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Advancing in single-cell RNA sequencing techniques enhances the resolution of cell heterogeneity study. Density-based unsupervised clustering has the potential to detect the representative anchor points and the number of clusters automatically. Meanwhile, discovering the true cell type of scRNA-seq data in the unsupervised scenario is still challenging. To this end, we proposed a tensor shared nearest neighbor anchor clustering for scRNA-seq data, named scTSNN, which first makes use of the tensor affinity learning module to mine the local-global balanced topological structures among cells, next designs density-based shared nearest neighbor measurement method to automatically detect anchor cells, finally partitions the non-anchor cells to obtain the clustering results. Validated on synthetic datasets and scRNA-seq datasets, scTSNN not only exactly detects the complicated structures but also has better performance in accuracy and robustness compared with the state-of-the-art methods. Moreover, case studies on mammalian cells and cervical cancer tumor cells demonstrate the selected anchor cells of scTSNN benefit the cell pseudotime inference and rare cell identification, which show good application and research value of scTSNN.

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As a notorious bacterial pathogen, Staphylococcus aureus (S. aureus) can readily induce infections in the community and hospital, causing significant morbidity and mortality. With the extensive rise of multiple resistance, conventional antibiotic therapy has rapidly become ineffective for related infections. Resveratrol is a naturally occurring polyphenolic substance that has been demonstrated to have effective antimicrobial activity against S. aureus. Resveratrol at sub-inhibitory doses can suppress the expression of virulence factors, contributing to attenuated biofilm formation, interference with quorum sensing and the inhibition of the production of toxins. As a promising efflux pump inhibitor, resveratrol enhances antibiotic susceptibility to a certain extent. In conjunction with conventional antibiotics, resveratrol displays unique synergistic effects with norfloxacin and aminoglycoside on S. aureus, yet antagonizes the lethal effects of daptomycin, oxacillin, moxifloxacin and levofloxacin. Nevertheless, given the low oral bioavailability of resveratrol, advanced formulations need to be developed to delay the rapid metabolism conversion to low or inactive conjugates. The present review discusses the antibacterial properties of resveratrol against S. aureus, in an aim to provide in-depth insight for researchers to address the challenges of antimicrobial resistance.

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Nanoparticles (NPs) are one of the promising strategies to deal with bacterial infections. As the main subset of NPs, metal and metal oxide NPs show destructive power against bacteria by releasing metal ions, direct contact of cell membranes and antibiotic delivery. Recently, a number of researchers have focused on the antibacterial activity of zinc oxide nanoparticles (ZnO NPs) against Staphylococcus aureus (S. aureus). Currently, there is a lack of a comprehensive review on ZnO NPs against S. aureus. Therefore, in this review, the antibacterial activity against S. aureus of ZnO NPs made by various synthetic methods was summarized, particularly the green synthetic ZnO NPs. The synergistic antibacterial effect against S. aureus of ZnO NPs with antibiotics was also summarized. Furthermore, the present review also emphasized the enhanced activities against S. aureus of ZnO nanocomposites, nano-hybrids and functional ZnO NPs.

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Background: Previous studies linked neutrophil to lymphocyte ratio (NLR) with short-term mortality after acute ischemic stroke (AIS), but its relationship with long-term mortality remains unclear. This study investigates the association between NLR and five-year mortality in AIS patients. Method: We analyzed 416 AIS patients from April 2012 to January 2016 at Zhangjiagang TCM Hospital. Admission NLR was divided into quartiles: Q1 (<2.00), Q2 (2.00-3.05), Q3 (3.06-5.46), and Q4 (≥5.46). We assessed 5-year all-cause and vascular mortality using Kaplan-Meier, Cox regression, and receiver operating characteristic (ROC) curve analyses. Results: Over five years, 134 (32.2 %) all-cause deaths and 114 (27.4 %) vascular deaths occurred. Elevated NLR was significantly associated with increased risks of all-cause and vascular mortality. Multivariate Cox analysis identified stroke history (HR: 1.57, 95 % CI 1.08-2.30), baseline National Institutes of Health Stroke Scale (NIHSS) score (HR: 1.09, 95 % CI 1.05-1.12), and NLR (HR: 1.09, 95 % CI 1.05-1.12) as independent risk factors for all-cause mortality. These factors also predicted 5-year vascular mortality: stroke history (HR: 1.65, 95 % CI 1.10-2.49), NIHSS score (HR: 1.10, 95 % CI 1.06-1.13), and NLR (HR: 1.08, 95 % CI 1.05-1.10). NLR quartiles were significantly linked to both outcomes: all-cause mortality HRs were Q2 (1.87, 95 % CI 1.00-3.51), Q3 (2.40, 95 % CI 1.31-4.39), Q4 (2.77, 95 % CI 1.47-5.24), P for trend = 0.001; vascular mortality HRs were Q2 (1.76, 95 % CI 0.88-3.55), Q3 (2.34, 95 % CI 1.14-4.40), Q4 (2.57, 95 % CI 1.28-5.16), P for trend = 0.002. Kaplan-Meier survival analysis revealed significantly higher mortality rates in higher NLR quartiles (log-rank p < 0.001). ROC analysis identified optimal NLR cutoff values of 3.42 for predicting 5-year all-cause mortality (AUC 0.689) and 3.51 for vascular-cause mortality (AUC 0.700), with moderate sensitivity and specificity. Conclusions: Higher NLR at admission was linked with five-year all-cause mortality and mortality attributed explicitly to vascular causes in AIS patients.

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BACKGROUND & AIMS: The protection provided by rotavirus (RV) vaccines is highly heterogeneous among individuals. We hypothesized that microbiota composition might influence RV vaccine efficacy. METHODS: First, we examined the potential of segmented filamentous bacteria (SFB) colonization to influence RV vaccine efficacy in mice. Next, we probed the influence of human microbiomes on RV vaccination via administering mice fecal microbial transplants (FMTs) from children with robust or minimal RV vaccine responsiveness. Post-FMT, mice were subjected to RV vaccination followed by RV challenge. RESULTS: SFB colonization induced a phenotype that was reminiscent of RV vaccine failure (ie, failure to generate RV antigens and, consequently, anti-RV antibodies following RV vaccination resulting in proneness to RV challenge after SFB levels diminished). FMTs from children to mice recapitulated donor vaccination phenotype. Specifically, mice receiving FMTs from high-responsive vaccinees copiously shed RV antigens and robustly generated anti-RV antibodies following RV vaccination. Concomitantly, such mice were impervious to RV challenge. In contrast, mice receiving FMTs from children who had not responded to RV vaccination exhibited only modest responses to RV vaccination and, concomitantly, remained prone to RV challenge. Microbiome analysis ruled out a role for SFB but suggested involvement of Clostridium perfringens. Oral administration of cultured C. perfringens to gnotobiotic mice partially recapitulated the RV vaccine non-responder phenotype. Analysis of published microbiome data found C. perfringens abundance in children modestly associated with RV vaccine failure. CONCLUSION: Microbiota composition influences RV vaccine efficacy with C. perfringens being one, perhaps of many, potential contributing taxa.

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Ulcerative colitis (UC) is a chronic inflammatory disease, the incidence of which is increasing worldwide. However, the etiology and pathogenesis of UC remains unclear. The n-butanol extract of Pulsatilla decoction (BEPD), a traditional Chinese medicine, has been shown to be effective in treating UC. This study aimed to explore the molecular mechanism underlying the effects of BEPD on UC, in particular its effects on neutrophil extracellular trap (NET) formation by neutrophils. High-performance liquid chromatography was used to determine the principal compounds of BEPD. UC was induced in mice using dextran sodium sulfate, and mice were treated with 20, 40, or 80 mg/kg BEPD daily for seven days. Colonic inflammation was determined by assessing the disease activity index, histopathology, colonic mucosal damage index, colonic mucosal permeability, and pro- and anti-inflammatory cytokine levels. The infiltration and activation status of neutrophils in the colon were determined by analyzing the levels of chemokine (C-X-C motif) ligand (CXCL) 1 and CXCL2, reactive oxygen species, Ly6G, and numerous NET proteins. The findings suggest that BEPD improved the disease activity index, histopathology, and colonic mucosal damage index scores of mice with UC, and restored colonic mucosal permeability compared with untreated mice. The expression levels of the pro-inflammatory cytokines interleukin-1ß, interleukin-6, and tumor necrosis factor-α in colon tissues were significantly decreased, while the expression levels of anti-inflammatory cytokines in colon tissues were significantly increased, exceeding those of control mice. In addition, BEPD reduced the expression of the neutrophil chemokines CXCL1 and CXCL2 in the colon tissue of mice with UC, reduced neutrophil infiltration, reduced reactive oxygen species levels, and significantly reduced the expression of NET proteins. BEPD also significantly reduced NET formation. The results of this study suggest that BEPD exerts therapeutic effects in a murine model of UC by inhibiting neutrophil infiltration and activation in the colon, as well as by inhibiting the expression of key proteins involved in NET formation and reducing NET formation, thereby alleviating local tissue damage and disease manifestations.

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BACKGROUND: The complexity of immunoglobulin G4 (IgG4)-related diseases and their potential connection to hematologic malignancies remains unclear. This article provided a review of the diagnosis and treatment of a patient with IgG4-related sclerosing cholangitis (SC) and essential thrombocythemia (ET), along with an analysis of relevant literature to enhance comprehension of this disease. CASE SUMMARY: A 56-year-old male was admitted to two hospitals with deteriorating jaundice and pruritus prior to hospitalization. Beyond our expectations, the patient was first diagnosed with IgG4-SC and ET with the Janus kinase 2 V617F mutation. Interestingly, the administration of acetate prednisone significantly resulted in improvements in both IgG4-SC and ET. Clinicians need to pay attention to immune disorders and inflammation as they contribute to the development of various disease phenotypes. CONCLUSION: When IgG4-SC is suspected without histopathological evidence, diagnostic therapy and long-term regular follow-up can lead to positive treatment outcomes. Clinicians should be mindful of the potential presence of concurrent hematologic diseases in patients with immune disorders.

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BACKGROUND: Lingguizhugan (LGZG) decoction, an ancient Chinese herbal remedy originating from the Eastern Han Dynasty, consists of Poria cocos, Cinnamomi ramulus, Atractylodes macrocephala, and Glycyrrhiza, as described in the Golden Chamber Synopsis. It has a history spanning over 1600 years, in which it has been primarily used for the treatment of inflammation, injuries, and fluid retention; however, the potential of LGZG decoction to ameliorate Alzheimer's disease (AD) progression by modulating the gut-brain axis through attenuation of gut microbiota and their metabolites remains unknown. PURPOSE: To examine the in vivo anti-AD effects and mechanism of LGZG decoction in alleviating AD cognitive impairment. STUDY DESIGN: Two-part experiments in vivo were designed, one for behavior tests, intestinal and brain histopathology, intestinal microbiome and quantitative determination, and another one for metabolite supplementation study. METHODS: AlCl3/D-gal was used to establish an AD-like mouse model. Behavioral tests, such as the Morris water maze test, were used to assess the effect of LGZG decoction on cognitive dysfunction. The concentration of proinflammatory mediators was measured by ELISA. The protein content was detected by western blot analysis and immunohistochemistry. The content of short-chain fatty acids was measured by LC-MS/MS. Evaluation of 16S rRNA gene sequencing for species and strain-level gut microbiome analysis was performed. RESULTS: LGZG decoction mitigated cognitive impairment in an AD-like mouse model, and decreased the deposition of amyloid-ß and the production of proinflammatory cytokines in the brain. LGZG decoction remodeled the intestinal microecology, enhanced the integrity of the intestinal and brain tissue barriers, and modulated Aß transportation through gut microbiota metabolite SCFAs. The neuroprotective effect of SCFAs on the AD-like model mice may be manifested through the inhibition of pP38 of the MAPK signaling pathway. CONCLUSION: Our results suggest that LGZG decoction reshapes the gut microbiota. SCFAs derived from the gut microbiota ameliorate the cognitive decline induced by AlCl3/D-gal through the gut-brain axis and reduce brain Aß aggregation. We propose LGZG decoction as a potential therapeutic option for AD.

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The coculture of patient-derived tumor organoids (PDOs) and autologous immune cells has been considered as a useful ex vivo surrogate of in vivo tumor-immune environment. However, the immune interactions between PDOs and autologous immune cells, including immune-mediated killing behaviors and immune-related cytokine variations, have yet to be quantitatively evaluated. This study presents a microfluidic chip for quantifying interactions between PDOs and autologous immune cells (IOI-Chip). A baffle-well structure is designed to ensure efficient trapping, long-term coculturing, and in situ fluorescent observation of a limited amount of precious PDOS and autologous immune cells, while a microbeads-based immunofluorescence assay is designed to simultaneously quantify multiple kinds of immune-related cytokines in situ. The PDO apoptosis and 2 main immune-related cytokines, TNF-α and IFN-γ, are simultaneously quantified using samples from a lung cancer patient. This study provides, for the first time, a capability to quantify interactions between PDOs and autologous immune cells at 2 levels, the immune-mediated killing behavior, and multiple immune-related cytokines, laying the technical foundation of ex vivo assessment of patient immune response.

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Complete discharge of spent lithium-ion batteries (LIBs) is a crucial step in LIB recycling, with the physical discharge method being particularly noted for its high discharge efficiency and environmental friendliness. However, previous studies and standards have focused on the performances of the discharge methods, neglecting the battery materials changes caused by discharge. Here we demonstrate that although prolonged discharge of spent batteries keeps the voltage around 0 V, an obvious current flow can be still observed, resulting from the dissolution and subsequent deposition of the copper foil. The deposited copper, primarily in the forms of Cu, Cu2O, and CuO, shows a gradient distribution on the surface of the anode and cathode active materials. This copper deposition significantly compromises the electrochemical performance of the discharged battery, with evident deterioration observed in the first charge-discharge capacity, cycling performance, and coulombic efficiency when compared to the original battery. This study provides guidance for the discharge methods and offers new insights into the materials failure mechanisms during discharge of spent batteries.

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Avoiding the stacking of active sites in catalyst structural design is a promising route for realizing active oxygen evolution reaction (OER). Herein, using a CoFe Prussian blue analoge cube with hollow structure (C-CoFe PBA) as a derived support, a highly effective Ni2P-FeP4-Co2P catalyst with a larger specific surface area is reported. Benefiting from the abundant active sites and fast charge transfer capability of the phosphide nanosheets, the Ni2P-FeP4-Co2P catalyst in 1 m KOH requires only overpotentials of 248 and 277 mV to reach current density of 10 and 50 mA cm-2 and outperforms the commercial catalyst RuO2 and most reported non-noble metal OER catalysts. In addition, the two-electrode system consisting of Ni2P-FeP4-Co2P and Pt/C is able to achieve a current density of 10 and 50 mA cm-2 at 1.529 and 1.65 V. This work provides more ideas and directions for synthesizing transition metal catalysts for efficient OER performance.

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Cardiac regeneration is a natural phenomenon that occurs in many species outside of humans. The goldfish (Carassius auratus) is an understudied model of cardiac wound response, despite its ubiquity as pets as well as its relationship to the better-studied zebrafish. In this study, we examined the response of the goldfish heart to a resection injury. We found that by 70 days post-injury, goldfish scarlessly heal cardiac wounds under a certain size, with local cardiomyocyte proliferation driving the restoration of the myocardial layer. We also found the upregulation of extracellular matrix components related to cardiac regeneration in the injury site. This upregulation correlated with the level of cardiomyocyte proliferation occurring in the injury site, indicating an association between the two that warrants further exploration.

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Objective. Macrophages and astrocytes play a crucial role in the aftermath of a traumatic spinal cord injury (SCI). Infiltrating macrophages adopt a pro-inflammatory phenotype while resident astrocytes adopt a neurotoxic phenotype at the injury site, both of which contribute to neuronal death and inhibit axonal regeneration. The cytokine interleukin-4 (IL-4) has shown significant promise in preclinical models of SCI by alleviating the macrophage-mediated inflammation and promoting functional recovery. However, its effect on neurotoxic reactive astrocytes remains to be elucidated, which we explored in this study. We also studied the beneficial effects of a sustained release of IL-4 from an injectable biomaterial compared to bolus administration of IL-4.Approach. We fabricated a heparin-based coacervate capable of anchoring and releasing bioactive IL-4 and tested its efficacyin vitroandin vivo. Main results. We show that IL-4 coacervate is biocompatible and drives a robust anti-inflammatory macrophage phenotype in culture. We also show that IL-4 and IL-4 coacervate can alleviate the reactive neurotoxic phenotype of astrocytes in culture. Finally, using a murine model of contusion SCI, we show that IL-4 and IL-4 coacervate, injected intraspinally 2 d post-injury, can reduce macrophage-mediated inflammation, and alleviate neurotoxic astrocyte phenotype, acutely and chronically, while also promoting neuroprotection with significant improvements in hindlimb locomotor recovery. We observed that IL-4 coacervate can promote a more robust regenerative macrophage phenotypein vitro, as well as match its efficacyin vivo,compared to bolus IL-4.Significance. Our work shows the promise of coacervate as a great choice for local and prolonged delivery of cytokines like IL-4. We support this by showing that the coacervate can release bioactive IL-4, which acts on macrophages and astrocytes to promote a pro-regenerative environment following a SCI leading to robust neuroprotective and functional outcomes.

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Carbic anhydride is an underappreciated starting material for 3D-printable, non-hydrogel photopolymers. Compared with other norbornene precursors, carbic anhydride is cheaper and reactive via aminolysis. As a result, the generalized and efficient functionalization with carbic anhydride can increase the utilization of thiol-norbornene photopolymers. Here, we report carbic anhydride's catalyst-free condensation with two commodity polymers: amine-functionalized polypropylene glycol and polydimethylsiloxane. The reaction completes in 1 h, produces water as the only byproduct, and does not require purification. It is therefore affordable, facile, and green. Mixing the product with thiol cross-linkers and the appropriate photoadditives produces photopolymers that are printable via Digital Light Processing. The photopolymers exhibit tunable tensile properties and a functional surface by varying the polymer backbone and thiol stoichiometry. Moreover, the photopolymers are 3D-printed into true-to-scale human aorta models and porous scaffolds with high resolution. The simple yet versatile platform will benefit additive manufacturing of soft materials and beyond.

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In recent years, significant improvement has been made in the management of non-small cell lung cancer (NSCLC), primarily driven by advances in targeted therapy and immunotherapy. Research on neoadjuvant targeted therapy has also experienced considerable development, primarily directed towards NSCLC harboring epidermal growth factor receptor or anaplastic lymphoma kinase mutations. Nevertheless, there remains a dearth of studies investigating neoadjuvant targeted therapy in the context of BRAF (V-Raf murine sarcoma viral oncogene homolog B) V600E mutant NSCLC. Herein, we describe the clinical trajectory of a stage IIIA NSCLC patient who underwent a two-month course of neoadjuvant targeted therapy comprising BRAF and MEK (mitogen-activated extracellular signal-regulated kinase) inhibitors prior to surgical intervention, and subsequent postoperative evaluation unveiled a pathological complete response. The case reported here indicates the efficacy and safety of combining BRAF and MEK inhibitors as neoadjuvant targeted therapy in BRAF V600E-mutant NSCLC and suggests the potential viability of such a therapeutic modality in improving treatment outcomes in this subset of NSCLC.

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BACKGROUND: Lung adenocarcinoma (LUAD) is the most common type of lung cancer and closely associated with the immune system. Emerging evidence suggests that blood immune cell phenotypes in patients with LUAD may undergo alterations. Nevertheless, the limited amount of relevant research makes it difficult to understand the causal links between LUAD and changes in the immune cells. This study aimed to reveal the potential causal relationships between 731 immune cell phenotypes and LUAD. METHODS: A bidirectional two-sample Mendelian randomization (MR) analysis was used to clarify causal relationships. Four types of immune phenotypes, absolute cell counts, relative cell counts, median fluorescence intensities (MFIs) of surface antigens, and morphological parameters, were investigated in this study. Heterogeneity tests, horizontal pleiotropy tests, and leave-one-out analyses were performed to validate the reliability of our study. RESULTS: A total of 26 immune cell characteristics were identified as contributing to the occurrence of LUAD. Memory B cells, IgD-CD38br cells, CD4+ regulatory T cells (Tregs), and plasmacytoid dendritic cells (DCs) may play a role in the development of LUAD. Through reverse MR, our study discovered that the presence of LUAD also induced changes in the expression levels of 16 immune cell traits involving specific surface markers and various types of immune cells, some of which pertain to antigen presentation and immune activation processes. CONCLUSION: Our study demonstrated causal links between several immune cell phenotypes and LUAD, thereby providing indications of the potentially oncogenic physiological state and early screening biomarkers for future research.

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Background: Various prevalences of asthma in coronavirus disease 2019 (COVID-19) have been reported in different regions, and the association between asthma and COVID-19 subsequent mortality has been in debate. Thus, this study aimed to investigate whether there was a significant association between asthma and COVID-19 mortality in Spain through a meta-analysis. Methods: The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were strictly complied with conducting this study. The pooled odds ratio (OR) with a corresponding 95% confidence interval (CI) was calculated by a random-effects model. The I 2 statistics for heterogeneity, sensitivity analysis for robustness, Begg's test, and Egger's test for publication bias, along with subgroup analyses for confounding bias, were also performed to support the foundation of this study. Results: The meta-analysis revealed that asthma was significantly associated with a lower risk of mortality among COVID-19 patients in Spain with a random-effects model (pooled OR = 0.78, 95% CI = 0.69-0.88, I 2 = 35%). Further subgroup analyses by male proportion and sample size also indicated that a statistically significant negative correlation did exist between asthma and COVID-19 mortality. Robustness and no publication on-bias were evidenced by sensitivity analysis, Egger's test, and Begg's test, respectively. Conclusion: In conclusion, patients with asthma were found to have a lower risk of mortality from COVID-19 in Spain, especially among elderly patients. In addition, asthmatic patients infected with COVID-19 may be at risk of death compared to non-asthmatic patients, which is not a cause for undue concern, thereby reducing the burden of medication.

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Introduction: Structural Variants (SVs) are a type of variation that can significantly influence phenotypes and cause diseases. Thus, the accurate detection of SVs is a vital part of modern genetic analysis. The advent of long-read sequencing technology ushers in a new era of more accurate and comprehensive SV calling, and many tools have been developed to call SVs using long-read data. Haplotype-tagging is a procedure that can tag haplotype information on reads and can thus potentially improve the SV detection; nevertheless, few methods make use of this information. In this article, we introduce HapKled, a new SV detection tool that can accurately detect SVs from Oxford Nanopore Technologies (ONT) long-read alignment data. Methods: HapKled utilizes haplotype information underlying alignment data by conducting haplotype-tagging using Whatshap on the reads to improve the detection performance, with three unique calling mechanics including altering clustering conditions according to haplotype information of signatures, determination of similar SVs based on haplotype information, and slack filtering conditions based on haplotype quality. Results: In our evaluations, HapKled outperformed state-of-the-art tools and can deliver better SV detection results on both simulated and real sequencing data. The code and experiments of HapKled can be obtained from https://github.com/CoREse/HapKled. Discussion: With the superb SV detection performance that HapKled can deliver, HapKled could be useful in bioinformatics research, clinical diagnosis, and medical research and development.

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MOTIVATION: Accurately predicting the driver genes of cancer is of great significance for carcinogenesis progress research and cancer treatment. In recent years, more and more deep-learning-based methods have been used for predicting cancer driver genes. However, deep-learning algorithms often have black box properties and cannot interpret the output results. Here, we propose a novel cancer driver gene mining method based on heterogeneous network meta-paths (MCDHGN), which uses meta-path aggregation to enhance the interpretability of predictions. RESULTS: MCDHGN constructs a heterogeneous network by using several types of multi-omics data that are biologically linked to genes. And the differential probabilities of SNV, DNA methylation, and gene expression data between cancerous tissues and normal tissues are extracted as initial features of genes. Nine meta-paths are manually selected, and the representation vectors obtained by aggregating information within and across meta-path nodes are used as new features for subsequent classification and prediction tasks. By comparing with eight homogeneous and heterogeneous network models on two pan-cancer datasets, MCDHGN has better performance on AUC and AUPR values. Additionally, MCDHGN provides interpretability of predicted cancer driver genes through the varying weights of biologically meaningful meta-paths. AVAILABILITY AND IMPLEMENTATION: https://github.com/1160300611/MCDHGN.

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