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Abstract Abdominal adhesions manifests following abdominal infections triggered by intestinal fistulas. The severity of such adhesions depends on the extent of fiber deposition and peritoneal fibrinolysis following peritoneal injury, which may be influenced by sustained inflammation within the abdominal cavity. In this regard, the visceral-to-subcutaneous fat area (VFA/SFA) ratio has been implicated as a potential marker of inflammation. This study aimed to explore the relationship between VFA/SFA and abdominal adhesions. This multicenter study was conducted across four tertiary institutions and involved patients who had undergone definitive surgery (DS) for intestinal fistula from January 2009 and October 2023. The presence of abdominal adhesions was determined intraoperatively. VFA/SFA was investigated as a potential risk factor for severe adhesions. The study comprised 414 patients with a median age of 50 [interquartile range (IQR) 35–66] years and a median body mass index of 20.0 (IQR 19.2–22.4) kg/m2, including 231 males with a median VFA/SFA of 1.0 (IQR 0.7–1.2) and 183 females a median VFA/SFA of 0.8 (0.6–1.1). VFA/SFA was associated with severe abdominal adhesions in males [odds ratio (OR) = 3.34, 95% CI 1.14–9.80, p = 0.03] and females (OR = 2.99, 95% CI 1.05–8.53, p = 0.04). J-shaped association between VFA/SFA ratio and severe adhesions was revealed in both sex. The increasing trend can be revealed when OR more than 0.8, and 0.6 in males and females respectively. Preoperative VFA/SFA demonstrates predictive value for statues of severe abdominal adhesions in DS for anastomotic fistula after small intestine resection.

Abstract This study aimed to evaluate the value of low-dose dual-input computed tomography perfusion (CTP) imaging in the differential diagnosis of benign and malignant pulmonary ground-glass opacity nodules (GGO). A retrospective study was conducted in patients with GGO who underwent CTP in our hospital from January 2021 to October 2023. All nodules were confirmed via pathological analysis or disappeared during follow-up. Postprocessing analysis was conducted using the dual-input perfusion mode (pulmonary artery and bronchial artery) of the body perfusion software to measure the perfusion parameters of the pulmonary GGOs. A total of 101 patients with pulmonary GGOs were enrolled in this study, including 43 benign and 58 malignant nodules. The dose length product of the CTP (348 mGy.cm) was

Abstract This study aimed to investigate body physical parameters as substitutes for water equivalent diameter (Dw) while calculating size-specific dose estimates (SSDEs) during adult chest computed tomography (CT). A retrospective analysis was conducted on 776 patients. Patients were divided into training set (542 patients) and validation set (234 patients) according to a ratio of 7:3. The correlations between physical parameters and Dw were analyzed. The differences between SSDEsubstitutes and the reference SSDE (SSDEreference) were compared. Strong positive correlations were observed between body mass index (BMI) and Dw as well as between weight and Dw in overall, male, and female patients (all p 0.05). The RMSEs of overall patients between SSDEweight and SSDEreference as well as between SSDEBMI and SSDEreference were 0.237 and 0.2, respectively. The use of sex-specific regression equations for BMI caused a slightly reduction in RMSE. Weight and BMI can be used as surrogate parameters for Dw when calculating SSDE in adult chest CT exams, with BMI being the preferred substitute parameter.

Abstract Previous research on the association between Family Doctor Contract Services (FDCS) and health has only considered a single indicator of health and has not considered the endogeneity of independent variables. This study aimed to evaluate the association from a multidimensional perspective of the health of middle-aged and older people using the instrumental variables method and determine the underlying mechanisms. Using data from the 2018 China Health and Retirement Longitudinal Study surveys, a total of 19,438 sample was obtained. Health was measured by health related-quality of life (HR-QoL), subjective well-being, and cognitive function. The instrumental variables method was used to estimate the association. Mediation analysis was employed to analyze the underlying mechanisms. The results of the instrumental variables method showed a correlation between FDCS and health, such as HR-QoL (η = 33.714, p

Objective To explore the correlations of genotype and phenotype of myopathic form of carnitine palmitoyltransferase Ⅱ (CPT Ⅱ) deficiency and to improve the clinical understanding of the disease. Methods The clinical data of a case of myopathic form of CPT Ⅱ deficiency were analyzed, including the results of gene detection, diagnosis, treatment, and follow-up. The literature was reviewed to summarize the clinical characteristics, diagnosis, and treatment of CPT Ⅱ deficiency. Results The patient, a 10-month-old girl, was admitted to the hospital with acute enteritis. The blood creatine kinase and myoglobin were significantly increased in the auxiliary examination. Her father had a history of weakness after regular exercise and myoglobinuria. Both the father and the daughter carried the heterozygous pathogenic mutation c.989dupTp. (Ile332fs) in the CPT2 gene, which confirmed the diagnosis of myopathic form of CPT Ⅱ deficiency. After treatment with infection control and supplementation of a large amount of carbohydrates, creatine kinase and myoglobin returned to normal levels. Following discharge, follow-up showed that the patient was in good condition. Conclusion Myopathic form of CPT Ⅱ deficiency is a common disease that affects the lipid metabolism in skeletal muscle and is a common cause of hereditary myoglobinuria. However, its symptoms can be quite subtle and are frequently overlooked in clinical practice. When a patient exhibits repeated increases in creatine kinase as well as exercise intolerance, myoglobinuria, or positive family history, the disease should be taken into consideration.

Abstract Disulfidptosis is a recently identified mode of regulated cell death. Regulating disulfidptosis in carcinoma is a promising therapeutic approach. Long non-coding RNAs (lncRNAs) have been reported to be related to the occurrence and development of many cancers. Disulfidptosis-related lncRNAs (DRLs) in HPV-negative oral squamous cell carcinoma (OSCC) have not been studied. Based on The Cancer Genome Atlas (TCGA) database, least absolute shrinkage selection operator (LASSO) analysis and Cox regression analysis were used to identify overall survival related DRLs and construct the signature. Kaplan–Meier, time-dependent receiver operating characteristics (ROC) and principal component analyses (PCA) were explored to demonstrate the prediction potential of the signature. Subgroup analysis stratified by different clinicopathological characteristics were conducted. Nomogram was established by DRLs signature and independent clinicopathological characteristics. The calibration plots were performed to reveal the accuracy of nomogram. Immune cell subset infiltration, immunotherapy response, drug sensitivity analysis, and tumor mutation burden (TMB) were conducted. Underlying functions and pathways were explored by Gene Set Enrichment Analysis (GSEA) analysis. Previous lncRNA signatures of OSCC were retrieved from PubMed for further validation. Gene expression omnibus (GEO) datasets (GSE41613 and GSE85446) were merged as an external validation for DRLs signature. Consensus clustering analysis of DRLs signature and experimental validation of DRLs were also explored. This research sheds light on the robust performance of DRLs signature in survival prediction, immune cell infiltration, immune escape, and immunotherapy of HPV-negative OSCC.

Abstract. Background:. Hepatitis B virus (HBV) infection is the primary cause of hepatocellular carcinoma (HCC) in China. The target population for HCC screening comprises individuals who test positive for hepatitis B surface antigen (HBsAg). However, current data on the prevalence of HBV infection among individuals who are eligible for HCC screening in China are lacking. We aimed to assess the seroepidemiology of HBV infection among Chinese individuals eligible for HCC screening to provide the latest evidence for appropriate HCC screening strategies in China. Methods:. Questionnaires including information of sex, age, ethnicity, marital status, educational level, source of drinking water, as well as smoking and alcohol consumption history and serum samples were collected from females aged 45–64 years and males aged 35–64 years in 21 counties from 4 provinces in eastern and central China between 2015 and 2023. Enzyme-linked immunosorbent assay methods were used to detect the serum HBV marker HBsAg. Results:. A total of 603,082 individuals were enrolled, and serum samples were collected for analysis from January 1, 2015 to December 31, 2023. The prevalence of HBsAg positive in the study population was 5.23% (31,528/603,082). The prevalence of HBsAg positive was greater in males than in females (5.60% [17,660/315,183] vs. 4.82% [13,868/287,899], χ2 = 187.52, P

Abstract Previous reports have established that rESWT fosters angiogenesis, yet the mechanism by which rESWT promotes cerebral angiogenesis remains elusive. rESWT stimulated HUVECs proliferation as evidenced by the CCK-8 test, with an optimal dosage of 2.0 Bar, 200 impulses, and 2 Hz. The tube formation assay of HUVECs revealed that tube formation peaked at 36 h post-rESWT treatment, concurrent with the lowest expression level of Bach1, as detected by both Western blot and immunofluorescence. The expression level of Wnt3a, β-catenin, and VEGF also peaked at 36 h. A Bach1 overexpression plasmid was transfected into HUVECs, resulting in a decreased expression level of Wnt3a, β-catenin, and VEGF. Upon treatment with rESWT, the down-regulation of Wnt3a, β-catenin, and VEGF expression in the transfected cells was reversed. The Wnt/β-catenin inhibitor DKK-1 was utilized to suppress Wnt3a and β-catenin expression, which led to a concurrent decrease in VEGF expression. However, rESWT treatment could restore the expression of these three proteins, even in the presence of DKK-1. Moreover, in the established OGD model, it was observed that rESWT could inhibit the overexpression of Bach1 and enhance VEGF and VEGFR-2 expression under the OGD environment.

Abstract In rural China, the aging population faces unique challenges that affect their life satisfaction. These challenges are compounded by disparities in access to resources compared to urban areas, making it crucial to address these issues to ensure a dignified and fulfilling later life. Understanding and improving life satisfaction for this demographic is essential, not only for the well-being of the elderly but also for the overall social stability and economic sustainability of these communities. Using a rural sample from the Chinese Social Survey (CSS), this study investigates the interplay between social quality factors and life satisfaction among older adults in rural China. It focuses on the roles of socioeconomic security, social cohesion, social inclusion, and social empowerment in shaping the well-being of this demographic. It was found that the four conditional factors of social quality—socioeconomic security, social cohesion, social inclusion, and social empowerment—have different influences on life satisfaction among older adults in rural areas. The statistical model shows that the influence of absolute family income on social and economic security does not have statistical significance. In contrast, housing, pension insurance participation, and public safety perception positively affect life satisfaction among older adults in rural areas. Among the social cohesion factors, higher social morality, legal system evaluation, social identity, grassroots government, and interpersonal trust contribute to the life satisfaction of older adults in rural areas. Regarding social inclusion factors, good social tolerance, social equity, and perception of government public services can significantly improve life satisfaction among older adults in rural areas. For social empowerment factors, social participation helps expand the social support network of older adults in rural areas, enhancing their life satisfaction. Paths to improving the quality of rural society should be explored to improve relative poverty in rural areas. They should continue to be pursued to strengthen the old-age security system for older adults in rural areas. Further, the National Medium- and Long-Term Plan for Actively Responding to Population Aging should be the base for forming an elderly-friendly society. A good atmosphere promotes the participation of people, families, and society; supports social cohesion; enhances inclusion; and promotes social participation, improving life satisfaction.

Background/Aims Roxadustat, an oral medication for treating renal anemia, is a hypoxia-inducible factor prolyl hydroxylase inhibitor used for regulating iron metabolism and promoting erythropoiesis. To investigate the efficacy and safety of roxadustat in patients undergoing peritoneal dialysis (PD) with erythropoietin hyporesponsiveness. Methods Single-center, retrospective study, 81 PD patients (with erythropoietin hyporesponsiveness) were divided into the roxadustat group (n = 61) and erythropoiesis-stimulating agents (ESAs) group (n = 20). Hemoglobin (Hb), total cholesterol, intact parathyroid hormone (iPTH), brain natriuretic peptide (BNP), related indicators of cardiac function and high-sensitivity C-reactive protein (hs-CRP) were collected. Additionally, adverse events were also recorded. The follow-up period was 16 weeks. Results The two groups exhibited similar baseline demographic and clinical characteristics. At baseline, the roxadustat group had a mean Hb level of 89.8 ± 18.9 g/L, while the ESAs group had a mean Hb level of 95.2 ± 16.0 g/L. By week 16, the Hb levels had increased to 118 ± 19.8 g/L (p < 0.05) in the roxadustat group and 101 ± 19.3 g/L (p > 0.05) in the ESAs group. The efficacy of roxadustat in improving anemia was not influenced by baseline levels of hs-CRP and iPTH. Cholesterol was decreased in the roxadustat group without statin use. An increase in left ventricular ejection fraction and stabilization of BNP were observed in the roxadustat group. Conclusions For PD patients with erythropoietin hyporesponsiveness, roxadustat can significantly improve renal anemia. The efficacy of roxadustat in improving renal anemia was not affected by baseline levels of hs-CRP0 and iPTH.

Abstract Inflammation and fibrosis often occur in the kidney after acute injury, resulting in chronic kidney disease and consequent renal failure. Recent studies have indicated that lymphangiogenesis can drive renal inflammation and fibrosis in injured kidneys. However, whether and how this pathogenesis affects the contralateral kidney remain largely unknown. In our study, we uncovered a mechanism by which the contralateral kidney responded to injury. We found that the activation of mineralocorticoid receptors and the increase in vascular endothelial growth factor C in the contralateral kidney after unilateral ureteral obstruction could promote lymphangiogenesis. Furthermore, mineralocorticoid receptor activation in lymphatic endothelial cells resulted in the secretion of myofibroblast markers, thereby contributing to renal fibrosis. We observed that this process could be attenuated by administering the mineralocorticoid receptor blocker eplerenone, which, prevented the development of fibrotic injury in the contralateral kidneys of rats with unilateral ureteral obstruction. These findings offer valuable insights into the intricate mechanisms underlying kidney injury and may have implications for the development of therapeutic strategies to mitigate renal fibrosis in the context of kidney disease.

Abstract Based on dynamic monitoring data on China’s population, by using complex networks, spatial analysis and mathematical measurement, this study reveals the spatial characteristics and influencing factors of the network of flows of highly educated talents in the Yangtze River Delta region from the national and local perspectives. In the two perspectives, the network has strong isomorphism and certain differences. The in-flow of highly educated talents from cities with high administrative levels and more developed economies to Shanghai constitutes the core of the entire network. From a national perspective, highly educated talents tend to converge to the Yangtze River Delta region. From a local perspective, it was found that these talents cluster towards a limited number of cities in the region. From both perspectives, the flow network has developed into a “core-periphery” progressive hierarchical structure, with Shanghai becoming the sole core city. There is little difference in the influencing factors of talent mobility from both macro and meso perspectives. Highly educated talents would frequently flow between cities with strong economic development levels, and cities with high education level, scientific and technological level, complete infrastructure, and good aesthetics. However, geographical distance still plays a hindering role in the flow of highly educated talents, and factors such as cultural identity, institutional, and social modality differences among regions also have a certain effect on the flow of these talents.

Abstract Rheumatoid arthritis (RA) is a persistent autoimmune condition characterized by synovitis and joint damage. Recent findings suggest a potential link to abnormal lactate metabolism. This study aims to identify lactate metabolism-related genes (LMRGs) in RA and investigate their correlation with the molecular mechanisms of RA immunity. Data on the gene expression profiles of RA synovial tissue samples were acquired from the gene expression omnibus (GEO) database. The RA database was acquired by obtaining the common LMRDEGs, and selecting the gene collection through an SVM model. Conducting the functional enrichment analysis, followed by immuno-infiltration analysis and protein–protein interaction networks. The results revealed that as possible markers associated with lactate metabolism in RA, KCNN4 and SLC25A4 may be involved in regulating macrophage function in the immune response to RA, whereas GATA2 is involved in the immune mechanism of DC cells. In conclusion, this study utilized bioinformatics analysis and machine learning to identify biomarkers associated with lactate metabolism in RA and examined their relationship with immune cell infiltration. These findings offer novel perspectives on potential diagnostic and therapeutic targets for RA.

Abstract The pathogenesis of Parkinson’s disease (PD) is strongly associated with neuroinflammation, and type I interferons (IFN-I) play a crucial role in regulating immune and inflammatory responses. However, the specific features of IFN in different cell types and the underlying mechanisms of PD have yet to be fully described. In this study, we analyzed the GSE157783 dataset, which includes 39,024 single-cell RNA sequencing results for five PD patients and six healthy controls from the Gene Expression Omnibus database. After cell type annotation, we intersected differentially expressed genes in each cell subcluster with genes collected in The Interferome database to generate an IFN-I-stimulated gene set (ISGs). Based on this gene set, we used the R package AUCell to score each cell, representing the IFN-I activity. Additionally, we performed monocle trajectory analysis, and single-cell regulatory network inference and clustering (SCENIC) to uncover the underlying mechanisms. In silico gene perturbation and subsequent experiments confirm NFATc2 regulation of type I interferon response and neuroinflammation. Our analysis revealed that microglia, endothelial cells, and pericytes exhibited the highest activity of IFN-I. Furthermore, single-cell trajectory detection demonstrated that microglia in the midbrain of PD patients were in a pro-inflammatory activation state, which was validated in the 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model as well. We identified transcription factors NFATc2, which was significantly up-regulated and involved in the expression of ISGs and activation of microglia in PD. In the 1-Methyl-4-phenylpyridinium (MPP+)-induced BV2 cell model, the suppression of NFATc2 resulted in a reduction in IFN-β levels, impeding the phosphorylation of STAT1, and attenuating the activation of the NF-κB pathway. Furthermore, the downregulation of NFATc2 mitigated the detrimental effects on SH-SY5Y cells co-cultured in conditioned medium. Our study highlights the critical role of microglia in type I interferon responses in PD. Additionally, we identified transcription factors NFATc2 as key regulators of aberrant type I interferon responses and microglial pro-inflammatory activation in PD. These findings provide new insights into the pathogenesis of PD and may have implications for the development of novel therapeutic strategies.

Abstract Super enhancers (SEs) consist of clusters of enhancers, harboring an unusually high density of transcription factors, mediator coactivators and epigenetic modifications. SEs play a crucial role in the maintenance of cancer cell identity and promoting oncogenic transcription. Super enhancer lncRNAs (SE-lncRNAs) refer to either transcript from SEs locus or interact with SEs, whose transcriptional activity is highly dependent on SEs. Moreover, these SE-lncRNAs can interact with their associated enhancer regions in cis and modulate the expression of oncogenes or key signal pathways in cancers. Inhibition of SEs would be a promising therapy for cancer. In this review, we summarize the research of SE-lncRNAs in different kinds of cancers so far and decode the mechanism of SE-lncRNAs in carcinogenesis to provide novel ideas for the cancer therapy.

Summary: Background: Severe burn wounds face two primary challenges: dysregulated cellular impairment functions following infection and an unbalanced wound hydration microenvironment leading to excessive inflammation and collagen deposition. These results in hypertrophic scar contraction, causing significant deformity and disability in survivors. Methods: A three-dimensional (3D) printed double-layer hydrogel (DLH) was designed and fabricated to address the problem of scar formation after burn injury. DLH was developed using methacrylated silk fibroin (SFMA) and gelatin methacryloyl (GelMA) for the upper layer, and GelMA and hyaluronic acid methacryloyl (HAMA) for the lower layer. To combat infection, copper-epigallocatechin gallate (Cu-EGCG) was incorporated into the lower layer bioink, collectively referred to as DLS. To balance wound hydration levels, HaCaT cells were additionally encapsulated in the upper layer, designed as DLS/c. Findings: DLH demonstrated suitable porosity, appropriate mechanical properties, and excellent biocompatibility. DLS exhibited potent antimicrobial properties, exerted anti-inflammatory effects by regulating macrophage polarisation, and may enhance angiogenesis through the HIF-1α/VEGF pathway. In the DLS/c group, animal studies showed significant improvements in epidermal formation, barrier function, and epidermal hydration, accompanied by reduced inflammation. In addition, Masson’s trichrome and Sirius red staining revealed that the structure and ratio of dermal collagen in DLS/c resembled that of normal skin, indicating considerable potential for scarless wound healing. Interpretation: This biomimetic matrix shows promise in addressing the challenges of burn wounds and aiming for scarless repair, with benefits such as anti-infection, epidermal hydration, biological induction, and optimised topological properties. Funding: Shown in Acknowledgements.

Abstract The use of trastuzumab emtansine (T‐DM1) has revealed significant efficacy in HER2‐positive metastatic breast cancer (MBC). However, optimal therapeutic strategies following T‐DM1 failure remain a subject of debate in clinical practice. In this multicenter, retrospective, real‐world study, we sought to examine the effectiveness and safety of tyrosine kinase inhibitors (TKIs) as a therapeutic strategy in HER2‐positive MBC who developed T‐DM1 resistance. Between September 2018 and December 2022, 66 patients were enrolled. The median progression‐free survival of TKIs‐based therapy was 10.1 months (95% CI, 4.7–15.6). Objective response rate and clinical benefit rate were 18.2 and 66.7%, respectively. TKIs‐based therapy demonstrated better effectiveness in patients who had previously derived benefit from T‐DM1 and featured acquired resistance to trastuzumab. The most common adverse events were diarrhea (36, 54.5%), hand‐foot syndrome (31, 47.0%), and leucopenia (30, 45.5%). In conclusion, TKIs‐based therapy showed promising effectiveness and safety in HER2‐positive MBC patients after T‐DM1 failure.

Abstract This study aims to develop and validate nomogram models utilizing clinical and thoracic aorta imaging factors to assess the risk of hypertension for lung cancer screening cohorts. We included 804 patients and collected baseline clinical data, biochemical indicators, coexisting conditions, and thoracic aorta factors. Patients were randomly divided into a training set (70%) and a validation set (30%). In the training set, variance, t-test/Mann–Whitney U-test and standard least absolute shrinkage and selection operator were used to select thoracic aorta imaging features for constructing the AIScore. Multivariate logistic backward stepwise regression was utilized to analyze the influencing factors of hypertension. Five prediction models (named AIMeasure model, BasicClinical model, TotalClinical model, AIBasicClinical model, AITotalClinical model) were constructed for practical clinical use, tailored to different data scenarios. Additionally, the performance of the models was evaluated using receiver operating characteristic (ROC) curves, calibration curves and decision curve analyses (DCA). The areas under the ROC curve for the five models were 0.73, 0.77, 0.83, 0.78, 0.84 in the training set, and 0.77, 0.78, 0.81, 0.78, 0.82 in the validation set, respectively. Furthermore, the calibration curves and DCAs of both sets performed well on accuracy and clinical practicality. The nomogram models for hypertension risk prediction demonstrate good predictive capability and clinical utility. These models can serve as effective tools for assessing hypertension risk, enabling timely non-pharmacological interventions to preempt or delay the future onset of hypertension.

Abstract Background To identify potential serum biomarkers for differentiating between axial psoriatic arthritis (axPsA) and peripheral psoriatic arthritis (pPsA). Methods Serum samples were collected from patients with PsA to create a biomarker discovery cohort and a verification cohort. Patients with PsA were classified into axial or peripheral subtypes based on imaging criteria. Untargeted proteomics technology was used in the discovery phase to screen for biomarkers, and candidate biomarkers were evaluated using enzyme-linked immunosorbent assay (ELISA) in the verification phase. Results We identified 45 significantly differentially expressed proteins (DEPs) between axPsA (n = 20) and pPsA (n = 20) with liquid chromatography-mass spectrometry. Among these DEPs, serum pigment epithelium-derived factor (PEDF) was identified as a candidate biomarker using the Boruta algorithm and lasso regression. Results of ELISA further confirmed that the level of serum PEDF expression was significantly higher in axPsA (n = 37) than in pPsA (n = 51) at the verification cohort (37.9 ± 10.1 vs. 30.5 ± 8.9 μg/mL, p

Abstract Collapse is a major engineering hazard in open-cut foundation pit construction, and risk assessment is crucial for considerably reducing engineering hazards. This study aims to address the ambiguity problem of qualitative index quantification and the failure of high-conflict evidence fusion in risk assessment. Thus, a fast-converging and high-reliability multi-source data fusion method based on the cloud model (CM) and improved Dempster–Shafer evidence theory is proposed. The method can achieve an accurate assessment of subway pit collapse risks. First, the CM is introduced to quantify the qualitative metrics. Then, a new correction parameter is defined for improving the conflicts among evidence bodies based on conflict degree, discrepancy degree and uncertainty, while a fine-tuning term is added to reduce the subjective effect of global focal element assignment. Finally, the risk assessment result is obtained according to the maximum affiliation principle. The method is successfully applied to Luochongwei Station, where the difference between the maximum value and the second largest value of the basic probability assignment is 0.624, and the global uncertainty degree is 0.087. Both values satisfy the decision evaluation condition; however, values of other methods only satisfy one or neither condition. In addition, the proposed method requires only four cycles to reach the steady state by fusing data of the same index, which has faster convergence compared with that of other methods. The proposed method has good universality and effectiveness in subway pit collapse risk assessment.

Abstract Background Primary biliary cholangitis (PBC) and autoimmune hepatitis (AIH) variant syndrome (VS) exhibit a complex overlap of AIH features with PBC, leading to poorer prognoses than those with PBC or AIH alone. The biomarkers associated with drug response and potential molecular mechanisms in this syndrome have not been fully elucidated. Methods Whole-transcriptome sequencing was employed to discern differentially expressed (DE) RNAs within good responders (GR) and poor responders (PR) among patients with PBC/AIH VS. Subsequent gene ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were conducted for the identified DE RNAs. Plasma metabolomics was employed to delineate the metabolic profiles distinguishing PR and GR groups. The quantification of immune cell profiles and associated cytokines was achieved through flow cytometry and immunoassay technology. Uni- and multivariable logistic regression analyses were conducted to construct a predictive model for insufficient biochemical response. The performance of the model was assessed by computing the area under the receiver operating characteristic (AUC) curve, sensitivity, and specificity. Findings The analysis identified 224 differentially expressed (DE) mRNAs, 189 DE long non-coding RNAs, 39 DE circular RNAs, and 63 DE microRNAs. Functional pathway analysis revealed enrichment in lipid metabolic pathways and immune response. Metabolomics disclosed dysregulated lipid metabolism and identified PC (18:2/18:2) and PC (16:0/20:3) as predictors. CD4+ T helper (Th) cells, including Th2 cells and regulatory T cells (Tregs), were upregulated in the GR group. Pro-inflammatory cytokines (IFN-γ, TNF-α, IL-9, and IL-17) were downregulated in the GR group, while anti-inflammatory cytokines (IL-10, IL-4, IL-5, and IL-22) were elevated. Regulatory networks were constructed, identifying CACNA1H and ACAA1 as target genes. A predictive model based on these indicators demonstrated an AUC of 0.986 in the primary cohort and an AUC of 0.940 in the validation cohort for predicting complete biochemical response. Conclusion A combined model integrating genomic, metabolic, and cytokinomic features demonstrated high accuracy in predicting insufficient biochemical response in patients with PBC/AIH VS. Early recognition of individuals at elevated risk for insufficient response allows for the prompt initiation of additional treatments.

Abstract Background Parkinson’s disease (PD), a chronic and severe neurodegenerative disease, is pathologically characterized by the selective loss of nigrostriatal dopaminergic neurons. Dopamine (DA), the neurotransmitter produced by dopaminergic neurons, and its metabolites can covalently modify proteins, and dysregulation of this process has been implicated in neuronal loss in PD. However, much remains unknown about the protein targets. Methods In the present work, we designed and synthesized a dopamine probe (DA-P) to screen and identify the potential protein targets of DA using activity-based protein profiling (ABPP) technology in combination with liquid chromatography-tandem mass spectrometry (LC–MS/MS). In situ pull-down assays, cellular thermal shift assays (CETSAs) and immunofluorescence were performed to confirm the DA modifications on these hits. To investigate the effects of DA modifications, we measured the enzymatic activities of these target proteins, evaluated glycolytic stress and mitochondrial respiration by Seahorse tests, and systematically analyzed the changes in metabolites with unbiased LC–MS/MS-based non-targeted metabolomics profiling. Results We successfully identified three glycolytic proteins, aldolase A, α-enolase and pyruvate kinase M2 (PKM2), as the binding partners of DA. DA bound to Glu166 of α-enolase, Cys49 and Cys424 of PKM2, and Lys230 of aldolase A, inhibiting the enzymatic activities of α-enolase and PKM2 and thereby impairing ATP synthesis, resulting in mitochondrial dysfunction. Conclusions Recent research has revealed that enhancing glycolysis can offer protection against PD. The present study identified that the glycolytic pathway is vulnerable to disruption by DA, suggesting a promising avenue for potential therapeutic interventions. Safeguarding glycolysis against DA-related disruption could be a potential therapeutic intervention for PD.

Abstract This study systematically analyzed the molecular mechanism and function of nuclear factor kappa B subunit 2 (NFKB2) in colorectal cancer (CRC) to investigate the potential of NFKB2 as a therapeutic target for CRC. Various experimental techniques, including RNA sequencing, proteome chip assays, and small molecule analysis, were used to obtain a deeper understanding of the regulation of NFKB2 in CRC. The results revealed that NFKB2 was upregulated in a significant proportion of patients with advanced hepatic metastasis of CRC. NFKB2 played an important role in promoting tumor growth through CD8+ T‐cell exhaustion. Moreover, NFKB2 directly interacted with signal transducer and activator of transcription 2 (STAT2), leading to increased phosphorylation of STAT2 and the upregulation of programmed death ligand 1 (PD‐L1). Applying a small molecule inhibitor of NFKB2 (Rg5) led to a reduction in PD‐L1 expression and improved response to programmed death‐1 blockade‐based immunotherapy. In conclusion, the facilitated NFKB2‐STAT2/PD‐L1 axis may suppress immune surveillance in CRC and targeting NFKB2 may enhance the efficacy of immunotherapeutic strategies. Our results provide novel insights into the molecular mechanisms underlying the contribution of NFKB2 in CRC immune escape.

‘Allen Eureka’ is a bud variety of Eureka lemon with excellent fruiting traits. However, it suffers from severe winter defoliation that leads to a large loss of organic nutrients and seriously affects the tree’s growth and development as well as the yield of the following year, and the mechanism of its response to defoliation is still unclear. In order to investigate the molecular regulatory mechanisms of different leaf abscission periods in lemon, two lemon cultivars (‘Allen Eureka’ and ‘Yunning No. 1’) with different defoliation traits were used as materials. The petiole abscission zone (AZ) was collected at three different defoliation stages, namely, the pre-defoliation stage (CQ), the mid-defoliation stage (CZ), and the post-defoliation stage (CH). Transcriptome sequencing was performed to analyze the gene expression differences between these two cultivars. A total of 898, 4,856, and 3,126 differentially expressed genes (DEGs) were obtained in CQ, CZ, and CH, respectively, and the number of DEGs in CZ was the largest. GO analysis revealed that the DEGs between the two cultivars were mainly enriched in processes related to oxidoreductase, hydrolase, DNA binding transcription factor, and transcription regulator activity in the defoliation stages. KEGG analysis showed that the DEGs were concentrated in CZ and involved plant hormone signal transduction, phenylpropanoid biosynthesis, glutathione metabolism, and alpha-linolenic acid metabolism. The expression trends of some DEGs suggested their roles in regulating defoliation in lemon. Eight gene families were obtained by combining DEG clustering analysis and weighted gene co-expression network analysis (WGCNA), including β-glucosidase, AUX/IAA, SAUR, GH3, POD, and WRKY, suggesting that these genes may be involved in the regulation of lemon leaf abscission. The above conclusions enrich the research related to lemon leaf abscission and provide reliable data for the screening of lemon defoliation candidate genes and analysis of defoliation pathways.

Abstract Motor proteins, encoded by Kinesin superfamily (KIF) genes, are critical for brain development and plasticity. Increasing studies reported KIF’s roles in neurodevelopmental disorders. Here, a 6 years and 3 months‐old Chinese boy with markedly symptomatic epilepsy, intellectual disability, brain atrophy, and psychomotor retardation was investigated. His parents and younger sister were phenotypically normal and had no disease‐related family history. Whole exome sequencing identified a novel heterozygous in‐frame deletion (c.265_267delTCA) in exon 3 of the KIF5C in the proband, resulting in the removal of evolutionarily highly conserved p.Ser90, located in its ATP‐binding domain. Sanger sequencing excluded the proband's parents and family members from harboring this variant. The activity of ATP hydrolysis in vitro was significantly reduced as predicted. Immunofluorescence studies showed wild‐type KIF5C was widely distributed throughout the cytoplasm, while mutant KIF5C was colocalized with microtubules. The live‐cell imaging of the cargo‐trafficking assay revealed that mutant KIF5C lost the peroxisome‐transporting ability. Drosophila models also confirmed p.Ser90del's essential role in nervous system development. This study emphasized the importance of the KIF5C gene in intracellular cargo‐transport as well as germline variants that lead to neurodevelopmental disorders and might enable clinicians for timely and accurate diagnosis and disease management in the future.

Abstract The importance of uncommon/rare oncogenic drivers in non‐small cell lung cancer (NSCLC) was underscored during the 20th China Lung Cancer Summit. These drivers, while present in a significant proportion of NSCLC patients, remain a challenge for diagnosis and therapeutic targeting. In the never‐smokers/low smokers category with mutations such as EGFR and HER2, the efficacy of immune checkpoint inhibitors (ICIs) remains suboptimal, attributed to lower PD‐L1 expression and tumor mutation burden (TMB). However, heavy smokers, often with mutations like KRAS, may derive benefits from ICIs, as supported by trials like CheckMate‐057. With the complex landscape of these drivers and their clinical implications, the summit culminated in six pivotal consensus points, aiming to guide future research and clinical decisions. Despite the advancements, the detection, interpretation, and therapeutic strategies involving these drivers necessitate further exploration and standardization.

Abstract The existing biomarkers are insufficient for predicting the prognosis of pancreatic ductal adenocarcinoma (PDAC). Intraductal papillary mucinous neoplasm (IPMN) is a precursor to PDAC; therefore, identifying biomarkers from differentially expressed genes (DEGs) of PDAC and IPMN is a new and reliable strategy for predicting the prognosis of PDAC. In this study, four datasets were downloaded from the Gene Expression Omnibus database and standardized using the R package ‘limma.’ A total of 51 IPMN and 81 PDAC samples were analyzed, and 341 DEGs in PDAC and IPMN were identified; DEGs were involved in the extracellular matrix and tumor microenvironment. An acceptable survival prognosis was demonstrated by SDC1 and ITGA2, which were highly expressed during in vitro PDAC cell proliferation, apoptosis, and migration. SDC1 high was enriched in interferon alpha (IFN-α) response and ITGA2 high was primarily detected in epithelial-mesenchymal transition (EMT), which was verified using western blotting. We concluded that SDC1 and ITGA2 are potential prognostic biomarkers for PDAC associated with IPMN. Downregulation of SDC1 and ITGA2 expression in PDAC occurs via a mechanism involving possible regulation of IFN-α response, EMT, and immunity, which may act as new targets for PDAC therapy.

Background Dyslipidemia is the most important and causal independent risk factor for atherosclerotic cardiovascular disease (ASCVD) . The prevalence of dyslipidemia in elderly residents in Guangdong Province is high, and it is urgent to analyze the specific prevalence of dyslipidemia and its influencing factors among the elderly, and to carry out targeted preventive and control measures for dyslipidemia. Objective To investigate the epidemiological status of dyslipidemia and its risk factors among elderly residents included in the national basic public health service in Yuexiu District, Guangzhou. Methods A total of 41 469 elderly residents aged 65 years and above with complete important variables were selected as subjects from the information system of community health service center in Yuexiu District, Guangzhou City in 2020, the 2020 health checkup data was used to describe the epidemiological characteristics of the included patients such as basic information, BMI and blood lipid levels. Restricted cubic spline (RCS) fitting Logistic regression model was used to analyze the relationship between age, BMI and the prevalence of dyslipidemia. Results The prevalence of dyslipidemia in 41 469 elderly residents was 53.65% (22 247/41 469) , with a standardized prevalence of 53.89%. The prevalence of hypercholesterolemia (HTC) , hypertriglyceridemia (HTG) , mixed hyperlipidemia and low high-density lipoprotein cholesterol was 21.43%, 16.50%, 14.51% and 3.80%, with the standardized prevalence of 21.57%, 16.53%, 14.61%, 3.78%, respectively. Multivariate Logistic regression analysis showed that gender, age, education level, exercise status, and BMI were all influencing factors for dyslipidemia in elderly residents, among which female, low age group, and high BMI were risk factors for dyslipidemia in elderly residents (P

Abstract Background Hepatic ischemia–reperfusion (IR) injury is the primary reason for complications following hepatectomy and liver transplantation (LT). Insulin-induced gene 2 (Insig2) is one of several proteins that anchor the reticulum in the cytoplasm and is essential for metabolism and inflammatory responses. However, its function in IR injury remains ambiguous. Methods Insig2 global knock-out (KO) mice and mice with adeno-associated-virus8 (AAV8)-delivered Insig2 hepatocyte-specific overexpression were subjected to a 70% hepatic IR model. Liver injury was assessed by monitoring hepatic histology, inflammatory responses, and apoptosis. Hypoxia/reoxygenation stimulation (H/R) of primary hepatocytes and hypoxia model induced by cobalt chloride (CoCl2) were used for in vitro experiments. Multi-omics analysis of transcriptomics, proteomics, and metabolomics was used to investigate the molecular mechanisms underlying Insig2. Results Hepatic Insig2 expression was significantly reduced in clinical samples undergoing LT and the mouse IR model. Our findings showed that Insig2 depletion significantly aggravated IR-induced hepatic inflammation, cell death and injury, whereas Insig2 overexpression caused the opposite phenotypes. The results of in vitro H/R experiments were consistent with those in vivo. Mechanistically, multi-omics analysis revealed that Insig2 is associated with increased antioxidant pentose phosphate pathway (PPP) activity. The inhibition of glucose-6-phosphate-dehydrogenase (G6PD), a rate-limiting enzyme of PPP, rescued the protective effect of Insig2 overexpression, exacerbating liver injury. Finally, our findings indicated that mouse IR injury could be attenuated by developing a nanoparticle delivery system that enables liver-targeted delivery of substrate of PPP (glucose 6-phosphate). Conclusions Insig2 has a protective function in liver IR by upregulating the PPP activity and remodeling glucose metabolism. The supplementary glucose 6-phosphate (G6P) salt may serve as a viable therapeutic target for alleviating hepatic IR.

Abstract Objective This study aimed to develop a simplified diagnostic tool for assessing sarcopenia and myosteatosis in gastrointestinal cancer patients, focusing on the creatinine to cystatin C ratio (CCR) as an evaluation marker. Methods 955 patients were split into training (n = 671) and validation (n = 284) cohorts. Using logistic regression, risk factors for sarcopenia and myosteatosis were identified. The predictive capacity of the developed model was examined. The association between CCR and muscle imaging parameters, along with its impact on clinical outcomes, was analyzed. Results No significant differences were observed in baseline traits between cohorts. CCR emerged as a significant risk factor for both sarcopenia and myosteatosis. Nomograms for diagnosing these conditions demonstrated strong predictive ability, with AUC values indicating high accuracy (sarcopenia AUC: 0.865–0.872; myosteatosis AUC: 0.848–0.849). The clinical utility of the nomograms was confirmed through decision curve analysis. CCR showed significant association with muscle imaging parameters and was a reliable indicator for assessing the risk of sarcopenia, myosteatosis, and cachexia. Moreover, CCR was able to differentiate between patient survival and disease progression rates. Conclusion A diagnostic tool for sarcopenia and myosteatosis in gastrointestinal cancer patients was developed, with CCR being a pivotal biomarker for disease diagnosis and prognosis prediction. Graphical Abstract

Abstract Ménière’s disease (MD) is associated with functional reorganization not only in the auditory or sensory cortex but also in other control and cognitive areas. In this study, we examined intranetwork and internetwork connectivity differences between 55 MD patients and 70 healthy controls (HC) in 9 well-defined resting-state networks. Functional connectivity degree was lower in MD compared to HC in 19 brain areas involved in the somatomotor, auditory, ventral attention, default mode, limbic, and deep gray matter networks. In addition, we observed lower intranetwork connectivity in the auditory, ventral attention, and limbic networks, as well as lower internetwork connectivity between the somatomotor and limbic networks, and between the auditory and somatomotor, deep gray matter, and ventral attention networks, and between the deep gray matter and default mode network. Furthermore, we identified 81 pairs of brain areas with significant differences in functional connectivity between MD patients and HC at the edge level. Notably, the left amygdala’s functional connectivity degree was positively correlated with MD’s disease stage, and the ventral attention network’s intranetwork connectivity was positively correlated with the healthy side vestibular ratio. Our findings suggest that these functional network reorganization alterations may serve as potential biomarkers for predicting clinical progression, evaluating disease severity, and gaining a better understanding of MD’s pathophysiology. Large-scale network studies using neuroimaging techniques can provide additional insights into the underlying mechanisms of MD.

The process of synthesizing radionuclide-coupled drugs, especially shutdown technology that links bipotent chelators with biomolecules, utilizes traditional coupling reactions, including emerging click chemistry; these reactions involve different drawbacks, such as complex and cumbersome reaction steps, long reaction times, and the use of catalysts at various pH values, which can negatively impact the effects of the chelating agent. To address the above problems in this study, This research designed a novel bipotent chelator coupled with peptides. In the present study, dichloromethane was used as a solvent, and the reaction was conducted at room temperature for 12 h. A one-step ring-opening method was employed to introduce the coupling functional group of tridentate amide acid. The coupling materials consisted of the amino active site of the peptide and diethylene glycol anhydride. In this paper, this study explored the reactions between different equivalents of acid anhydride coupled to the peptide (peptide sequence: HLRKLRKR) and determined that the maximum conversion of the peptide feedstock was 87%. To determine the selectivity of the reaction sites in this polypeptide, This study identified the peptide sequence at the reaction site using nuclear magnetic resonance (NMR) and liquid chromatography–mass spectrometry (LC-MS). For the selected peptide, the first reactive site was on the terminal amino group, followed by the amino group on the tetra- and hepta-lysine side chains. The tridentate amic acid framework functions as a chelating agent, capable of binding a range of lanthanide ions. This significantly reduces and optimizes the time and cost associated with synthesizing radionuclide-coupled drugs.

Digital transformation enables small and medium enterprises (SMEs) to reduce or overcome their reliance on resources and energy, thereby minimizing their environmental impact and providing them with sustainable green competitive advantages. However, the reasons for this phenomenon are not yet clear. To further investigate this issue, we selected 391 Chinese SMEs to examine the relationships among green transformation, green innovation, government regulation, and green competitive advantages. Green innovation includes green product innovation and green process innovation, while government regulation includes incentive regulation, constraint regulation, and guidance regulation. The empirical results show that digital transformation can enhance SMEs' green competitive advantages. Additionally, the hypothesized mediating effect of green product innovation and green process innovation between digital transformation and green competitive advantages is supported, while the moderating effect of incentive regulation, constraint regulation, and guidance regulation on the relationship between digital transformation and green product innovation and green process innovation is also confirmed. The findings of this study may contribute to more effective management of digital transformation and green innovation in SMEs, thereby promoting their development.

The land use changes driven by human activities press a incredible menace to zonal ecological security. As the most active urban cluster, the uncontrolled expansion of cities in the bay area exerts enormous pressure on the ecosystem. Therefore, from the perspective of ecological conservation, exploring future land use optimization patterns and spatial structure is extremely essential for the long-term thriving of the bay area. On this basis, this research integrated the System Dynamics model (SD) as the quantity forecast model and the PLUS model as the spatial emulation model and established the Land Use/Cover Change (LUCC) Simulation Framework by setting the constraints of Ecological Security Multi-Scenario Patterns (ESMP). By setting four scenarios in future, that is, Business As Usual (BAU), Priority of Ecological Protection (PEP), Balanced Development Scenario (BD), and Priority of Urban development (PUD), this research predicts LUCC in the Zhejiang Greater Bay Area (ZGBA) in 2035 and explored land use optimization patterns. The results indicate that by 2035, under the scenarios of BAU, BD, and PUD, the construction land will observably grow by 38.86%, 19.63%, and 83.90%, respectively, distributed mainly around the Hangzhou Bay Area, Taizhou Bay Area, and Wenzhou Bay Area, primarily achieved by sacrificing ecologically sensitive lands such as forests to achieve regional high economic growth. Under PEP, the growth of construction land retards, and forest experiences net growth (11.27%), with better landscape connectivity and more cohesive patches compared to other scenarios. Combining regional planning and analysis at the city scale, Hangzhou Bay area (Hangzhou, Huzhou, Jiaxing, Shaoxing, Ningbo) can adopt the BD development scenario, while Zhoushan, Taizhou, Wenzhou and Fuyang County of Hangzhou can adopt the PEP development scenario. This research furnishes a novel mechanism for optimizing land use pattern in ecological security perspective and offers scientific guidance for land resource management and spatial planning in ZGBA.

'Allen Eureka' is a bud variety of Eureka lemon with excellent fruiting traits, but severe winter defoliation affects the following year's yield, and the response mechanism of lemon defoliation is currently unknown. Two lemon cultivars ('Allen Eureka' and 'Yunning No. 1') with different defoliation traits were used as materials to investigate the molecular regulatory mechanisms of different leaf abscission periods in lemons. The petiole abscission zone was collected at three different defoliation stages, namely, the predefoliation stage (k15), the middefoliation stage (k30), and the postdefoliation stage (k45). Transcriptome sequencing was performed to analyze the gene expression differences between these two cultivars. A total of 1141, 2695, and 1433 differentially expressed genes (DEGs) were obtained in k15, k30, and k45, respectively, and the number of DEGs in k30 was the largest. GO analysis revealed that the DEGs between the two cultivars were mainly enriched in processes related to hydrolase activity, chitinase activity, oxidoreductase activity, and transcription regulator activity in the defoliation stages. KEGG analysis showed that the DEGs were concentrated in k30, which involved plant hormone signal transduction, phenylpropanoid biosynthesis, and biosynthesis of amino acids. The expression trends of some DEGs suggested their roles in regulating defoliation in Lemon. Seven genes were obtained by WGCNA, including sorbitol dehydrogenase (CL9G068822012_alt, CL9G068820012_alt, CL9G068818012_alt), abscisic acid 8'-hydroxylase (CL8G064053012_alt, CL8G064054012_alt), and asparagine synthetase (CL8G065162012_alt, CL8G065151012_alt), suggesting that these genes may be involved in the regulation of lemon leaf abscission.

The primary energy consumption structure of BRICS countries is dominated by fossil energy, particularly coal. Coal consumption in BRICS countries is a major driver underlying increased carbon emissions. Therefore, this study developed a spatiotemporal decoupling mode and incorporated factors related to coal consumption-induced carbon emissions into a spatiotemporal decoupling analysis method to provide differentiated and targeted policies for energy restructuring and emission reduction targets in BRICS countries. Moreover, a temporal-spatial decomposition logarithmic mean Divisia index model was developed using the spatiotemporal decoupling index method. The model is based on CO2 emissions generated by coal consumption in BRICS countries, with a primary focus on data from Brazil, Russia, South Africa, India, and China. The findings reveal distinct spatiotemporal distributions and driving effects of coal consumption and carbon dioxide emissions across various countries. Factors such as CO2 emission intensity, coal consumption intensity, economic output per capita, and population structure exerted either positive or negative effects on the distributional effect of the carbon emission-economic output per capita association in BRICS countries. Additionally, country-level heterogeneity in the influence of the distributional effects of CO2 emissions was observed within each BRICS country. Thus, different policies are needed to achieve carbon emission reduction targets in different countries.

Introduction Hysterectomy is the most common surgical procedure in the field of gynaecology. The traditional multiport laparoscopy, transumbilical laparoendoscopic single-site surgery (TU-LESS) and transvaginal natural orifice transluminal endoscopic surgery (vNOTES) hysterectomy approaches have been implemented to varying degrees in clinical practice. At present, although their feasibility has been proven, there are no large randomised controlled studies on postoperative rehabilitation. This study aims to evaluate postoperative recovery and assess the safety and effectiveness of these three surgical approaches for total laparoscopic hysterectomy.Method and analysis This is a multicentre, randomised, single-blind, three-arm, parallel-group, interventional clinical trial. Recruitment will be carried out in five tertiary hospitals in China. Patients diagnosed with benign uterine disease or precancerous lesions will be assigned to the vNOTES group, TU-LESS group and conventional laparoscopy group at a 1:1:1 ratio. The achievement rate of comprehensive indices of enhanced recovery after surgery (ERAS) within 24 hours postoperatively will be considered the primary outcome (the comprehensive indicators of ERAS include fluid intake, passing flatus, urination after catheter removal, ambulation and a Visual Analogue Scale score ≤3.) This study will use a non-inferiority test, with a power (1−ß) of 80% and a margin of −0.15, at a one-sided α of 0.0125. The sample size will be 480 patients (including an assumed 15% dropout rate), calculated according to the primary outcome.Ethics and dissemination This study was approved on 25 April 2022 by the Medical Ethics Committee of West China Second University Hospital (2022(057)), Sichuan University, Chengdu, China. All participants will be required to provide informed consent before their participation in the study. The results of the trial will be submitted for publication in a peer-reviewed journal and presented at international conferences.Protocol version V.3.0, 31 August 2023.Trial registration number ChiCTR2200057405.

Quinidine has been used as an anticonvulsant to treat patients with KCNT1-related epilepsy by targeting gain-of-function KCNT1 pathogenic mutant variants. However, the detailed mechanism underlying quinidine’s blockade against KCNT1 (Slack) remains elusive. Here, we report a functional and physical coupling of the voltage-gated sodium channel NaV1.6 and Slack. NaV1.6 binds to and highly sensitizes Slack to quinidine blockade. Homozygous knockout of NaV1.6 reduces the sensitivity of native sodium-activated potassium currents to quinidine blockade. NaV1.6-mediated sensitization requires the involvement of NaV1.6’s N- and C-termini binding to Slack’s C-terminus and is enhanced by transient sodium influx through NaV1.6. Moreover, disrupting the Slack-NaV1.6 interaction by viral expression of Slack’s C-terminus can protect against SlackG269S-induced seizures in mice. These insights about a Slack-NaV1.6 complex challenge the traditional view of ‘Slack as an isolated target’ for anti-epileptic drug discovery efforts and can guide the development of innovative therapeutic strategies for KCNT1-related epilepsy.

Abstract To establish a pre-test probability model of coronary heart disease (CHD) combined with cardiopulmonary exercise test (CPET) indexes and to compare the clinical effectiveness with Duke clinical score (DCS) and updated Diamond-Forrester model (UDFM), thus further explore the predictive value. 342 cases were used to establish the prediction model equation and another 80 cases were used to verify the effectiveness. The patients were divided into CHD group (n = 157) and non-CHD group (n = 185) according to coronary artery stenosis degree >50% or not. Combining DCS and UDFM as reference models with CPET indexes, a multivariate logistic regression model was established. The area under the ROC curve of the three models were calculated to compare the predictive effectiveness. There were significant differences in gender, chest pain type, myocardial infarction history, hypertension history, smoking, pathological Q wave and ST-T change between two groups (P

Abstract Background Chronic remote ischemic conditioning (CRIC) has been shown to improve myocardial ischemia in experimental animal studies; however, its effectiveness in patients with chronic stable angina (CSA) has not been investigated. We conducted a proof-of-concept study to investigate the efficacy and safety of a six-month CRIC treatment in patients with CSA. Methods The EARLY-MYO-CSA trial was a prospective, randomized, controlled trial evaluating the CRIC treatment in patients with CSA with persistent angina pectoris despite receiving ≥ 3-month guideline-recommended optimal medical therapy. The CRIC and control groups received CRIC (at 200 mmHg) or sham CRIC (at 60 mmHg) intervention for 6 months, respectively. The primary endpoint was the 6-month change of myocardial flow reserve (MFR) on single-photon emission computed tomography. The secondary endpoints were changes in rest and stress myocardial blood flow (MBF), angina severity according to the Canadian Cardiovascular Society (CCS) classification, the Seattle Angina Questionnaire (SAQ), and a 6-min walk test (6-MWT). Results Among 220 randomized CSA patients, 208 (105 in the CRIC group, and 103 in the control group) completed the treatment and endpoint assessments. The mean change in MFR was significantly greater in the CRIC group than in the control group (0.27 ± 0.38 vs. − 0.04 ± 0.25; P

Abstract Joshimath has received much attention for its massive ground subsidence at the beginning of the year. Rapid urbanization and its unique geographical location may have been one of the factors contributing to the occurrence of this geological disaster. In high mountain valley areas, the complex occurrence mechanism and diverse disaster patterns of geological hazards highlight the inadequacy of manual monitoring. To address this problem, the inversion of deformation of the Joshimath surface in multiple directions can be achieved by multidimensional InSAR techniques. Therefore, in this paper, the multidimensional SBAS-InSAR technique was used to process the lift-track Sentinel-1 data from 2020 to 2023 to obtain the two-dimensional vertical and horizontal deformation rates and time series characteristics of the Joshimath ground surface. To discover the causes of deformation and its correlation with anthropogenic activities and natural disasters by analyzing the spatial and temporal evolution of surface deformation. The results show that the area with the largest cumulative deformation is located in the northeastern part of the town, with a maximum cumulative subsidence of 271.2 mm and a cumulative horizontal movement of 336.5 mm. The spatial distribution of surface deformation is based on the lower part of the hill and develops towards the upper part of the hill, showing a trend of expansion from the bottom to the top. The temporal evolution is divided into two phases: gentle to rapid, and it is tentatively concluded that the decisive factor that caused the significant change in the rate of surface deformation and the early onset of the geological subsidence hazard was triggered by the 4.7 magnitude earthquake that struck near the town on 11 September 2021.

Abstract There are concerns about the risk of injuries caused by marathons in China. Since male and female runners have different injury risks, gender differences in running shoe functionality should be further complemented. A supervised questionnaire survey of 626 marathon runners was collected. The questionnaire was categorized into four sections: (1) participant profile, (2) importance of shoe properties, (3) functional evaluation of shoe properties and (4) importance ranking of shoe properties. The Mann–Whitney U test, Fisher’s exact test of cross tabulation and Chi-square test, and two-way ANOVA were used to analyze the results of this survey. The significance level was set at P

Objective To study the correlation between platelet transfusion efficacy and KIR receptor-HLA ligand. Methods Thirty-three leukemia patients with positive HLA antibody were tested for cross-matching with donor platelets. Platelets from suitable donors were selected for transfusion, and the 24-hour platelet corrected count increment (CCI) was used to determine the transfusion effect. KIR and ligand genotyping were performed on blood samples from patients and donors by PCR-SSP method, and the relationship between platelet transfusion effects and KIR receptor-HLA ligand was analyzed. Results In 74 occasions of platelet transfusion, 42 were ineffective and 32 were effective. When the donor had C2 gene and HLA-B Bw4-80T gene, the frequency of ineffective platelet transfusion in the recipient was 69.0% (29/42) and 52.4% (22/35), respectively, which was significantly higher than that in the effective group [25.0% (8/32) and 25.0% (8/32)]. When the donor had C1 gene, and the frequency of effective platelet transfusion in the recipient was 100.0%(32/32), which was higher than that in the ineffective group [83.3%(35/42)]. When the recipient-donor matching mode was KIR2DL1-C2 and KIR3DL1-(HLA-B Bw4-80T), the frequency of ineffective platelet transfusion was 69.0%(29/42) and 40.5%(22/42),higher than that of the effective group [25% (8/32) and 18.8% (6/32)]. When the recipient-donor matching model was KIR2DL3-C1, the rate of effective platelet transfusion in 32 patients (100.0%), which was higher than that (35 patients 83. 3%) in the ineffective group. When the mismatch mode of recipient iKIR+donor HLA ligand receptor was KIR2DL1-C2, the frequency of effective platelet transfusion in the recipient was 78.1% (25/32), which was much higher than that in the ineffective group [31.0% (13/42)]. When the mismatch mode was KIR3DL1-(HLA-B Bw4-80T), the rate of effective platelet transfusion in the recipient was 68.8% (22/32), which was higher than that in the ineffective group (42.9%, 18/42). The difference between the above groups was statistically significant(P

Abstract In this study, we aim to develop and validate a radiomics model for pretreatment prediction of RPS6K expression in hepatocellular carcinoma (HCC) patients, thus helping clinical decision-making of mTOR-inhibitor (mTORi) therapy. We retrospectively enrolled 147 HCC patients, who underwent curative hepatic resection at First Affiliated Hospital Zhejiang University School of Medicine. RPS6K expression was determined with immunohistochemistry staining. Patients were randomly split into training or validation cohorts on a 7:3 ratio. Radiomics features were extracted from T2-weighted and diffusion-weighted images. Machine learning algorithms including multiple logistic regression (MLR), supporting vector machine (SVM), random forest (RF), and artificial neural network (ANN) were applied to construct the predictive model. A nomogram was further built to visualize the possibility of RPS6K expression. The area under the receiver operating characteristic (AUC) was used to evaluate the performance of diagnostic models. 174 radiomics features were confirmed correlated with RPS6K expression. Amongst all built models, the ANN-based hybrid model exhibited best predictive ability with AUC of 0.887 and 0.826 in training and validation cohorts. ALB was identified as the key clinical index, and the nomogram displayed further improved ability with AUC of 0.917 and 0.845. In this study, we proved MRI-based radiomics model and nomogram can accurately predict RPS6K expression non-invasively, thus providing help for clinical decision making for mTORi therapy.

Abstract Background The feasibility of DNA methylation-based assays in detecting minimal residual disease (MRD) and postoperative monitoring remains unestablished. We aim to investigate the dynamic characteristics of cancer-related methylation signals and the feasibility of methylation-based MRD detection in surgical lung cancer patients. Methods Matched tumor, tumor-adjacent tissues, and longitudinal blood samples from a cohort (MEDAL) were analyzed by ultra-deep targeted sequencing and bisulfite sequencing. A tumor-informed methylation-based MRD (timMRD) was employed to evaluate the methylation status of each blood sample. Survival analysis was performed in the MEDAL cohort (n = 195) and validated in an independent cohort (DYNAMIC, n = 36). Results Tumor-informed methylation status enabled an accurate recurrence risk assessment better than the tumor-naïve methylation approach. Baseline timMRD-scores were positively correlated with tumor burden, invasiveness, and the existence and abundance of somatic mutations. Patients with higher timMRD-scores at postoperative time-points demonstrated significantly shorter disease-free survival in the MEDAL cohort (HR: 3.08, 95% CI: 1.48–6.42; P = 0.002) and the independent DYNAMIC cohort (HR: 2.80, 95% CI: 0.96–8.20; P = 0.041). Multivariable regression analysis identified postoperative timMRD-score as an independent prognostic factor for lung cancer. Compared to tumor-informed somatic mutation status, timMRD-scores yielded better performance in identifying the relapsed patients during postoperative follow-up, including subgroups with lower tumor burden like stage I, and was more accurate among relapsed patients with baseline ctDNA-negative status. Comparing to the average lead time of ctDNA mutation, timMRD-score yielded a negative predictive value of 97.2% at 120 days prior to relapse. Conclusions The dynamic methylation-based analysis of peripheral blood provides a promising strategy for postoperative cancer surveillance. Trial registration This study (MEDAL, MEthylation based Dynamic Analysis for Lung cancer) was registered on ClinicalTrials.gov on 08/05/2018 (NCT03634826). https://clinicaltrials.gov/ct2/show/NCT03634826 .

Abstract. Background:. Large disparities exist in liver cancer burden trends across countries but are poorly understood. We aimed to investigate the global trajectories of liver cancer burden, explore the driving forces, and predict future trends. Methods:. Data on the liver cancer burden in 204 countries and territories from 1990 to 2019 were extracted from the Global Burden of Disease Study. The age-standardized incidence rate (ASIR) and age-standardized mortality rate (ASMR) trajectories were defined using growth mixture models. Five major risk factors contributing to changes in the ASIR or ASMR and socioeconomic determinants were explored using the identified trajectories. A Bayesian age–period–cohort model was used to predict future trends through 2035. Results:. Three trajectories of liver cancer burden were identified: increasing, stable, and decreasing groups. Almost half of the American countries were classified in the decreasing group (48.6% for ASIR and ASMR), and the increasing group was the most common in the European region (ASIR, 49.1%; ASMR, 37.7%). In the decreasing group, the decrease of liver cancer due to hepatitis B contributed 63.4% and 60.4% of the total decreases in ASIR and ASMR, respectively. The increase of liver cancer due to alcohol use, hepatitis C, and hepatitis B contributed the most to the increase in the increasing group (30.8%, 31.1%, and 24.2% for ASIR; 33.7%, 30.2%, and 22.2% for ASMR, respectively). The increasing group was associated with a higher sociodemographic index, gross domestic product per capita, health expenditure per capita, and universal health coverage (all P