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Abstract Background Understanding the role of cytokines in tooth development is critical for advancing dental tissue engineering. Fibroblast growth factor 9 (FGF9) is the only FGF consistently expressed throughout dental epithelial tissue, from the initiation of tooth bud formation to tooth maturation. However, mice lacking Fgf9 (Fgf9 −/− ) surprisingly show no obvious abnormalities in tooth development, suggesting potential compensation by other FGFs. Here we report findings from an Fgf9 S99N mutation mouse model, a loss-of-function mutation with a dominant negative effect. Our study reveals that Fgf9 is crucial for dental epithelial stem cell (DESC) survival and enamel formation. Methods To dissect the role of Fgf9 in tooth development, we performed the micro-CT, histomorphological analysis and gene expression assay in mice and embryos with S99N mutation. In addition, we assessed the effect of FGF9 on the DESC survival and dental epithelial differentiation by DESC sphere formation assay and tooth explant culture. Cell/tissue culture methods, gene expression analysis, specific inhibitors, and antibody blockage analysis were employed to explore how Fgf9 regulates enamel differentiation and DESC survival through both direct and indirect mechanisms. Results The Fgf9 S99N mutation in mice led to reduced ameloblasts, impaired enamel formation, and increased apoptosis in the cervical loop (CL). DESC sphere culture experiments revealed that FGF9 facilitated DESC survival via activating ERK/CREB signaling, without affecting cell proliferation. Furthermore, in vitro tissue culture experiments demonstrated that FGF9 promoted enamel formation in a manner dependent on the presence of mesenchyme. Interestingly, FGF9 stimulation inhibited enamel formation in isolated enamel epithelia and DESC spheres. Further investigation revealed that FGF9 supports DESC survival and promotes amelogenesis by stimulating the secretion of FGF3 and FGF10 in dental mesenchymal cells via the MAPK/ERK signaling pathway. Conclusions Our study demonstrates that Fgf9 is essential for DESC survival and enamel formation. Fgf9 performs as a dual-directional regulator of the dental enamel epithelium, not only inhibiting DESC differentiation into ameloblasts to preserve the stemness of DESC, but also promoting ameloblast differentiation through epithelial-mesenchymal interactions.

Abstract With the increasingly intense academic competition, the stressors faced by doctoral students are gradually escalating. Based on the Job Demands-Resources Model, this study proposed a moderated moderation to explore how hindrance research stressors affect doctoral students’ research creativity. Explicitly, the present study investigates whether the relationship between hindrance research stressors and research creativity is contingent on inclusive mentoring style and academic resilience. By analyzing the survey data from 538 valid questionnaire responses of doctoral students in China, this study has revealed that hindrance research stressors negatively relate to doctoral students’ research creativity, and inclusive mentoring style from academic supervisors can mitigate the negative impact of hindrance research stressors on the research creativity of doctoral students. Furthermore, academic resilience strengthens the moderating effect of inclusive mentoring style. Specifically, it buffers the negative impact of hindrance research stressors on research creativity among doctoral students who receive high inclusive mentoring, but not among those with low levels of inclusive mentoring. These findings emphasize that effective strategies to enhance the research creativity of doctoral students who encounter hindrance stressors may require the joint consideration of contextual and personal resources.

In order to investigate the potential risk of organic pollutants in coal mining water, the persistence, bioaccumulation and toxicity of known organic pollutants in coal mining water were systematically simulated and assessed by using EPI Suite and toxicolgical data, and the analytic hierarchy process (AHP) was used to establish an evaluation system for priority organic pollutants in coal mining water based on two primary indexes and seven secondary indicators of toxic and environmental effects. The results showed that: ① there were 13 persistent persistent substances, 8 bioaccumulative substances and 1 toxic substances among 54 organic pollutants, halgenated hydrocarbons have the strongest persistence, polycyclic aromatic hydrocarbons have the strongest bioaccumulation, and the general trend of reaction rate with hydroxyl radicals (OH•) is as follows: ether>esters>halgenated hydrocarbons; aliphatic>aromatic. (Short-chain halgenated) aliphatic compounds have no bioaccumulative substances, and the bioaccumulation of polycyclic aromatic hydrocarbons is generally high, moreover, there were 4 or more benzene rings in the molecular structure of the bioaccumulative ones, and the increase in the number of benzene rings would lead to the enhancement of the bioaccumulation of polycyclic aromatic hydrocarbons. Triphenyl phosphate is a significant toxic substance, which needs to be focused on during coal mining water treatment. ② The 20 organic pollutants with the higher comprehensive score were screened out as priority pollutants in coal mining water, among which dichloromethane, 1,2-dichloroethane, toluene, dibutyl phthalate, di(2-ethylhexyl) phthalate, naphthalene, benzo [a] pyrene, dibenzo [a, h] anthracene, benzo [b] fluoranthracene, benzo [k] fluoranthracene and benzo [a] anthracene have the characteristics of emerging contaminants, however, the level of organic pollutants detected in coal mining water is insufficient to pose risks to human health and ecolgical environment presently, but with the implementation of national policies and the increase in demand for high-quality treatment and utilization of coal mining water. The control of organic pollutants in coal mining water will become an realistic demand for the protection and utilization of regional water resources, and the potential risk assessment system of priority organic pollutants constructed in this study can be used to screen out priority pollutants in coal mining water, and provide a theoretical basis for the future control of organic pollutants.

Abstract In recent years, the prevalence and fatality rates of atherosclerotic cardiovascular disease have not only shown a consistent rise that cannot be ignored, but have also become a pressing social health problem that requires urgent attention. While interventional surgery and drug therapy offer significant therapeutic results, they often come with common side effects. Geniposide, an active component extracted from the Chinese medicine Gardenia jasminoides Ellis, shows promise in the management of cardiac conditions. This review comprehensively outlines the underlying pharmacological mechanisms by which geniposide exerts its effects on atherosclerosis. Geniposide exhibits a range of beneficial effects including alleviating inflammation, inhibiting the development of macrophage foam cells, improving lipid metabolism, and preventing platelet aggregation and thrombosis. It also demonstrates mitochondrial preservation, anti-apoptotic effects, and modulation of autophagy. Moreover, geniposide shows potential in improving oxidative stress and endoplasmic reticulum stress by maintaining the body’s antioxidant and oxidative balance. Additionally, this review comprehensively details the biological properties of geniposide, including methods of extraction and purification, as well as its pharmacokinetics and toxicological characteristics. It further discusses the clinical applications of related biopharmaceuticals, emphasizing the potential of geniposide in the prevention and treatment of atherosclerotic cardiovascular diseases. Furthermore, it highlights the limitations of current research, aiming to provide insights for future studies. Graphical Abstract

Abstract Glioblastoma (GBM) is the most common brain tumor and remains incurable. Primary GBM cultures are widely used tools for drug screening, but there is a lack of genomic and pharmacological characterization for these primary GBM cultures. Here, we collect 50 patient-derived glioma cell (PDGC) lines and characterize them by whole genome sequencing, RNA sequencing, and drug response screening. We identify three molecular subtypes among PDGCs: mesenchymal (MES), proneural (PN), and oxidative phosphorylation (OXPHOS). Drug response profiling reveals that PN subtype PDGCs are sensitive to tyrosine kinase inhibitors, whereas OXPHOS subtype PDGCs are sensitive to histone deacetylase inhibitors, oxidative phosphorylation inhibitors, and HMG-CoA reductase inhibitors. PN and OXPHOS subtype PDGCs stably form tumors in vivo upon intracranial transplantation into immunodeficient mice, whereas most MES subtype PDGCs fail to form tumors in vivo. In addition, PDGCs cultured by serum-free medium, especially long-passage PDGCs, carry MYC/MYCN amplification, which is rare in GBM patients. Our study provides a valuable resource for understanding primary glioma cell cultures and clinical translation and highlights the problems of serum-free PDGC culture systems that cannot be ignored.

Abstract Background Spinal muscular atrophy (SMA) is a progressive neurodegenerative disorder that can be treated with intrathecal nusinersen, an antisense oligonucleotide. In addition to efficacy, safety is a determining factor in the success of any therapy. Here, we aim to assess the safety of nusinersen therapy in paediatric patients with SMA. Methods Laboratory data of paediatric patients with SMA who received nusinersen between October 2019 and May 2022 were retrospectively analysed. Results During the observation period, 46 infants and children aged 2.9 months to 13.6 years received a total of 213 nusinersen doses without safety concerns. Inflammatory markers were stable throughout the study. International normalized ratio was increased by 0.09 per injection. Urea levels were increased by 0.108 mmol/L, and cystatin C decreased by 0.029 mg/L per injection. There were no significant changes in platelet count, activated partial thrombin time, creatinine levels or liver enzyme levels during treatment. The cerebrospinal fluid (CSF) leukocyte count remained stable, and total protein increased by 24.038 mg/L per injection. Conclusion Our data showed that nusinersen therapy is generally safe in children with SMA. Laboratory monitoring did not identify any persistent or significantly abnormal findings. CSF protein should be monitored to gain more insights.

Abstract Background Primary ciliary dyskinesia (PCD) is an autosomal recessive hereditary disease characterized by recurrent respiratory infections. In clinical manifestations, DNAH5 (NM_001361.3) is one of the recessive pathogenic genes. Primary familial brain calcification (PFBC) is a neurodegenerative disease characterized by bilateral calcification in the basal ganglia and other brain regions. PFBC can be inherited in an autosomal dominant or recessive manner. A family with PCD caused by a DNAH5 compound heterozygous variant and PFBC caused by a MYORG homozygous variant was analyzed. Methods In this study, we recruited three generations of Han families with primary ciliary dyskinesia combined with primary familial brain calcification. Their clinical phenotype data were collected, next-generation sequencing was performed to screen suspected pathogenic mutations in the proband and segregation analysis of families was carried out by Sanger sequencing. The mutant and wild-type plasmids were constructed and transfected into HEK293T cells instantaneously, and splicing patterns were detected by Minigene splicing assay. The structure and function of mutations were analyzed by bioinformatics analysis. Results The clinical phenotypes of the proband (II10) and his sister (II8) were bronchiectasis, recurrent pulmonary infection, multiple symmetric calcifications of bilateral globus pallidus and cerebellar dentate nucleus, paranasal sinusitis in the whole group, and electron microscopy of bronchial mucosa showed that the ciliary axoneme was defective. There was also total visceral inversion in II10 but not in II8. A novel splice variant C.13,338 + 5G > C and a frameshift variant C.4314delT (p. Asn1438lysfs *10) were found in the DNAH5 gene in proband (II10) and II8. c.347_348dupCTGGCCTTCCGC homozygous insertion variation was found in the MYORG of the proband. The two pathogenic genes were co-segregated in the family. Minigene showed that DNAH5 c.13,338 + 5G > C has two abnormal splicing modes: One is that part of the intron bases where the mutation site located is translated, resulting in early translation termination of DNAH5; The other is the mutation resulting in the deletion of exon76. Conclusions The newly identified DNAH5 splicing mutation c.13,338 + 5G > C is involved in the pathogenesis of PCD in the family, and forms a compound heterozygote with the pathogenic variant DNAH5 c.4314delT lead to the pathogenesis of PCD.

Abstract Microplastics (MPs) are defined as plastic particles smaller than 5 mm in size, and nanoplastics (NPs) are those MPs with a particle size of less than 1000 nm or 100 nm. The prevalence of MPs in the environment and human tissues has raised concerns about their potential negative effects on human health. Macrophages are the major defence against foreign substances in the intestine, and can be polarized into two types: the M1 phenotype and the M2 phenotype. However, the effect of NPs on the polarization of macrophages remains unclear. Herein, we selected polystyrene, one of the most plastics in the environment and controlled the particle sizes at 50 nm and 500 nm respectively to study the effects on the polarization of macrophages. We used mouse RAW264.7 cell line models in this macrophage-associated study. Experiments on cell absorption showed that macrophages could quickly ingest polystyrene nanoplastics of both diameters with time-dependent uptake. Compared to the untreated group and 10 μg/mL treatment group, macrophages exposed to 50 μg/mL groups (50 nm and 500 nm) had considerably higher levels of CD86, iNOS, and TNF-α, but decreased levels of aCD206, IL-10, and Arg-1. According to these findings, macrophage M1 and M2 polarization can both be induced and inhibited by 50 μg/mL 50 nm and 500 nm polystyrene nanoplastics. This work provided the first evidence of a possible MPs mode of action with appropriate concentration and size through the production of polarized M1, providing dietary and environmental recommendations for people, particularly those with autoimmune and autoinflammatory illnesses.

Abstract Background The combination of immune checkpoint inhibitors with radiotherapy can enhance the immunomodulation by RT and reduce the growth of distant unirradiated tumors (abscopal effect); however, the results are still not very satisfactory. Therefore, new treatment options are needed to enhance this effect. Our previous study showed that the combination of Bifidobacterium (Bi) and its specific monoclonal antibody (mAb) could target and alleviate hypoxia at the tumor site and act as a radiosensitizer. In this study, we explored the anti-tumor efficacy of quadruple therapy (Bi + mAb and RT + αPD-1). The current study also aimed to probe into the complex immune mechanisms underlying this phenomenon. Methods Constructed 4T1 breast and CT26 colon cancer tumor models. A comprehensive picture of the impact of constructed quadruple therapy was provided by tumor volume measurements, survival analysis, PET/CT imaging, immune cell infiltration analysis and cytokine expression levels. Results The abscopal effect was further amplified in the “cold” tumor model and prolonged survival in tumor-bearing mice. Bi can colonized in primary and secondary tumors and direct the mAb to reach the tumor site, activate complement, enhance the ADCC effect and initiate the innate immune response. Then combined with αPD-1 and radiotherapy to stimulate adaptive immune response and synergize with cytokines to expand the immune efficacy and generate effective anti-tumor immune response. Conclusions Bi was used as an artificially implanted anaerobic target to cause a transient “infection” at the tumor, causing the tumor to become locally inflamed and “hot”, and at the same time, mAb was used to target Bi to enhance the local immune effect of the tumor, and then combined with radiotherapy and αPD-1 to amplify the abscopal effect in multiple dimensions. Therefore, the present study provided a new idea for the multipotent immune-activating function of antibody-targeted anaerobic bacteria for the RT treatment of extensively metastasized cancer patients.

Abstract An increased risk of target organ damage (TOD) has been reported in patients with primary aldosteronism (PA). However, there is relatively little related research on the correlation between the degree of TOD and those with and without PA in newly diagnosed hypertensive patients. The aim of this study was to assess the association between PA and TOD among patients with newly diagnosed hypertension. Newly diagnosed hypertensive patients were consecutively recruited from January 2015 to June 2020 at the University of Hong Kong‐Shenzhen Hospital. Patients were stratified into those with and without PA. Data for left ventricular mass index (LVMI), carotid intima‐media thickness (CIMT) and plaque, and microalbuminuria were systematically collected. A total of 1044 patients with newly diagnosed hypertension were recruited, 57 (5.5%) of whom were diagnosed with PA. Patients with PA had lower blood pressure, serum lipids, body mass index, and plasma renin activity and a higher incidence of hypokalemia than those without PA. In contrast, the prevalence of left ventricular hypertrophy, increased CIMT, and microalbuminuria was higher in patients with PA than in those without PA. Multivariable regression analysis demonstrated that PA was independently associated with increased LVMI, CIMT and microalbuminuria. Among patients with newly diagnosed hypertension, those with PA had more severe TOD, including a higher LVMI, CIMT and microalbuminuria, than those without PA. These findings emphasize the need for screening TOD in newly diagnosed hypertension due to underlying PA.

The second-to-fourth digit (2D:4D) ratio is thought to be associated with prenatal androgen exposure. However, the relationship between the 2D:4D ratio and hypospadias is poorly understood, and its molecular mechanism is not clear. In this study, by analyzing the hand digit length of 142 boys with hypospadias (23 distal, 68 middle, and 51 proximal) and 196 controls enrolled in Shanghai Children’s Hospital (Shanghai, China) from December 2020 to December 2021, we found that the 2D:4D ratio was significantly increased in boys with hypospadias (P < 0.001) and it was positively correlated with the severity of the hypospadias. This was further verified by the comparison of control mice and prenatal low testosterone mice model obtained by knocking out the risk gene (dynein axonemal heavy chain 8 [DNAH8]) associated with hypospadias. Furthermore, the discrepancy was mainly caused by a shift in 4D. Proteomic characterization of a mouse model validated that low testosterone levels during pregnancy can impair the growth and development of 4D. Comprehensive mechanistic explorations revealed that during the androgen-sensitive window, the downregulation of the androgen receptor (AR) caused by low testosterone levels, as well as the suppressed expression of chondrocyte proliferation-related genes such as Wnt family member 5a (Wnt5a), Wnt5b, Smad family member 2 (Smad2), and Smad3; mitochondrial function-related genes in cartilage such as AMP-activated protein kinase (AMPK) and nuclear respiratory factor 1 (Nrf-1); and vascular development-related genes such as myosin light chain (MLC), notch receptor 3 (Notch3), and sphingosine kinase 1 (Sphk1), are responsible for the limitation of 4D growth, which results in a higher 2D:4D ratio in boys with hypospadias via decreased endochondral ossification. This study indicates that the ratio of 2D:4D is a risk marker of hypospadias and provides a potential molecular mechanism.

Abstract Background The alteration of the immune microenvironment in the axillary metastatic lymph nodes of luminal A breast cancer patients is still unclear. Methods Postsurgical tissues from the enrolled luminal A BCs were divided into five categories: primary BC lesion at stage N0 (PL1), primary BC lesion at stage N1 (PL2), negative axillary lymph node at stage N0 BC (LN1), negative axillary lymph node at stage N1 BC (LN2), and positive axillary lymph node at stage N1 BC (LN3). The frequencies of positive immune markers (CD4, CD8, PD1, PD-L1, T-cell immunoglobulin and mucin domain 3 (TIM3), and forkhead box protein 3 (Foxp3)) in the above tissues were quantified by AKOYA Opal Polaris 7 Color Manual IHC Detection Kit. Results A total of 50 female patients with luminal A BC were enrolled in this study. Among these patients, 23 had stage N1 disease, and 27 had stage N0 disease. Compared with that in the PL2 subgroup, the frequency of PD-1-positive cells was significantly greater in the PL1 subgroup, whether at the stromal or intratumoral level (P value

Abstract Background Pretransplant type 2 diabetes mellitus (T2DM) is associated with increased cardiovascular and all-cause mortality after heart transplant (HT), but the underlying causes of this association remain unclear. The purpose of this research was to examine the impact of T2DM on left ventricular (LV) myocardial deformation and myocardial perfusion following heart transplantation using cardiovascular magnetic resonance imaging. Methods We investigated thirty-one HT recipients with pretransplant T2DM [HT(DM+)], thirty-four HT recipients without pretransplant T2DM [HT(DM−)] and thirty-six controls. LV myocardial strains, including the global longitudinal, radial, and circumferential strain (GLS, GRS and GCS, respectively), were calculated and compared among groups, as were resting myocardial perfusion indices, which included time to peak myocardial signal intensity (TTM), maximum signal intensity (MaxSI), and Upslope. The relationships between LV strain parameters or perfusion indices and biochemical indicators were determined through Spearman’s analysis. The impact of T2DM on LV strains in HT recipients was assessed using multivariable linear regression analyses with backward stepwise selection. Results In the HT(DM+) group, the LV GLS, GRS, and GCS exhibited significantly lower magnitudes than those in both the HT(DM−) and control groups. TTM was higher in the HT(DM+) group than in both the HT(DM−) and control groups, while no significant differences were observed among the groups regarding Upslope and MaxSI. There was a negative correlation between glycated hemoglobin and the magnitude of strains (longitudinal, r = − 0.399; radial, r = − 0.362; circumferential, r = − 0.389) (all P

Abstract The development of Type I photosensitizers (PSs) is of great importance due to the inherent hypoxic intolerance of photodynamic therapy (PDT) in the hypoxic microenvironment. Compared to Type II PSs, Type I PSs are less reported due to the absence of a general molecular design strategy. Herein, we report that the combination of typical Type II PS and natural substrate carvacrol (CA) can significantly facilitate the Type I pathway to efficiently generate superoxide radical (O2 –•). Detailed mechanism study suggests that CA is activated into thymoquinone (TQ) by local singlet oxygen generated from the PS upon light irradiation. With TQ as an efficient electron transfer mediator, it promotes the conversion of O2 to O2 –• by PS via electron transfer-based Type I pathway. Notably, three classical Type II PSs are employed to demonstrate the universality of the proposed approach. The Type I PDT against S. aureus has been demonstrated under hypoxic conditions in vitro. Furthermore, this coupled photodynamic agent exhibits significant bactericidal activity with an antibacterial rate of 99.6% for the bacterial-infection female mice in the in vivo experiments. Here, we show a simple, effective, and universal method to endow traditional Type II PSs with hypoxic tolerance.

Abstract Gamma delta (γδ) T cells demonstrate strong cytotoxicity against diverse cancer cell types in an MHC-independent manner, rendering them promising contenders for cancer therapy. Although amplification and adoptive transfer of γδ T cells are being evaluated in the clinic, their therapeutic efficacy remains unsatisfactory, primarily due to the influence of the immunosuppressive tumor microenvironment (TME). Currently, the utilization of targeted therapeutic antibodies against inhibitory immune checkpoint (ICP) molecules is a viable approach to counteract the immunosuppressive consequences of the TME. Notably, PD-1/PD-L1 checkpoint inhibitors are considered primary treatment options for diverse malignancies, with the objective of preserving the response of αβ T cells. However, γδ T cells also infiltrate various human cancers and are important participants in cancer immunity, thereby influencing patient prognosis. Hence, it is imperative to comprehend the reciprocal impact of the PD-1/PD-L1 axis on γδ T cells. This understanding can serve as a therapeutic foundation for improving γδ T cells adoptive transfer therapy and may offer a novel avenue for future combined immunotherapeutic approaches.

Abstract Background Gastric cancer is the fifth most common cancer type. Most patients are diagnosed at advanced stages with poor prognosis. A non-invasive assay for the detection of early-stage gastric cancer is highly desirable for reducing associated mortality. Methods We collected a prospective study cohort of 110 stage I–II gastric cancer patients and 139 non-cancer individuals. We performed whole-genome sequencing with plasma samples and profiled four types of cell-free DNA (cfDNA) characteristics, fragment size pattern, copy number variation, nucleosome coverage pattern, and single nucleotide substitution. With these differential profiles, we developed an ensemble model to detect gastric cancer signals. Further, we validated the assay in an in-house first validation cohort of 73 gastric cancer patients and 94 non-cancer individuals and an independent second validation cohort of 47 gastric cancer patients and 49 non-cancer individuals. Additionally, we evaluated the assay in a hypothetical 100,000 screening population by Monte Carlo simulation. Results Our cfDNA-based assay could distinguish early-stage gastric cancer from non-cancer at an AUROC of 0.962 (95% CI: 0.942–0.982) in the study cohort, 0.972 (95% CI: 0.953–0.992) in the first validation cohort and 0.937 (95% CI: 0.890–0.983) in the second validation cohort. The model reached a specificity of 92.1% (128/139) and a sensitivity of 88.2% (97/110) in the study cohort. In the first validation cohort, 91.5% (86/94) of non-cancer individuals and 91.8% (67/73) of gastric cancer patients were correctly identified. In the second validation cohort, 89.8% (44/49) of non-cancer individuals and 87.2% (41/47) of gastric cancer patients were accurately classified. Conclusions We introduced a liquid biopsy assay using multiple dimensions of cfDNA characteristics that could accurately identify early-stage gastric cancer from non-cancerous conditions. As a cost-effective non-invasive approach, it may provide population-wide benefits for the early detection of gastric cancer. Trial registration This study was registered on ClinicalTrials.gov under the identifier NCT05269056 on March 7, 2022.

Abstract Percutaneous coronary intervention (PCI) addresses myocardial ischaemia, but a significant subset of patients encounter major adverse cardiovascular events (MACE) post‐treatment. This meta‐analysis investigated the relationship between the post‐PCI triglyceride‐glucose (TyG) index and MACE. Comprehensive searches of the Embase, PubMed, Cochrane Library, and Web of Science databases were conducted up to 3 March 2023, using relevant keywords. The effect size was determined based on I2 statistic using random‐effects models. Cluster‐robust standard errors crafted the dose–response curve, and the GRADE Evaluation Scale was employed to rate the quality of evidence. The group with the highest TyG index had significantly higher post‐PCI MACE rates than the lowest index group, with hazard ratios (HRs) of 2.04 (95% CI 1.65–2.52; I2 = 77%). Each unit increase in TyG index corresponded to HRs of 1.82 for MACE (95% CI 1.34–2.46; I2 = 92%), 2.57 for non‐fatal MI (95% CI 1.49–4.41; I2 = 63%), and 2.06 for revascularization (95% CI 1.23–3.50; I2 = 90%). A linear relationship between TyG index and MACE risk was established (R2 = 0.6114). For all‐cause mortality, the HR was 1.93 (95% CI 1.35–2.75; I2 = 50%), indicating a higher mortality risk with elevated TyG index. The GRADE assessment yielded high certainty for non‐fatal MI but low certainty for all‐cause mortality, revascularization, and MACE. The TyG index may predict risks of post‐PCI MACE, all‐cause mortality, non‐fatal MI, and revascularization, with varied levels of certainty. A potential linear association between the TyG index and MACE post‐PCI was identified. Future research should validate these findings.

Zero-dimensional heterometallic halide hybrids have emerged as multifunctional emitters, due to their multiple emission features. Herein, high pressure is employed to regulate the multiple emissions of (C9NH20)9[Pb3Br11](MnBr4)2. Pressure-triggered rigidness of [Pb3Br11]5- alters the emission equilibrium of STEs, generating a new blue-shifted STE emission. Meanwhile, [MnBr4]2- contraction promotes the confinement effect to increase the 4D-6A1 transition efficiency. Notably, [Pb3Br11]5- could act as ‘antenna' to enhance the Mn2+ emission with blocked back-energy transfer. It indicates that enough incident energy could excite the STE emission and 4D-6A1 transitions simultaneously, which clarifies the conventional understanding of the emission origin at ambient conditions.

We report a new land snail species representing a new genus from the mountainous area of Zhejiang, China. The snail has a depressed shell with granules all over the surface. The soft part of the new taxon is characterized by the presence of a mantle lobe whose form is reviewed herein across a wide range of helicoid snails, the presence of a developed epiphallic papilla, and the absence of a penial sheath, a dart sac apparatus and a flagellum. As indicated by a molecular-based phylogeny (16S + ITS2), the new taxon is deeply nested in the eastern Asian camaenid genera and shows a close relationship with the camaenids distributed in Central China.

Abstract Only a minority of cancer patients benefit from immune checkpoint blockade therapy. Sophisticated cross-talk among different immune checkpoint pathways as well as interaction pattern of immune checkpoint molecules carried on circulating small extracellular vesicles (sEV) might contribute to the low response rate. Here we demonstrate that PD-1 and CD80 carried on immunocyte-derived sEVs (I-sEV) induce an adaptive redistribution of PD-L1 in tumour cells. The resulting decreased cell membrane PD-L1 expression and increased sEV PD-L1 secretion into the circulation contribute to systemic immunosuppression. PD-1/CD80+ I-sEVs also induce downregulation of adhesion- and antigen presentation-related molecules on tumour cells and impaired immune cell infiltration, thereby converting tumours to an immunologically cold phenotype. Moreover, synchronous analysis of multiple checkpoint molecules, including PD-1, CD80 and PD-L1, on circulating sEVs distinguishes clinical responders from those patients who poorly respond to anti-PD-1 treatment. Altogether, our study shows that sEVs carry multiple inhibitory immune checkpoints proteins, which form a potentially targetable adaptive loop to suppress antitumour immunity.

Abstract Objective This study aimed to conduct a comprehensive analysis, evaluating the prognostic significance of the baseline Advanced Lung Cancer Inflammation Index (ALI) and Gustave Roussy Immune (GRIm) Score in patients undergoing immune checkpoint inhibitor (ICI) therapy. Methods A comprehensive search was performed across various databases, including PubMed, the Cochrane Library, EMBASE, and Google Scholar, until October 21, 2023, to compile relevant articles for analysis. The investigation encompassed diverse clinical outcomes, including overall survival (OS) and progression-free survival (PFS). Results This analysis included a total of 15 articles, comprising 19 studies involving 3335 patients. Among the 19 studies, nine studies focused on NSCLC, and six studies were conducted on HCC. Pooled results revealed that patients with elevated ALI levels experienced prolonged OS (HR: 0.51, 95% CI: 0.37–0.70, p 1 was associated with reduced OS (HR: 2.07, 95% CI: 1.47–2.92, p 2 showed a substantially decreased risk of mortality compared to individuals with HCC-GRIm score ≤ 2 (HR: 2.63, 95% CI: 1.89–3.65, p

Abstract Pancreatic ductal adenocarcinoma (PDAC) develops through step-wise genetic and molecular alterations including Kras mutation and inactivation of various apoptotic pathways. Here, we find that development of apoptotic resistance and metastasis of Kras G12D -driven PDAC in mice is accelerated by deleting Plk3, explaining the often-reduced Plk3 expression in human PDAC. Importantly, a 41-kDa Plk3 (p41Plk3) that contains the entire kinase domain at the N-terminus (1-353 aa) is activated by scission of the precursor p72Plk3 at Arg354 by metalloendopeptidase nardilysin (NRDC), and the resulting p32Plk3 C-terminal Polo-box domain (PBD) is removed by proteasome degradation, preventing the inhibition of p41Plk3 by PBD. We find that p41Plk3 is the activated form of Plk3 that regulates a feed-forward mechanism to promote apoptosis and suppress PDAC and metastasis. p41Plk3 phosphorylates c-Fos on Thr164, which in turn induces expression of Plk3 and pro-apoptotic genes. These findings uncover an NRDC-regulated post-translational mechanism that activates Plk3, establishing a prototypic regulation by scission mechanism.

Abstract Background Early water intake has gained widespread attention considering enhanced recovery after surgery (ERAS). In the present systematic evaluation and meta-analysis, we assessed the effects of early water intake on the incidence of vomiting and aspiration in adult patients who received general anaesthesia on regaining consciousness during the resuscitation period. Objective To systematically analyse the results of randomised controlled trials on early postoperative water intake in patients who underwent different types of surgery under general anaesthesia, both at home and abroad, to further explore the safety and application of early water intake and provide an evidence-based foundation for clinical application. Design Systematic review and meta-analysis. Methods To perform the systematic evaluation and meta-analysis, we searched the Web of Science, CINAHL, Embase, PubMed, Cochrane Library, Sinomed, China National Knowledge Infrastructure (CNKI), Wanfang, and Vipshop databases to identify randomised controlled trial studies on early water intake in adult patients who received general anaesthesia. Results Herein, we included 10 publications with a total sample size of 5131 patients. Based on statistical analysis, there was no statistically significant difference in the incidence of vomiting (odds ratio [OR] = 0.81; 95% confidence interval [CI] [0.58–1.12]; p = 0.20; I-squared [I2] = 0%) and aspiration (OR = 0.78; 95%CI [0.45–1.37]; p = 0.40; I2 = 0%) between the two groups of patients on regaining consciousness post-general anaesthesia. Conclusion Based on the available evidence, early water intake after regaining consciousness post-anaesthesia did not increase the incidence of adverse complications when compared with traditional postoperative water abstinence. Early water intake could effectively improve patient thirst and facilitate the recovery of gastrointestinal function.

Abstract Hypomyelinating leukodystrophy (HLD) is a rare genetic heterogeneous disease that can affect myelin development in the central nervous system. This study aims to analyze the clinical phenotype and genetic function of a family with HLD-7 caused by POLR3A mutation. The proband (IV6) in this family mainly showed progressive cognitive decline, dentin dysplasia, and hypogonadotropic hypogonadism. Her three old brothers (IV1, IV2, and IV4) also had different degrees of ataxia, dystonia, or dysarthria besides the aforementioned manifestations. Their brain magnetic resonance imaging showed bilateral periventricular white matter atrophy, brain atrophy, and corpus callosum atrophy and thinning. The proband and her two living brothers (IV2 and IV4) were detected to carry a homozygous mutation of the POLR3A (NM_007055.4) gene c. 2300G > T (p.Cys767Phe), and her consanguineous married parents (III1 and III2) were p.Cys767Phe heterozygous carriers. In the constructed POLR3A wild-type and p.Cys767Phe mutant cells, it was seen that overexpression of wild-type POLR3A protein significantly enhanced Pol III transcription of 5S rRNA and tRNA Leu-CAA. However, although the mutant POLR3A protein overexpression was increased compared to the wild-type protein overexpression, it did not show the expected further enhancement of Pol III function. On the contrary, Pol III transcription function was frustrated (POLR3A, BC200, and tRNA Leu-CAA expression decreased), and MBP and 18S rRNA expressions were decreased. This study indicates that the POLR3A p.Cys767Phe variant caused increased expression of mutated POLR3A protein and abnormal expression of Pol III transcripts, and the mutant POLR3A protein function was abnormal.

Tumor hypoxia diminishes the effectiveness of traditional type II photodynamic therapy (PDT) due to oxygen consumption. Type I PDT, which can operate independently of oxygen, is a viable option for treating hypoxic tumors. In this study, we have designed and synthesized JSK@PEG-IR820 NPs that are responsive to the tumor microenvironment (TME) to enhance type I PDT through glutathione (GSH) depletion. Our approach aims to expand the sources of therapeutic benefits by promoting the generation of superoxide radicals (O2−.) while minimizing their consumption. The diisopropyl group within PEG-IR820 serves a dual purpose: it functions as a pH sensor for the disassembly of the NPs to release JSK and enhances intermolecular electron transfer to IR820, facilitating efficient O2−. generation. Simultaneously, the release of JSK leads to GSH depletion, resulting in the generation of nitric oxide (NO). This, in turn, contributes to the formation of highly cytotoxic peroxynitrite (ONOO−.), thereby enhancing the therapeutic efficacy of these NPs. NIR-II fluorescence imaging guided therapy has achieved successful tumor eradication with the assistance of laser therapy.

Background Diagnosis of the cause of cerebral thrombi is vital for recurrence prevention but also challenging. The presence of the microbiome has recently been confirmed in thrombus, suggesting a novel approach to distinguish cerebral thrombi of different origins. However, little is known about whether there is heterogeneity in microbiological colonization of cerebral thrombi of different sources. Methods and Results Forty patients experiencing acute ischemic stroke were included and clinical data were collected. Metagenomic next‐generation sequencing was adopted to detect bacterial and genomic signatures of human cerebral thrombi samples. We found similar species diversity between the large‐artery atherosclerosis thrombi and cardioembolic thrombi but different species composition and distribution of cerebral thrombus microbiota. Compared with the group with cardioembolism, the group with large‐artery atherosclerosis showed a significantly higher relative abundance of Ralstonia insidiosa among the top 10 bacterial species in cerebral thrombi. Twenty operational taxonomy units were correlated with 11 clinical indicators of ischemic stroke. The Gene Ontology enrichment analysis revealed 9 different enriched biological processes (translation and carbohydrate metabolic process, etc). The enriched Kyoto Encyclopedia of Genes and Genomes pathways included ribosome, butanoate metabolism, and sulfur metabolism. Conclusions This study, based on the approach of metagenomic next‐generation sequencing, provides a diagnostic microbiological method to discriminate individuals with cardioembolic thrombi from those with large‐artery atherosclerosis thrombi with human cerebral thrombi samples. Our findings provide a fresh perspective on microbial heterogeneity of cerebral thrombi and demonstrate biological processes and pathway features of cerebral thrombi.

BackgroundThe Nottingham prognostic index (NPI) has been shown to negatively impact survival in breast cancer (BC). However, its ability to predict the locoregional recurrence (LRR) of BC remains still unclear. This study aims to determine whether a higher NPI serves as a significant predictor of LRR in BC.MethodsIn total, 238 patients with BC were included in this analysis, and relevant clinicopathological features were collected. Correlation analysis was performed between NPI scores and clinicopathological characteristics. The optimal nomogram model was determined by Akaike information criterion. The accuracy of the model’s predictions was evaluated using receiver operating characteristic curves (ROC curves), calibration curves and goodness of fit tests. The clinical application value was assessed through decision curve analysis.ResultsSix significant variables were identified, including age, body mass index (BMI), TNM stage, NPI, vascular invasion, perineural invasion (P

BackgroundCNV in KCTD13 has been identified to influence androgen receptor function via its changes in gene dosage, which might contribute to hypospadias. However, there is lack of population-level evidence to assess the contribution of KCTD13 CNV to hypospadias.Methods349 isolated hypospadias patients were recruited and their genotyping was performed using real-time qPCR. We use Database of Genomic Variants (DGV) and CNV calls from SNP-array intensity data in 1,008 Chinese healthy men as reference.Results11.17% of patients were identified to have KCTD13 CNV deletion, significantly higher than 0.05% in DGV (P 0.05).ConclusionsWe demonstrate KCTD13 CNV deletion is strongly associated with hypospadias and its severity, but duplication is not, characterizing KCTD13 genetic variation in more detail than previously described.

ObjectiveTo develop a machine learning-based nomogram for distinguishing between supratentorial extraventricular ependymoma (STEE) and supratentorial glioblastoma (GBM).MethodsWe conducted a retrospective analysis on MRI datasets obtained from 140 patients who were diagnosed with STEE (n=48) and GBM (n=92) from two institutions. Initially, we compared seven different machine learning algorithms to determine the most suitable signature (rad-score). Subsequently, univariate and multivariate logistic regression analyses were performed to identify significant clinical predictors that can differentiate between STEE and GBM. Finally, we developed a nomogram by visualizing the rad-score and clinical features for clinical evaluation.ResultsThe TreeBagger (TB) outperformed the other six algorithms, yielding the best diagnostic efficacy in differentiating STEE from GBM, with area under the curve (AUC) values of 0.735 (95% CI: 0.625-0.845) and 0.796 (95% CI: 0.644-0.949) in the training set and test set. Furthermore, the nomogram incorporating both the rad-score and clinical variables demonstrated a robust predictive performance with an accuracy of 0.787 in the training set and 0.832 in the test set.ConclusionThe nomogram could serve as a valuable tool for non-invasively discriminating between STEE and GBM.

Cleft palate presents multifaceted challenges impacting speech, hearing, appearance, and cognition, significantly affecting patients’ quality of life (QoL). While surgical advancements aim to restore function and improve appearance, traditional clinical measures often fail to comprehensively capture patients’ experiences. Patient-reported outcomes measure (PROMs) have emerged as crucial tools in evaluating QoL, offering insights into various aspects such as esthetic results, speech function, and social integration. This review explores PROMs relevant to cleft palate complications, including velopharyngeal insufficiency, oronasal fistulas, maxillary hypoplasia, sleep-disordered breathing, and caregiver QoL. Additionally, the review highlights the need for cleft palate-specific scales to better address the unique challenges faced by patients. By incorporating PROMs, healthcare providers can achieve more personalized, patient-centered care, improve communication, and enhance treatment outcomes. Future research should focus on developing and validating specialized PROMs to further refine patient assessments and care strategies.

This study was designed to examine the protective effects of extract of Astragalus membranaceus (EAM) against stress, which induced by high stocking density, Cu and trichlorfon exposure in Jian carp (Cyprinus carpio var. Jian). The husbandry period (23.0 ± 1 °C) for high stocking density (0.97 fish/L) was 60 days with the initial fish weight 7.2 ± 0.2 g, and Cu (0.7 mg/L) and trichlorfon (2.2 mg/L) exposure was 4 days after feeding trial (30 days) with the initial fish weight 10.5 ± 0.3 g. Stress of high stocking density and Cu exposure decrease 48.2 % of fish weight gain and reduced 97.6 % of feed intake. Meanwhile, trichlorfon exposure induced 100 % fish rollover. High stocking densities and Cu exposure decreased activities of amylase, trypsin, as well as Na+/K+-ATPase and alkaline phosphatase and increased malonaldehyde content in fish digestive organs (P < 0.05), indicating an interruption of digestive ability and antioxidant status. Furthermore, trichlorfon exposure decreased activities of lactate dehydrogenase, superoxide dismutase, catalase, glutamate-oxaloacetate transaminase and glutamate-pyruvate transaminase in fish muscles (P < 0.05), indicating an interruption on bioenergetic homeostasis and antioxidant status. Dietary EAM supplementation relieved these detrimental effect, which induced by high stocking density, Cu and trichlorfon exposure. The optimum dietary EAM supplementation were 5.23, 4.79 and 5.12 g kg/diet for Jian carp under high stocking densities, Cu and trichlorfon exposure, respectively. Our study indicates that dietary EAM supplementation offers a feasible way for relieving the stress which induced by inappropriate high stocking densities, Cu, as well as trichlorfon.

BackgroundAlport syndrome (AS) is a common cause of end-stage renal disease (ESRD) with various clinical symptoms and incomplete manifestation. Patients with AS and other renal disorders are often misdiagnosed. This study reported three X-linked dominant Alport syndrome (XLAS) pedigrees with nephrotic syndrome (NS) as the predominant phenotype and analyzed COL4A5 gene alterations.MethodsThree Han Chinese XLAS pedigrees were recruited, and clinical phenotypes were obtained. The pre-certified individuals’ peripheral blood DNA was taken, and whole-genome next-generation sequencing (NGS) was performed for candidate genes and mutation screening, followed by NGS or Sanger sequencing of suspected mutant types in participating family members.ResultsBoth probands A and B were diagnosed with NS through biochemical tests, and X-linked Alport syndrome-associated renal injury was diagnosed by renal biopsy. The biopsy revealed focal foamy cells in the renal interstitium, tearing and delamination changes in the glomerular basement membrane, and negative α3 and α5 chains of type IV collagen. Proband C, who was earlier diagnosed with NS, has now advanced to ESRD, along with his mother and proband A’s mother. Genetic sequencing of all three pedigrees identified three mutations, namely, c.5020C>T, c.4435_4445del, and c.1584_1587+6del in the X-linked dominant gene COL4A5 (NM_000495.5). These mutations lead to the production of shortened proteins, potentially impacting the function of COL4A5 and causing pathogenic effects.ConclusionThe novel c.4435_4445del and c.1584_1587+6del mutations not only enrich the spectrum of mutations in the COL4A5 gene but also indicate that carriers of both mutation sites and those with mutation c.5020C>T may present NS as their primary clinical manifestation.

Power-to-gas (P2G) facilities use surplus electricity to convert to natural gas in integrated energy systems (IES), increasing the capacity of wind power to be consumed. However, the capacity limitation of P2G and the anti-peaking characteristic of wind power make the wind abandonment problem still exist. Meanwhile, the oxygen generated by P2G electrolysis is not fully utilized. Therefore, this study proposes a low-carbon economic dispatch model considering the utilization of hydrogen and oxygen energy. First, the two-stage reaction model of P2G is established, and the energy utilization paths of hydrogen blending and oxygen-rich deep peaking are proposed. Specifically, hydrogen energy is blended into the gas grid to supply gas-fired units, and oxygen assists oxygen-rich units into deep peaking. Subsequently, the stochastic optimization is used to deal with the uncertainty of the system, and the objective function and constraints of the IES are given to establish a low-carbon dispatch model under the energy utilization model. Finally, the effectiveness of the proposed method is verified based on the modified IEEE 39-node electric network, 20-node gas network and 6-node heat network models.

Abstract The Yunnan‐Guizhou Plateau (YGP) is characterized by the distinctive isolated habitat of the limestone Karst Islands and features the Wumeng Mountains, which divide the YGP into the two Plateaus of Yunnan and Guizhou. This study aimed to assess the effects of geographic isolation and past climate fluctuation on the distribution of flora in the YGP. To achieve this, we carried out the phylogeographical pattern and genetic structure based on chloroplast and nuclear ribosomal DNA sequence in relation to past (Last Glacial Maximum) and present distributions based on ecological niche modeling for Morella nana, an important wild plant resource and endemic to the YGP once considered a vulnerable species. The results suggest that the genetic and chlorotype network structures of M. nana are divided into at least two groups: cpDNA chlorotype H2 (or dominant nrDNA haplotypes h1 and h2), distributed primarily to the east of the Wumeng Mountains, and cpDNA chlorotypes H1 and H3–H10 (or dominant nrDNA haplotype h2 and h3), distributed to the west of the Wumeng Mountains. A deep genetic split was noted within the two groups to reach 25 steps, especially for the cpDNA fragment variation. This east–west divergence reveals the existence of a natural geographical isolation boundary in the form of the Wumeng Mountains, and supports the existence of at least two glacial refuges during the Quaternary glacial period, along with two genetic diversity center, and at least two large geographic protection units for the important species of M. nana. This study indicates that the phylogeographical pattern of M. nana can be attributed to geographic/environmental isolation caused by the Wumeng Mountains and climate fluctuation during the last glacial maximum, and proposes an effective strategy to protecting this important plant resource.

IntroductionOlder adults commonly face the risk of social isolation, which poses a significant threat to their quality of life. This study explores the association between social participation and life satisfaction among older Chinese adults.MethodsData were sourced from the 2018 China Health and Retirement Longitudinal Study. Regression analysis and mediation analysis were employed to examine the relationship between social participation and life satisfaction, with a focus on the roles of loneliness and self-rated health.ResultsThe results indicate that social participation is significantly positively associated with older adults' life satisfaction. Furthermore, the positive association is more pronounced with increased diversity in social activities. Mediation analysis reveals that reductions in feelings of loneliness and improvements in health levels mediate the relationship between social participation and life satisfaction. Further analysis showed that social participation had a greater positive association among rural older adults and those lacking family companionship.DiscussionThis study provides evidence for enhancing life satisfaction among older adults and highlights the importance of diversity in social participation.

ObjectiveThe purpose of this study is to investigate potential associations between osteopenia, osteosarcopenia, and postoperative outcomes in patients with hepatobiliary-pancreatic cancer (HBPC).MethodsThree online databases, including Embase, PubMed, and the Cochrane Library, were thoroughly searched for literature describing the relationship between osteopenia, osteosarcopenia, and outcomes of surgical treatment of HBPC patients from the start of each database to September 29, 2023. The Newcastle-Ottawa Scale was used to rate the quality of the studies.ResultsThis analysis included a total of 16 articles with a combined patient cohort of 2,599 individuals. The results demonstrated that HBPC patients with osteopenia had significantly inferior OS (HR: 2.27, 95% CI: 1.70-3.03, p < 0.001) and RFS (HR: 1.96, 95% CI: 1.42-2.71, p < 0.001) compared to those without osteopenia. Subgroup analysis demonstrated that these findings were consistent across univariate and multivariate analyses, as well as hepatocellular carcinoma, biliary tract cancer, and pancreatic cancer. The risk of postoperative major complications was significantly higher in patients with osteopenia compared to those without osteopenia (OR: 1.66, 95% CI: 1.19-2.33, p < 0.001). Besides, we also found that the presence of osteosarcopenia in HBPC patients was significantly related to poorer OS (HR: 3.31, 95% CI: 2.00-5.48, p < 0.001) and PFS (HR: 2.50, 95% CI: 1.62-3.84, p < 0.001) in comparison to those without osteosarcopenia.ConclusionPreoperative osteopenia and osteosarcopenia can predict poorer OS and RFS with HBPC after surgery.

Abstract Liquid–liquid phase separation (LLPS), an emerging biophysical phenomenon, can sequester molecules to implement physiological and pathological functions. LLPS implements the assembly of numerous membraneless chambers, including stress granules and P‐bodies, containing RNA and protein. RNA–RNA and RNA–protein interactions play a critical role in LLPS. Scaffolding proteins, through multivalent interactions and external factors, support protein–RNA interaction networks to form condensates involved in a variety of diseases, particularly neurodegenerative diseases and cancer. Modulating LLPS phenomenon in multiple pathogenic proteins for the treatment of neurodegenerative diseases and cancer could present a promising direction, though recent advances in this area are limited. Here, we summarize in detail the complexity of LLPS in constructing signaling pathways and highlight the role of LLPS in neurodegenerative diseases and cancers. We also explore RNA modifications on LLPS to alter diseases progression because these modifications can influence LLPS of certain proteins or the formation of stress granules, and discuss the possibility of proper manipulation of LLPS process to restore cellular homeostasis or develop therapeutic drugs for the eradication of diseases. This review attempts to discuss potential therapeutic opportunities by elaborating on the connection between LLPS, RNA modification, and their roles in diseases.

Wasp venom injections from wasp stings can damage several organs, most commonly the kidneys. Despite literature evidence, wasp sting-induced acute kidney injury (AKI) is rare and involves complex pathophysiological processes. While acute tubular necrosis (ATN) is the most prevalent histological result of wasp sting-induced AKI, uncommon combinations of chronic renal lesions have been described, alerting us to the patient's underlying illness. We report a 55-year-old hypertensive patient with unknown renal function who got AKI following multiple wasp stings. His renal function had not improved after continuous hemodialysis and plasma exchange; therefore, a kidney biopsy was performed. The pathology revealed that in addition to ATN, his kidney's distinguishing feature was a mix of chronic interstitial renal disease and chronic glomerulosclerosis. We think that his current renal pathological results were caused by hypertension in addition to wasp venom.

BackgroundEvidence for anorexia and bulimia in relation to the risk of ulcerative colitis (UC) is limited and inconsistent. The objective of this research was to utilize bi-directional, two-sample Mendelian randomization (MR) analysis to predict the causal association between anorexia nervosa and bulimia nervosa with UC.MethodsThe genome-wide association studies (GWAS) provided data for anorexia and bulimia from the UK Biobank, utilizing single-nucleotide polymorphisms (SNP) as instrumental variables. Additionally, genetic associations with UC were collected from various sources including the FinnGen Biobank, the UK Biobank and the International Inflammatory Bowel Disease Genetics Consortium (IIBDGC). The main analytical approach utilized in this study was the inverse-variance-weighted (IVW) method. To evaluate horizontal pleiotropy, the researchers conducted MR-Egger regression and MR-PRESSO global test analyses. Additionally, heterogeneity was assessed using the Cochran’s Q test.ResultsThis study found a negative association between genetically predicted bulimia (OR = 0.943, 95% CI: 0.893–0.996; p = 0.034) and the risk of UC in the IIBDGC dataset, indicating that individuals with bulimia have approximately a 5.7% lower risk of developing UC. No association was observed in the other two datasets. Conversely, genetically predicted anorexia was not found to be causally associated with UC. In bi-directional Mendelian randomization, UC from the IIBDGC dataset was negatively associated with the risk of anorexia (OR = 0.877, 95% CI: 0.797–0.965; p = 0.007), suggesting that UC patients have approximately a 12.3% lower risk of developing anorexia, but not causally associated with bulimia.ConclusionGenetically predicted bulimia may have a negative association with the onset of UC, while genetically predicted anorexia does not show a causal relationship with the development of UC. Conversely, genetically predicted UC may have a negative association with the development of anorexia.

The nitrogen (N) cycle is the foundation of the biogeochemistry on Earth and plays a crucial role in global climate stability. It is one of the most important nutrient cycles in high-altitude lakes. The biogeochemistry of nitrogen is almost entirely dependent on redox reactions mediated by microorganisms. However, the nitrogen cycling of microbial communities in the high-altitude saline lakes of the Qinghai-Tibet Plateau (QTP), the world’s “third pole” has not been investigated extensively. In this study, we used a metagenomic approach to investigate the microbial communities in four high-altitude pristine saline lakes in the Altun mountain on the QTP. We observed that Proteobacteria, Bacteroidota, and Actinobacteriota were dominant in these lakes. We reconstructed 1,593 bacterial MAGs and 8 archaeal MAGs, 1,060 of which were found to contain nitrogen cycle related genes. Our analysis revealed that nitrite reduction, nitrogen fixation, and assimilatory nitrate reduction processes might be active in the lakes. Denitrification might be a major mechanism driving the potential nitrogen loss, while nitrification might be inactive. A wide variety of microorganisms in the lake, dominated by Proteobacteria, participate together in the nitrogen cycle. The prevalence of the dominant taxon Yoonia in these lakes may be attributed to its well-established nitrogen functions and the coupled proton dynamics. This study is the first to systematically investigate the structure and nitrogen function of the microbial community in the high-altitude pristine saline lakes in the Altun mountain on the QTP. As such, it contributes to a better comprehension of biogeochemistry of high-altitude saline lakes.

Cancer and cardiovascular diseases are major contributors to global morbidity and mortality, and their seemingly separate pathologies are intricately intertwined. In the context of cancer, the cardiovascular disease encompasses not only the side effects arising from anti-tumor treatments but also the metabolic shifts induced by oncological conditions. A growing body of research indicates that lipid metabolic reprogramming serves as a distinctive hallmark of tumors. Furthermore, anomalies in lipid metabolism play a significant role in the development of cardiovascular disease. This study delves into the cardiac implications of lipid metabolic reprogramming within the cancer context, closely examining abnormalities in lipid metabolism present in tumors, cardiac tissue, and immune cells within the microenvironment. Additionally, we examined risk factors such as obesity and anti-tumor therapy. Despite progress, a gap remains in the availability of drugs targeting lipid metabolism modulation for treating tumors and mitigating cardiac risk, with limited advancement seen in prior studies. Here, we present a review of previous research on natural drugs that exhibit both shared and distinct therapeutic effects on tumors and cardiac health by modulating lipid metabolism. Our aim is to provide insights for potential drug development.

Excavated rock from underground tunneling activities constitutes a significant portion of the overall construction and demolition (C&D) waste, yet its efficient reuse is challenging. Here we propose an integrated approach combining the utilization of the excavated rock and the production of an eco-friendly ultra-high performance concrete (UHPC). As the first steps to assess the feasibility of the approach, the workability, mechanical properties, fracture toughness test, phase stability and shrinkage of the UHPC were comprehensively studied. The results show that increasing excavated rock content in UHPC leads to a reduction in flowability but improves flexural performance with the enhancement of phase stability. However, this enhancement effect diminishes with larger excavated rock sizes. The compressive strength of the mixture with 400 kg/m³ dosage and 5–10 mm size range achieve 104.1 MPa, which is better than the reference UHPC. Meanwhile, elevated excavated rock content obviously reduces UHPC shrinkage, notably within size 5–10 mm. In addition, an overall assessment was performed to evaluate the UHPC from both environmental and economic perspectives. The results indicate that incorporating excavated rock as aggregates into UHPC can result in cost savings of up to 9.5%, an 11% reduction in embodied energy, and a 15.5% decrease in embodied carbon. Additionally, this integration can yield superior properties compared to reference UHPC. This approach also reduces dependence on natural aggregates, promoting sustainability.

Rosa roxburghii fruit is rich in flavonoids, but little is known about their biosynthetic pathways. In this study, we employed transcriptomics and metabolomics to study changes related to the flavonoids at five different stages of R. roxburghii fruit development. Flavonoids and the genes related to their biosynthesis were found to undergo significant changes in abundance across different developmental stages, and numerous quercetin derivatives were identified. We found three gene expression modules that were significantly associated with the abundances of the different flavonoids in R. roxburghii and identified three structural UDP-glycosyltransferase genes directly involved in the synthesis of quercetin derivatives within these modules. In addition, we found that RrBEH4, RrLBD1 and RrPIF8 could significantly increase the expression of downstream quercetin derivative biosynthesis genes. Taken together, these results provide new insights into the metabolism of flavonoids and the accumulation of quercetin derivatives in R. roxburghii.

Abstract Aims Frequent and extensive within-day glycemic variability (GV) in blood glucose levels may increase the risk of hypoglycemia and long-term mortality in hospitalized patients with diabetes. We aimed to assess the amplitude and frequency of within-day GV in inpatients with type 2 diabetes and to explore the factors influencing within-day GV. Methods We conducted a single-center, retrospective observational study by analyzing hospital records and 10-day real-time continuous glucose monitoring data. Within-day GV was assessed using the coefficient of variation (%CV). The primary outcome was the amplitude and frequency of within-day GV. The frequency of within-day GV was assessed by the consecutive days (CD) of maintaining within the target %CV range after first reaching it (CD after first reaching the target) and the maximum consecutive days of maintaining within the target %CV range (Max-CD). The target %CV range was less than 24.4%. We evaluated the factors influencing within-day GV using COX regression and Poisson regression models. Results A total of 1050 cases were analyzed, of whom 86.57% reduced the amplitude of within-day GV before the sixth day of hospitalization. Of the 1050 hospitalized patients, 66.57% stayed within the target %CV range for less than two days after first reaching the target and 69.71% experienced a Max-CD of fewer than four days. Reducing the average postprandial glucose excursion (hazard ratio [HR]: 0.81, 95% confidence interval [CI]: 0.77–0.85; incidence rate ratios [IRR]: 0.72, 95% CI: 0.69–0.74) and the use of α-glucosidase inhibitors (IRR: 1.1, 95% CI: 1.01–1.18) and glucagon-like peptide-1 agonist (IRR: 1.30, 95% CI: 1.02–1.65) contributed to reducing the amplitude and decreasing the frequency of within-day GV. However, the use of insulin (HR: 0.64, 95% CI: 0.55–0.75; IRR: 0.86, 95% CI: 0.79–0.93) and glinide (HR: 0.47, 95% CI: 0.31–0.73; IRR: 0.84, 95% CI: 0.73–0.97) may lead to an increased frequency of within-day GV. Conclusions An increasing frequency of within-day GV was observed during the hospitalization in patients with type 2 diabetes, despite the effective reduction in the amplitude of within-day GV. Using medications designed to lower postprandial blood glucose could contribute to minimize the risk of frequent within-day GV.

The collaborative governance of inclusive preschool education (IPE) is a process in which multiple subjects work together to promote the advancement and development of IPE by taking a series of governance measures. Based on precise identification of multiple stakeholders in collaborative governance of integrated preschool education, it applied the quadrilateral evolutionary game model and Lyapunov's first law to analyze the stability of behavioral strategy choice by multiple subjects in promoting the practice of collaborative governance of IPE and the possible equilibrium points in the system. The influence of key elements on the system evolution is analyzed using MATLAB 2019 simulation. The study reveals that the evolution and trend of one game agent's behavior are closely related to the strategy choice of others. The willingness of the main body of kindergarten, social organization, and parents to participate in the collaborative governance of IPE are related to the government's active promotion to perform its leading functions at the government level. The willingness for collaborative governance of integrated education can help improve mutual trust and the main body's benefits, thus promoting the collaborative behavior of multiple subjects. Complementary resources, strict supervision, reasonable rewards and punishments can promote the collaborative behavior of multiple subjects.