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The sodium taurocholate co-transporting polypeptide (NTCP), a bile acids transporter, has been identified as a new therapeutic target for the treatment of liver disease. This paper thoroughly investigates the function of NTCP for regulating bile acid regulation, its correlation with hepatitis B and D infections, and its association with various liver diseases. Additionally, in this review we examine recent breakthroughs in creating NTCP inhibitors and their prospective applications in liver disease treatment. While this review emphasizes the promising potential of targeting NTCP, it concurrently underscores the need for broader and more detailed research to fully understand the long-term implications and potential side effects associated with NTCP inhibition.

Dysregulation of lncRNAs is a critical factor in the migration and invasion of tumors. Here our study reveals that lncRNA HIF1A-AS2 is highly expressed in breast cancer tissues and various TNBC cell lines. Moreover, we present compelling evidence supporting the role of HIF1A-AS2 in promoting TNBC cell proliferation, metastasis, invasion, and resistance to paclitaxel treatment. Additionally, our transcriptome sequencing analysis identifies MRPS23 as a potential downstream target protein regulated by HIF1A-AS2 and knockdown of HIF1A-AS2 leads to decreased expression of MRPS23 in TNBC cells. Moreover, MRPS23 exhibits similar effects on enhancing cell proliferation, metastasis, invasion, and paclitaxel resistance in TNBC cells. Furthermore, downregulating HIF1A-AS2 suppresses the enhanced functionality observed in TNBC cells due to upregulated MRPS23 expression. These findings suggest that modulation of MRPS23 protein expression by HIF1A-AS2 may influence cellular processes and paclitaxel sensitivity in TNBC cells.

Background: Observational studies have shown that the correlation between neurodegenerative diseases and colorectal cancer (CRC) remains controversial. Therefore, this study aimed to verify the causal association between these two diseases. Methods: Mendelian randomization (MR) analysis was used to assess the causal relationships between five major neurodegenerative diseases and CRC. Multivariable MR (MVMR) analysis was conducted to assess the direct causal effect of neurodegenerative diseases on CRC. Colocalization and pathway enrichment analyses were conducted to further elucidate our results. Sensitivity analysis was conducted to assess the robustness of the results. Results: Genetically predicted Alzheimer's disease (AD) nominally increased CRC risk (OR = 1.0620, 95%CI = 1.0127–1.1136, P = 0.013). There was no causal effect of genetically predicted CRC on neurodegenerative diseases. Furthermore, we demonstrated that genetically predicted AD marginally increased colon cancer risk (OR = 1.1621, 95%CI = 1.0267–1.3153, P = 0.017). Genetically predicted Lewy body dementia (LBD) had a significant causal effect on the increasing risk of colon cancer (IVW OR = 1.1779, 95%CI = 1.0694–1.2975, P = 0.001). MVMR indicated that effect of AD on colon cancer was driven by LBD, type 2 diabetes, body mass index, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglyceride, total cholesterol (TC), processed meat consumption, smoking, alcohol consumption, and educational attainment, whereas the effect of LBD on colon cancer was only influenced by TC. Colocalization and pathway enrichment analysis suggested that LBD and colon cancer possibly shared causal variants (nearby gene APOE), and ERBB4 signaling and lipid metabolism may mediate the causal association between LBD and colon cancer. Sensitivity analysis confirmed the reliability of our findings. Conclusions: Our study demonstrated that genetic vulnerabilities to AD nominally increased the overall risk of CRC and colon cancer. Genetically predicted LBD indicated an elevated risk of colon cancer, potentially linked to ERBB4 signaling and lipid metabolism.

Summary: Exo70, a key exocyst complex component, is crucial for cell motility and extracellular matrix (ECM) remodeling in cancer metastasis. Despite its potential as a drug target, Exo70’s post-translational modifications (PTMs) are poorly characterized. Here, we report that Exo70 is transamidated on Gln5 with Lys56 of cystatin A by transglutaminases TGM1 and TGM3, promoting tumor metastasis. This modification enhances Exo70’s association with other exocyst subunits, essential for secreting matrix metalloproteinases, forming invadopodia, and delivering integrins to the leading edge. Tumor suppressor liver kinase B1 (LKB1), whose inactivation accelerates metastasis, phosphorylates TGM1 and TGM3 at Thr386 and Thr282, respectively, to inhibit their interaction with Exo70 and the following transamidation. Cantharidin, a US Food and Drug Administration (FDA)-approved drug, inhibits Exo70 transamidation to restrain tumor cell migration and invasion. Together, our findings highlight Exo70 transamidation as a key molecular mechanism and target and propose cantharidin as a therapeutic strategy with direct clinical translational value for metastatic cancers, especially those with LKB1 loss.

Background: Most ovarian tumors exhibit a pure histological characteristic. Nevertheless, a combination of tumors with the same histogenetic origin but different histologic subtypes is relatively common. Additionally, co-occurrence of tumors with different histogenetic origins is very rare. Typically, these mixed tumors include mixed epithelial tumors, mixed epithelial-stromal tumors, mixed germ cell-sex cord-stromal tumors, and mixed germ cell tumors. However, mixed epithelial-sex cord stromal-lymphohematopoietic system tumors are rare. Currently, clinicians have limited knowledge of this type of tumor, and the epidemiology, diagnosis, and treatment of this disease are yet to be established. Case presentation: We report a case of a 73-year-old woman with abdominal distension and pain for three months. Imaging evaluation revealed a large pelvic mass, with ultrasound suggesting a benign ovarian cyst along with leiomyoma. Furthermore, computed tomography (CT) and magnetic resonance imaging (MRI) revealed a malignant tumor. Blood tests showed significant increases in CA125 and CA199 levels. The patient underwent a total abdominal hysterectomy and bilateral salpingo-oophorectomy. During the surgery, a large multinodular cystic solid mass was observed in the right ovary, and the maximum nodular diameter was 14.2 cm. The solid areas of the mass appeared gray-white and taupe, whereas the cystic areas contained clear liquid with smooth walls 0.2 cm thick and no intracystic solid areas. The left ovary had solitary nodules, the largest being 4 cm in diameter. Microscopic examination of the right ovary revealed three different cell types. The first type of cell area was analogous, round, fusiform, and staggered mixed cells with unclear boundaries and rare nucleolus or mitosis. The second type of cell area was the cystic dilatation area. The cyst wall was covered with a single layer of flat epithelium, rich eosinophilic cytoplasm, uniform nuclear chromatin, and no papillary structures. The third type was a diffuse lymphoid region with uniform medium-sized cells, rough nuclear chromatin and evident nucleoli and mitosis. The morphology of the left ovarian cell was single, which was consistent with the first type of cell area in the right ovary. Immunohistochemistry of the right ovary indicated that the first region expressed vimentin, inhibin-α, calretinin, SF-1, WT-1 and CD56, with Ki-67 at 5 %, and no CKpan expression. The second region expressed CKpan, with Ki-67 at 1 %. The third region expressed CD20, Pax-5, Bcl-6, Bcl-2, MUM1, CD45, and C-myc, with Ki-67 at 70 %, and positive IGH clonal gene rearrangement. Lastly, the pathological diagnosis was a mixed ovarian tumor in the right ovary, comprising thecoma-fibroma, serous cystadenoma, diffuse large B-cell lymphoma, and a thecoma-fibroma in the left ovary. A follow-up examination of the patient after 15 months showed no mass or lymph node enlargement in other parts of the body, and no recurrence or metastasis was observed. Conclusions: We present a case of a postmenopausal woman with a rare combination of thecoma-fibroma, serous cystadenoma and diffuse large B-cell lymphoma in the ovary. To the best of our knowledge, this is the first reported case of such a combination. Typical pathological morphology and immunohistochemistry are crucial for the diagnosis of this disease. Owing to the limited knowledge of the disease, its pathogenesis and tissue origin are unknown. Clinicians should be careful about such patients. We believe this case report may provide some novel insights into the diagnosis and therapy of patients with this type of tumor.

Background: Non-alcoholic fatty liver disease (NAFLD) is a common liver disorder characterized by hepatic steatosis, inflammation and fibrosis. Ganfule (GFL), a traditional Chinese medicine, has demonstrated therapeutic potential in the treatment of NAFLD but the mechanisms involved are not fully understood.To evaluate the biochemical mechanisms of GFL in treating NAFLD by examining its effects on biological networks, key therapeutic targets, histopathological changes and clinical implications. Methods: Chemical component screening, key target prediction, biological functional enrichment analysis, lipid profile localization analysis and complex network analysis were performed on GFL using multi-database mining, network analysis and molecular docking. An NAFLD rat model was then established and treated with different doses of GFL. Histopathological evaluation and western blotting were used to verify the expression levels of key target proteins in GFL-treated NAFLD rats. Results: Network analysis analysis identified 12 core targets, 12 core active ingredients and 7 core Chinese medicinal herbs in GFL potentially involved in the treatment of NAFLD. Biological functional enrichment analysis revealed the involvement of lipid metabolism, apoptosis and intracellular signaling pathways. Molecular docking confirmed a strong affinity between GFL's core compounds and certain target proteins. Histopathological examination of an NAFLD rat model showed reduced hepatocellular steatosis after GFL treatment. Western blotting revealed significant downregulation of PPARA and PPARD protein expression and upregulation of PIK3CG and PRKACA protein expression in NAFLD rats treated with lower doses of GFL. Conclusions: Our results suggest that GFL modulates key proteins involved in lipid metabolism and apoptosis pathways. GFL improved the histopathological features of NAFLD rats by regulating lipid metabolism as well as reducing hepatocyte apoptosis and hepatocellular steatosis. These findings offer insights into the biochemical mechanism of action of GFL and support its use in the treatment for NAFLD.

Lipids are components of cytomembranes that are involved in various biochemical processes. High-altitude hypoxic environments not only affect the body’s energy metabolism, but these environments can also cause abnormal lipid metabolism involved in the hypoxia-induced cognitive impairment. Thus, comprehensive lipidomic profiling of the brain tissue is an essential step toward understanding the mechanism of cognitive impairment induced by hypoxic exposure. In the present study, mice showed reduced new-object recognition and spatial memory when exposed to hypobaric hypoxia for 1 day. Histomorphological staining revealed significant morphological and structural damage to the hippocampal tissue, along with prolonged exposure to hypobaric hypoxia. Dynamic lipidomics of the mouse hippocampus showed a significant shift in both the type and distribution of phospholipids, as verified by spatial lipid mapping. Collectively, a diverse and dynamic lipid composition in mice hippocampus was uncovered, which deepens our understanding of biochemical changes during sustained hypoxic exposure and could provide new insights into the cognitive decline induced by high-altitude hypoxia exposure.

Background: Multiple empirical investigations have indicated a connection between asthma and adverse pregnancy outcomes (APOs). Nevertheless, the effects of asthma on APOs remain uncertain. Methods: We performed bi-directional Univariable Mendelian randomization (UVMR) analyses using combined information obtained from genome-wide association studies (GWAS) data that is publicly accessible. The principal approach used to analyze the causal association between asthma or age when diagnosed and APOs was the inverse variance weighted (IVW) method. The two types of data regarding exposure originate from the IEU Open GWAS project, which includes 56,167 and 47,222 European asthma patients, respectively. The data of four APOs were acquired via the GWAS dataset of the FinnGen collaboration. In addition, we implemented multivariable Mendelian randomization (MVMR), controlling for confounding factors such as smoking status, frequent drinking, body mass index (BMI), and live birth quantity. Furthermore, we executed several meticulous sensitivity studies to ascertain the reliability of our MR results. Results: Following the implementation of the Bonferroni adjustment, the UVMR assessment revealed that in the IVW model, asthma was significantly linked to an elevated risk of spontaneous abortion (SA) (odds ratio [OR]: 1.115; 95 % confidence interval [CI]: 1.031–1.206; P = 0.006) and gestational diabetes mellitus (GDM) (OR: 1.125; 95 % CI: 1.037–1.220; P = 0.005). However, there was no causal correlation between asthma and preterm birth (PTB) (OR: 0.979; 95 % CI: 0.897–1.068; P = 0.629) or preeclampsia (PE) (OR: 1.059; 95 % CI: 0.951–1.179; P = 0.297). After adjusting for confounding factors, including smoking status, frequent drinking, BMI, and live birth quantity, the MVMR analysis shows a statistically significant causal relationship between asthma and SA or GDM. Furthermore, our investigation's findings did not reveal a substantial correlation between the age of asthma onset based on genetics and the likelihood of SA or GDM. The inverse MR outcomes indicate a lack of causal connection linking APOs to the incidence of asthma. The validity of these findings were verified by sensitivity analyses. Conclusions: The evidence provided by this study proves that genetically determined asthma is linked to a higher likelihood of SA and GDM. Further research is required to examine potential pathways. However, no conclusive evidence has been found to support the increased risk of SA and GDM in early asthma diagnosis or the interaction between asthma and PTB or PE, indicating that confounding factors may affect the results of previous observational studies.

The functional backfilling in mining achieves synergistic co-mining of deep-earth deposits-geothermal, and the development of functional filling materials with suitable phase change parameters and excellent physicochemical properties is imminent. This study aims to investigate the optimal composition of phase change energy storage backfill material based on MicroPCM. To address the issues of reduced compressive strength and specific heat capacity of MicroPCM-backfill, silicon carbide (SiC) is introduced to prepare MPSC-backfill. Box-Behnken Design (BBD) is proposed to design and analyze according to four factors (ash-sand ratio, slurry concentration, MicroPCM, SiC), three levels (compressive strength, thermal conductivity, specific heat capacity) and three center points. Based on the Response Surface Methodology, the multivariate quadratic polynomial model was used to perform multiple linear regression and binomial fitting analysis to explore the optimal ratio. Combined with SEM-EDS (Scanning Electron Microscope with Energy-Dispersive X-ray Spectroscopy) analysis, the following conclusions were drawn. SiC exhibits an overall enhancement of the compressive strength of the backfill, and the thermal conductivity tends to increase almost linearly. The specific heat capacity grows in a small amount of silicon carbide doping, but excessive amounts lead to a decrease, with an overall limited impact. The addition of SiC does not affect the phase change ability of MicroPCM. And within a certain range of added quantities, it optimizes specific heat capacity, thermal conductivity, and compressive strength. Experimental validation based on the obtained optimal composition shows errors within a 5% margin, indicating the response model's good accuracy and predictability. High and low-temperature cyclic tests confirm the long-term thermal energy storage stability of MPSC-backfill during phase change cycles.

Shallow purple soils (Entisols) were widely distributed in hilly areas of southwest China and were easily subjected to drought due to the weak soil water retention capacity, which largely reduced the crop productivity. However, the impact of solum thickness on ecological traits and water use strategies of crops remain poorly understood under the shallow Entisol environment. In this study, water use patterns and physiological adaptation of maize with different solum thicknesses were investigated to ascertain the optimum solum thickness based on an in-situ experiment. Isotopic (2H and 18O) tracing technique was used to investigate the water sources for maize growth in sloping croplands with solum of 20 cm (C1), 40 cm (C2), 60 cm (C3), 80 cm (C4), 100 cm (C5) thickness. The morphological and physiological characteristics were also discussed under different soil moisture regimes. The results showed the soil water storage capacity significantly increased with solum thickness. The isotopes of xylem water in shallow solum (≦40 cm) were more enriched, indicating more contributions from the bottom soil water, especially under dry regimes (62.3% for C1, 42.8% for C2, at Jul. 09). The water sources utilized by maize in the treatments with solum thickness greater than 60 cm were relatively evenly distributed throughout the soil profile (mean 19.3%, 19.6% and 17.6%, respectively, in the 0–10 cm, 10–20 cm, 20–40 cm soil layer), and the water niche breadth increased with the solum thickness. Maize in shallow solum (≦40 cm) had lower biomass and higher specific leaf area (SLA) to reduce transpiration rate and improved water use efficiency (WUEi) (highest for C1, P60 cm) had significantly higher yields than in shallower solum (P

Background: In December 2015, the World Health Organization, the World Animal Health Organization, and the Food and Agriculture Organization of the United Nations convened the International Congress on the elimination of rabies in Geneva. How to use epidemiological factors of post-exposure prophylaxis to prevent rabies has become the focus of attention. Objective: To analyze the epidemiological characteristics of 9772 patients with rabies in a four-year period in one hospital, to clarify the outbreak law of rabies and to explore the corresponding prevention and control strategies. Methods: The epidemiological data of rabies patients were collected from the infectious disease reporting information management system of the hospital from July 2018 to June 2022. The distributional characteristics of 13 influencing factors were analyzed using the chi-square test and linear regression. Results: There was a significant correlation between the number of wounds and age, and the numbers of female and male patients were close. People over the age of 44 were more likely to get bites or scratches on their lower extremity (P

Objective: The goal of the research is to investigate the link between serum potassium levels and death after 28 days in sepsis patients, utilizing an extensive sample of patients from the multi-center Medical Information Mart for Intensive Care IV (MIMIC-IV) database. Current research on serum potassium levels and 28-day mortality in sepsis patients is questionable. This study adds to the growing body of evidence linking serum potassium levels to the 28-day possibility of death in patients with sepsis. Methods: We collected 349,08 patients with sepsis from the retrospective cohort MIMIC-IV database, using serum potassium level on the first day of admission to the intensive care unit as the exposure variable and mortality at 28 days as the outcome variable. And controlled for confounding characteristics including gender, age, ethnicity, and vital signs during admission. Results: Serum potassium has a U-shaped connection with 28-day mortality in patients suffering from sepsis. The turning point was 4.10 mmol/L (95 % confidence interval: 4.03 to 4.22). Serum potassium and 28-day mortality were negatively linked on the inflection point’s left side (OR: 0.72; 95 % CI: 0.63 to 0.83, P

Polycyclic aromatic hydrocarbons (PAHs) and carbon dioxide primarily originate from the combustion of fossil fuels and biomass. The implementation of the Chinese “double carbon strategy” is expected to impact the distribution of PAH emissions, consequently influencing the spatial distribution trend of PAHs in surface soil. Therefore, it is crucial to quantitatively evaluate the effectiveness of the Chinese “double carbon strategy” on soil PAH pollution for the purpose of “the reduction of pollution and carbon emissions”. This study utilized 15,088 individual PAH concentration data from 943 soil samples collected between 2003 and 2020 in China, in conjunction with PAH emissions at a 10 km resolution, for meta-analysis. The calculated PAH emissions in this study are in line with the global PAH emission inventory (PKU-PAH-2007), with a relative standard deviation at the provincial level of less than 25 %. Subsequently, a novel method was developed using emission density and Kow of PAHs to predict PAH concentrations in surface soil based on a least-squares regression model. Compared to other environmental models, the method established in this study significantly reduced the percent sample deviation to less than 70 %. Furthermore, energy consumption data for China were simulated based on the implementation plan of the “double carbon strategy” to project PAH emissions and soil PAH levels for the years 2030 and 2060. The predicted PAH emissions in China were estimated to decrease to 41,300 t in 2030 and 10,406.5 t in 2060 from 78,815 t in 2020. Moreover, the heavily contaminated areas of soil PAHs (i.e., total PAH concentrations in soil exceeding 1000 μg kg−1) were projected to decrease by 45 % and 82 % in 2030 and 2060, respectively, compared to levels in 2020. These findings suggest that the implementation of the “double carbon strategy” can fundamentally reduce the pollution of PAHs in surface soil of China.

Background: Phthalates (PAEs) are endocrine-disrupting chemicals ubiquitously found in the environment. This study aimed to examine the association between exposure of PAEs and subfecundity in preconception couples. Methods: This is a nested case-control study based on preconception cohort. Preconception couples with intention to conceive were enrolled and followed up until a clinically confirmed pregnancy or 12 menstrual cycles of preparation for conception. A total of 107 couples with subfecundity- time to pregnancy (TTP) more than 12 menstrual cycles, and 144 couples ≤12 cycles were included in the analysis. The levels of PAE metabolites in one spot urine samples were detected and compared between the groups. The weighted quantile sum (WQS) regression model and Bayesian kernel machine regression (BKMR) model were used to examine the joint effects of couples’ exposure to PAEs on subfecundity. Results: Using the multivariate binary logistic regression model, compared to the lowest quartile of urinary ∑PAEs concentration group, both preconception females (aOR=2.42, 95% CI: 1.10–5.30, p=0.027) and males (aOR=2.99, 95% CI: 1.36–6.58, p=0.006) in the highest quartile group had an increased risk of subfecundity, and a dose-response relationship was observed between PAEs and the risk of subfecundity. The WQS analyses found that co-exposure to PAE mixture was a risk factor for subfecundity in preconception female (aOR=1.76, 95% CI: 1.38–2.26, p

As a local specialty of Tibet, Qingke baijiu (QB) is made from highland barley, and is referred to as the manufacturing process of light-aroma baijiu. Using highland barley in the Qu-making and the high-temperature stacking process of sauce-aroma baijiu results in a novel Qingke baijiu (NQB). This study analyzed two kinds of NQBs by GC-MS, GC×GC-MS, and GC-O-MS, and compared them with QB, light-aroma, strong-aroma, and sauce-aroma baijiu. A total of 346 volatile compounds and 60 aroma-active compounds were detected in NQB. There were 14 compounds with FD≥27 and OAVs ≥1. Although NQB and QB shared 39 volatile compounds, NQB has more than three times the overall concentration of volatile compounds than QB. In contrast to QB, NQB exhibited a richer flavor profile and a more intense fruity, floral, and acidic aroma. Meanwhile, the distilled grains and sorghum aroma were comparatively diminished.

Epilepsy is a chronic, relapsing neurological disorder, and current treatments focus primarily on neurons, yet one-third of patients still develop drug-resistant epilepsy. Therefore, there is an urgent need to explore new therapeutic targets. Interestingly, astrocytes can transfer their healthy mitochondria into neighboring neurons, thus preventing neuronal damage. Astrocyte mitochondria have been shown to have a therapeutic role in stroke and neurodegenerative diseases. However, their therapeutic effect in epilepsy and its related mechanisms have been less studied. In this review, we mainly summarize the regulatory role of astrocyte mitochondria in glutamate, calcium ion, and adenosine triphosphate (ATP) homeostasis and outline the protective role of astrocyte mitochondria in nervous system diseases, revealing a new target for epilepsy treatment.

Osteoarthritis (OA) is characterized by cartilage degradation, inflammatory responses, and osteophyte formation. Matrix metalloproteinase 13 (MMP13) is a hallmark of OA development, and increased MMP13 expression is closely associated with extracellular matrix degradation. MMP13 expression varies significantly at different stages of OA progression. While cyclooxygenase 2 (COX-2) inhibitors are commonly used to treat OA, their long-term systemic administration increases the risks of adverse effects. Therefore, with the aim of achieving localized and responsive delivery of the COX-2 inhibitor celecoxib, the current study investigated an innovative MMP13-responsive micro-nano hydrogel microsphere system. Celecoxib-loaded cationic liposomes are non-covalently attached within the microsphere, enabling controlled drug release for OA treatment. In an OA environment with elevated MMP13 expression, the system is degraded via the action of MMP13 substrate peptide (MMP13sp), facilitating accelerated release of drug-loaded liposomes to improve the inflammatory microenvironment and treat OA rapidly. Compared to a phosphate-buffered saline solution with hyaluronidase (HAase), the prepared hyaluronic acid methacrylate microspheres HAMA/MMP13sp/Lipo@celecoxib exhibited rapid degradation in a solution containing a physiological concentration of MMP13/HAase, demonstrating specific enzyme responsiveness for precise anti-inflammatory drug release. The MMP13-responsive hydrogel microsphere system achieves intelligent and controllable drug release in OA, effectively decelerating disease progression and promoting articular cartilage repair.

Background: While hepatocellular carcinoma (HCC) represents a highly heterogeneous disease with variable oncogenesis mechanisms and biological features, little is understood about differences in distant metastasis (DM) and prognosis between early-onset and late-onset HCC. This study defined early-onset disease as cancer diagnosed at age younger than 50 years and aimed to present a comprehensive analysis to characterize these disparities based on age. Methods: Information of HCC patients was retrospectively collected from the SEER database and our hospital. Patient demographics, tumor characteristics, and survival were compared between the two groups. A 1:1 propensity score matching (PSM) was adopted to adjust confounding factors. Logistic and cox analysis were utilized to explore risk factors of DM and prognosis, respectively. Besides, the survival differences were assessed by the Kaplan–Meier curve and log-rank test. Results: In total, 19187 HCC patients obtained from the SEER database and 129 HCC patients obtained from our own center were enrolled. Among 19187 patients with HCC, 3376 were identified in the matched cohort, including 1688 early-onset patients and 1688 late-onset patients. Compared with late-onset HCC, early-onset HCC was more likely to occur in female (25.2% vs. 22.9%, P = 0.030), have large tumors (>10.0 cm, 24.1% vs. 14.6%, P = 0.000), harbor poorly differentiated/undifferentiated cancers (17.0% vs. 14.0%, P = 0.003), present advanced clinical stage (T3+T4, 33.7% vs. 28.5%; N1, 9.2% vs. 6.7%; P = 0.000), and develop DM (13.0% vs. 9.5%, P = 0.000). After adjustment for confounders by PSM, we discovered that early-onset HCC remained an independent risk factor for DM. However, combined with Kaplan–Meier curve and cox analysis, early-onset HCC was an independent favorable predictor of survival. We validated these data on an independent cohort from our hospital. Conclusion: In this population-based study, despite developing DM more frequently, early-onset HCC exhibited a superior prognosis than late-onset HCC. Nevertheless, further research is warranted to understand the underlying aetiologic basis for the disparities.

Summary: The question of whether serofast status of syphilis patients indicates an ongoing low-grade Treponema pallidum (T. pallidum) infection remains unanswered. To address this, we developed a machine learning model to identify T. pallidum in cell-free DNA (cfDNA) using next-generation sequencing (NGS). Our findings showed that a TP_rate cut-off of 0.033 demonstrated superior diagnostic performance for syphilis, with a specificity of 92.3% and a sensitivity of 71.4% (AUROC = 0.92). This diagnosis model predicted that 20 out of 92 serofast patients had a persistent low-level infection. Based on these predictions, re-treatment was administered to these patients and its efficacy was evaluated. The results showed a statistically significant decrease in RPR titers in the prediction-positive group compared to the prediction-negative group after re-treatment (p

In this study, the enteric swelling layer of capsules was prepared by optimizing the ratio of pullulan to gellan gum. The enteric-coating solution was prepared by dissolving polyacrylic acid resin III in 85 % ethanol, and the two were combined to form pullulan enteric-coated capsules (PECs). To elaborate further, Pullulan enteric-coated thin films (PEFs) were fabricated using the casting method, and their oxygen permeability (OP) and water vapor permeability (WVP) were assessed. Enteric capsules were prepared employing a secondary impregnation method. The cap gap and surface roughness of the capsules were characterized using Scanning Electron Microscopy (SEM) and Atomic Force Microscopy (AFM). The water content and hygroscopicity of the capsules were examined by employing the drying weight loss method. The pullulan-based enteric capsules (PECs) exhibited attributes such as low water content, hygroscopicity, brittleness, leakage resistance, and high impermeability. Finally, the in vitro release of aspirin from the enteric capsules was investigated. Results demonstrated the excellent combination of the enteric-coating layer and the swelling layer in the PECs. Compared with Gelatin enteric-coated capsules (GECs) on the market, it had a smaller cap gap, lower brittleness, weaker moisture absorption, and a good dissolution effect. Thus, it met the requirements of Chinese pharmacopeia, i.e., the ability to maintain integrity for 2 h in simulated gastric fluid and a drug-release rate reaching 80 % within 30 min in simulated intestinal fluid. This capsule also exhibited certain characteristics of a pulsatile drug-delivery system. This work proposed a potential method of preparing enteric hard capsules by using pullulan combined with polyacrylic acid resin III.

MAX phases and its derived two-dimensional MXenes have attracted considerable interest because of their rich structural chemistry and multifunctional applications. Lewis acid molten salt route provides an opportunity for structure design and performance manipulation of new MAX phases and MXenes, Although a series of new MAX phases and MXenes were successfully prepared via Lewis acid melt route in recent years, few work is explored on nitride MAX phases and MXenes. Herein, a new copper-based 413-type Ti4CuN3 MAX phase was synthesized through isomorphous replacement reaction using Ti4AlN3 MAX phase precursor in molten CuCl2. In addition, it was found that at high temperature Ti4N3Clx MXene will transform into two-dimensional cubic TiNα nanosheets with improved structural stability.

Carbon quantum dots (CQDs), which belong to the category of zero-dimensional nanomaterials, exhibit remarkable properties including chemical stability, water dispersion, low cytotoxicity, small size, biocompatibility, and photoluminescence. Although there are several methods for production of CQDs, there is an increasing interest in using low-cost and environmentally friendly synthetic methods. Biomass-based CQDs are a branch of CQDs which are considered the most ideal fluorescent nanomaterial by green synthesis strategy. The typical green route can be the conversion of waste products into high-value biomass-based CQDs, reducing resource waste and enabling sustainable development. This review will emphasize the benefits of biomass-based CQDs in synthetic methods, material properties, and their research in the area of biology. Additionally, the applications of biomass-based CQDs as plant growth promoters and sensors, and for improving plant stress tolerance and bioimaging were also discussed. Herein, this review summarizes the current investigations on synthesis of biomass-based CQDs from 1970 to 2023 and their application in agriculture. The objective of the review article is to use different biomass-based CQDs to improve plant resistance in stressful environments, so as to make plant growth better. In a word, biomass-based CQDs have strong potential in sustainable agricultural development.

As the world’s fourth most deadly cancer, colorectal cancer (CRC) still needed the novel therapeutic drugs and target urgently. Although cyclin-dependent kinase 12 (CDK12) has been shown to be implicated in the malignancy of several types of cancer, its functional role and mechanism in CRC remain largely unknown. Here, we found that suppression of CDK12 inhibited tumor growth in CRC by inducing apoptosis. And CDK12 inhibition triggered autophagy by upregulating autophagy related gene 7 (ATG7) expression. Inhibition of autophagy by ATG7 knockdown and chloroquine (CQ) further decreased cell viability induced by CDK12 inhibition. Further mechanism exploration showed that CDK12 interacted with protein kinase B (AKT) regulated autophagy via AKT/forkhead box O3 (AKT/FOXO3) pathway. FOXO3 transcriptionally upregulated ATG7 expression and autophagy when CDK12 inhibition in CRC. Level of CDK12 and p-FOXO3/FOXO3 ratio were correlated with survival in CRC patients. Moreover, CDK12 inhibition improved the efficacy of anti-programmed cell death 1(PD-1) therapy in CRC murine models by enhancing CD8 + T cells infiltration. Thus, our study founded that CDK12 inhibition upregulates ATG7 triggering autophagy via AKT/FOXO3 pathway and enhances anti-PD-1 efficacy in CRC. We revealed the roles of CDK12/FOXO3/ATG7 in regulating CRC progression, suggesting potential biomarkers and therapeutic target for CRC.

Thirteen kojic acid-coumarin derivatives were synthesized using the principle of molecular hybridization, and their structures were characterized by 1H NMR, 13C NMR, and HRMS. In vitro enzyme inhibition experiments showed that all newly synthesized derivatives have excellent inhibition of tyrosinase (TYR) activity. As a mixed inhibitor, compound 6f has the strongest activity, with an IC50 value of 0.88 ± 0.10 µM. Multispectral experiments have confirmed that the mode of action of compound 6f on TYR was static quenching. In addition, compound 6f formed a new complex with TYR, which increased the hydrophobicity of the enzyme microenvironment, reduced the content of the α-helix in the enzyme, and changed the secondary structure. The experimental results showed that compound 6f effectively inhibited the browning of lotus root slices and had low cytotoxicity. Therefore, compound 6f is believed to have great development potential as a TYR inhibitor in the food industry.

Background: Cancer immunotherapies aimed at activating immune system, especially by blocking immune checkpoints, have become a successful modality for treating patients with advanced cancers. However, its clinical practice is frequently conceded by high outcomes, low initial response rates and severe side effects. New strategies are necessary to complement and advance this biological therapy. Erzhi Pills (EZP) have diverse pharmaceutical effects including immune regulation, anti-tumor and anti-senescence. We hypothesized that EZP could exert its antitumor effect through immunomodulation. Purpose: The aim of this study was to investigate the effects of EZP on anti-tumor activities, and define its molecular mechanisms. Methods: By applying melanoma model with high immune infiltrates, we determined the anti-melanoma effect of EZP. To identify whether this effect was mediated by direct targeting tumor cells, cell viability and apoptosis were examined in vitro. Network pharmacology analysis was used to predict the potential mechanisms of EZP for melanoma via immune response. Flow cytometry, immunohistochemistry (IHC), enzyme-linked immunosorbent assay (ELISA) and crystal violet (CV) experiments were performed to detect T cell infiltrations and functions mediated by EZP. The mechanism of EZP was further investigated by western blotting both in vivo and in vitro. Results: The administration of EZP significantly inhibited tumor weight and volume. EZP extract could only slightly reduce cell viability and induce melanoma apoptosis. Network pharmacology analysis predicted that JAK-STAT signaling pathway and T cell receptor signaling pathway might be involved during EZP treatment. Flow cytometry and IHC analyses showed that EZP increased the number of CD4+ T cells and enhanced the function of CD8+ T cells. In co-culture experiments, EZP elevated killing ability of T cells. Western blotting showed that EZP treatment reduced PD-L1 signaling pathway. Conclusion: These findings indicated that EZP exerted anti-melanoma effects by inducing apoptosis and blocking PD-L1 to activate T cells. EZP might represent a promising candidate drug for cancer immunotherapies.

Molybdenum selenide (MoSe2) as a nano near-infrared absorber has been widely studied in the field of photothermal therapy of cancer. However, there are few studies on its application in the treatment of ovarian cancer. In this paper, a new type of carbon-coated MoSe2 (MEC) nanoparticle was prepared by a one-step hydrothermal method. MEC was successfully synthesized as avidenced by chemical characterization. A large number of biological experiments confirmed that MEC + Laser group had the lowest cell viability (61.6 % ± 8.9 %), inhibited the proliferation of human ovarian cancer (SKOV-3) cells in G2/M phase, induced apoptosis (apoptosis rate: 43.24 % ± 0.85 %), and increased the intracellular ROS level (93.86 % ± 1.42 %). Furthermore, MEC nanoparticles displayed excellent photothermal therapy in tumor-bearing mice with no obvious side effects on major organs. Finally, the therapeutic mechanism of MEC nanoparticles was explored, and it was found that they had higher absorbance and could generate more heat during laser irradiation, thereby improving their therapeutic effect on ovarian cancer. MEC nanoparticles, as photothermal agents, have good anticancer ability. And they have the potential to become an important candidate for the treatment of ovarian cancer.

Drug-induced liver injury is a prevalent severe adverse event in clinical settings, leading to increased medical burdens for patients and presenting challenges for the development and commercialization of novel pharmaceuticals. Research has revealed a close association between gut microbiota and drug-induced liver injury in recent years. However, there has yet to be a consensus on the specific mechanism by which gut microbiota is involved in drug-induced liver injury. Gut microbiota may contribute to drug-induced liver injury by increasing intestinal permeability, disrupting intestinal metabolite homeostasis, and promoting inflammation and oxidative stress. Alterations in gut microbiota were found in drug-induced liver injury caused by antibiotics, psychotropic drugs, acetaminophen, antituberculosis drugs, and antithyroid drugs. Specific gut microbiota and their abundance are associated closely with the severity of drug-induced liver injury. Therefore, gut microbiota is expected to be a new target for the treatment of drug-induced liver injury. This review focuses on the association of gut microbiota with common hepatotoxic drugs and the potential mechanisms by which gut microbiota may contribute to the pathogenesis of drug-induced liver injury, providing a more comprehensive reference for the interaction between drug-induced liver injury and gut microbiota.

In the contemporary digital economy, economic development increasingly relies on the innovation and dissemination of knowledge. Academic entrepreneurship, as a direct channel for knowledge dissemination into the marketplace, is significantly influenced by digital technology. Consequently, how to improve academic entrepreneurial ability has become a hot research topic. This study is grounded in the theory of reciprocal determinism within the context of the digital economy. We use the “2019 China Digital Economy Development Index White Paper” and collect data from 1843 survey questionnaires in China to conduct empirical research with a ridge regression model. It primarily focuses on the following individual factors and social environmental factors on academic entrepreneurial ability of teachers (AEAT): digital economy (DE), organizational support (OS), policy environment (PE), and personal learning growth (PLG). First, the findings show that the DE, OS, PE, and PLG have a significant positive impact on improving AEAT. Second, the results also indicate that social environmental factors relative to personal factors will have a greater impact. Finally, this study not only presents the first attempt to establish a connection between DE and AEAT but also holds significant managerial implications for enhancing AEAT within the context of the DE. Despite the increasing body of literature on academic entrepreneurship, the research domain pertaining specifically to AEAT remains fragmented and lacks comprehensive theoretical development. There is a pressing need for more systematic and thorough investigations to unveil the black box of factors influencing AEAT in the context of the DE.

Ecosystem services (ES) are defined as the benefits of the natural environment that sustain human life. The analyses of the balance of ecosystem services (ES balance) and its driving factors are critical for achieving the region’s sustainable development goals. This study explored the ES balance in the Beijing-Tianjin-Hebei-Inner Mongolia (JJJM) region, considering the region’s rapid urbanization, implementation of ecological restoration projects, and intense agricultural and pastoral activities. It quantified the ES balance on different scales and selected nine natural and anthropogenic driving factors to reveal its spatio-temporal heterogeneity and change characteristics in 2000–2020. The main conclusions were as follows: (1) The ES balance in the JJJM region exhibited a significant spatial differentiation: generally higher in its eastern and northern areas and lower in its western and southern parts; (2) The ES balance in the Beijing-Tianjin-Hebei region showed a general trend of initial increase and subsequent decrease, while Inner Mongolia exhibited a continuous upward trend. High-value areas (>46) and low-value areas (

Introduction: The R-loop is a naturally formed three-strand nucleic acid structure that recently has been reported to participate in multiple biological processes and helped answer some previously unexplained scientific questions. Meiosis process involves multiple chromatin-related events such as DNA double-stranded breaks (DSB) formation, repairing and transcriptional dynamics. Objectives: Explore the regulatory roles and physiological functions of R-loops in the mammalian meiosis process. Methods: In our study, using genome-wide S9.6 CUT & Tag seq, we first mapped the genomic distribution and dynamic changes of R-loop during the meiotic process in mice, from spermatogonia to secondary spermatocytes. And we further explore the role of R-loop in physiological conditions by constructing conditional knockout mice of Rnaseh1, which deleted the R-loop endonuclease before meiosis entry. Results: R-loop predominantly distributes at promoter-related regions and varies across different meiotic stages. By joint analysis with the corresponding transcriptome, we found that the R-loop was closely related to transcription during the meiotic process. The high frequency of promoter-related R-loop in meiotic cells is usually accompanied by high transcription activity, and we further verified this in the leptotene/zygotene to the pachytene transition process. Moreover, the lack of RNase H1 caused sterility in male mice with R-loop accumulation and abnormal DSB repair in spermatocytes. Further analysis showed that abnormal R-loop accumulation in the leptotene/zygotene stages influenced transcriptional regulation in the pachytene stage. Conclusion: The mutual regulation of the R-loop and transcription plays an essential role in spermatogenesis. And R-loop is also important for the normal repair process of DSB during meiosis.

In this paper, aging precipitates and their high effects on mechanical properties of squeeze-cast Al–5Cu-0.6Li-0.5Mn-0.3Mg-0.15Ti alloy (a novel Al–Cu–Li–Mn alloy) were investigated to reveal strengthening & toughening mechanism. After T6 heat treatment (i.e., solution treatment at 530 °C for 10 h + aging at 180 °C for 8 h), its ultimate tensile strength (UTS), yield strength (YS) and elongation (El.) are 465 MPa, 310 MPa and 16.5%, respectively. Compared with the as-cast Al–Cu–Li–Mn alloy, the UTS and YS are increased by 55% and 63.2%, respectively, with almost no loss in ductility. Interestingly, the product of UTS and El. (i.e., UTS•El.) of the T6-treated Al–Cu–Li–Mn alloy reaches 7.67 GPa%, which is 50.4% higher than that of the as-cast Al–Cu–Li–Mn alloy and better than that of most third-generation or fourth-generation Al–Li and Li-free 2xxx alloys prepared by casting or plastic deformation followed by heat treatment. The uniformly dispersed submicron-sized T (AlxMnyCuz), nano-sized T1 (Al2CuLi) and much smaller θ' (Al2Cu) phases precipitated in the T6-treated Al–Cu–Li–Mn alloy are coherent or semi-coherent with aluminum matrix, which not only enhances strength but also delays strain localization and fracture. In addition, the actual average thickness of T1 and θ′ precipitates are about 2 nm and 3.5 nm, which are much larger than their critical values for the conversion of their strengthening mechanisms. Therefore, the main strengthening mechanism of the squeeze-cast Al–Cu–Li–Mn alloy is the Orowan bypassing mechanism rather than the shearing mechanism.

ABSTRACT: We report a comprehensive drug synergy study in acute myeloid leukemia (AML). In this work, we investigate a panel of cell lines spanning both MLL-rearranged and non-rearranged subtypes. The work comprises a resource for the community, with many synergistic drug combinations that could not have been predicted a priori, and open source code for automation and analyses. We base our definitions of drug synergy on the Chou-Talalay method, which is useful for visualizations of synergy experiments in isobolograms, and median-effects plots, among other representations. Our key findings include drug synergies affecting the chromatin state, specifically in the context of regulation of the modification state of histone H3 lysine-27. We report open source high throughput methodology such that multidimensional drug screening can be accomplished with equipment that is accessible to most laboratories. This study will enable preclinical investigation of new drug combinations in a lethal blood cancer, with data analysis and automation workflows freely available to the community.

Introduction: With the mounting number of cancer survivors, the complications following cancer treatment become novel conundrums and starve for countermeasures. Intravenous immunoglobulin (IVIg) is a purified preparation for immune-deficient and autoimmune conditions. Objectives: Here, we investigated whether IVIg could be employed to fight against radiation injuries and explored the underlying mechanism. Methods: Hematopoietic or gastrointestinal (GI) tract toxicity was induced by total body or abdominal local irradiation. High-throughput sequencing was performed to analyze the gut microbiota configurations and gene expression profile of small intestine. The untargeted metabolomics of gut microbiome was assessed by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) analyses. Hydrodynamic-based gene delivery was used to knockdown the target genes in vivo. Results: Intravenous injection of IVIg protected against radiation-induced hematopoietic and GI tract toxicity in female mice but not in males. IVIg structured sex-characteristic gut microbiota configurations in abdominal irradiated mice. The irradiation enriched gut Lachnospiraceae in female mice but reduced those in males. IVIg injection combined with oral gavage of Lachnospiraceae or its metabolite hypoxanthine, alleviated radiation toxicity in male mice however, Lachnospiraceae or hypoxanthine alone failed to ameliorate the injuries. Abdominal local irradiation drove sex-distinct gene expression signatures in small intestine. Mechanistic investigation showed that replenishment of Lachnospiraceae or hypoxanthine offset abdominal radiation-reduced PLD1 expression in male mice. In females, irradiation elevated PLD1 expression. Deletion of PLD1 in GI tract of female mice erased the radioprotective effects of IVIg. Conclusion: IVIg battles against radiation injuries in a sex-specific, gut microbiome-dependent way through Lachnospiraceae/hypoxanthine/PLD1 axis. Our findings provide a sex-precise therapeutic avenue to improve the prognosis of cancer patients with radiotherapy in pre-clinical settings.

Introduction: We previously reported a phenomenon called exercise hypertrophic preconditioning (EHP), the underlying mechanisms of which need further clarification. Objectives: We aimed to investigate whether circular RNAs (circRNAs) are involved in EHP. Methods: CircRNA sequencing of myocardial tissue was performed in male C57BL/6 mice with EHP and sedentary. Bioinformatics analysis and Sanger sequencing were used to screen hub circRNA expression and to detect full-length circRNAs, respectively. Loss-of-function analyses were conducted to assess the effects of circ-Ddx60 (c-Ddx) on EHP. After 21 days of swimming training or resting, mice underwent transverse aortic constriction (TAC) or sham surgery. Echocardiography, invasive hemodynamic measurement and histological analysis were used to evaluate cardiac remodeling and function. The presence of interaction between c-Ddx and proteins was investigated using comprehensive identification of RNA-binding proteins by mass spectrometry (ChIRP-MS). Results: In this study, we identified a novel circRNA, named c-Ddx that was preferentially expressed in myocardial tissue and significantly up-regulated in EHP mice. Silencing of c-Ddx attenuated the antihypertrophic effect of EHP and worsened heart failure in mice that underwent TAC. ChIRP-MS and molecular docking analysis validated the combination of c-Ddx and eukaryotic elongation factor 2 (eEF2). Mechanistically, c-Ddx silencing inhibited the increase of phosphorylation of eEF2 and its upstream AMP-activated protein kinase (AMPK) induced by EHP. Conclusions: C-Ddx contributes to the antihypertrophic memory of EHP by binding and activating eEF2, which would provide opportunity to search new therapeutic targets for pathological hypertrophy of heart.

Urban green spaces shaped by the post-industrial landscape possess distinctive characteristics and aesthetic features due to the exceptional properties of industrial remains. Previous studies have indicated that various types of urban green spaces without industrial remains, such as urban parks, waterfronts, and streets, have a positive impact on the public's physiological and psychological well-being. However, the extent and mechanisms of the public's response to post-industrial landscapes remain unclear. To investigate mechanisms of public perceptions of and preferences for post-industrial landscape types and elements, we conducted quantitative analysis by coupling multimodal data and comparative or difference analyses among urban green spaces. We conducted a randomized controlled experiment with 48 participants who viewed images of different combinations of post-industrial landscapes in a distraction-free environment. After a pause, Positive-Negative perception and Preference questionnaires were completed. Eye tracking data were recorded during the experiment. Changes in electrodermal activity and heart rate variability were used to measure physiological stress. This study employed Pearson's correlation model to examine the relationships between objective data and subjective data. The ANOVA test was utilized to investigate the variability of objective and subjective data across different groups. Additionally, a multiple-stepwise regression model was employed to analyze the specific influencing factors and their respective degrees of influence. We found that (1) artificial landscape elements in post-industrial landscapes were more appealing to participants and heightened their sense of stress; natural landscape elements can alleviate stress and promote restoration. (2) The percentage of flowering shrub and tree elements was significantly positively correlated with preference, while the percentage of ground-covering plant elements was significantly negatively correlated with preference. (3) Industrial construction was significantly positively correlated with the sense of historical value while industrial construction and pavement elements negatively correlated with preference. However, pavement elements significantly mitigated the sense of insecurity, poor accessibility, and pollution risk. (4) Industrial construction and pavement distinguished the post-industrial landscape from other green spaces without industrial remains while maximizing historical value and curiosity helped increase positive effects. Although impact mechanisms of natural elements in other green spaces without industrial remains showed homogeneous similarities, the scene composed of industrial mixed with natural elements may lead to different perceptions. Our findings indicate that multimodal data coupled with comparative analysis of multiple green space types can help to fully identify mechanisms by which landscape types and elements influence public perceptions and preferences. This understanding can help increase public satisfaction with post-industrial landscapes and enable researchers to determine the sustainability of post-industrial sites using interrogative design.

The intestinal flora lives in the human intestine, and affects the health of the host through the protection of the intestine and its participation in the regulation of the body's metabolism. Gut microbiota plays a key role in regulating psychological behavior by regulating the integrity of the intestinal barrier, significantly alleviating depression, aversion, and anxiety-like emotions, while also regulating and improving human cognition and emotion. It has been proven that the right intake of probiotics and moderate exercise can maintain the homeostasis of the intestinal microbiota, and effectively regulate the composition and structure of the intestinal flora, thus having a positive effect on the regulation of human cognition and emotion. This review discusses the relationship between gut microbiota and health, and further explores the mechanism of maintaining gut microbiota homeostasis through diet and exercise to improve cognitive ability and emotion.

Summary: Focal adhesions (FAs) are dynamic protein assemblies that connect cytoskeletons to the extracellular matrix and are crucial for cell adhesion and migration. KANKs are scaffold proteins that encircle FAs and act as key regulators of FA dynamics, but the molecular mechanism underlying their specified localization and functions remains poorly understood. Here, we determine the KANK1 structures in complex with talin and liprin-β, respectively. These structures, combined with our biochemical and cellular analyses, demonstrate how KANK1 scaffolds the FA core and associated proteins to modulate the FA shape in response to mechanical force. Additionally, we find that KANK1 undergoes liquid-liquid phase separation (LLPS), which is important for its localization at the FA edge and cytoskeleton connections to FAs. Our findings not only indicate the molecular basis of KANKs in bridging the core and periphery of FAs but also provide insights into the LLPS-mediated dynamic regulation of FA morphology.

Land exhibits distinct carbon source/sink states under varying utilization conditions. Under the climate change environment, developing low-carbon land use optimization strategies has become an urgent problem. Thus, this study examines the characteristics of land use carbon emissions (LUCE) resulting from land use and land cover change (LUCC) in Chongqing under five shared socioeconomic pathways (SSPs). The results show: (1) From 2000 to 2020, the LUCE in Chongqing increased significantly and then decreased slightly. The improvement of energy technology can limit carbon emissions from expanding construction. (2) In 2030, Chongqing will have the highest LUCE in SSP5 scenario, followed by SSP4 scenario, and the lowest in SSP2 scenario. However, some districts and counties in Chongqing City have the opposite situation to the whole research area. (3) In the study area, LUCE exhibits a significant positive spatial correlation with Moran's indices of 0.48, 0.27, and 0.39 in 2000, 2010, and 2020, respectively. Carbon emissions in Chongqing primarily concentrate in the main urban areas, with high-emission areas spreading outward from specific centers in the districts and counties. In 2030, spatial LUCE aggregation will decrease significantly, especially in the SSP3 scenario, with a Moran's index of 0.25. When adjusting the land use structure, policymakers need to implement differentiated land use management strategies, considering the characteristics of LUCE and their development directions. This study confirms that socioeconomic development has a direct impact on LUCE. The results of this study provide a reference for the government’s land-use assessment, achieving low-carbon development goals, and identifying regional development patterns.

This study investigates synergies between individual and national variables that promote opportunity and necessity entrepreneurship with a framework based on the national system of entrepreneurship. A qualitative comparative analysis of fuzzy sets of 39 country cases shows that institutional or individual cognitive elements are not necessary for high-opportunity or high-necessity entrepreneurship but that enhancing entrepreneurs’ ability perceptions play a universal role. The study's findings reveal optimal pathways that combine the institutional environment and individual perceptions to promote the synergistic development of opportunity and necessity entrepreneurship and reduce differences in entrepreneurial activities between countries.

Purpose: Temporomandibular joint osteoarthritis (TMJ-OA) is one of the most complex temporomandibular disorders, causing pain and dysfunction. The main pathological feature of TMJ-OA is neurovascular invasion from the subchondral bone to the condylar cartilage. This study aimed to discover the cells and genes that play an important role in the neurovascular–osteochondral network crosstalk in human TMJ-OA. Materials and methods: Condylar cartilages from patient with TMJ-OA were divided into OA group, and others from patients with benign condylar hyperplasia (CH) were used as control for further single-cell RNA-sequencing (scRNA-seq). Hematoxylin and eosin staining were performed. The cells and genes in the condylar cartilage were identified and analyzed by scRNA-seq. Results: Histological analysis revealed blood vessel invasion and ossification in the TMJ-OA condylar cartilage. The scRNA-seq identified immune cells, endothelial cells, and chondrocytes in the TMJ-OA condylar cartilage. Macrophages, especially M1-like macrophages, contributed to the inflammation, angiogenesis, and innervation. CD31+ endothelial cells contributed to the bone mineralization. The TMJ-OA cartilage chondrocytes highly expressed genes related to inflammation, angiogenesis, innervation, and ossification. The hub genes contributing to these processes in the TMJ-OA chondrocytes included CTGF, FBN1, FN1, EGFR, and ITGA5. Conclusion: Our study marks the first time scRNA-seq was used to identify the cells and genes in a human TMJ-OA condylar cartilage, and neurovascular–osteochondral network crosstalk during the human TMJ-OA process was demonstrated. Targeting the crosstalk of these processes may be a potential comprehensive and effective therapeutic strategy for human TMJ-OA.

Background: The rhizome of Atractylodes chinensis (RAC), also known as “Cangzhu”, is a well-known Chinese herbal medicine (CHMs). Due to the scarcity of wild resources, cultivated RAC and counterfeit products derived from the rhizome of Atractylodes japonica (RAJ) are also prevalent on the market. Diverse origins lead to varying quality. At present, the Chinese Pharmacopoeia (2020 edition) uses atractylodin as the only quantitative index component for RAC, and there is a lack of research on quality markers (Q-markers) that are closely related to efficacy. Purpose: This work aims to discover the Q-markers of RAC based on chemical and pharmacological strategies. Methods: The chemical composition of RAC was analyzed and identified through gas chromatography-mass spectrometry (GC–MS). The ″Chromatographic Fingerprint Similarity Evaluation System for Traditional Chinese Medicine″ was utilized to assess the similarity of the samples and identify the characteristic peaks. Network pharmacology was employed to screen targets and pathways for characteristic components of the RAC, construct “active ingredients–targets–pathways” network diagrams, and predict the Q-markers. The Q-markers for RAC were identified through an integrated analysis of the chemical components, network pharmacology, pharmacological activities and clinical applications. In addition, a preliminary evaluation of 28 batches of “Cangzhu” from different origins were conducted by GC–MS and chemical pattern recognition. Results: A total of 16 specific components of RAC were identified by GC–MS fingerprint. The network pharmacology study found that these 16 components primarily function through 29 core targets and 23 pathways. Three compounds, hinesol, atractylon, and β-eudesmol were identified as the potential Q-markers for RAC. The evaluation of 28 batches of “Cangzhu” showed that these three Q-markers could effectively distinguish RAC from RAJ, and RAJ could not be used as a substitute for RAC. There was no significant difference between cultivated RAC and wild RAC, and the quality of cultivated RAC was more uniform than wild RAC. Conclusion: This study identified and verified three potential Q-markers for RAC by using a comprehensive strategy combing of “GC–MS fingerprinting – network pharmacology – chemical pattern recognition”. It provides a basis for the establishment of a more reasonable RAC quality evaluation system. Furthermore, it provides a reference for the discovery of Q-markers in other CHMs.

Pulmonary fibrosis (PF) is a pathological change caused by repeated injuries and repair dysfunction of the alveolar epithelium. Our previous study revealed that the residues Asn3 and Asn4 of peptide DR8 (DHNNPQIR-NH2) could be modified to improve stability and antifibrotic activity, and the unnatural hydrophobic amino acids α-(4-pentenyl)-Ala and d-Ala were considered in this study. DR3penA (DHα-(4-pentenyl)-ANPQIR-NH2) was verified to have a longer half-life in serum and to significantly inhibit oxidative damage, epithelial–mesenchymal transition (EMT) and fibrogenesis in vitro and in vivo. Moreover, DR3penA has a dosage advantage over pirfenidone through the conversion of drug bioavailability under different routes of administration. A mechanistic study revealed that DR3penA increased the expression of aquaporin 5 (AQP5) by inhibiting the upregulation of miR-23b-5p and the mitogen-activated protein kinase (MAPK) pathway, indicating that DR3penA may alleviate PF by regulating MAPK/miR-23b-5p/AQP5. Safety evaluation showed that DR3penA is a peptide drug without obvious toxicity or acute side effects and has significantly improved safety compared to DR8. Thus, our findings suggest that DR3penA, as a novel and low-toxic peptide, has the potential to be a leading compound for PF therapy, which provides a foundation for the development of peptide drugs for fibrosis-related diseases.

Introduction: Increasing evidence demonstrates that the activation states and diverse spectrum of macrophage subtypes display dynamic heterogeneity in the tumor microenvironment, which plays a critical role in a variety of cancer types. Objectives: To investigate the heterogeneity and the homeostasis of different macrophage subtypes, as well as their effect on biological and clinical manifestations of ovarian cancer (OV). Method: Integrated immunogenomic analysis of single-cell and bulk tissue transcriptome profiling was performed to systematically investigate the association between macrophage activation and prognostic and therapeutic efficacy. Consensus clustering analysis was used to define novel macrophage subtypes. An artificial neural network was used to simulate the dynamic activation of macrophages. Results: The pan-cohort results suggested that high relative infiltration abundance of M0 and M1 macrophages was associated with improved outcome and therapeutic efficacy. However, it was the opposite for M2 macrophages. Unsupervised consensus clustering analysis revealed two OV subgroups characterized by a balance between M0, M1 and M2 macrophages with distinct clinical and immunological behaviors. Finally, a macrophage polarization-derived artificial neural network model was proposed to serve as a robust prognostic factor and predictive biomarker for therapeutic efficacy, which was validated in different independent patient cohorts. Conclusion: The present study provides a new understanding of macrophage heterogeneity and its association with OV prognosis and underlines the future clinical potential of a macrophage activation model for tumor prevention and treatment.

Summary: Background: Regulatory T cells (Tregs) can alleviate the development of autoimmune and inflammatory diseases, thereby proposing their role as a new therapeutic strategy. Parasitic helminths have co-evolved with hosts to generate immunological privilege and immune tolerance through inducing Tregs. Thus, constructing a “Tregs-induction”-based discovery pipeline from parasitic helminth is a promising strategy to control autoimmune and inflammatory diseases. Methods: The gel filtration chromatography and reverse-phase high-performance liquid chromatography (RP-HPLC) were used to isolate immunomodulatory components from the egg extracts of Schistosoma japonicum. The extracted peptides were evaluated for their effects on Tregs suppressive functions using flow cytometry, ELISA and T cell suppression assay. Finally, we carried out colitis and psoriasis models to evaluate the function of Tregs induced by helminth-derived peptide in vivo. Findings: Here, based on target-driven discovery strategy, we successfully identified a small 3 kDa peptide (SjDX5-53) from egg extracts of schistosome, which promoted both human and murine Tregs production. SjDX5-53 presented immunosuppressive function by arresting dendritic cells (DCs) at an immature state and augmenting the proportion and suppressive capacity of Tregs. In mouse models, SjDX5-53 protected mice against autoimmune-related colitis and psoriasis through inducing Tregs and inhibiting inflammatory T-helper (Th) 1 and Th17 responses. Interpretation: SjDX5-53 exhibited the promising therapeutic effects in alleviating the phenotype of immune-related colitis and psoriasis. This study displayed a screening and validation pipeline of the inducer of Tregs from helminth eggs, highlighting the discovery of new biologics inspired by co-evolution of hosts and their parasites. Funding: This study was supported by the Natural Science Foundation of China (82272368) and Natural Science Foundation of Jiangsu Province (BK20211586).

Wearable flexible pressure sensors are a novel class of human activity detection device. However, the preparation of pressure sensors with high sensitivity and wide sensing range still faces great challenges. This study reveals an flexible heat-resistant variable density point pressure sensing array (PSA) with ultra-wide sensing range based on Ti3C2Tx-MXene. MXene containing polar oxygen-containing functional groups coated polyester fiber fabricated the pressure sensing layer while a stainless steel wire core is used as a flexible electrode for signal collection. The signal processing device rapidly converts the mechanical signal into electrical signal output to increase the transmission speed and range. Experimental results show that the PSA can effectively sense dynamic and static pressures with high sensitivity (0.14–0.87 kPa−1 over a pressure range of 7.2 Pa–2000 kPa), a wide sensing range (0–15000 kPa), fast response time (80 ms), 10,000 cycles (2000 kPa) stability and maintains a 81.25% current response. The noval fully woven structural flexible PSA exhibited larger area, of which the weave density is varied to control resolution and the pressure mapping is referenced to each pixel point to qualitatively and quantitatively analyze shape and pressure distribution. Variable density points pressure sensor with wide sensing range and spatial pressure mappinghas promising applications in healthcare.

Summary: Background: Various studies have reported cell-free RNAs (cfRNAs) as noninvasive biomarkers for detecting hepatocellular carcinoma (HCC). However, they have not been independently validated, and some results are contradictory. We provided a comprehensive evaluation of various types of cfRNA biomarkers and a full mining of the biomarker potential of new features of cfRNA. Methods: We first systematically reviewed reported cfRNA biomarkers and calculated dysregulated post-transcriptional events and cfRNA fragments. In 3 independent multicentre cohorts, we further selected 6 cfRNAs using RT-qPCR, built a panel called HCCMDP with AFP using machine learning, and internally and externally validated HCCMDP's performance. Findings: We identified 23 cfRNA biomarker candidates from a systematic review and analysis of 5 cfRNA-seq datasets. Notably, we defined the cfRNA domain to describe cfRNA fragments systematically. In the verification cohort (n = 183), cfRNA fragments were more likely to be verified, while circRNA and chimeric RNA candidates were neither abundant nor stable as qPCR-based biomarkers. In the algorithm development cohort (n = 287), we build and test the panel HCCMDP with 6 cfRNA markers and AFP. In the independent validation cohort (n = 171), HCCMDP can distinguish HCC patients from control groups (all: AUC = 0.925; CHB: AUC = 0.909; LC: AUC = 0.916), and performs well in distinguishing early-stage HCC patients (all: AUC = 0.936; CHB: AUC = 0.917; LC: AUC = 0.928). Interpretation: This study comprehensively evaluated full-spectrum cfRNA biomarker types for HCC detection, highlighted the cfRNA fragment as a promising biomarker type in HCC detection, and provided a panel HCCMDP. Funding: National Natural Science Foundation of China, and The National Key Basic Research Program (973 program).

N6-methyladenosine (m6A), the most common internal modification in RNA, can be regulated by three types of regulators, including methyltransferases (writers), demethylases (erasers), and m6A binding proteins (readers). Recently, immunotherapy represented by immune checkpoint blocking has increasingly become an effective cancer treatment, and increasing shreds of evidence show that m6A RNA methylation affects cancer immunity in various cancers. Until now, there have been few reviews about the role and mechanism of m6A modification in cancer immunity. Here, we first summarized the regulation of m6A regulators on the expression of target messenger RNAs (mRNA) and their corresponding roles in inflammation, immunity response, immune process and immunotherapy in various cancer cells. Meanwhile, we described the roles and mechanisms of m6A RNA modification in tumor microenvironment and immune response by affecting the stability of non-coding RNA (ncRNA). Moreover, we also discussed the m6A regulators or its target RNAs which might be used as predictor of cancer diagnosis and prognosis, and shed light on the potentiality of m6A methylation regulators as therapeutic targets in cancer immunity.

Objectives: Influenza vaccination is an effective method for preventing influenza virus infection. Herein, we performed a meta-analysis to quantify global influenza vaccination rates (IVRs) and the factors influencing its uptake in the general population, individuals with chronic diseases, pregnant women, and healthcare workers. Methods: Related articles were obtained from online databases and screened according to the inclusion criteria. The pooled IVRs were calculated using the random effects model. Subgroup analyses and multivariate meta-regression were performed to determine the factors associated with influenza vaccine uptake. Results: We included 522 studies from 68 countries/regions. Most studies were conducted in the European region (247 studies), followed by the Western Pacific (135 studies) and American regions (100 studies). The IVRs with 95% confidence intervals (CIs) in the general population were lower (24.96%, 23.45%-26.50%) than in individuals with chronic diseases (41.65%, 40.08%-43.23%), healthcare workers (36.57%, 33.74%-39.44%), and pregnant women (25.92%, 23.18%-28.75%). The IVRs in high-income countries/regions were significantly higher than that in middle-income countries/regions. A free national or regional vaccination policy, perception of influenza vaccine efficacy and disease severity, a recommendation from healthcare workers, and having a history of influenza vaccination were positive factors for vaccine uptake (P

The electricity trading market promotes the frequency and scale of power exchange in the distribution network, the uncertainty of trading volume, trading duration, and trading partners affect the total supply capability (TSC) of the distribution network (DN). The paper proposed a TSC model of DN with electric trading market. Firstly, the load clearing model of electricity trading is established. Then, the least square method is used to fit the growth curve functions of conventional load and power trading load. TSC model of DN is developed based on the growth functions of two loads. Finally, the TSC model is solved by the improved repetitive power flow algorithm (RPA). The simulation results of the improved IEEE 54-bus test system verify the feasibility and applicability of the proposed TSC model.