Podophyllotoxin derivatives-tubulin complex reveals a potential binding site of tubulin polymerization inhibitors in α-tubulin adjacent to colchicine site.

The colchicine site of ß-tubulin has been proven to be essential binding sites of microtubule polymerization inhibitors. Recent studies implied that GTP pocket of α-tubulin adjacent to colchicine sites is a potential binding site for developing tubulin polymerization inhibitors. However, the structural basis for which type of structural fragments was more beneficial for enhancing the affinity of α-tubulin is still unclear. Here, podophyllotoxin derivatives-tubulin complex crystals indicated that heterocyclic with the highly electronegative and small steric hindrance was conducive to change configuration and enhance the affinity of the residues in GTP pocket of α-tubulin. Triazole with lone-pairs electrons and small steric hindrance exhibited the strongest affinity for enhancing affinity of podophyllotoxin derivatives by forming two hydrogen bonds with αT5 Ser178. Pyrimidine with the secondary strong affinity could bind C:Asn101 to make the αH7 configuration deflection, which reduces the stability of tubulin result in its depolymerization. Conversely, 4ß-quinoline-podophyllotoxin with the weakest affinity did not interact with α-tubulin. The molecular dynamics simulation and protein thermal shift results showed that 4ß-triazole-podophyllotoxin-tubulin was the most stable mainly due to two hydrogen bonds and the higher van der Waals force. This work provided a structural basis of the potential binding sites for extending the α/ß-tubulin dual-binding sites inhibitors design strategy.

Self-Rolled-Up WSe2 One-Dimensional/Two-Dimensional Homojunctions: Enabling High-Performance Self-Powered Polarization-Sensitive Photodetectors.

Mixed-dimensional heterostructures integrate materials of diverse dimensions with unique electronic functionalities, providing a new platform for research in electron transport and optoelectronic detection. Here, we report a novel covalently bonded one-dimensional/two-dimensional (1D/2D) homojunction structure with robust junction contacts, which exhibits wide-spectrum (from the visible to near-infrared regions), self-driven photodetection, and polarization-sensitive photodetection capabilities. Benefiting from the ultralow dark current at zero bias voltage, the on/off ratio and detectivity of the device reach 1.5 × 103 and 3.24 × 109 Jones, respectively. Furthermore, the pronounced anisotropy of the WSe2 1D/2D homojunction is attributed to its low symmetry, enabling polarization-sensitive detection. In the absence of any external bias voltage, the device exhibits strong linear dichroism for wavelengths of 638 and 808 nm, with anisotropy ratios of 2.06 and 1.96, respectively. These results indicate that such mixed-dimensional structures can serve as attractive building blocks for novel optoelectronic detectors.

van der Waals Integration of Large-Area Monocrystalline 3D Perovskite Thin Films on Arbitrary Semiconductor Substrates for Heterojunctions.

Perovskite monocrystalline films are regarded as desirable candidates for the integration of high-performance optoelectronics due to their unique photophysical properties. However, the heterogeneous integration of a perovskite monocrystalline film with other semiconductors is fundamentally limited by the lattice mismatch, which hinders direct epitaxy. Herein, the van der Waals (vdW) integration strategy for 3D perovskites is developed, where perovskite monocrystalline films are epitaxially grown on the mother substrate, followed by its peeling off and transferring to arbitrary semiconductors, forming monocrystalline heterojunctions. The as-achieved CsPbBr3-Nb-doped SrTiO3 (Nb:STO) vdW p-n heterojunction exhibited comparable performance to their directly epitaxial counterpart, demonstrating the feasibility of vdW integration for 3D perovskites. Furthermore, the vdW integration could be extended to silicon substrates, rendering the CsPbBr3-n-Si and CsPbCl3-p-Si p-n heterojunction with apparent rectification behaviors and photoresponse. The vdW integration significantly enriches the selections of semiconductors hybridizing with perovskites and provides opportunities for monocrystalline perovskite optoelectronics with complex configurations and multiple functionalities.

High-Entropy Transition Metal Phosphorus Trichalcogenides for Rapid Sodium Ion Diffusion.

High-entropy strategies are regarded as a powerful means to enhance performance in energy storage fields. The improved properties are invariably ascribed to entropy stabilization or synergistic cocktail effect. Therefore, the manifested properties in such multicomponent materials are usually unpredictable. Elucidating the precise correlations between atomic structures and properties remains a challenge in high-entropy materials (HEMs). Herein, atomic-resolution scanning transmission electron microscopy annular dark field (STEM-ADF) imaging and four dimensions (4D)-STEM are combined to directly visualize atomic-scale structural and electric information in high-entropy FeMnNiVZnPS3. Aperiodic stacking is found in FeMnNiVZnPS3 accompanied by high-density strain soliton boundaries (SSBs). Theoretical calculation suggests that the formation of such structures is attributed to the imbalanced stress of distinct metal-sulfur bonds in FeMnNiVZnPS3. Interestingly, the electric field concentrates along the two sides of SSBs and gradually diminishes toward the two-dimensional (2D) plane to generate a unique electric field gradient, strongly promoting the ion-diffusion rate. Accordingly, high-entropy FeMnNiVZnPS3 demonstrates superior ion-diffusion coefficients of 10-9.7-10-8.3 cm2 s-1 and high-rate performance (311.5 mAh g-1 at 30 A g-1). This work provides an alternative way for the atomic-scale understanding and design of sophisticated HEMs, paving the way for property engineering in multi-component materials.

Lipoprotein (a)-Related Inflammatory Imbalance: A Novel Horizon for the Development of Atherosclerosis.

PURPOSE OF REVIEW: The primary objective of this review is to explore the pathophysiological roles and clinical implications of lipoprotein(a) [Lp(a)] in the context of atherosclerotic cardiovascular disease (ASCVD). We seek to understand how Lp(a) contributes to inflammation and arteriosclerosis, aiming to provide new insights into the mechanisms of ASCVD progression. RECENT FINDINGS: Recent research highlights Lp(a) as an independent risk factor for ASCVD. Studies show that Lp(a) not only promotes the inflammatory processes but also interacts with various cellular components, leading to endothelial dysfunction and smooth muscle cell proliferation. The dual role of Lp(a) in both instigating and, under certain conditions, mitigating inflammation is particularly noteworthy. This review finds that Lp(a) plays a complex role in the development of ASCVD through its involvement in inflammatory pathways. The interplay between Lp(a) levels and inflammatory responses highlights its potential as a target for therapeutic intervention. These insights could pave the way for novel approaches in managing and preventing ASCVD, urging further investigation into Lp(a) as a therapeutic target.

Single-Cell Molecular Profiling of Head and Neck Squamous Cell Carcinoma Reveals Five Dysregulated Signaling Pathways Associated With Circulating Tumor Cells.

OBJECTIVES: To determine the dysregulated signaling pathways of head and neck squamous cell carcinoma associated with circulating tumor cells (CTCs) via single-cell molecular characterization. INTRODUCTION: Head and neck squamous cell carcinoma (HNSCC) has a significant global burden and is a disease with poor survival. Despite trials exploring new treatment modalities to improve disease control rates, the 5 year survival rate remains low at only 60%. Most cancer malignancies are reported to progress to a fatal phase due to the metastatic activity derived from treatment-resistant cancer cells, regarded as one of the most significant obstacles to develope effective cancer treatment options. However, the molecular profiles of cancer cells have not been thoroughly studied. METHODS: Here, we examined in-situ HNSCC tumors and pairwisely followed up with the downstream circulating tumor cells (CTCs)-based on the surrogate biomarkers to detect metastasis that is established in other cancers - not yet being fully adopted in HNSCC treatment algorithms. RESULTS: Specifically, we revealed metastatic HNSCC patients have complex CTCs that could be defined through gene expression and mutational gene profiling derived from completed single-cell RNASeq (scRNASeq) that served to confirm molecular pathways inherent in these CTCs. To enhance the reliability of our findings, we cross-validated those molecular profiles with results from previously published studies. CONCLUSION: Thus, we identified 5 dysregulated signaling pathways in CTCs to derive HNSCC biomarker panels for screening HNSCC in situ tumors.

ObjectivesInvestigating the dysregulated signaling pathways of head and neck squamous cell carcinoma (HNSCC) linked with circulating tumor cells (CTCs) using single-cell molecular characterization.IntroductionHNSCC poses a significant global health burden with poor survival rates despite advancements in treatment. Metastatic activity from treatment-resistant cancer cells remains a major challenge in developing effective treatments. However, the molecular profiles of cancer cells, particularly CTCs, are not well-understood.MethodsWe analyzed in-situ HNSCC tumors and corresponding CTCs using surrogate biomarkers to detect metastasis, a technique not widely used in HNSCC treatment protocols.ResultsOur study revealed complex CTCs in metastatic HNSCC patients characterized by gene expression and mutational gene profiling via single-cell RNASeq (scRNASeq). These profiles confirmed molecular pathways inherent in CTCs, further validated by previous research.ConclusionThrough our research, we identified five dysregulated signaling pathways in CTCs, suggesting potential biomarker panels for HNSCC screening in situ tumors.

DeepDecon accurately estimates cancer cell fractions in bulk RNA-seq data.

Understanding the cellular composition of a disease-related tissue is important in disease diagnosis, prognosis, and downstream treatment. Recent advances in single-cell RNA-sequencing (scRNA-seq) technique have allowed the measurement of gene expression profiles for individual cells. However, scRNA-seq is still too expensive to be used for large-scale population studies, and bulk RNA-seq is still widely used in such situations. An essential challenge is to deconvolve cellular composition for bulk RNA-seq data based on scRNA-seq data. Here, we present DeepDecon, a deep neural network model that leverages single-cell gene expression information to accurately predict the fraction of cancer cells in bulk tissues. It provides a refining strategy in which the cancer cell fraction is iteratively estimated by a set of trained models. When applied to simulated and real cancer data, DeepDecon exhibits superior performance compared to existing decomposition methods in terms of accuracy.

Ozone decomposition on transition-metal-atom anchored graphdiyne: Insights from computation and experiment.

Transition-metal-atom anchored graphdiynes (TM@GDY, TM = Mn, Fe, Co, Ni and Cu) have already been synthesized and found applications in hydrogen evolution, nitrogen fixation and etc. By means of first-principle predictions and test experiments, we propose here that Fe@GDY and Co@GDY are efficient catalysts for the sustainable conversion of O3 to O2. These two catalysts can spontaneously chemisorb O3 with zero reaction barrier and have low O3 conversion barriers (0.31 eV and 0.19 eV, respectively). The O3 decomposition experiment in a continuous flow membrane reactor and electron paramagnetic resonance results verify that Fe@GDY and Co@GDY are efficient catalysts under humid conditions. Raman spectra prove the formation of the key Fe-O/Co-O and FeOO and CoOO intermediates. The hydrophobic nature of graphdiyne and the strongest chemisorption of O3 among tested ambient gases, make Fe@GDY and Co@GDY ideal catalysts under both dry and humid conditions. These findings would stimulate future explorations on metal anchored GDY-based catalysts for applications of toxic gas decomposition or fixation.

Self-healing polyacrylates based on dynamic disulfide and quadruple hydrogen bonds.

Herein, a self-healing polyacrylate system was successfully prepared by introducing crosslinking agents containing disulfide bonds and monomers capable of forming quadruple hydrogen bonds through free radical copolymerization. This polymer material exhibited good toughness and self-healing properties through chemical and physical dual dynamic networks while maintaining excellent mechanical properties, which expanded the development path of self-healing acrylate materials. Compared to uncrosslinked and single dynamically crosslinked polymers, its elongation at break was as high as 437%, and its tensile strength was 5.48 MPa. Due to the presence of dual reversible dynamic bonds in the copolymer system, good self-healing was also achieved at 60 °C. In addition, differential scanning calorimetry and thermogravimetric analysis measurements confirmed that the thermal stability and glass transition temperature of the material were improved owing to the presence of physical and chemical cross-linking networks.

High-Order Neighbors Aware Representation Learning for Knowledge Graph Completion.

As a building block of knowledge acquisition, knowledge graph completion (KGC) aims at inferring missing facts in knowledge graphs (KGs) automatically. Previous studies mainly focus on graph convolutional network (GCN)-based KG embedding (KGE) to determine the representations of entities and relations, accordingly predicting missing triplets. However, most existing KGE methods suffer from limitations in predicting tail entities that are far away or even unreachable in KGs. This limitation can be attributed to the related high-order information being largely ignored. In this work, we focus on learning the information from the related high-order neighbors in KGs to improve the performance of prediction. Specifically, we first introduce a set of new nodes called pedal nodes to augment the KGs for facilitating message passing between related high-order entities, effectively injecting the information of high-order neighbors into entity representation. Additionally, we propose strength-guided graph neural networks to aggregate neighboring entity representations. To address the issue of transmitting irrelevant higher order information to entities through pedal nodes, which can potentially hurt entity representation, we further propose to dynamically integrate the aggregated representation of each node with its corresponding self-representation. Extensive experiments have been conducted on three benchmark datasets and the results demonstrate the superiority of our method compared to strong baseline models.

Enabling Rapid and Stable Sodium Storage via a P2-Type Layered Cathode with High-Voltage Zero-Phase Transition Behavior.

Currently, a major target in the development of Na-ion batteries is the concurrent attainment of high-rate capacity and long cycling stability. Herein, an advanced Na-ion battery with high-rate capability and long cycle stability based on Li/Ti co-doped P2-type Na0.67 Mn0.67 Ni0.33 O2 , a host material with high-voltage zero-phase transition behavior and fast Na+ migration/conductivity during dynamic de-embedding process, is constructed. Experimental results and theoretical calculations reveal that the two-element doping strategy promotes a mutually reinforcing effect, which greatly facilitates the transfer capability of Na+ . The cation Ti4+ doping is a dominant high voltage, significantly elevating the operation voltage to 4.4 V. Meanwhile, doping Li+ shows the function in charge transfer, improving the rate performance and prolonging cycling lifespan. Consequently, the designed P2-Na0.75 Mn0.54 Ni0.27 Li0.14 Ti0.05 O2 cathode material exhibits discharge capacities of 129, 104, and 85 mAh g- 1 under high voltage of 4.4 V at 1, 10, and 20 C, respectively. More importantly, the full-cell delivers a high initial capacity of 198 mAh g-1 at 0.1 C (17.3 mA g-1 ) and a capacity retention of 73% at 5 C (865 mA g-1 ) after 1000 cycles, which is seldom witnessed in previous reports, emphasizing their potential applications in advanced energy storage.

Role of TGF-ß3 in modulating inflammatory responses and wound healing processes in ischemic ulcers in atherosclerotic patients.

Ischemic ulcers pose a multifaceted clinical dilemma for patients with atherosclerosis, frequently compounded by suboptimal wound healing mechanisms. The dual function of Transforming Growth Factor Beta 3 (TGF-ß3) in ischemic ulcer healing is not fully comprehended, despite its involvement in modulating inflammatory responses and tissue regeneration. The main aim of this investigation was to clarify the functions and mechanisms by which TGF-ß3 regulates inflammatory responses and promotes wound healing in patients with ischemic ulcers who have atherosclerosis. Between August 2022 and November 2023, this cross-sectional investigation was conducted on 428 patients diagnosed with atherosclerotic ischemic ulcers in Haikou, China. The expression and function of TGF-ß3 were examined throughout the different stages of wound healing, including inflammation, proliferation and remodelling. In addition to documenting patient demographics and ulcer characteristics, an analysis was conducted on biopsy samples to determine the expression of TGF-ß3, pro-inflammatory and anti-inflammatory markers. A subset of patients were administered topical TGF-ß3 in order to evaluate its therapeutic effects. The expression pattern of TGF-ß3 was found to be stage-dependent and significant, exhibiting increased levels during the phase of inflammation and reduced activity in subsequent phases. TGF-ß3 levels were found to be greater in ulcers that were larger and deeper, especially in inflammatory phase. TGF-ß3 applied topically induced discernible enhancement in ulcer healing parameters, such as reduction in ulcer depth and size. The therapeutic significance of TGF-ß3 was emphasised due to its twofold function of regulating the inflammatory environment and facilitating the regeneration of damaged tissues. Ischemic ulcer lesion healing is significantly influenced by TGF-ß3, which functions as an anti-inflammatory and pro-inflammatory mediator. Its correlation with ulcer characteristics and stages of healing suggests that it may have utility as a targeted therapeutic agent.

Adaptive class augmented prototype network for few-shot relation extraction.

Relation extraction is one of the most essential tasks of knowledge construction, but it depends on a large amount of annotated data corpus. Few-shot relation extraction is proposed as a new paradigm, which is designed to learn new relationships between entities with merely a small number of annotated instances, effectively mitigating the cost of large-scale annotation and long-tail problems. To generalize to novel classes not included in the training set, existing approaches mainly focus on tuning pre-trained language models with relation instructions and developing class prototypes based on metric learning to extract relations. However, the learned representations are extremely sensitive to discrepancies in intra-class and inter-class relationships and hard to adaptively classify the relations due to biased class features and spurious correlations, such as similar relation classes having closer inter-class prototype representation. In this paper, we introduce an adaptive class augmented prototype network with instance-level and representation-level augmented mechanisms to strengthen the representation space. Specifically, we design the adaptive class augmentation mechanism to expand the representation of classes in instance-level augmentation, and class augmented representation learning with Bernoulli perturbation context attention to enhance the representation of class features in representation-level augmentation and explore adaptive debiased contrastive learning to train the model. Experimental results have been demonstrated on FewRel and NYT-25 under various few-shot settings, and the proposed model has improved accuracy and generalization, especially for cross-domain and different hard tasks.

Mesenchymal Stem Cells for Prophylaxis of Chronic Graft-vs-Host Disease After Haploidentical Hematopoietic Stem Cell Transplant: An Open-Label Randomized Clinical Trial.

Importance: Chronic graft-vs-host disease (GVHD) limits the long-term benefit of haploidentical hematopoietic stem cell transplant (HSCT). This clinical trial evaluated repeated infusions of umbilical cord mesenchymal stem cells (MSCs) during the early stage (45 days and 100 days) after haplo-HSCT to prevent chronic GVHD. Objective: To determine whether repeated infusions of MSCs during the early stage after haplo-HSCT decreases the incidence of severe chronic GVHD. Design, Setting, and Participants: This open-label, multicenter, parallel randomized clinical trial was conducted from April 2016 to January 2022. Eligibility criteria included a diagnosis of acute leukemia and having a haploidentical, suitable related donor for HSCT. The median (range) follow-up time was 39.0 (1.5-67.0) months. Interventions: The enrolled patients with a haploidentical relative for HSCT received the modified busulfan/cyclophosphamide + antithymocyte globulin modified regimen and standard GVHD prophylaxis. Patients were randomly chosen to receive MSCs (the MSC group) (1 × 106 cells/kg, every 2 weeks, starting from 45 days after transplant, 4 times total) or regular prophylaxis (control group). Main Outcome and Measure: The cumulative incidence of severe chronic GVHD. Results: Of 158 patients, 58 (36.7%) were female individuals; the median (range) age for the MSC and control groups was 28 (18-60) years and 28 (18-56) years, respectively. A total of 158 patients were screened, and 148 patients were randomly assigned to the MSC group (n = 74) or control group (n = 74) 1 day before MSCs infusion. The estimated 2-year cumulative incidence of severe chronic GVHD was 5.4% (95% CI, 1.8%-14.0%) in the MSC group and 17.4% (95% CI, 10.1%-28.5%) in the control group (hazard ratio [HR], 0.29; 95% CI, 0.10-0.88; P = .03). There was no difference between the MSC and control groups in the cumulative incidence of leukemia relapse (HR, 1.17; 95% CI, 0.55-2.47; P = .68). The cumulative incidence of stage II to IV acute GVHD in the MSC group was significantly lower than that in the control group (HR, 0.25; 95% CI, 0.09-0.67; P = .01). The MSC group had better GVHD-free and relapse-free survival rates than the control group (HR, 0.62; 95% CI, 0.39-0.98; P = .04). Conclusions and Relevance: The results of this randomized clinical trial show that early repeated infusions of MSCs decreased the incidence and severity of chronic GVHD, and the incidence and severity of acute GVHD manifested as a better GVHD-free and relapse-free survival rate for patients after haplo-HSCT. Trial Registration: Chinese Clinical Trial Registry: ChiCTR-IIR-16007806.

Identification of the chemical composition of distiller's grain polyphenols and their effects on the fecal microbial community structure.

Distiller grains are the main by-products of Baijiu production and are usually discarded, ignoring their abundant functional phytochemicals. The free and bound polyphenols from distiller grains were extracted and their potential effect on modulating fecal microbiota was investigated using in vitro fecal fermentation. The results showed that 34 polyphenols were quantified from distiller grains. The antioxidant activity was positively correlated with quercetin, myricetin, epicatechin, and naringenin. The abundance of Bifidobacterium, Ruminobacterium, Lactobacillus, Akkermansia, and butyrate-producing bacteria was enhanced by distiller's grain polyphenols by approximately 10.66-, 6.39-, 7.83-, 2.59-, and 7.74-fold, respectively. Moreover, the production of short-chain fatty acids (SCFAs), especially acetic, butyric, and propionic acid, was promoted (increased 1.99-, 1.71-, and 1.34-fold, respectively). Correlated analysis revealed quercetin, daidzein, and kaempferol as the key polyphenols by analyzing the effects on gut microbiota and SCFAs. This study could provide a reference for converting distiller grains into high-nutrient functional food ingredients and feeds.

Acute-on-chronic liver failure induced by antiviral therapy for chronic hepatitis C: A case report.

BACKGROUND: There have been no reports of acute-on-chronic liver failure (ACLF) during treatment of chronic hepatitis C (CHC) with direct-acting antivirals (DAAs). CASE SUMMARY: We report a 50-year-old male patient with CHC. The patient sought medical attention from the Department of Infectious Diseases at our hospital due to severe yellowing of the skin and sclera, which developed 3 mo previously and attended two consecutive hospitals without finding the cause of liver damage. It was not until 1 mo ago that he was diagnosed with CHC at our hospital. After discharge, he was treated with DAAs. During treatment, ACLF occurred, and timely measures such as liver protection, enzyme lowering, anti-infective treatment, and suppression of inflammatory storms were implemented to control the condition. CONCLUSION: DAA drugs significantly improve the cure rate of CHC. However, when patients have factors such as autoimmune attack, coinfection, or unclear hepatitis C virus genotype, close monitoring is required during DAA treatment.

Effect of free and bound polyphenols from Rosa roxburghii Tratt distiller's grains on moderating fecal microbiota.

Rosa roxburghii Tratt distiller's grains (R. roxburghii DGs), the main by-product of wine processing, showed functional value and potential for high-value usage which benefited from their rich polyphenols. In this study, the free and bound polyphenols from R. roxburghii DGs were extracted and their potential effect on modulating fecal microbiota was investigated using in vitro fecal fermentation. The free polyphenols (26.32-26.45 mg GAE/g) showed higher antioxidant activity compared to the bound polyphenols (8.76-9.01 mg GAE/g). The free and bound polyphenols significantly improved the fecal microbiota community structure and enhanced short chain fatty acids concentrations after the stimulated colonic fermentation for 24 h. Furthermore, the effect of R. roxburghii DGs polyphenols on modulating fecal microbiota was primarily attributed to quercetin, catechin, kaempferol, cyanidin and baicalin. This research suggests that R. roxburghii DGs are a promising source of natural antioxidants and prebiotic foods.

BCR-ABL1-driven exosome-miR130b-3p-mediated gap-junction Cx43 MSC intercellular communications imply therapies of leukemic subclonal evolution.

Rationale: In the bone marrow microenvironment (BMME), mesenchymal stem/stromal cells (MSCs) control the self-renewal of both healthy and cancerous hematopoietic stem/progenitor cells (HSPCs). We previously showed that in vivo leukemia-derived MSCs change neighbor MSCs into leukemia-permissive states and boost leukemia cell proliferation, survival, and chemotherapy resistance. But the mechanisms behind how the state changes are still not fully understood. Methods: Here, we took a reverse engineering approach to determine BCR-ABL1+ leukemia cells activated transcriptional factor C/EBPß, resulting in miR130a/b-3p production. Then, we back-tracked from clinical specimen transcriptome sequencing to cell co-culture, molecular and cellular assays, flow cytometry, single-cell transcriptome, and transcriptional regulation to determine the molecular mechanisms of BCR-ABL1-driven exosome-miR130b-3p-mediated gap-junction Cx43 MSC intercellular communications. Results: BCR-ABL1-driven exosome-miR130a/b-3p mediated gap-junction Cx43 (a.k.a., GJA1) BMSC intercellular communications for subclonal evolution in leukemic microenvironment by targeting BMSCs-expressed HLAs, thereby potentially maintaining BMSCs with self-renewal properties and reduced BMSC immunogenicity. The Cx43low and miR-130a/bhigh subclonal MSCs subsets of differentiation state could be reversed to Cx43high and miR-130a/blow subclones of the higher stemness state in Cx43-overexpressed subclonal MSCs. Both miR-130a and miR-130b might only inhibit Cx43 translation or degrade Cx43 proteins and did not affect Cx43 mRNA stability. The subclonal evolution was further confirmed by single-cell transcriptome profiling of MSCs, which suggested that Cx43 regulated their stemness and played normal roles in immunomodulation antigen processing. Thus, upregulated miR-130a/b promoted osteogenesis and adipogenesis from BMSCs, thereby decreasing cancer progression. Our clinical data validated that the expression of many genes in human major histocompatibility was negatively associated with the stemness of MSCs, and several immune checkpoint proteins contributing to immune escape in tumors were overexpressed after either miR-130a or miR-130b overexpression, such as CD274, LAG3, PDCD1, and TNFRSF4. Not only did immune response-related cytokine-cytokine receptor interactions and PI3K-AKT pathways, including EGR3, TNFRSF1B, but also NDRG2 leukemic-associated inflammatory factors, such as IFNB1, CXCL1, CXCL10, and CCL7 manifest upon miR-130a/b overexpression. Either BCR siRNAs or ABL1 siRNAs assay showed significantly decreased miR-130a and miR-130b expression, and chromatin immunoprecipitation sequencing confirmed that the regulation of miR-130a and miR-130b expression is BCR-ABL1-dependent. BCR-ABL1 induces miR-130a/b expression through the upregulation of transcriptional factor C/EBPß. C/EBPß could bind directly to the promoter region of miR-130b-3p, not miR-130a-3p. BCR-ABL1-driven exosome-miR130a-3p could interact with Cx43, and further impact GJIC in TME. Conclusion: Our findings shed light on how leukemia BCR-ABL1-driven exosome-miR130b-3p could interact with gap-junction Cx43, and further impact GJIC in TME, implications for leukemic therapies of subclonal evolution.

Microbial Community Succession and Its Correlation with Quality Characteristics during Gray Sufu Fermentation.

Gray sufu, a traditional fermented food derived from soybeans, undergoes a complex fermentation process. This study aimed to investigate the dynamics of the microbial community during sufu fermentation and its relationship with key quality characteristics. Through systematic sampling of sufu at different phases of fermentation, 143 bacterial genera and 84 fungal genera involved in the process were identified. Among these, Chishuiella, Enterococcus, Lactococcus, and Weissella emerged as the predominant bacterial communities. After seven days of ripening fermentation, Trichosporon supplanted Diutina as the predominant fungus, accounting for more than 84% of all fungi. Using redundancy analysis, significant correlations between microbiota and physicochemical properties were uncovered. Chishuiella and Empedobacter displayed positive relationships with pH, soluble protein, and amino nitrogen content. In addition, five biogenic amines were detected, and it was determined that tyramine accounted for more than 75% of the total biogenic amines in the final gray sufu products. Spearman correlation analysis revealed significant positive relationships between Lactococcus, Enterococcus, Tetragenococcus, Halanaerobium, and Trichosporon and the five biogenic amines examined. These findings shed light on the complex interactions between microorganisms and biogenic amines during the fermentation of gray sufu, thereby facilitating the development of microbial regulation strategies for better quality control.

Pepsin Increases the Proliferation of Vocal Cord Leukoplakia Epithelial Cells by Inducing Autophagy.

OBJECTIVE: To investigate the role of H+ /K+ ATPase in the proliferation of pepsin-induced vocal cord leukoplakia (VCL) cells. STUDY DESIGN: Translation research. SETTING: Affiliated Hospital of University. METHODS: Immunohistochemistry was used to detect pepsin, H+ /K+ ATPase (ATP4A and ATP4B subunits) in VCL cells with varying degrees of dysplasia. After primary cultures of VCL cells had been established, the effects of acidified pepsin on the proliferation, autophagy, and H+ /K+ -ATPase distribution of VCL cells were investigated. RESULTS: The levels of pepsin, ATP4A, and ATP4B were significantly higher in VCL tissue with moderate-to-severe dysplasia than in normal tissue (p < .05); these levels gradually increased according to dysplasia severity. The expression levels of ATP4A and ATP4B were significantly correlated with the amount of pepsin in VCL cells (p < .01). Acidified pepsin enhanced the levels of proliferation and autophagy in human VCL epithelial cells. The cloning- and autophagy-promoting effects of acidified pepsin on VCL cells were partially reversed by pantoprazole; these effects were completely blocked by the autophagy inhibitor chloroquine. Finally, acidified pepsin promoted the colocalization of H+ /K+ -ATPase and lysosomes in VCL cells; it also mediated lysosome acidification. CONCLUSION: Pepsin and H+ /K+ -ATPase may contribute to the progression of VCL. Specifically, acidified pepsin may regulate lysosome acidification by promoting lysosomal localization of H+ /K+ -ATPase.