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Natural earthquakes and micro-seismicity resulting from hydraulic fracturing or other engineering practices display distinctively different spatial-temporal features, like mixed burst- and swarm-like features or predominantly swarm-like features. The mechanism(s) contributing to such observations can be diverse. We present the inspections on the dynamic formation process of the single swarm-like tree in laboratory acoustic emission (AE) catalogs. Such largest swarm-like trees can contain >97% AE events from the entire catalog within a test; and all catalogs under investigation display scale-invariance features. The formation of the largest swarm-like tree correlates with the rock fracture process analogue of the source pervasive process, where its AE releases exhibit significant spatial well-organization. Comparison to other laboratory catalogs under different laboratory settings helps us identify the spatial continuity of the rock fracture process as the primary factor in forming the largest swarm-like trees at laboratory scale. The stress transfer process is involved in the rock fracture process for the tests having pre-existing spatial discontinuity. Artificial perturbations on the spatial information induced by the stress transfer process further confirm that stress transfer also serves to shift the pure swarm-like catalog into a mixed burst- and swarm-like catalog. These laboratory observations may provide inspirational insights for understanding the field-scale mechanism(s) shaping the spatial-temporal energy release features.

Abstract Background Empathy of medical students is crucial, yet it tends to decline as students enter later academic years. Empathy appeared to be affected by the learning environment (LE), which could be a potential contributor. We conducted a cross-sectional study to investigate the association between LE and empathy. Method The study comprised overall 10,901 medical students from 12 Chinese medical schools. Jefferson Scale of Empathy (JSE) was utilized to assess empathy, while a 5-point question and the Johns Hopkins Learning Environment Scale were employed to evaluate LE. JSE scores were compared across LE levels using Pearson Chi-square, Welch’s ANOVA, and univariable linear regression. After adjusting for covariates, multivariable linear and logistic regression were used to assess the independent connection between LE and empathy. Confounders were controlled by stratified subgroup analysis. Results LE was significantly associated with medical students’ empathy, as shown by the Pearson Chi-square test (p

Abstract Background Alzheimer’s disease (AD) is a prevalent neurodegenerative disorder worldwide, and microglia are thought to play a central role in neuroinflammatory events occurring in AD. Chemerin, an adipokine, has been implicated in inflammatory diseases and central nervous system disorders, yet its precise function on microglial response in AD remains unknown. Methods The APP/PS1 mice were treated with different dosages of chemerin-9 (30 and 60 µg/kg), a bioactive nonapeptide derived from chemerin, every other day for 8 weeks consecutively. The primary mouse microglia were stimulated by amyloid beta 42 (Aβ42) oligomers followed by treatment with chemerin-9 in vitro. ChemR23 inhibitor α-NETA was further used to investigate whether the effects of chemerin-9 were ChemR23-dependent. Results We found that the expression of chemerin and ChemR23 was increased in AD. Intriguingly, treatment with chemerin-9 significantly ameliorated Aβ deposition and cognitive impairment of the APP/PS1 mice, with decreased microglial proinflammatory activity and increased phagocytic activity. Similarly, chemerin-9-treated primary microglia showed increased phagocytic ability and decreased NLRP3 inflammasome activation. However, the ChemR23 inhibitor α-NETA abolished the neuroprotective microglial response of chemerin-9. Conclusions Collectively, our data demonstrate that chemerin-9 ameliorates cognitive deficits in APP/PS1 transgenic mice by boosting a neuroprotective microglial phenotype. Graphical Abstract

Abstract Background Hepatic encephalopathy (HE) represents a critical complications of end-stage liver disease, serving as an independent predictor of mortality among patients with cirrhosis. Despite effective treatment with rifaximin, some patients with HE still progress to recurrent episodes, posing a significant therapeutic challenge. Recurrent HE is defined as experiencing two or more episodes within a 6-month period. Previous research has suggested that FMT may emerge as a promising treatment for recurrent HE. However, there remains a critical need to explore the optimal dosage. This trial aims to abscess the efficacy and safety of two FMT dosages: 800 ml or 400 ml total bacterial count, including mortality and quality of life. Methods This multicenter, prospective, randomized controlled trial will enroll 100 eligible patients from 31 hospitals in China. Participants will be randomly assigned in a 1:1 ratio to either the high-dose group (800 ml total bacterial count) or the low-dose group (400 ml total bacterial count). The primary objective is to assess the efficacy and safety of both dosages on outcomes at 24 and 48 weeks, including mortality and quality of life. Discussion If either or both dosages of FMT demonstrate safe and effective treatment of recurrent HE, leading to improve quality of life and survival at 24 and 48 weeks, this trial would address a significant gap in the management of recurrent HE, carrying innovative and clinically significant implications. Trial registration NCT05669651 on ClinicalTrials.gov. Registered on 29 December 2022. CHiCTR2200067135 on China Registered Clinical Trial Registration Center. Registered on 27 December 2022.

Abstract Hepatitis B is one of the public health priorities worldwide, especially in the Southwest China. Our study aimed to investigate the relationship between genotypes and drug resistance mutations among HBV patients in Southwest China, with the objective of providing guidance for clinical antiviral treatment. A total of 4266 chronic hepatitis B (CHB) patients treated in the Qianjiang Hospital of Chongqing University were included in our study from 2014 to 2020. Both genotypes and drug-resistant mutations of CHB patients were determined by polymerase chain reaction (PCR). Genotype B and genotype C were the main HBV genotypes in our study. We found 54 mutation patterns, including 9 single-site mutations and 45 multiple-site mutations, accounting for 57.64% and 42.36%, respectively. rtM204I/V/S (485/1936) was the most common single-site mutation type, and rtL180M + rtM204I/V (482/1936) was the most common multiple-site mutation type. 1372 CHB patients were resistant to LAM + LDT, and 342 CHB patients were resistant to ADV. There was only 1 CHB patient who exhibited resistance to LAM + LDT + ADV + ETV, with a specific mutation pattern of rtA181T + rtT184L + rtM204V. Our study demonstrated trends in genetic mutations and drug resistance in CHB patients to enable timely adjustment of antiviral treatment strategies.

Objective: To investigate the efficacy and safety of Liqingtong (LQT) granules in patients with dampness-heat hyperuricemia. Methods: A randomized, double-blind, placebo-controlled pilot trial was conducted at the 983rd Hospital of the Joint Logistic Support Force of the People's Liberation Army from March 15, 2023, to August 10, 2023. In total, 119 participants were enrolled in this trial, and participants were given either LQT granules or placebo for 60 days based on a health education. The primary outcome was serum uric acid (SUA) level, and the secondary outcome was the traditional Chinese medicine (TCM) symptom score, measured on days 0, 30, and 60. Safety indicators, including liver function, kidney function, blood routine, glucose, blood lipid, blood pressure, and heart rate were tested on days 0 and 60 of the trial. The data were analyzed using Prism 9 software, and the significance level was set at P

Purpose: This study aimed to investigate the efficacy of orthopedic insoles, specifically three-dimensional (3D)-printed orthopedic insoles, for treatment of symptomatic flexible flatfoot in school-age children. Methods: A systematic review of PubMed and China National Knowledge Infrastructure (CNKI) from database inception to March 2024 was conducted to determine additional studies. This single-center study included 38 participants, including 20 who chose ordinary orthopedic insoles and 18 who chose 3D printed orthopedic insoles, presented from January 2021 to December 2022. Pain symptom relief was compared between the two groups after 1 year of follow-up. Results: A systematic review identified an additional six publications, involving 206 samples, and meta-analysis indicated that the force-bearing area, arch index, and heel valgus angle after treatment were 0.74 (95 ​% confidence interval [CI]: 0.65–1.01), 0.20 (95 ​% CI: 0.03–1.35), and 0.10 (95 ​% CI: 0.03–0.28) of those before treatment, respectively. The 1-year follow-up study revealed that because of its good comfort, 3D printed orthopedic insole can significantly improve the wearing time of both male (P ​

Wood scrimber as a promising eco-friendly material in wood technology. This study evaluated the physical and mechanical properties of ginkgo scrimber, focusing on density, moisture content, water absorption, thickness swelling, flexural modulus of elasticity, bending strength, tensile modulus of elasticity, tensile strength, compressive modulus of elasticity, compressive strength, and shear strength. The results showed that the material had low variation in density and moisture content, indicating good homogeneity of the material. Mechanical properties tests showed that the material’s mechanical properties met high-quality standards, although variability in bending strength suggested potential issues with adhesive application. Some specimens experienced fractures perpendicular to adhesive layers, affecting strength. Despite this, ginkgo scrimber exhibited mechanical properties comparable to or exceeding those of reconstituted bamboo and laminated veneer lumber. The findings highlight its potential for construction, with recommendations for improved adhesive application and manufacturing processes to enhance performance stability.

Abstract Background The clinical response rate to immune checkpoint blockade (ICB) therapy in melanoma remains low, despite its widespread use. Circular non-coding RNAs (circRNAs) are known to play a crucial role in cancer progression and may be a key factor limiting the effectiveness of ICB treatment. Methods The circRNAs that were downregulated after coadministration compared with single administration of PD-1 inhibitor administration were identified through RNA-seq and Ribo-seq, and thus the circPIAS1 (mmu_circ_0015773 in mouse, has_circ_0008378 in human) with high protein coding potential was revealed. Fluorescence in situ hybridization (FISH) assays were conducted to determine the localization of circPIAS1 in human and mouse melanoma cells, as well as its presence in tumor and adjacent tissues of patients. Validation through dual-luciferase reporter assay and LC–MS/MS confirmed the ability of circPIAS1 to encode a novel 108 amino acid polypeptide (circPIAS1-108aa). Specific antisense oligonucleotides (ASOs) targeting the junction site of circPIAS1 were developed to reduce its intracellular levels. Proliferation changes in melanoma cells were assessed using CCK8, EdU, and colony formation assays. The impact of circPIAS1-108aa on the ferroptosis process of melanoma cells was studied through GSH, MDA, and C11-BODIPY staining assays. Western Blot, Immunoprecipitation (IP), and Immunoprecipitation-Mass Spectrometry (IP-MS) techniques were employed to investigate the impact of circPIAS1-108aa on the P-STAT1/SLC7A11/GPX4 signaling pathway, as well as its influence on the balance between STAT1 SUMOylation and phosphorylation. Additionally, a melanoma subcutaneous transplanted tumor mouse model was utilized to examine the combined effect of reducing circPIAS1 levels alongside PD-1 inhibitor. Results Compared with the group treated with PD-1 inhibitor alone, circPIAS1 was significantly down-regulated in the coadministration group and demonstrated higher protein coding potential. CircPIAS1, primarily localized in the nucleus, was notably upregulated in tumor tissues compared to adjacent tissues, where it plays a crucial role in promoting cancer cell proliferation. This circRNA can encode a unique polypeptide consisting of 108 amino acids, through which it exerts its cancer-promoting function and impedes the effectiveness of ICB therapy. Mechanistically, circPIAS1-108aa hinders STAT1 phosphorylation by recruiting SUMO E3 ligase Ranbp2 to enhance STAT1 SUMOylation, thereby reactivating the transduction of the SLC7A11/GPX4 signaling pathway and restricting the immunogenic ferroptosis induced by IFNγ. Furthermore, the combination of ASO-circPIAS1 with PD-1 inhibitor effectively inhibits melanoma growth and significantly enhances the efficacy of immune drugs in vivo. Conclusions Our study uncovers a novel mechanism regarding immune evasion in melanoma driven by a unique 108aa peptide encoded by circPIAS1 in melanoma that dramatically hinders immunogenic ferroptosis triggered by ICB therapy via modulating the balance between SUMOylation and phosphorylation of STAT1. This work reveals circPIAS1-108aa as a critical factor limiting the immunotherapeutic effects in melanoma and propose a promising strategy for improving ICB treatment outcomes.

To determine the appropriate stiffness coefficient k values for rubber belts used in dynamic testing of the elastic modulus and shear modulus of timber and solid wood composite materials, this study employed three different thicknesses of rubber belts. Dynamic tests were conducted on straw boards, Laminated Veneer Lumber (LVL), and Spruce-Pine-Fir (SPF) materials, and the results were validated and analyzed using static four-point bending tests. The conclusions drawn from this research indicate that the range of stiffness coefficient k values for the rubber belts obtained through dynamic testing fell between 0.05 and 0.28 N/m. The correctness of the dynamic testing method was verified through static four-point bending tests. The error levels for elastic modulus E and shear modulus G of the same type of board measured using the three different rubber belts were below 9.5% and 9.8%, respectively.

Purpose: This study aims to assess whether dual anti-HER2 therapy with trastuzumab and pertuzumab increases early cardiac toxicity compared to trastuzumab alone in breast cancer (BC) patients receiving postoperative radiation therapy (RT). Methods: Consecutive operable BC patients receiving postoperative RT and trastuzumab with or without pertuzumab between January 2017 and September 2020 at seven tertiary hospitals in China were retrospectively reviewed. Cardiac examinations included echocardiography, electrocardiogram (ECG), NT-proBNP, and cTnI at baseline before RT and during the follow-up. The cardiac event is any new-onset symptomatic heart disease or abnormality in the cardiac examination after RT. Results: In total, 681 patients were enrolled in the analysis, of whom 567 were treated with trastuzumab-alone and 124 patients received dual anti-HER2 therapy. The median follow-up was 11 months. Multivariate analysis showed that left-sided breast cancer (HR 2.38; 95%CI 1.65–3.44, p 50 years is an independent risk factor for developing LVDD (HR 5.16; 95%CI 1.17–22.73, P-value = 0.030). Dosimetric analysis showed that patients who developed subclinical cardiac events had increased mean heart dose (412.0 ± 249.6 vs. 347.2 ± 242.6 cGy, P-value = 0.010). Among right-sided patients or patients receiving anthracycline-based chemotherapy, the dual-targeted cohort had a higher risk of developing ECG abnormalities compared to the trastuzumab-only cohort. Conclusion: Compared with trastuzumab-only, dual anti-HER2 therapy does not increase early cardiac toxicity in combination with postoperative RT in BC patients. Cardiac radiation exposure remains the primary risk factor for early toxicity.

Pain after surgery causes significant suffering. Opioid analgesics cause severe side effects and accidental death. Therefore, there is an urgent need to develop non-opioid therapies for managing post-surgical pain. Local application of Clarix Flo (FLO), a human amniotic membrane (AM) product, attenuated established post-surgical pain hypersensitivity without exhibiting known side effects of opioid use in mice. This effect was achieved through direct inhibition of nociceptive dorsal root ganglion (DRG) neurons via CD44-dependent pathways. We further purified the major matrix component, the heavy chain-hyaluronic acid/pentraxin 3 (HC-HA/PTX3) from human AM that has greater purity and water solubility than FLO. HC-HA/PTX3 replicated FLO-induced neuronal and pain inhibition. Mechanistically, HC-HA/PTX3-induced cytoskeleton rearrangements to inhibit sodium current and high-voltage activated calcium current on nociceptive DRG neurons, suggesting it is a key bioactive component mediating pain relief. Collectively, our findings highlight the potential of naturally derived biologics from human birth tissues as an effective non-opioid treatment for post-surgical pain. Moreover, we unravel the underlying neuronal mechanisms of pain inhibition induced by FLO and HC-HA/PTX3.

Abstract Background Medical school learning environment (MSLE) has a holistic impact on students’ psychosomatic health, academic achievements, and personal development. Students in different grades perceive MSLE in different ways. Thus, it is essential to investigate the specific role of student’s grade in the perception of MSLE. Methods Using the Johns Hopkins Learning Environment Scale (JHLES) as a quantification instrument for the perception level of MSLE, 10,901 medical students in 12 universities in China were categorized into low or high JHLES group according to their questionnaires. We investigated the relationship between student’s grade and JHLES category by univariate analysis employing Pearson Chi-square test and Welch’s ANOVA. Then multivariable logistic regression analysis confirmed the predictive efficacy of student’s grade. A nomogram concerning the prediction of low JHLES score probability in medical students was also constructed. Results A significant difference between two JHLES categories among students in different grades was observed (p

Abstract Sestrin2 (Sesn2) has been previously confirmed to be a stress-response molecule. However, the influence of Sesn2 on myogenic differentiation remains elusive. This study was conducted to analyze the role of Sesn2 in the myogenic differentiation of C2C12 myoblasts and related aspects in mdx mice, an animal model of Duchenne muscular dystrophy (DMD). Our results showed that knockdown of Sesn2 reduced the myogenic differentiation capacity of C2C12 myoblasts. Predictive analysis from two databases suggested that miR-182-5p is a potential regulator of Sesn2. Further experimental validation revealed that overexpression of miR-182-5p decreased both the protein and mRNA levels of Sesn2 and inhibited myogenesis of C2C12 myoblasts. These findings suggest that miR-182-5p negatively regulates myogenesis by repressing Sesn2 expression. Extending to an in vivo model of DMD, knockdown of Sesn2 led to decreased Myogenin (Myog) expression and increased Pax7 expression, while its overexpression upregulated Myog levels and enhanced the proportion of slow-switch myofibers. These findings indicate the crucial role of Sesn2 in promoting myogenic differentiation and skeletal muscle regeneration, providing potential therapeutic targets for muscular dystrophy.

Abstract Age at first farrowing (AFF) is a reproductive trait with low heritability and high importance in the pig industry. To enhance the statistical power of genome‐wide association study (GWAS) and further explore the genetic nature of AFF, we first conducted GWAS meta‐analysis using three Yorkshire populations, and then integrated the Pig Genotype‐Tissue Expression (PigGTEx) resources to interpret their potential regulatory mechanism. Additionally, we compared the AFF in pig with the age at first birth (AFB) of human using GWAS summary statistics. We detected 18 independent variants in GWAS meta‐analysis and 8 genes in gene‐based association analysis significantly associated with AFF. By integrating the PigGTEx resource, we conducted transcriptome‐wide association study (TWAS) and colocalization analysis on 34 pig tissues. In TWAS, we detected 18 significant gene‐tissue pairs, such as DCAF6 in uterus and CREG1 in blood. In colocalization, we found 111 potential candidate tissue‐gene pairs, such as GJD4 and LYPLAL1. We found that the homologous gene, CHST10, might be the potential candidate gene between humans in AFB and pigs in AFF. In conclusion, integrating GWAS meta‐analysis and PigGTEx resources is a meaningful way to decipher the genetic architecture of complex traits. We found that DCAF6, CREG1, GJD4, and LYPLAL1 are candidate genes with high reliability for AFF in swine. The comparative analysis showed that CHST10 might play a potentially critical role in AFB/AFF across human and pigs.

Abstract Background The epidemiology and risk factors for postoperative complications related to free flap reconstruction in head and neck cancer patients admitted to the Intensive Care Unit (ICU) are unknown. Methods We performed a retrospective cohort study of patients with free flap reconstruction of head and neck cancer between September 2015 and April 2023 admitted to the ICU of Beijing Tongren Hospital. The univariate and multivariate analyses were used to explore the risk factors for postoperative complications related to free flap reconstruction admitted to ICU, including flap necrosis, bleeding, fistula, and infection. Results A total of 239 patients were included in this study, and 38 (15.9%) patients had postoperative complications related to free flap reconstruction. The median length of ICU stay was 1 day (interquartile range, 1–2 days). Multivariate analysis found that low BMI (P

Abstract Background Global human activities were significantly impacted by the emergence of the coronavirus disease 2019 (COVID-19) pandemic caused by the 2019 novel coronavirus. This study aimed to investigate the prevalence and genotype distribution of HPV infection in Central Fujian Province during the pandemic. Methods Cervical samples were collected from 21,612 outpatients and 12,664 females who underwent physical examinations and HPV screening at the People’s Hospital of Fujian Province in Fuzhou from April 2020 to April 2023. HPV detection and genotyping were conducted using PCR hybridization. Results The overall HPV infection rate was 16.1% during the COVID-19 pandemic, with the outpatient group exhibiting a greater infection rate (19.0%) than did the healthy group (12.3%). The top five high-risk HPV (HR-HPV) genotypes in both groups were HPV52, HPV53, HPV58, HPV16, and HPV51. Additionally, HPV81 and HPV43 were the two most common low-risk HPV (LR-HPV) genotypes in the patient group, while HPV81 and HPV42 were the two most common LR-HPV genotypes in the healthy group. The highest prevalence of HPV infection was observed in individuals aged ≤ 24 years (28.4%, 95% CI 25.9–30.9), followed by those aged ≥ 55 years (23.6%, 95% CI 21.6–24.7) and other age groups. The prevalence decreased from 23.0% (95% CI 22.4–23.7) in 2018–2019 to 13.8% (95% CI 12.0-15.5) in 2023. Conclusion This study provides valuable insights into the prevalence and genotypes of HPV infection in the female population of Central Fujian Province from 2020 to 2023. The findings indicate that the prevalence of HPV infection in Central Fujian Province remains relatively low compared to the national average. Furthermore, the prevalence of HPV decreased during the COVID-19 pandemic; however, as the pandemic waned, there was potential for an increase in HPV infection rates. Therefore, it is crucial to strengthen HPV screening and vaccination strategies to prevent the potential spread of HPV.

Abstract Background Fostering empathy has been continuously emphasized in the global medical education. Empathy is crucial to enhance patient-physician relationships, and is associated with medical students’ academic and clinical performance. However, empathy level of medical students in China and related influencing factors are not clear. Methods This was a cross-sectional study among medical students in 11 universities. We used the Jefferson Scale of Empathy Student-version of Chinese version to measure empathy level of medical students. Factors associated with empathy were identified by the univariate and multivariate logistic regression analyses. Based on the variables identified above, the nomogram was established to predict high empathy probability of medical students. Receiver operating characteristic curve, calibration plot and decision curve analysis were used to evaluate the discrimination, calibration and educational utility of the model. Results We received 10,901 samples, but a total of 10,576 samples could be used for further analysis (effective response rate of 97.02%). The mean empathy score of undergraduate medical students was 67.38 (standard deviation = 9.39). Six variables including gender, university category, only child or not, self-perception doctor-patient relationship in hospitals, interest of medicine, Kolb learning style showed statistical significance with empathy of medical students (P

Abstract Background Abnormal remodeling of distal pulmonary arteries in patients with pulmonary arterial hypertension (PAH) leads to progressively increased pulmonary vascular resistance, followed by right ventricular hypertrophy and failure. Despite considerable advancements in PAH treatment prognosis remains poor. We aim to evaluate the potential for using the cytokine resistin as a genetic and biological marker for disease severity and survival in a large cohort of patients with PAH. Methods Biospecimens, clinical, and genetic data for 1121 adults with PAH, including 808 with idiopathic PAH (IPAH) and 313 with scleroderma-associated PAH (SSc-PAH), were obtained from a national repository. Serum resistin levels were measured by ELISA, and associations between resistin levels, clinical variables, and single nucleotide polymorphism genotypes were examined with multivariable regression models. Machine-learning (ML) algorithms were applied to develop and compare risk models for mortality prediction. Results Resistin levels were significantly higher in all PAH samples and PAH subtype (IPAH and SSc-PAH) samples than in controls (P

Abstract Background This study sought to investigate the prognostic value of basement membrane (BM)-associated gene expressions in oral cancer. Methods We harvested and integrated data on BM-associated genes (BMGs), the oral cancer transcriptome, and clinical information from public repositories. After identifying differentially expressed BMGs, we used Cox and Lasso regression analyses to create a BMG-based risk score for overall survival at various intervals. We then validated this score using the GSE42743 cohort as a validation set. The prognostic potential of the risk scores and their relations to clinical features were assessed. Further, we conducted functional pathway enrichment, immune cell infiltration, and immune checkpoint analyses to elucidate the immunological implications and therapeutic potential of the BMG-based risk score and constituent genes. To confirm the expression levels of the BMG LAMA3 in clinical samples of oral cancer tissue, we performed quantitative real-time PCR (qRT-PCR) and immunohistochemical staining. Results The BMGs LAMA3, MMP14, and GPC2 demonstrated notable prognostic significance, facilitating the construction of a BMG-based risk score. A higher risk score derived from BMGs correlated with a poorer survival prognosis for oral cancer patients. Moreover, the risk-associated BMGs exhibited a significant relationship with immune function variability (P

PurposeThis study aimed to develop a model to predict the risk of axillary lymph node (ALN) metastasis in breast cancer patients, using gray-scale ultrasound and clinical pathological features.MethodsA retrospective analysis of 212 breast cancer patients who met the inclusion criteria from January 2011 to December 2021 was carried out. Clinical and pathological characteristics, including age, tumor size, pathological type, molecular subtype, estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and proliferation cell nuclear antigen (Ki-67), were examined. Preoperative ultrasound examinations were performed, and ultrasound radiomics features of breast cancer lesions were extracted using Pyradiomics software. The data was divided into training (70%) and testing (30%) sets. A predictive model for axillary lymph node metastasis (ALNM) was established by combining clinical and ultrasound features. The diagnostic performance of the model was evaluated using receiver operating characteristic (ROC) curves and five-fold cross-validation.ResultsThe rate of lymph node metastasis was 41.51%. Using LASSO algorithm, 17 features linked to ALN metastasis were extracted from a comprehensive databank of 8 clinical features and 1314 ultrasound radiomic attributes. Of these, four were clinical-pathological features (tumor size, tumor type, age, and expression levels of the Ki-67 protein), and 13 were radiomic features. And the following features exhibited both high weights and correlation coefficients: tumor size (R=0.29, weight=0.071), tumor type (R=-0.24, weight=-0.048), wavelet-LH_glcm_Imc1 (R=0.28, weight=0.029363), wavelet-LH_glszm_SZNUN (R=-0.20, weight=-0.028507), and squareroot_ firstorder_ Minimum (R= -0.25, weight= -0.059). The ROC area under the curve for the model in the training and testing sets was 0.882 (95% CI: 0.830-0.935) and 0.853 (95% CI: 0.762-0.945), respectively. The predictive model demonstrated a sensitivity of 87.5% on the training set and 79.2% on the test set, with corresponding specificities of 75.0% and 77.5%, accuracy of 80.4% and 78.1%, respectively. When evaluated using 5-fold cross-validation, the model achieved an average test set area under the curve (AUC) of 0.799 and a training set AUC of 0.852.ConclusionThe clinical-radiomic model has the potential to predict axillary lymph node metastasis in breast cancer.

Abstract Persister cells (PS) selected for anticancer therapy have been recognized as a significant contributor to the development of treatment‐resistant malignancies. It is found that imposing glutamine restriction induces the generation of PS, which paradoxically bestows heightened resistance to glutamine restriction treatment by activating the integrated stress response and initiating the general control nonderepressible 2‐activating transcription factor 4‐alanine, serine, cysteine‐preferring transporter 2 (GCN2‐ATF4‐ASCT2) axis. Central to this phenomenon is the stress‐induced ATF4 translational reprogramming. Unfortunately, directly targeting ATF4 protein has proven to be a formidable challenge because of its flat surface. Nonetheless, a G‐quadruplex structure located within the promoter region of ATF4 (ATF4‐G4) is uncovered and resolved, which functions as a transcriptional regulator and can be targeted by small molecules. The investigation identifies the natural compound coptisine (COP) as a potent binder that interacts with and stabilizes ATF4‐G4. For the first time, the high‐resolution structure of the COP‐ATF4‐G4 complex is determined. The formation of this stable complex disrupts the interaction between transcription factor AP‐2 alpha (TFAP2A) and ATF4‐G4, resulting in a substantial reduction in intracellular ATF4 levels and the eventual death of cancer cells. These seminal findings underscore the potential of targeting the ATF4‐G4 structure to yield significant therapeutic advantages within the realm of persister cancer cells induced by glutamine‐restricted therapy.

Chemotherapeutics can induce immunogenic cell death (ICD) in tumor cells, offering new possibilities for cancer therapy. However, the efficiency of the immune response generated is insufficient due to the inhibitory nature of the tumor microenvironment (TME). Here, we developed a pH/reactive oxygen species (ROS) dual-response system to enhance chemoimmunotherapy for melanoma. The system productively accumulated in tumors by specific binding of phenylboronic acid (PBA) to sialic acids (SA). The nanoparticles (NPs) rapidly swelled and released quercetin (QUE) and doxorubicin (DOX) upon the stimulation of tumor microenvironment (TME). The in vitro and in vivo results consistently demonstrated that the NPs improved anti-tumor efficacy and prolonged survival of mice, significantly enhancing the effects of the combination. Our study revealed DOX was an ICD inducer, stimulating immune responses and promoting maturation of dendritic cells (DCs). Additionally, QUE served as a TME regulator by inhibiting the cyclooxygenase-2 (COX2)-prostaglandin E2 (PGE2) axis, which influenced various immune cells, including increasing cytotoxic T cells (CLTs) infiltration, promoting M1 macrophage polarization, and reducing regulatory T cells (Tregs) infiltration. The combination synergistically facilitated chemoimmunotherapy efficacy by remodeling the immunosuppressive microenvironment. This work presents a promising strategy to increase anti-tumor efficiency of chemotherapeutic agents.

Abstract Background Structural variations (SVs) have significant impacts on complex phenotypes by rearranging large amounts of DNA sequence. Results We present a comprehensive SV catalog based on the whole-genome sequence of 1060 pigs (Sus scrofa) representing 101 breeds, covering 9.6% of the pig genome. This catalog includes 42,487 deletions, 37,913 mobile element insertions, 3308 duplications, 1664 inversions, and 45,184 break ends. Estimates of breed ancestry and hybridization using genotyped SVs align well with those from single nucleotide polymorphisms. Geographically stratified deletions are observed, along with known duplications of the KIT gene, responsible for white coat color in European pigs. Additionally, we identify a recent SINE element insertion in MYO5A transcripts of European pigs, potentially influencing alternative splicing patterns and coat color alterations. Furthermore, a Yorkshire-specific copy number gain within ABCG2 is found, impacting chromatin interactions and gene expression across multiple tissues over a stretch of genomic region of ~200 kb. Preliminary investigations into SV’s impact on gene expression and traits using the Pig Genotype-Tissue Expression (PigGTEx) data reveal SV associations with regulatory variants and gene-trait pairs. For instance, a 51-bp deletion is linked to the lead eQTL of the lipid metabolism regulating gene FADS3, whose expression in embryo may affect loin muscle area, as revealed by our transcriptome-wide association studies. Conclusions This SV catalog serves as a valuable resource for studying diversity, evolutionary history, and functional shaping of the pig genome by processes like domestication, trait-based breeding, and adaptive evolution.

Abstract Background The fusiform aneurysm is a nonsaccular dilatation affecting the entire vessel wall over a short distance. Although PDGFRB somatic variants have been identified in fusiform intracranial aneurysms, the molecular and cellular mechanisms driving fusiform intracranial aneurysms due to PDGFRB somatic variants remain poorly understood. Methods In this study, single-cell sequencing and immunofluorescence were employed to investigate the phenotypic changes in smooth muscle cells within fusiform intracranial aneurysms. Whole-exome sequencing revealed the presence of PDGFRB gene mutations in fusiform intracranial aneurysms. Subsequent immunoprecipitation experiments further explored the functional alterations of these mutated PDGFRB proteins. For the common c.1684 mutation site of PDGFRβ, we established mutant smooth muscle cell lines and zebrafish models. These models allowed us to simulate the effects of PDGFRB mutations. We explored the major downstream cellular pathways affected by PDGFRBY562D mutations and evaluated the potential therapeutic effects of Ruxolitinib. Results Single-cell sequencing of two fusiform intracranial aneurysms sample revealed downregulated smooth muscle cell markers and overexpression of inflammation-related markers in vascular smooth muscle cells, which was validated by immunofluorescence staining, indicating smooth muscle cell phenotype modulation is involved in fusiform aneurysm. Whole-exome sequencing was performed on seven intracranial aneurysms (six fusiform and one saccular) and PDGFRB somatic mutations were detected in four fusiform aneurysms. Laser microdissection and Sanger sequencing results indicated that the PDGFRB mutations were present in smooth muscle layer. For the c.1684 (chr5: 149505131) site mutation reported many times, further cell experiments showed that PDGFRBY562D mutations promoted inflammatory-related vascular smooth muscle cell phenotype and JAK-STAT pathway played a crucial role in the process. Notably, transfection of PDGFRBY562D in zebrafish embryos resulted in cerebral vascular anomalies. Ruxolitinib, the JAK inhibitor, could reversed the smooth muscle cells phenotype modulation in vitro and inhibit the vascular anomalies in zebrafish induced by PDGFRB mutation. Conclusion Our findings suggested that PDGFRB somatic variants played a role in regulating smooth muscle cells phenotype modulation in fusiform aneurysms and offered a potential therapeutic option for fusiform aneurysms.

Leukoaraiosis (LA) manifests as cerebral white matter hyperintensities on T2-weighted magnetic resonance imaging scans and corresponds to white matter lesions or abnormalities in brain tissue. Clinically, it is generally detected in the early 40s and is highly prevalent globally in individuals aged >60 years. From the imaging perspective, LA can present as several heterogeneous forms, including punctate and patchy lesions in deep or subcortical white matter; lesions with periventricular caps, a pencil-thin lining, and smooth halo; as well as irregular lesions, which are not always benign. Given its potential of having deleterious effects on normal brain function and the resulting increase in public health burden, considerable effort has been focused on investigating the associations between various risk factors and LA risk, and developing its associated clinical interventions. However, study results have been inconsistent, most likely due to potential differences in study designs, neuroimaging methods, and sample sizes as well as the inherent neuroimaging heterogeneity and multi-factorial nature of LA. In this article, we provided an overview of LA and summarized the current knowledge regarding its epidemiology, neuroimaging classification, pathological characteristics, risk factors, and potential intervention strategies.

Abstract Selective molecular recognition is an important alternative to the energy-intensive industrial separation process. Porous coordination polymers (PCPs) offer designing platforms for gas separation because they possess precise controllability over structures at the molecular level. However, PCPs-based gas separations are dominantly achieved using strong adsorptive sites for thermodynamic recognition or pore-aperture control for size sieving, which suffer from insufficient selectivity or sluggish kinetics. Developing PCPs that work at high temperatures and feature both high uptake capacity and selectivity is urgently required but remains challenging. Herein, we report diffusion-rate sieving of propylene/propane (C3H6/C3H8) at 300 K by constructing a PCP material whose global and local dynamics cooperatively govern the adsorption process via the mechanisms of the gate opening for C3H6 and the diffusion regulation for C3H8, respectively, yielding substantial differences in both uptake capacity and adsorption kinetics. Dynamic separation of an equimolar C3H6/C3H8 mixture reveals outstanding sieving performance with a C3H6 purity of 99.7% and a separation factor of 318.

West Lake holds a significant position internationally. This article studies the spatial distribution, historical development, functions, and the lake–city spatial relationship of 81 West Lakes (WLs), as well as their landscape characteristics. The results indicate the following: (1) The overall spatial distribution of WLs is related to China’s history of water conservancy development. (2) The evolution of and functional changes in WLs are influenced by multiple factors such as politics, economy, and culture during different historical periods and are directly related to the will of local administrators. (3) The initial functions of WLs can be categorized into three types, primarily related to urban infrastructure. (4) In terms of spatial relationships, there are four types of spatial relationships between WLs and their water sources and three types of spatial relationships between WLs and cities, forming a common pattern of “Mountains/Hills(–Water)–WL(–Water)–Cities(–Water, River, Sea)” or “WL(–Water)–Cities(–Water, River, Sea)”. (5) The scenery of WLs comprises six elements, including natural basements, water conservancy facilities, human settlements, secularization, landscape architecture, and animal and human activities, all imbued with poetic cultural connotations. Furthermore, this study summarizes three causes of WLs’ scenery; excavates the historical wisdom of WLs in terms of a holistic approach, ecological techniques, dynamic management, and landscape esthetics; and subsequently proposes recommendations for lake ecological governance and landscape construction.

The quality of pork meat directly influences the price and consumption. The genetic improvement of pigs has mainly focused on high productive efficiency, which has resulted in poor meat quality. Crossbreeds containing commercial and indigenous breeds could improve the meat quality, but identifying breed composition was difficult because of the lack of an ancestry reference panel. Therefore, we first constructed an abundant reference panel and convenient pipeline to identify ancestry/breed composition. The ancestry reference panel consisted of 517 reliable individuals, including three commercial breeds (Duroc, Landrace, and Yorkshire) and 38 indigenous Chinese breeds. The nature of the reference panel showed that the European domestic breed (EUD) and Asian domestic breed (ASD) were distinctly divided into two clusters. The evaluation of ancestry identification revealed that the reference panel performed well in identifying EUD and ASD ancestry proportions for commercial breeds, indigenous breeds, and crossbreeds. In addition, the ancestry reference panel also performed excellently in identifying breed composition for 3 commercial and 38 indigenous breeds. Specifically, the reference panel showed the outstanding identification of breed composition for crossbred individuals. These results suggested that the ancestry reference panel and convenient pipeline played a good role in identifying breed composition for pigs.

BackgroundStudy engagement is regarded important to medical students’ physical and mental wellbeing. However, the relationship between learning environment of medical schools and the study engagement of medical students was still unclear. This study was aimed to ascertain the positive effect of learning environment in study engagement.MethodsWe collected 10,901 valid questionnaires from 12 medical universities in China, and UWES-S was utilized to assess the study engagement levels. Then Pearson Chi-Square test and Welch’s ANOVA test were conducted to find the relationship between study engagement and learning environment, and subgroup analysis was used to eradicate possible influence of confounding factors. After that, a multivariate analysis was performed to prove learning environment was an independent factor, and we constructed a nomogram as a predictive model.ResultsWith Pearson Chi-Square test (p

BackgroundMigraine is a common primary headache that has a significant impact on patients’ quality of life. The co-occurrence of migraine and depression is frequent, resulting in more complex symptoms and a poorer prognosis. The evidence suggests that depression and migraine comorbidity share a polygenic genetic background.ObjectiveThe aim of this study is to identify related genetic variants that contribute to genetic susceptibility to migraine with and without depression in a Chinese cohort.MethodsIn this case-control study, 263 individuals with migraines and 223 race-matched controls were included. Eight genetic polymorphism loci selected from the GWAS were genotyped using Sequenom’s MALDI-TOF iPLEX platform.ResultsIn univariate analysis, ANKDD1B rs904743 showed significant differences in genotype and allele distribution between migraineurs and controls. Furthermore, a machine learning approach was used to perform multivariate analysis. The results of the Random Forest algorithm indicated that ANKDD1B rs904743 was a significant risk factor for migraine susceptibility in China. Additionally, subgroup analysis by the Boruta algorithm showed a significant association between this SNP and migraine comorbid depression. Migraineurs with depression have been observed to have worse scores on the Beck Anxiety Inventory (BAI) and the Migraine Disability Assessment Scale (MIDAS).ConclusionThe study indicates that there is an association between ANKDD1B rs904743 and susceptibility to migraine with and without depression in Chinese patients.

Genomic selection (GS) has been widely used in livestock, which greatly accelerated the genetic progress of complex traits. The population size was one of the significant factors affecting the prediction accuracy, while it was limited by the purebred population. Compared to directly combining two uncorrelated purebred populations to extend the reference population size, it might be more meaningful to incorporate the correlated crossbreds into reference population for genomic prediction. In this study, we simulated purebred offspring (PAS and PBS) and crossbred offspring (CAB) base on real genotype data of two base purebred populations (PA and PB), to evaluate the performance of genomic selection on purebred while incorporating crossbred information. The results showed that selecting key crossbred individuals via maximizing the expected genetic relationship (REL) was better than the other methods (individuals closet or farthest to the purebred population, CP/FP) in term of the prediction accuracy. Furthermore, the prediction accuracy of reference populations combining PA and CAB was significantly better only based on PA, which was similar to combine PA and PAS. Moreover, the rank correlation between the multiple of the increased relationship (MIR) and reliability improvement was 0.60–0.70. But for individuals with low correlation (Cor(Pi, PA or B), the reliability improvement was significantly lower than other individuals. Our findings suggested that incorporating crossbred into purebred population could improve the performance of genetic prediction compared with using the purebred population only. The genetic relationship between purebred and crossbred population is a key factor determining the increased reliability while incorporating crossbred population in the genomic prediction on pure bred individuals.

Abstract Background Rural settlements are undergoing significant changes under the rapid urbanisation, and understanding their evolution characteristics and surrounding land use will provide a basis for land spatial planning. This study takes Pingnan County, Fujian Province, China as study area, reveals the characteristics of spatial–temporal evolution and surrounding land use transition of settlements during 1985–2020 through landscape metrics, spatial “hot spot” analysis, scale classification statistics, rank-size model, Gini index, land use transition matrix. Results The results show that: (1) Concerning the size and morphological characteristics, the settlements have witnessed a considerable increase in number and scale while remaining stable in shape. (2) Regarding spatial distribution characteristics, the settlements became more evenly spread, forming three main hotspot clusters. (3) Concerning scale structure characteristics, there are significant differences in scale, growth rates, and polarisation of settlements; the polarisation of large settlements shifted from a marked divergence before 2010 to a more balanced trend after 2010. (4) The land use transition around settlements differed in buffer zones and periods. During 1985–2010, settlement expansion heavily depended on cropland, depleting nearby resources, with an increase of woodland and grassland. During 2010–2020, expansion integrated cropland, woodland, and grassland, with cropland growth mainly encroaching on woodland and grassland. Conclusions The study's findings are significant for optimising rural settlement structure in mountains and promoting sustainable land resource use.

Abstract This study focuses on the application of deep learning for transforming semantic point clouds into semantic Building Information Models (BIM) to create a Heritage Digital Twin, centering on Taoping Village, a site of historical and cultural significance in Sichuan, China. Utilizing advanced technologies such as unmanned aerial vehicles and terrestrial laser scanning, we capture detailed point cloud data of the village. A pivotal element of our methodology is the KP-SG neural network, which exhibits outstanding overall performance, particularly excelling in accurately identifying 11 categories. Among those categories, buildings and vegetation, achieves recognition rates of 81% and 83% respectively, and a 2.53% improvement in mIoU compared to KP-FCNN. This accuracy is critical for constructing detailed and accurate semantic BIM models of Taoping Village, facilitating comprehensive architecture and landscape analysis. Additionally, the KP-SG’s superior segmentation capability contributes to the creation of high-fidelity 3D models, enriching virtual reality experiences. We also introduce a digital twin platform that integrates diverse datasets, their semantic information, and visualization tools. This platform is designed to support process automation and decision-making and provide immersive experiences for tourists. Our approach, integrating semantic BIM models and a digital twin platform, marks a significant advancement in preserving and understanding traditional villages like Taoping and demonstrates the transformative potential of deep learning in cultural heritage conservation.

Abstract Background Copy number variation (CNV) of X chromosome can lead to a variety of neonatal abnormalities, especially for male fetuses. In recent years, due to the high sensitivity and high specificity of NIPS, its application has gradually expanded from chromosome aneuploidy to CNV. Few prenatal cases involving the detection of Xq duplication and deletion by NIPS have been reported, but it is of great significance for genetic counseling. Case presentation A 36-year-old woman was referred for prenatal diagnosis and genetic counseling at 17 weeks of gestation because of abnormal result of noninvasive prenatal screening (NIPS). Multiple congenital malformations, hydrocephalus, and enlarged gallbladder were observed by prenatal ultrasound. Amniocentesis revealed the karyotype of the fetus as 46, XN, add(X) (p22.2) and the result of chromosomal microarray analysis was arr[hg19] Xq27.1q28(138,506,454–154896094) × 2 and arr[hg19] Xp22.33p22.32(168,551–5,616,964) × 1. CNV-seq showed that the mother shares a 16.42 Mb duplication in the Xq27.1-q28 region and a 2.97 Mb deletion in the Xp22.33-p22.32 region. After genetic counseling, the couple chose to terminate the pregnancy. Conclusion The combination of NIPS and CMA would be of values in detection of subchromosomal duplications and/or deletions at fetal stage. The detection of X chromosome aberration in a male fetus should give suspicion of the possibility of maternal inheritance.

Abstract Background Gelsemium elegans is a traditional Chinese medicinal plant and temperature is one of the key factors affecting its growth. RAV (related to ABI3/VP1) transcription factor plays multiple roles in higher plants, including the regulation of plant growth, development, and stress response. However, RAV transcription factor in G. elegans has not been reported. Results In this study, three novel GeRAV genes (GeRAV1-GeRAV3) were identified from the transcriptome of G. elegans under low temperature stress. Phylogenetic analysis showed that GeRAV1-GeRAV3 proteins were clustered into groups II, IV, and V, respectively. RNA-sequencing (RNA-seq) and real-time quantitative PCR (qRT-PCR) analyses indicated that the expression of GeRAV1 and GeRAV2 was increased in response to cold stress. Furthermore, the GeRAV1 gene was successfully cloned from G. elegans leaf. It encoded a hydrophilic, unstable, and non-secretory protein that contained both AP2 and B3 domains. The amino acid sequence of GeRAV1 protein shared a high similarity of 81.97% with Camptotheca acuminata CaRAV. Subcellular localization and transcriptional self-activation experiments demonstrated that GeRAV1 was a nucleoprotein without self-activating activity. The GeRAV1 gene was constitutively expressed in the leaves, stems, and roots of the G. elegans, with the highest expression levels in roots. In addition, the expression of the GeRAV1 gene was rapidly up-regulated under abscisic acid (ABA), salicylic acid (SA), and methyl jasmonate (MeJA) stresses, suggesting that it may be involved in hormonal signaling pathways. Moreover, GeRAV1 conferred improved cold and sodium chloride tolerance in Escherichia coli Rosetta cells. Conclusions These findings provided a foundation for further understanding on the function and regulatory mechanism of the GeRAV1 gene in response to low-temperature stress in G. elegans.

Gelsemium elegans is a traditional Chinese medicinal plant, with indole alkaloids as its main active ingredient. The plant can be used as medicine, mainly for pain relief, anti-inflammation and anti-tumor. Exogenous stress, such as low temperature, methyl jasmonate (MeJA), and salicylic acid (SA), can affect the growth of G. elegans and the synthesis of secondary metabolites. Under these conditions, there are only a few reports on the selection and validation of internal reference genes in G. elegans. In this study, seven candidate internal reference genes that showed stable expression abundance in the transcriptome database of G. elegans were selected. The stability and reliability of these genes were analyzed in different G. elegans tissues and under low temperature, MeJA, and SA stresses. The results showed that CUL was the optimal reference gene for expression analysis in different G. elegans tissues and under cold stress, SA stress, followed by eEF-1α. Under MeJA stress, the best one was eEF-1α, and the next was CUL. Furthermore, the expression patterns of three different G. elegans genes, including GPPS, ERF, and 60S, were carried out to confirm that single reference gene (CUL or eEF-1α) or double reference genes (CUL + eEF-1α) can be selected as the best or perfect combination of reference genes for gene expression analysis in G. elegans. This study lays a foundation for the accurate normalization and quantification of gene expression in G. elegans.

Abstract. As one of the most malignant tumors worldwide, lung cancer, fueled by metastasis, has shown rising mortality rates. However, effective clinical strategies aimed at preventing metastasis are lacking owing to its dynamic multi-step, complicated, and progressive nature. Immunotherapy has shown promise in treating cancer metastasis by reversing the immunosuppressive network of the tumor microenvironment. However, drug resistance inevitably develops due to inadequate delivery of immunostimulants and an uncontrolled immune response. Consequently, adverse effects occur, such as autoimmunity, from the non-specific immune activation and non-specific inflammation in off-target organs. Nanocarriers that improve drug solubility, permeability, stability, bioavailability, as well as sustained, controlled, and targeted delivery can effectively overcome drug resistance and enhance the therapeutic effect while reducing adverse effects. In particular, nanomedicine-based immunotherapy can be utilized to target tumor metastasis, presenting a promising therapeutic strategy for lung cancer. Nanotechnology strategies that boost the immunotherapy effect are classified based on the metastatic cascade related to the tumor immune microenvironment; the breaking away of primary tumors, circulating tumor cell dissemination, and premetastatic niche formation cause distant secondary site colonization. In this review, we focus on the opportunities and challenges of integrating immunotherapy with nanoparticle formulation to establish nanotechnology-based immunotherapy by modulating the tumor microenvironment for preclinical and clinical applications in the management of patients with metastatic lung cancer. We also discuss prospects for the emerging field and the clinical translation potential of these techniques.

Background: The biologics derived from human amniotic membranes (AMs) demonstrate potential pain-inhibitory effects in clinical settings. However, the molecular basis underlying this therapeutic effect remains elusive. HC-HA/PTX3 is a unique water-soluble regenerative matrix that is purified from human AMs. We examined whether HC-HA/PTX3 can modulate the gene networks and transcriptional signatures in the dorsal root ganglia (DRG) neurons transmitting peripheral sensory inputs to the spinal cord. Methods: We conducted bulk RNA-sequencing (RNA-seq) of mouse DRG neurons after treating them with HC-HA/PTX3 (15 µg/mL) for 10 min and 24 h in culture. Differential gene expression analysis was performed using the limma package, and Gene Ontology (GO) and protein–protein interaction (PPI) analyses were conducted to identify the networks of pain-related genes. Western blotting and in vitro calcium imaging were used to examine the protein levels and signaling of pro-opiomelanocortin (POMC) in DRG neurons. Results: Compared to the vehicle-treated group, 24 h treatment with HC-HA/PTX3 induced 2047 differentially expressed genes (DEGs), which were centered on the ATPase activity, receptor–ligand activity, and extracellular matrix pathways. Importantly, PPI analysis revealed that over 50 of these DEGs are closely related to pain and analgesia. Notably, HC-HA/PTX3 increased the expression and signaling pathway of POMC, which may affect opioid analgesia. Conclusions: HC-HA/PTX3 induced profound changes in the gene expression in DRG neurons, centered around various neurochemical mechanisms associated with pain modulation. Our findings suggest that HC-HA/PTX3 may be an important biological active component in human AMs that partly underlies its pain inhibitory effect, presenting a new strategy for pain treatment.

Polder landscapes, as a representative of lowland agriculture landscapes, possess diverse natural and cultural values. However, polder landscapes are facing multiple challenges arising from economic and climate changes, including increasing flood threats and the fragmentation of landscape patterns. These issues have severely threatened the safety and regional characteristics of the polder landscape. Therefore, this study aims to preserve the regional characteristics of polder landscapes while promoting the sustainable development of lowland environments, and the objective is to provide a foundation and baseline for the management and planning of polder landscapes. In this study, the Dongting Lake Area (DLA) was selected as a representative case of polder landscapes. To identify the landscape character and delineate the landscape management zones, this study employed the Landscape Character Assessment (LCA) method in conjunction with a polder typology method at two scales. As a result, the polder landscape types were identified and visualized at two different scales. At the Lake Scale, a comprehensive identification method for polder unit types and polder landscape regions was established, achieving a stepwise transition from polder areas to polder clusters and ultimately to individual polder units. At the Local Scale, an integrative analysis of landscape character diversity (LCD) and land construction suitability (LCS) was employed to establish five landscape management zones for polder landscapes, thereby realizing a balance between the conservation of polder landscape diversity with the sustainable development of wetland environments. This study contributes a set of cross-scale ideas and methods for identifying landscape characters and delineating management zones in polder landscapes, which could be expanded to other lowland agricultural landscapes.

This paper presents a compound laser surface modification strategy to enhance the tribological performance of biomedical titanium alloys involving femtosecond laser nitriding and femtosecond laser texturing. First, high-repetition-rate femtosecond pulses (MHz) were used to melt the surface under a nitrogen atmosphere, forming a wear-resistant TiN coating. Subsequently, the TiN layer was ablated in air with low-repetition-rate femtosecond pulses (kHz) to create squared textures. The effects of the combined nitriding and texturing treatment on bio-tribological performance was investigated. Results show that compared with the untreated samples, the single femtosecond laser nitriding process increased the surface hardness from 336 HV to 1455 HV and significantly enhanced the wear resistance of titanium, with the wear loss decreasing from 9.07 mg to 3.41 mg. However, the friction coefficient increased from 0.388 to 0.655, which was attributed to the increased hardness, roughness within the wear scars, and the formation of hard debris. After combined treatment, the friction coefficient decreased to 0.408 under the optimal texture density of 65%. The mechanisms for the improvement in friction behavior are the reduction in contact area and the trapping of hard debris.

Abstract Background Studies exploring influencing factors of emotional engagement among medical students are scarce. Thus, we aimed to identify influencing factors of medical students’ emotional engagement. Methods We carried out a multi-center cross-sectional study among 10,901 medical students from 11 universities in China. The Chinese version of Utrecht Work Engagement Scale-Student version (UWES-S) was used to evaluate emotional engagement level of medical students. The predictors related to engagement level were determined by the logistic regression analysis. Furthermore, we constructed a nomogram to predict emotional engagement level of medical students. Results A total of 10,576 sample were included in this study. The mean emotional engagement score was 74.61(± 16.21). In the multivariate logistic regression model, we found that males showed higher engagement level compared with females [odds ratio (OR) (95% confidence interval (CI)): 1.263 (1.147, 1.392), P

Abstract Purpose Serum neurofilament light chain (sNfL) can reflect nerve damage. Whether migraine can cause neurological damage remain unclear. This study assesses sNfL levels in migraine patients and explores whether there is nerve damage in migraine. Methods A case–control study was conducted in Xiamen, China. A total of 138 migraine patients and 70 healthy controls were recruited. sNfL (pg/mL) was measured on the single-molecule array platform. Univariate, Pearson correlation and linear regression analysis were used to assess the relationship between migraine and sNfL levels, with further subgroup analysis by migraine characteristics. Results Overall, 85.10% of the 208 subjects were female, with a median age of 36 years. sNfL levels were higher in the migraine group than in the control group (4.85 (3.49, 6.62) vs. 4.11 (3.22, 5.59)), but the difference was not significant (P = 0.133). The two groups showed an almost consistent trend in which sNfL levels increased significantly with age. Subgroup analysis showed a significant increase in sNfL levels in patients with a migraine course ≥ 10 years (β = 0.693 (0.168, 1.220), P = 0.010). Regression analysis results show that age and migraine course are independent risk factors for elevated sNfL levels, and there is an interaction between the two factors. Patients aged

Abstract Background Cancer-associated fibroblasts (CAFs) play pivotal roles in chemoresistance of pancreatic ductal adenocarcinoma (PDAC). However, the underlying mechanisms are poorly understood. Revealing the cross-talk network between tumor stroma and pancreatic cancer and developing effective strategies against oxaliplatin resistance are highly desired in the clinic. Methods High-throughput sequence was used to screened the key circRNAs transmitted by extracellular vesicles (EVs) from CAFs to pancreatic cancer cells. The associations between EV-packaged circBIRC6 and chemotherapy responsiveness were validated in a cohort of 82 cases of advanced PDAC patients. Then, the effects of EV-packaged circBIRC6 on CAF-induced oxaliplatin resistance were investigated by flow cytometry, colony formation, viability of pancreatic cancer organoids in vitro and by xenograft models in vivo. RNA pulldown, RNA immunoprecipitation, and sites mutation assays were used to reveal the underlying mechanism. Results We identified a circRNA, circBIRC6, is significantly upregulated in CAF-derived EVs and is positively associated with oxaliplatin-based chemoresistance. In vitro and in vivo functional assays showed that CAF-derived EV-packaged circBIRC6 enhance oxaliplatin resistance of pancreatic cancer cells and organoids via regulating the non-homologous end joining (NHEJ) dependent DNA repair. Mechanistically, circBIRC6 directly binds with XRCC4 and enhanced the interaction of XRCC4 with SUMO1 at the lysine 115 residue, which facilitated XRCC4 chromatin localization. XRCC4K115R mutation dramatically abrogated the EV-packaged circBIRC6 induced effect. Moreover, combination of antisense oligonucleotide inhibitors against circBIRC6 with Olaparib dramatically suppressed chemoresistance in patient-derived xenograft models. Conclusions Our study revealed that EV-packaged circBIRC6 confer oxaliplatin resistance in PDAC by mediating SUMOylation of XRCC4, introducing a promising predictive and therapeutic target for PDAC on oxaliplatin resistance.

Contractor’s consummate performance behavior (CPB) is the key to achieve consummate performance. However, the mechanism of reasonable contract risk allocation incentives for Contractor’s CPB is unknown. The objective of this study is to reveal the effective ways to encourage contractor’s CPB by contract risk allocation based on the contract reference point theory and selecting the contractor’s trust perception and fair perception as mediating variables. Through an empirical analysis of the valid questionnaires collected, the results are as follows: (1) Although the economic benefits generated by reasonable contract risk allocation can induce contractor’s fair perception, fair perception has no mediating effect in the relationship between contract risk allocation and contractor’s CPB; (2) The cooperative value generated by reasonable contract risk allocation can induce contractor’s trust perception, and trust perception plays a part mediating role between contract risk allocation and contractor’s CPB. The findings also provide insights into how risk allocation facilitates contractor’s CPB in the construction industry.

BackgroundIncreasing evidence has suggested that alterations in the gut microbiome are correlated with autoimmune neurologic disorders, yet the causal relationship between them has yet to be established.MethodsFrom the published genome-wide association study (GWAS) summary statistics, we obtained data on the gut microbiota and three autoimmune neurologic disorders (Multiple Sclerosis, Guillain-Barré Syndrome, and Myasthenia Gravis). We then implemented a two-sample Mendelian Randomization (MR) to determine the causal relationship between the gut microbiota and the diseases. To validate the results, we conducted a series of sensitivity analyses. Finally, to verify the direction of causality, a reverse-causality analysis was done.ResultsWe discovered that a higher relative abundance of the genus Ruminococcus2 (OR: 1.213, 95% CI: 1.006–1.462, p = 0.043, PFDR = 0.048) and the genus Roseburia (OR: 1.255, 95% CI: 1.012–1.556, p = 0.038, PFDR = 0.048) were associated with a higher risk of MS. Furthermore, the higher the abundance of the class Mollicutes (OR: 3.016, 95% CI: 1.228–7.411, p = 0.016, PFDR = 0.021), the genus Eubacterium (hallii group) (OR: 2.787, 95% CI: 1.140–6.816, p = 0.025, PFDR = 0.025), and the phylum Tenericutes (OR: 3.016, 95% CI: 1.228–7.411, p = 0.016, PFDR = 0.021) was linked to a greater probability of GBS. Additionally, the higher the abundance of the genus Ruminococcaceae UCG005 (OR: 2.450, 95% CI: 1.072–5.598, p = 0.034, PFDR = 0.036), the genus Holdemania (OR: 2.437, 95% CI: 1.215–4.888, p = 0.012, PFDR = 0.024), genus Lachnoclostridium (OR: 3.681, 95% CI: 1.288–10.521, p = 0.015, PFDR = 0.025) and the genus Eubacterium (ruminantium group) (OR: 2.157, 95% CI: 1.211–3.843, p = 0.003, PFDR = 0.016) correlated with a greater chance of MG occurrence. No SNPs were identified as outliers through sensitivity analysis. Then, the results of the reverse MR analysis did not indicate any reverse causality.ConclusionOur findings demonstrate a causal relationship between the gut microbiota and three autoimmune neurologic disorders, providing novel insights into the mechanisms of these autoimmune neurologic disorders that are mediated by gut microbiota.

To clarify the mechanism of resistance of Bacillus velezensis TP-1 to gray mold, a marker strain TP-1R was screened for resistance to 300 μg/mL of rifampicin by an antibiotic marker method in this study. The genetic stability of the resistance of the marker strains and their antagonism to gray mold of grapes were studied, and their colonization in grapes and their effect on the activity of defence enzymes in the grapes were analysed. The results showed that the labeled strain could still grow stably in the medium containing rifampicin after 15 times of subculture, and the antagonistic effect of the labeled strain against gray mold was not significantly different from that of the original strain. The colonization amount of the labeled strain reached the peak of 4.32×106 CFU/g on the 15th day of storage (20 ℃), and was still 3.11×106 CFU/g on the 30th day of storage, indicating that strain TP-1 could be stably colonized on grapes. Inoculation of strain TP-1 fermentation broth could effectively inhibit the occurrence of gray mold and resultantly reduced the decay rate of grapes. During storage, the activity of grape defence enzymes PAL, PPO and APX increased first and then decreased, and the activity of the three enzymes in the group treated with the antagonistic bacterium TP-1 was significantly higher than CK (P

Abstract The quasi-1D chiral edge states in a quantum anomalous Hall insulator are dissipationless, while the 2D helical surface states in a topological insulator are insensitive to spin-independent scatterings due to the topological protection. Both serve as essential ingredients for topological electronics. Here, we integrate these states into a single device using selective area epitaxy based on the molecular beam epitaxy technique. The chiral edge state comes from the quantum anomalous Hall insulator Cr:(Bi,Sb)2Te3, while the helical surface state comes from the intrinsic topological insulator (Bi,Sb)2Te3 which only interfaces with a partial edge of the former, forming a selective-area heterostructure. At the heterointerface, the chiral state in Cr:(Bi,Sb)2Te3 is allowed to be scattered into (Bi,Sb)2Te3 so that the incoming current will be redistributed according to the coordination between the chirality and helicity. Our device enables the collaboration between chiral and helical states for low-dissipative transport with tunable current dimension.