strategies has yielded suboptimal results. Therefore, it is necessary to comprehensively analyze the expression patterns of immune checkpoints and identify optimal combination regimens of anti-PD-1 inhibitors with other immune checkpoint inhibitors. Methods Leveraging single-cell RNA sequencing (scRNA-seq) and multivariate linear regression interaction models, we dissected the immune checkpoint expression characteristics of CD8+ T cells in gastric cancer and the immune checkpoint expression pattern (ICEP) mediating anti-PD-1 treatment resistance. Furthermore, we employed transcription factor analysis and CellOracle to explore the transcriptional regulatory mechanisms governing CD8+ T cell differentiation fates. Finally, we utilized Nichenet and spatial transcriptomic analysis to investigate the spatial expression patterns of immune checkpoints. Results Interaction analysis indicated that, among the known immune checkpoints, co-expression of NKG2A and PD-1 might exert a more profound inhibitory effect on the proliferative capacity of CD8+ T cells. The co-expression analysis revealed differential co-expression pattern of PD-1 and NKG2A, defined as ICEP1 (CD8+ T cells co-expressing PD-1, CTLA-4, TIGIT, LAG-3 or CD38) and ICEP2 (CD8+ T cells solely expressing NKG2A or co-expressing with other immune checkpoints), reflecting the co-occurrence pattern of PD-1 and the mutual exclusivity of NKG2A. Further, these two ICEP CD8+ T cell subsets represented distinct CD8+ T cell differentiation fates governed by MSC and RUNX3. Notably, ICEP2 CD8+ T cells were associated with anti-PD-1 therapy resistance in gastric cancer. This phenomenon may be attributed to the recruitment of LGMN+ macrophages mediated by the CXCL16-CXCR6 signaling pathway. Conclusion This study unveiled two distinct ICEPs and the mutually exclusivity and co-occurrence characteristics of CD8+ T cells in gastric cancer. The ICEP2 CD8+ T cell subset, highly expressed in gastric cancer patients resistant to anti-PD-1 therapy, may be recruited by LGMN+ macrophages through CXCL16-CXCR6 axis. These findings provide evidence for NKG2A as a novel immunotherapeutic target in gastric cancer and offer new insights into combination strategies for immune checkpoint inhibitors in gastric cancer. Graphical Abstract

Abstract FVP is a polysaccharide extracted from Flammulina velutipes with immunomodulatory, anti-tumor, and anti-oxidation activities. In this study, we obtained the crude polysaccharide FVP-C from the water extract of Flammulina velutipes, and its main component FVP-S1 was obtained after further purification. Upon structural identification, we found that FVP-C is a neutral polysaccharide, and FVP-S1 was an acidic golden mushroom polysaccharide, consisting of glucuronic acid, xylose, and glucose. Lung adenocarcinoma (A549) was treated with FVP-S1 and FVP-C, respectively, and we found that FVP-S1 and FVP-C inhibited the proliferation and migration ability of tumor cells, as well as changed the morphology of the tumor cells and caused chromosome sheteropythosis, among which FVP-S1 had the best inhibition effect. The results of flow cytometry experiments and mitochondrial membrane potential, RT-qPCR, and Western blot showed that FVP-S1 and FVP-C were able to decrease the mitochondrial membrane potential, increase the expression level of apoptotic proteins Casepase-3 and Casepase-9 proteins, and at the same time, increase the ratio of Bax and Bcl-2, which promoted apoptosis of tumor cells. In conclusion, these data indicated that FVP-S1 and FVP-C were able to induce apoptosis in A549 cells through the mitochondrial pathway, which played an important role in inhibiting tumor cells.

Abstract Teratoma, due to its remarkable ability to differentiate into multiple cell lineages, is a valuable model for studying human embryonic development. The similarity of the gene expression and chromatin accessibility patterns in these cells to those observed in vivo further underscores its potential as a research tool. Notably, teratomas derived from human naïve (pre-implantation epiblast-like) pluripotent stem cells (PSCs) have larger embryonic cell diversity and contain extraembryonic lineages, making them more suitable to study developmental processes. However, the cell type-specific epigenetic profiles of naïve PSC teratomas have not been yet characterized. Using single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq), we analyzed 66,384 cell profiles from five teratomas derived from human naïve PSCs and their post-implantation epiblast-like (primed) counterparts. We observed 17 distinct cell types from both embryonic and extraembryonic lineages, resembling the corresponding cell types in human fetal tissues. Additionally, we identified key transcription factors specific to different cell types. Our dataset provides a resource for investigating gene regulatory programs in a relevant model of human embryonic development.

Objective Percutaneous repair is an alternative to open surgical repair of the Achilles tendon with comparable, functional results and low re‐rupture and infection rates; however, sural nerve injury is a known complication. The purpose of this study is to design a new surgical procedure, the minimally invasive peritendinous submembrane access technique (MIS‐PSAT). It offers optimal results, with excellent functional outcomes, and with minimal soft tissue complications and sural nerve injury. Methods This retrospective study included 249 patients with acute closed Achilles tendon ruptures treated at our institution between 2009 and 2019. All patients underwent MIS‐PSAT at our institution and were followed up for 8–48 months. Functional evaluation was based on the Achilles tendon total rupture score (ATRS) and the American Orthopedic Foot and Ankle Society Ankle‐Hindfoot Scale (AOFAS‐AHS), associated with local complications and isokinetic tests. Results None of the patients had infection, necrosis, or sural nerve injury. Re‐rupture occurred in two cases. The average times to return to work and sports was 10.4 and 31.6 weeks, respectively. The average ATRS and AOFAS‐AHS scores were 90.2 and 95.7, respectively, with an excellent rate of 99.5%. Isokinetic tests showed that ankle function on the affected side was comparable with that on the healthy side (p > 0.05). Conclusion The MIS‐PSAT for acute Achilles tendon rupture is easy to perform with few complications. Importantly, the surgical technique reduces the risk of sural nerve injuries. Patients have high postoperative satisfaction, low re‐rupture rates, and muscle strength, and endurance can be restored to levels similar to those on the healthy side.

Explosives, a type of energetic material (EM), face a high-pressure environment in the detonation process or under shock conditions. Determining their high-pressure behavior is critical to their explosion and safety. 1-Methyl-3,4,5-trinitropyrazole (MTNP), a carrier of melt-cast explosives, exhibits the potential for replacing trinitrotoluene (TNT). However, there is limited knowledge about its structural evolvement at high pressure. Using a diamond anvil cell (DAC), this study investigated the structural variation of MTNP through in situ high-pressure synchrotron angle-dispersive X-ray diffraction (ADXRD) experiments and Raman measurements. As evidenced by the results, MTNP underwent phase transition at 8.7 GPa and amorphization at 15.3 GPa due to high pressure. Through the analysis of first-principles calculations and Raman spectra, this study proposed the mechanisms behind the changes in MTNP at high pressure. Furthermore, this study systematically explored the structural evolvement of MTNP and the evolution of its weak intermolecular interactions at high pressure, gaining further understanding of MTNP's detonation and safety.

Abstract 2′,4′‐Dihydroxy‐6′‐methoxy‐3′,5′‐dimethylchalcone (DMC) is a typical and abundant chalcone compound from the buds of Cleistocalyx operculatus, which is well‐known for its edible and medicinal qualities. In this study, DMC showed effective cell cycle arrest at G2/M on MDA‐MB‐231 cells, though dual impacts, including the inhibition of microtubule polymerization through binding to β‐tubulin and the stimulation of reactive oxygen species (ROS) production by inhibiting catalase activity. The increased ROS level inhibited PI3K/Akt/mTOR pathway and further suppressed the expression level of Cdc2, Cdc25C, and Cyclin B1, alongside stimulated the expression level of p21 and p27. Above 29.5% MDA‐MB‐231 cells were arrested at G2/M phase, subsequently undergoing apoptosis due to heightened levels of apoptosis‐related proteins Bax and caspase 3. In summary, this study demonstrated that DMC concomitantly plays dual roles in apoptotic inducing by inhibiting the ROS consumption and microtubules formation in triple‐negative breast cancer cells.

Abstract Background Lung cancer (LC), characterized by high incidence and mortality rates, presents a significant challenge in oncology. Despite advancements in treatments, early detection remains crucial for improving patient outcomes. The accuracy of screening for LC by detecting volatile organic compounds (VOCs) in exhaled breath remains to be determined. Methods Our systematic review, following PRISMA guidelines and analyzing data from 25 studies up to October 1, 2023, evaluates the effectiveness of different techniques in detecting VOCs. We registered the review protocol with PROSPERO and performed a systematic search in PubMed, EMBASE and Web of Science. Reviewers screened the studies’ titles/abstracts and full texts, and used QUADAS-2 tool for quality assessment. Then performed meta-analysis by adopting a bivariate model for sensitivity and specificity. Results This study explores the potential of VOCs in exhaled breath as biomarkers for LC screening, offering a non-invasive alternative to traditional methods. In all studies, exhaled VOCs discriminated LC from controls. The meta-analysis indicates an integrated sensitivity and specificity of 85% and 86%, respectively, with an AUC of 0.93 for VOC detection. We also conducted a systematic analysis of the source of the substance with the highest frequency of occurrence in the tested compounds. Despite the promising results, variability in study quality and methodological challenges highlight the need for further research. Conclusion This review emphasizes the potential of VOC analysis as a cost-effective, non-invasive screening tool for early LC detection, which could significantly improve patient management and survival rates.

Abstract Background Stress hyperglycemia occurs frequently in patients following acute myocardial infarction (AMI) and may aggravate myocardial stiffness, but relevant evidence is still lacking. Accordingly, this study aimed to examine the impact of admission stress hyperglycemia on left ventricular (LV) myocardial deformation in patients following AMI. Methods A total of 171 patients with first AMI (96 with normoglycemia and 75 with hyperglycemia) underwent cardiac magnetic resonance (CMR) examination were included. AMI patients were classified according to admission blood glucose level (aBGL): < 7.8 mmol/L (n = 96), 7.8–11.1 mmol/L (n = 41) and ≥ 11.1 mmol/L (n = 34). LV strains, including global radial/circumferential/longitudinal peak strain (PS)/peak systolic strain rate (PSSR)/peak diastolic strain rate (PDSR), were measured and compared between groups. Further, subgroup analyses were separately conducted for AMI patients with and without diabetes. Multivariate analysis was employed to assess the independent association between aBGL and LV global PS in AMI patients. Results LV global PS, PSSR and PDSR were decreased in radial, circumferential and longitudinal directions in hyperglycemic AMI patients compared with normoglycemic AMI patients (all P

Abstract Background Despite the efficacy of absolute ethanol (EtOH), its radiolucency introduces several risks in interventional therapy for treating vascular malformations. This study aims to develop a novel radiopaque ethanol injection (REI) to address this issue. Methods Iopromide is mixed with ethanol to achieve radiopacity and improve the physicochemical properties of the solution. Overall, 82 male New Zealand white rabbits are selected for in vivo radiopacity testing, peripheral vein sclerosis [animals were divided into the following 5 groups (n = 6): negative control (NC, saline, 0.250 ml/kg), positive control (EtOH, 0.250 ml/kg), low-dose REI (L-D REI, 0.125 ml/kg), moderate-dose REI (M-D REI, 0.250 ml/kg), and high-dose REI (H-D REI 0.375 ml/kg)], pharmacokinetic analyses (the blood sample was harvested before injection, 5 min, 10 min, 20 min, 40 min, 1 h, 2 h, 4 h, and 8 h after injection in peripheral vein sclerosis experiment), peripheral artery embolization [animals were divided into the following 5 groups (n = 3): NC (saline, 0.250 ml/kg), positive control (EtOH, 0.250 ml/kg), L-D REI (0.125 ml/kg), M-D REI (0.250 ml/kg), and H-D REI (0.375 ml/kg)], kidney transcatheter arterial embolization [animals were divided into the following 4 groups (n = 3): positive control (EtOH, 0.250 ml/kg), L-D REI (0.125 ml/kg), M-D REI (0.250 ml/kg), and H-D REI (0.375 ml/kg); each healthy kidney was injected with saline as negative control], and biosafety evaluations [animals were divided into the following 5 groups (n = 3): NC (0.250 ml/kg), high-dose EtOH (0.375 ml/kg), L-D REI (0.125 ml/kg), M-D REI (0.250 ml/kg), and H-D REI (0.375 ml/kg)]. Then, a prospective cohort study involving 6 patients with peripheral venous malformations (VMs) is performed to explore the clinical safety and effectiveness of REI. From Jun 1, 2023 to August 31, 2023, 6 patients [age: (33.3 ± 17.2) years] with lingual VMs received sclerotherapy of REI and 2-month follow-up. Adverse events and serious adverse events were evaluated, whereas the efficacy of REI was determined by both the traceability of the REI under DSA throughout the entire injection and the therapeutic effect 2 months after a single injection. Results The REI contains 81.4% ethanol (v/v) and 111.3 mg/ml iodine, which can be traced throughout the injection in the animals and patients. The REI also exerts a similar effect as EtOH on peripheral venous sclerosis, peripheral arterial embolization, and renal embolization. Furthermore, the REI can be metabolized at a similar rate compared to EtOH and Ultravist® and did not cause injury to the animals’ heart, liver, spleen, lungs, kidneys and brain. No REI-related adverse effects have occurred during sclerotherapy of VMs, and 4/6 patients (66.7%) have achieved complete response at follow-up. Conclusion In conclusion, REI is safe, exerts therapeutic effects, and compensates for the radiolucency of EtOH in treating VMs. Trial registration The clinical trial was registered as No. ChiCTR2300071751 on May 24 2023.

Abstract Background The risk factors for subsequent fractures following an initial hip fracture are not entirely understood. This study examined the clinical characteristics of hip fracture patients to identify potential risk factors associated with a higher risk of experiencing subsequent fractures. Methods We conducted a nested case-control study using data from the Chinese PLA General Hospital Hip Fracture Cohort between January 2008 and March 2022. The cases were individuals who experienced subsequent fractures following an initial hip fracture. Each case was matched with up to 2 controls who did not develop subsequent fractures. Important clinical factors were compared across groups, including traditional fracture risk factors and potential risk factors (e.g., comorbidities, falls risk, physical impairment, calcium or vitamin D use, and anti-osteoporosis medications). Conditional logistic regression analyses were used to evaluate the impact of these clinical features as potential risk factors for subsequent fractures. Results A total of 96 individuals who suffered from subsequent fractures were matched with 176 controls. The median time between the initial hip fracture and the subsequent fracture was 2.1 years. The overall proportion of patients receiving anti-osteoporosis treatment after initial hip fracture was 25.7%. In the multivariable regression analysis, living in a care facility (OR = 3.78, 95%CI: 1.53–9.34), longer hospital stays (OR = 1.05, 95%CI: 1.00–1.11), and falls after discharge (OR = 7.58, 95%CI: 3.37–17.04) were associated with higher odds of subsequent fractures. Conclusions This study showed that living in a care facility, longer hospital stays, and falls after discharge may be independent risk factors for repeat fractures following an initial hip fracture. These findings could be used to identify and manage patients at high risk of subsequent fractures.

Abstract We present an improved calculation of the $$D_{(s)}^*D_{(s)}V$$ D ( s ) ∗ D ( s ) V and $$B_{(s)}^*B_{(s)}V$$ B ( s ) ∗ B ( s ) V coupling constants, where V denotes $$\rho $$ ρ , $$K^*$$ K ∗ , $$\omega $$ ω , and $$\phi $$ ϕ mesons. These couplings govern the long-distance quantum chromodynamics (QCD) in interactions between heavy pseudo-scalar/vector mesons and light vector mesons. Our analysis is conducted within the framework of QCD light-cone sum rules (LCSRs) by utilizing the light-cone distribution amplitudes (LCDAs) of light vector mesons. By systematically incorporating the subleading power corrections and higher-twist contributions at the leading order (LO) and including the next-to-leading order (NLO) corrections at leading power, we achieve enhanced accuracy in the light-cone operator product expansion (OPE) for the underlying correlation function. In assessing the reliability of the established LCSRs, we consider uncertainties arising from the choice of the quark–hadron duality region in the double dispersion relation. Building upon these improvements, we accomplish an optimized computation and analysis for the strong coupling constants $$g_{H^*HV}$$ g H ∗ H V which are used to extract the effective coupling $$\lambda $$ λ in the heavy meson chiral perturbation theory (HM $$\chi $$ χ PT). Furthermore, we investigate the SU(3) flavor symmetry-breaking effects in detail and compare our sum rule calculations with previous studies in an exploratory way.

Abstract Background The crossbreeding of specialized beef cattle breeds with Chinese indigenous cattle is a common method of genetic improvement. Xia’nan cattle, a crossbreed of Charolais and Nanyang cattle, is China’s first specialized beef cattle breed with independent intellectual property rights. After more than two decades of selective breeding, Xia’nan cattle exhibit a robust physique, good environmental adaptability, good tolerance to coarse feed, and high meat production rates. This study analyzed the population genetic structure, genetic diversity, and genomic variations of Xia’nan cattle using whole-genome sequencing data from 30 Xia’nan cattle and 178 published cattle genomic data. Result The ancestry estimating composition analysis showed that the ancestry proportions for Xia’nan cattle were mainly Charolais with a small amount of Nanyang cattle. Through the genetic diversity studies (nucleotide diversity and linkage disequilibrium decay), we found that the genomic diversity of Xia’nan cattle is higher than that of specialized beef cattle breeds in Europe but lower than that of Chinese native cattle. Then, we used four methods to detect genome candidate regions influencing the excellent traits of Xia’nan cattle. Among the detected results, 42 genes (θπ and CLR) and 131 genes (F ST and XP-EHH) were detected by two different detection strategies. In addition, we found a region in BTA8 with strong selection signals. Finally, we conducted functional annotation on the detected genes and found that these genes may influence body development (NR6A1), meat quality traits (MCCC1), growth traits (WSCD1, TMEM68, MFN1, NCKAP5), and immunity (IL11RA, CNTFR, CCL27, SLAMF1, SLAMF7, NAA35, and GOLM1). Conclusion We elucidated the genomic features and population structure of Xia’nan cattle and detected some selection signals in genomic regions potentially associated with crucial economic traits in Xia’nan cattle. This research provided a basis for further breeding improvements in Xia’nan cattle and served as a reference for genetic enhancements in other crossbreed cattle.

Circular RNAs (circRNAs) are ideal biomarkers of oral squamous cell carcinoma (OSCC) because of their highly stable closed-loop structure, and they can act as microRNA (miRNA) sponges to regulate OSCC progression. By analyzing clinical samples, we identified circCPNE1, a dysregulated circRNA in OSCC, and its expression level was negatively correlated with the clinical stage of OSCC patients. Gain-of-function assays revealed the tumor-suppressive effect of circCPNE1, which was then identified as a miR-330-3p sponge. MiR-330-3p was recognized as a tumor promoter in multiple studies, consistent with our finding that it could promote the proliferation, migration, and invasion of OSCC cells. These results indicated that selective inhibition of miR-330-3p could be an effective strategy to inhibit OSCC progression. Therefore, we designed cationic polylysine-cisplatin prodrugs to deliver antagomiR-330-3p (a miRNA inhibitory analog) via electrostatic interactions to form PP@miR nanoparticles (NPs). Paratumoral administration results revealed that PP@miR NPs effectively inhibited subcutaneous tumor progression and achieved partial tumor elimination (2/5), which confirmed the critical role of miR-330-3p in OSCC development. These findings provide a new perspective for the development of OSCC treatments.

The latest study published in Nature by Andrew R. Burns, Peter J. Roy and co-authors is highlighted in this paper, they investigated a series of novel nematicidal compounds, including Selectivin-A and Selectivin-E, and explored their mechanism of action. Experiments have displayed that the Selectivin compound is inactive to human cells, fish, fungi, insects and even beneficial nematodes. In the exploration of its mechanism of action, it was found that the mechanism of action of Selectivin is different with those of commercial nematocides: Selectivin needs to be activated by biotin produced by nematodes, after that they can be transformed into compounds with high nematicidal activity. This proves that the family of Selectivin compounds has the advantages of high selectivity and environmental friendliness, and their mechanism of action is completely new, proposing a completely new path for the development of new nematicides.

Background The heterogeneity of myelodysplastic syndromes (MDS) is strong, with poor efficacy of existing therapeutic regimens and large individual differences in patient prognosis. B-cell lymphomato-2 (Bcl-2) protein is highly expressed in patients with myeloid tumors, which has been proved by previous to be associated with disease progression, chemotherapy resistance, and shortened overall survival. The Bcl-2 inhibitor Veneckla (VEN) is approved for elderly patients with newly diagnosed acute myeloid leukemia (AML) who are not eligible for intensive therapy, and there is less data on its use in MDS patients. The difference in Bcl-2 expression in MDS patients and its correlation with the efficacy and prognosis of VEN therapy haven't been reported. Objective To analyse the expression of Bcl-2 protein in MDS patients and assess its correlation with the efficacy and prognosis of VEN treatment. Methods The clinical data of 71 patients with MDS admitted to Sichuan Academy of Medical Sciences·Sichuan Provincial People's Hospital from July 2018 to December 2022 were retrospectively analyzed. Baseline data of patients including gender, age, blood routine, blood biochemistry, bone marrow hemocytology, flow cytometry, chromosome karyotype, myeloid gene mutation, fusion gene mutation and MDS-EB typing were collected. The expression of Bcl-2 protein was detected by immunohistochemical staining. According to the modified International Prognostic Score System (IPSS-R), the patients were divided into 5 risk levels of very low risk (0 case), low risk (1 case), medium risk (7 cases), high risk (40 cases) and very high risk (23 cases). Patients with bone marrow Bcl-2 positivity≥10% were defined as Bcl-2 positive and0.05) . Conclusion Bcl-2 protein contributes to MDS fusion gene mutation and myeloid gene mutation; Bcl-2 positive expression was not associated with the survival of MDS patients. There was no difference in survival rate between Bcl-2 positive and Bcl-2 negative patients who received the VA combination regimen.

Abstract Background To explore the relationship between occupational stress, burnout and depressive symptoms among railroad workers in Fuzhou, and to analyze the interaction of burnout and occupational stress on depressive symptoms. Methods In this study, 861 railway employees of Fuzhou railway bureau were randomly selected from January to April, 2022. Occupational stress inventory revised edition (OSI-R), China job burnout inventory (CMBI) and Symptom Checklist-90 (SCL-90) were used to investigate the occupational stress, job burnout and depressive symptoms of railway workers. Interactions associated with depressive symptoms were assessed by linear hierarchical regression analysis and SPSS macros (PROCESS). Results Occupational stress, job burnout and depressive symptoms accounted for 50.58%, 93.47%, and 11.19% of the study population, respectively. There were intergroup differences between age, marriage status, and length of service (P

Abstract Background The impacts of long-term exposure to air pollution on the risk of subsequent non-alcoholic fatty liver disease (NAFLD) among participants with type 2 diabetes (T2D) is ambiguous. The modifying role of Life’s Essential 8 (LE8) remains unknown. Methods This study included 23,129 participants with T2D at baseline from the UK Biobank. Annual means of nitrogen dioxide (NO2), nitrogen oxides (NOX), and particulate matter (PM2.5, PM2.5–10, PM10) were estimated using the land-use regression model for each participant. The associations between exposure to air pollution and the risk of severe NAFLD were evaluated using Cox proportional hazard models. The effect modification of LE8 was assessed through stratified analyses. Results During a median 13.6 years of follow-up, a total of 1,123 severe NAFLD cases occurred. After fully adjusting for potential covariates, higher levels of PM2.5 (hazard ratio [HR] = 1.12, 95%CI:1.02, 1.23 per interquartile range [IQR] increment), NO2 (HR = 1.15, 95%CI:1.04, 1.27), and NOX (HR = 1.08, 95%CI:1.01, 1.17) were associated with an elevated risk of severe NAFLD. In addition, LE8 score was negatively associated with the risk of NAFLD (HR = 0.97, 95% CI: 0.97, 0.98 per point increment). Compared with those who had low air pollution and high LE8, participants with a high air pollution exposure and low LE8 had a significantly higher risk of severe NAFLD. Conclusions Our findings suggest that long-term exposure to air pollution was associated with an elevated risk of severe NAFLD among participants with T2D. A lower LE8 may increase the adverse impacts of air pollution on NAFLD.

Abstract Basal progenitor cells are crucial for maintaining foregut (the esophagus and forestomach) homeostasis. When their function is dysregulated, it can promote inflammation and tumorigenesis. However, the mechanisms underlying these processes remain largely unclear. Here, we employ genetic mouse models to reveal that Jag1/2 regulate esophageal homeostasis and foregut tumorigenesis by modulating the function of basal progenitor cells. Deletion of Jag1/2 in mice disrupts esophageal and forestomach epithelial homeostasis. Mechanistically, Jag1/2 deficiency impairs activation of Notch signaling, leading to reduced squamous epithelial differentiation and expansion of basal progenitor cells. Moreover, Jag1/2 deficiency exacerbates the deoxycholic acid (DCA)-induced squamous epithelial injury and accelerates the initiation of squamous cell carcinoma (SCC) in the forestomach. Importantly, expression levels of JAG1/2 are lower in the early stages of human esophageal squamous cell carcinoma (ESCC) carcinogenesis. Collectively, our study demonstrates that Jag1/2 are important for maintaining esophageal and forestomach homeostasis and the onset of foregut SCC.

Abstract Introduction Neonatal respiratory failure (NRF) is a serious condition that often has high mortality and morbidity, effective interventions can be delivered in the future by identifying the risk factors associated with morbidity and mortality. However, recent advances in respiratory support have improved neonatal intensive care units (NICUs) care in China. We aimed to provide an updated review of the clinical profile and outcomes of NRF in the Jiangsu province. Methods Infants treated for NRF in the NICUs of 28 hospitals between March 2019 and March 2022 were retrospectively reviewed. Data collected included baseline perinatal and neonatal parameters, NICU admission- and treatment-related data, and patient outcomes in terms of mortality, major morbidity, and survival without major morbidities. Results A total of 5548 infants with NRF were included in the study. The most common primary respiratory disorder was respiratory distress syndrome (78.5%). NRF was managed with non-invasive and invasive respiratory support in 59.8% and 14.5% of patients, respectively. The application rate of surfactant therapy was 38.5%, while that of neonatal extracorporeal membrane oxygenation therapy was 0.2%. Mortality and major morbidity rates of 8.5% and 23.2% were observed, respectively. Congenital anomalies, hypoxic-ischemic encephalopathy, invasive respiratory support only and inhaled nitric oxide therapy were found to be significantly associated with the risk of death. Among surviving infants born at < 32 weeks of gestation or with a birth weight < 1500 g, caffeine therapy and repeat mechanical ventilation were demonstrated to significantly associate with increased major morbidity risk. Conclusion Our study demonstrates the current clinical landscape of infants with NRF treated in the NICU, and, by proxy, highlights the ongoing advancements in the field of perinatal and neonatal intensive care in China.

Abstract Background Polygonum multiflorum (PM), a widely used traditional Chinese medicine herb, is divided into two forms, namely raw polygonum multiflorum (RPM) and polygonum multiflorum praeparata (PMP), according to the processing procedure. Emerging data has revealed the differential hepatotoxicity of RPM and PMP, however, its potential mechanism is still unclear. Methods In our study, we investigated the differential hepatotoxicity of RPM and PMP exerted in C57BL/6 mice. First, sera were collected for biochemical analysis and HE staining was applied to examine the morphological alternation of the liver. Then we treated L02 cells with 5 mg / mL of RPM or PMP. The CCK8 and EdU assays were utilized to observe the viability and proliferation of L02 cells. RNA sequencing was performed to explore the expression profile of L02 cells. Western blotting was performed to detect the expression level of ferroptosis-related protein. Flow cytometry was used to evaluate ROS accumulation. Results In our study, a significant elevation in serum ALT, AST and TBIL levels was investigated in the RMP group, while no significant differences were observed in the PMP group, compared to that of the CON group. HE staining showed punctate necrosis, inflammatory cell infiltration and structural destruction can be observed in the RPM group, which can be significantly attenuated after processing. In addition, we also found RPM could decrease the viability and proliferation capacity of L02 cells, which can be reversed by ferroptosis inhibitor. RNA sequencing data revealed the adverse effect of PM exerted on the liver is closely associated with ferroptosis. Western blotting assay uncovered the protein level of GPX4, HO-1 and FTL was sharply decreased, while the ROS content was dramatically elevated in L02 cells treated with RPM, which can be partially restored after processing. Conclusions The hepatotoxicity induced by RPM was significantly lower than the PMP, and its potential mechanism is associated with ferroptosis.

Abstract Supramolecular polymeric materials have exhibited attractive features such as self-healing, reversibility, and stimuli-responsiveness. However, on account of the weak bonding nature of most noncovalent interactions, it remains a great challenge to construct supramolecular polymeric materials with high robustness. Moreover, high usage of supramolecular units is usually necessary to promote the formation of robust supramolecular polymeric materials, which restrains their applications. Herein, we describe the construction of highly robust supramolecular polymer networks by using only a tiny amount of metallacycles as the supramolecular crosslinkers. A norbornene ring-opening metathesis copolymer with a 120° dipyridine ligand is prepared and self-assembled with a 60° or 120° Pt(II) acceptor to fabricate the metallacycle-crosslinked polymer networks. With only 0.28 mol% or less pendant dipyridine units to form the metallacycle crosslinkers, the mechanical properties of the polymers are significantly enhanced. The tensile strengths, Young’s moduli, and toughness of the reinforced polymers reach up to more than 20 MPa, 600 MPa, and 150 MJ/m3, respectively. Controllable destruction and reconstruction of the metallacycle-crosslinked polymer networks are further demonstrated by the sequential addition of tetrabutylammonium bromide and silver triflate, indicative of good stimuli-responsiveness of the networks. These remarkable performances are attributed to the thermodynamically stable, but dynamic metallacycle-based supramolecular coordination complexes that offer strong linkages with good adaptive characteristics.

Background The bark of Chinese fir (Cunninghamia lanceolata), the largest afforestation tree species in the forest areas of southern China, is susceptible to injuries and bites from small animals. The population of small animals has recently increased owing to improvements in the ecological environment across various forested areas, thus increasing the incidence of injuries in the bark of Chinese fir. Following such injuries, the bark secretes light yellow or milky white secretions, the function of which remains unclear. The present study aimed to reveal the antibacterial effect of exudates of different Chinese fir cultivars on five bacterial species. Methods The research involved three-year-old plantations of Taxus chinensis var. koraiensis and Yangkou3 and three-year-old container plantations of Taxus chinensis var. pendula, Yang 061, and Yang 020. The antibacterial effects of exudates were analyzed using the filter paper diffusion method. The minimum inhibitory concentration for each secretion and the bacterial inhibition zone were determined. Results The exudates of the different Chinese fir bark exhibited notable antibacterial effects on Bacillus subtilis, Salmonella paratyphi B, Pseudomonas aeruginosa, Escherichia coli, and Staphylococcus aureus. However, the extent of these antibacterial effects varied among the different Chinese fir cultivars, as the minimum inhibitory concentrations (MICs) of the exudates against the five bacterial species varied. The mean MIC of Pseudomonas aeruginosa was lower potency, whereas that of Escherichia coli was the lowest. Notably, the antibacterial efficacy of the exudates was mainly influenced by the composition of the secretions rather than the number of secretions, with organic acid compounds and terpenoids potentially contributing to the antibacterial effects against E. coli and Bacillus subtilis, respectively. Conclusion This study demonstrates the antibacterial effect of wound secretion of different Chinese fir cultivars, highlighting their varying efficacy on different bacterial species. Moreover, the antibacterial ability of the exudates of the strains was mainly determined by the composition of the wound secretions, and there was no noticeable relationship with the number of wound secretions. The results of this study offers a theoretical basis for screen Chinese fir cultivars with high-disease-resistant.

The utilization of Cobalt (Co) has surged due to it is critical role in renewable energy technologies and other high-tech applications. Concurrently, the potential health risks associated with Co exposure have raised concerns. Previous studies, including our own, have shown that Co can impair learn and memory functions as an epigenetic hazard, even at low concentrations. In this study, we explore the mechanisms of Co-induced ferroptosis in neurodegenerative damage both in vivo and in vitro, focusing on the epigenetic regulation by N6-methyladenosine (m6A) demethylase alkB homolog 5 (ALKBH5). We identify heme oxygenase-1 (HO-1) as a direct target gene of ALKBH5, playing a crucial role in mitigating Co-induced ferroptosis. ALKBH5 deficiency affects the post-transcriptional regulation of HO-1 through m6A modification, which in turn influences mRNA’s stability, intracellular distribution, and alternative splicing, thereby enhancing susceptibility to Co-induced ferroptosis. Additionally, we discuss the potential involvement of heterogeneous nuclear ribonucleoprotein M (hnRNPM) in regulating alternative splicing of HO-1 mRNA, potentially mediated by m6A modifications. This study provides new epigenetic insights into the post-transcriptional regulatory mechanisms involved in Co-induced ferroptosis and highlights the broader implications of environmental hazards in neurodegenerative damage.

Abstract Orthopedic diseases, such as osteoarthritis and fractures, place a significant burden on individuals and healthcare systems worldwide. Extracellular vesicles (EVs), which are membrane‐derived particles, have emerged as a novel tool in the field of orthopedics. EVs play a crucial role in diagnosing, regenerating, and treating orthopedic diseases. In terms of diagnosis, EVs serve as potential biomarkers, carrying unique donor cell information and circulating effectively in bodily fluids. Specific biomolecules within EVs, including proteins, nucleic acids, and microRNAs, hold promise as biological markers for the early detection and monitoring of orthopedic diseases. EVs have shown significant potential in promoting bone and cartilage regeneration. They can enhance tissue regeneration by stimulating various stem cells to proliferate, migrate, and differentiate into mature chondrocytes and osteocytes. EVs can also target specific tissues, making them attractive candidates for drug delivery in orthopedic diseases. They can efficiently deliver therapeutic cargo, such as anti‐inflammatory agents and growth factors, to the affected sites, enhancing treatment efficacy while minimizing toxicity and adverse effects. In conclusion, EVs have significant potential in diagnosing, regenerating, and treating orthopedic diseases.

Human papillomaviruses (HPVs) account for more than 30% of cancer cases, with definite identification of the oncogenic role of viral E6 and E7 genes. However, the identification of high-risk HPV genotypes has largely relied on lagged biological exploration and clinical observation, with types unclassified and oncogenicity unknown for many HPVs. In the present study, we retrieved and cleaned HPV sequence records with high quality and analyzed their genomic compositional traits of dinucleotide (DNT) and DNT representation (DCR) to overview the distribution difference among various types of HPVs. Then, a deep learning model was built to predict the oncogenic potential of all HPVs based on E6 and E7 genes. Our results showed that the main three groups of Alpha, Beta, and Gamma HPVs were clearly separated between/among types in the DCR trait for either E6 or E7 coding sequence (CDS) and were clustered within the same group. Moreover, the DCR data of either E6 or E7 were learnable with a convolutional neural network (CNN) model. Either CNN classifier predicted accurately the oncogenicity label of high and low oncogenic HPVs. In summary, the compositional traits of HPV oncogenicity-related genes E6 and E7 were much different between the high and low oncogenic HPVs, and the compositional trait of the DCR-based deep learning classifier predicted the oncogenic phenotype accurately of HPVs. The trained predictor in this study will facilitate the identification of HPV oncogenicity, particularly for those HPVs without clear genotype or phenotype.

ObjectiveWe performed this pooled analysis for the first time to comprehensively explore the prognostic value of tumor-associated high endothelial venules (TA-HEVs) and determine their relationships with clinicopathological features in solid tumors.MethodsFour online databases, including PubMed, Web of Science, Embase, and Cochrane Library, were comprehensively searched to identify studies assessing the effect of TA-HEVs on prognosis or clinicopathological features. Hazard ratios (HRs) with 95% confidence intervals (CIs) were applied to evaluate survival outcomes, including overall survival (OS), disease-free survival (DFS), progression-free survival (PFS), and cancer-specific survival (CSS). The association between TA-HEV status and clinicopathological characteristics was assessed by odds ratios (ORs) combined with 95% CIs. Subgroup analysis was conducted to explore sources of heterogeneity. The sensitivity analysis was performed to evaluate the stability of our findings. Meanwhile, Funnel plots were employed to visually evaluate potential publication bias, and both Begg’s and Egger’s tests were adopted to quantitatively determine publication bias.ResultsA total of 13 retrospective cohort studies, involving 1,933 patients were finally included in this meta-analysis. Effect-size pooling analysis showed that the positivity of TA-HEVs was related to improved OS (pooled HR: 0.75, 95% CI: 0.62-0.93, P

Wheat germ protein (WGP) was extracted from wheat germ powder by alkali dissolution and acid precipitation, and WGP was modified by microwave and metal ion treatment. The functional properties, structure, and molecular mass of WGP before and after modification were determined. The results showed that compared with the control group, the solubility of WGP was increased by 86.61% after the combined treatment, the water-holding capacity (WHC) and oil-holding capacity (OHC) were increased by 22.86% and 82.16%, the emulsifying capacity, emulsion stability and foaming capacity were increased by 120.90%, 15.64% and 116.91%, respectively, and the foaming stability was reduced. The results of Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) showed that there was no significant change in the molecular mass of WGP after the combined treatment, while the structure became looser, and the secondary structure exhibited a trend toward a disordered state, mainly manifested as an increase of β-turn and random coil. The combined treatment was superior to either microwave or metal ion treatment alone in improving the functional characteristics of WGP. The combined treatment with microwave and metal ions offers WGP with good functional characteristics, thereby providing WGP the potential to be developed into a new functional food.

In human body, the endocrine system, nervous system and immune system jointly shoulder the important responsibility of life support. Hormones are the material basis for coordination of endocrine system. Steroid hormones, also known as steride hormone, belong to a large category of hormones. The synthesis process of steroid hormones takes cholesterol as the precursor. Through the participation of various metabolic enzymes, steroid hormones are synthesized in the human adrenal cortex, mitochondria of placental cells, smooth Endoplasmic reticulum and gonads, producing 21C, 19C or 18C-backbones with different chemical structures. According to pharmacological effects, steroid hormones are mainly divided into progestogens, corticosteroids and sex hormones, which play an important role in regulating human growth, development, reproduction and maintaining the stability of human body environment. In clinical practice, the level of steroid hormones is used as diagnostic indicator for adrenal and psychiatric diseases. Therefore, accurate determination of steroid hormone content is very important. Steroid hormones in the human body can be detected using various methods, such as radioimmunoassay, chemiluminescence immunoassay, enzyme-linked immunosorbent assay, gas chromatography-tandem mass spectrometry (GC-MS/MS), and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Mass spectrometry has obvious advantages in terms of detection sensitivity and accuracy compared with immunoassay. GC-MS has been the main technique for steroid analysis due to its high specificity, wide analyte coverage, and sufficient sensitivity. However, the samples need to be derivatized, and the experimental processes are tedious. LC-MS/MS has the inherent advantages of high sensitivity and specificity, and has a high-throughput characteristic, thus it is an ideal tool for routine diagnosis. At present, common pretreatment techniques for serum samples include protein precipitation, liquid-liquid extraction, and solid phase extraction. Some new pretreatment methods have emerged in recent years, such as dispersed liquid-liquid extraction, ultrasonic-assisted extraction, and supramolecular extraction. Each pretreatment technique has its own advantages and disadvantages. For example, solid phase extraction (SPE) can achieve good recovery but requires more time and economic factors. In selection of pretreatment methods, the physical and chemical properties of analytes, the characteristics of matrices, the simplicity and durability of method establishment, and time, reliability, and cost required should be comprehensively considered. This article reviewed the application of LC-MS/MS in the determination of endogenous steroid hormones, especially in sample pretreatment, chromatographic and mass spectrometric conditions, so as to provide more accurate basis for clinical diagnosis and treatment based on steroid hormones.

Abstract Mouse auditory cortex is composed of six sub-fields: primary auditory field (AI), secondary auditory field (AII), anterior auditory field (AAF), insular auditory field (IAF), ultrasonic field (UF) and dorsoposterior field (DP). Previous studies have examined thalamo-cortical connections in the mice auditory system and learned that AI, AAF, and IAF receive inputs from the ventral division of the medial geniculate body (MGB). However, the functional and thalamo-cortical connections between nonprimary auditory cortex (AII, UF, and DP) is unclear. In this study, we examined the locations of neurons projecting to these three cortical sub-fields in the MGB, and addressed the question whether these cortical sub-fields receive inputs from different subsets of MGB neurons or common. To examine the distributions of projecting neurons in the MGB, retrograde tracers were injected into the AII, UF, DP, after identifying these areas by the method of Optical Imaging. Our results indicated that neuron cells which in ventral part of dorsal MGB (MGd) and that of ventral MGB (MGv) projecting to UF and AII with less overlap. And DP only received neuron projecting from MGd. Interestingly, these three cortical areas received input from distinct part of MGd and MGv in an independent manner. Based on our foundings these three auditory cortical sub-fields in mice may independently process auditory information.