Aloperine Suppresses Cancer Progression by Interacting with VPS4A to Inhibit Autophagosome-lysosome Fusion in NSCLC.

Aloperine (ALO), a quinolizidine-type alkaloid isolated from a natural Chinese herb, has shown promising antitumor effects. Nevertheless, its common mechanism of action and specific target remain elusive. Here, it is demonstrated that ALO inhibits the proliferation and migration of non-small cell lung cancer cell lines in vitro and the tumor development in several mouse tumor models in vivo. Mechanistically, ALO inhibits the fusion of autophagosomes with lysosomes and the autophagic flux, leading to the accumulation of sequestosome-1 (SQSTM1) and production of reactive oxygen species (ROS), thereby inducing tumor cell apoptosis and preventing tumor growth. Knockdown of SQSTM1 in cells inhibits ROS production and reverses ALO-induced cell apoptosis. Furthermore, VPS4A is identified as a direct target of ALO, and the amino acids F153 and D263 of VPS4A are confirmed as the binding sites for ALO. Knockout of VPS4A in H1299 cells demonstrates a similar biological effect as ALO treatment. Additionally, ALO enhances the efficacy of the anti-PD-L1/TGF-ß bispecific antibody in inhibiting LLC-derived subcutaneous tumor models. Thus, ALO is first identified as a novel late-stage autophagy inhibitor that triggers tumor cell death by targeting VPS4A.

[Distribution and Drug Resistance Characteristics of Pathogenic Bacteria in the Elderly Population in China in 2021]. / 2021å¹´ä¸­å›½è€å¹´äººç¾¤æ„ŸæŸ“ç— åŽŸèŒåˆ†å¸ƒå’Œè€è¯æ€§ç‰¹å¾.

Objective: To study the distribution and drug resistance characteristics of pathogenic bacteria in the elderly population of China by collecting and analyzing the standardized case data on the pathogens of infections in elderly patients, and to facilitate the establishment of a standardized layered surveillance system for pathogenic bacteria in China. Methods: We collected the case data of elderly patients (≥65 years old) from 62 sentinel hospitals across the country in 2021. Then, we statistically analyzed the data by patient age, their geographical region, the distribution of pathogenic bacteria, and the drug resistance characteristics of main pathogens. Results: A total of 3468 cases from across the country were included in the study. The top three sources of patients were the intensive care unit (13.2%), the department of respiratory medicine (11.2%), and the department of general surgery (8.4%). The top three types of specimens were urine (25.5%), sputum (20.6%), and blood (18.7%). A total of 3468 strains of pathogens were isolated, among which, 78.9% were gram-negative bacteria and 21.1% were gram-positive bacteria. The top five types of bacteria were Escherichia coli (20.9%), Klebsiella pneumoniae (18.3%), Pseudomonas aeruginosa (11.2%), Staphylococcus aureus (9.0%), and Acinetobacter baumannii (7.0%). The isolation rates of common important drug-resistant bacteria were 38.0% for methicillin-resistant Staphylococcus aureus (MRSA), 68.7% for carbapenem-resistant Acinetobacter baumannii (CRAB), and 38.2% for carbapenem-resistant Pseudomonas aeruginosa (CRPA), 20.1% for carbapenem-resistant Klebsiella pneumoniae (CRKP), 5.2% for carbapenem-resistant Escherichia coli (CRECO), and 2.1% for vancomycin-resistant Enterococcus (VRE). There were differences in the isolation rates of CRAB and CRKP in clinical care in the elderly population in seven geographical regions of China (P<0.05). Klebsiella pneumoniae is the most important pathogen in the elderly population ≥85 years old, and the isolation rates of CRKP showed significant differences in different age groups (P<0.05). Conclusion: There are significant differences in the drug resistance of pathogenic bacteria in the elderly populations of different regions and age groups in China. Therefore, monitoring the distribution and drug resistance of pathogenic bacteria in the elderly population and formulating targeted treatment plans according to the characteristics of the specific regions and age groups are of great significance to the improvement in the treatment outcomes and prognosis of the elderly population.

Exploring the biological basis of acupuncture treatment for traumatic brain injury: a review of evidence from animal models.

Traumatic brain injury (TBI) occurs when external physical forces impact the brain, potentially causing long-term issues such as post-traumatic stress disorders and cognitive and physical dysfunctions. The diverse nature of TBI pathology and treatment has led to a rapid acceleration in research on its biological mechanisms over the past decade. This surge presents challenges in assessing, managing, and predicting outcomes for TBI cases. Despite the development and testing of various therapeutic strategies aimed at mitigating neurological decline after TBI, a definitive cure for these conditions remains elusive. Recently, a growing focus has been on preclinical research investigating acupuncture as a potential treatment method for TBI sequelae. Acupuncture, being a cost-effective non-pharmacological therapy, has demonstrated promise in improving functional outcomes after brain injury. However, the precise mechanisms underlying the anticipated improvements induced by acupuncture remain poorly understood. In this study, we examined current evidence from animal studies regarding acupuncture's efficacy in improving functional outcomes post-TBI. We also proposed potential biological mechanisms, such as glial cells (microglia astrocytes), autophagy, and apoptosis. This information will deepen our understanding of the underlying mechanisms through which acupuncture exerts its most beneficial effects post-TBI, assisting in forming new clinical strategies to maximize benefits for these patients.

A novel method for cell deconvolution using DNA methylation in PCA space.

BACKGROUND: In this study, we present a novel method for reference-based cell deconvolution using data from DNA methylation arrays. Different from existing methods like IDOL-Ext, which operate on probe-level data, our approach represents features in the principal component analysis (PCA) space for cell type deconvolution. RESULTS: Our method's accuracy in estimating cell compositions is validated across various public datasets, including blood samples from glioma patients. It demonstrates precision comparable to IDOL-Ext, with R2 values ranging from 0.73 to 0.99 for most cell types, while offering improved discrimination between similar cell types, particularly T cell subtypes in glioma patient samples (R2 0.42-0.75 vs. 0.36-0.66 for IDOL-Ext). However, both methods showed lower accuracy for certain cell types, such as memory CD8 T cells in glioma patients (R2 0.42 vs. 0.36 for IDOL-Ext), highlighting the challenges in distinguishing closely related cell populations. We have made this method available as an R package "BloodCellDecon" on GitHub. CONCLUSIONS: Our study confirms the efficacy of cell type deconvolution in PCA space. The results indicate wide-ranging applicability and potential for adaptation to other forms of genomic data.

RBM25 depletion suppresses the growth of colon cancer cells through regulating alternative splicing of MNK2.

Increasing evidence suggests that deregulated RNA splicing factors play critical roles in tumorigenesis; however, their specific involvement in colon cancer remains largely unknown. Here we report that the splicing factor RBM25 is overexpressed in colon cancer, and this increased expression correlates with a poor prognosis of patients with colon cancer. Functionally, RBM25 ablation suppresses the growth of colon cancer cells both in vitro and in vivo. Mechanistically, our transcriptome-wide analysis of splicing events revealed that RBM25 regulates a large number of cancer-related alternative splicing events across the human genome in colon cancer. Particularly, RBM25 regulates the splicing of MNK2 by interacting with the poly G rich region in exon 14a, thereby inhibiting the selection of the proximal 3' splice site (ss), resulting in the production of the oncogenic short isoform, MNK2b. Knockdown of RBM25 leads to an increase in the MNK2a isoform and a decrease in the MNK2b isoform. Importantly, re-expression of MNK2b or blocking the 3' ss of the alternative exon 14a with ASO partially reverses the RBM25 knockdown mediated tumor suppression. Moreover, MNK2b levels were significantly increased in colon cancer tissues, which is positively correlated with the expression level of RBM25. Collectively, our findings uncover the critical role of RBM25 as a key splicing factor in colon cancer, suggesting its potential as a prognostic marker and therapeutic target.

Plasma Olink Proteomics Reveals Novel Biomarkers for Prediction and Diagnosis in Dilated Cardiomyopathy with Heart Failure.

In this study, we utilized the Olink Cardiovascular III panel to compare the expression levels of 92 cardiovascular-related proteins between patients with dilated cardiomyopathy combined with heart failure (DCM-HF) (n = 20) and healthy normal people (Normal) (n = 18). The top five most significant proteins, including SPP1, IGFBP7, F11R, CHI3L1, and Plaur, were selected by Olink proteomics. These proteins were further validated using ELISA in plasma samples collected from an additional cohort. ELISA validation confirmed significant increases in SPP1, IGFBP7, F11R, CHI3L1, and Plaur in DCM-HF patients compared to healthy controls. GO and KEGG analysis indicated that NT-pro BNP, SPP1, IGFBP7, F11R, CHI3L1, Plaur, BLM hydrolase, CSTB, Gal-4, CCL15, CDH5, SR-PSOX, and CCL2 were associated with DCM-HF. Correlation analysis revealed that these 13 differentially expressed proteins have strong correlations with clinical indicators such as LVEF and NT-pro BNP, etc. Additionally, in the GEO-DCM data sets, the combined diagnostic value of these five core proteins AUC values of 0.959, 0.773, and 0.803, respectively indicating the predictive value of the five core proteins for DCM-HF. Our findings suggest that these proteins may be useful biomarkers for the diagnosis and prediction of DCM-HF, and further research is prompted to explore their potential as therapeutic targets.

Efficacy and safety of en-bloc resection versus debulking for spinal tumor: a systematic review and meta-analysis.

BACKGROUND: This systematic review and meta-analysis aimed to consolidate the existing evidence regarding the comparison between en-bloc resection surgery and debulking surgery for spinal tumors, including both primary and metastatic tumors. MATERIALS AND METHODS: The databases of PubMed, Embase, Cochrane database, Web of Science, Scopus, Chinese National Knowledge Infrastructure (CNKI), Chongqing VIP Database (VIP), and Wan Fang Database was carried out and included all studies that directly compared en-bloc resection surgery with debulking surgery for spinal tumors in patients through March 2024. The primary outcomes included recurrence rate, postoperative metastasis rate, mortality rate, overall survival (OS), recurrence-free survival (RFS), complication, and so on. The statistical analysis was conducted using Review Manager 5.3. RESULTS: We systematically reviewed 868 articles and included 27 studies involving 1135 patients who underwent either en-bloc resection surgery (37.89%) or debulking surgery (62.11%). Our meta-analysis demonstrated significant advantages of en-bloc resection over debulking surgery. Specifically, the en-bloc resection group had a lower recurrence rate (OR = 0.19, 95%CI: 0.13-0.28, P < 0.00001), lower postoperative metastasis rate (P = 0.002), and lower mortality rate (P < 0.00001). Additionally, en-bloc resection could improve OS and RFS (HR = 0.45, 95%CI: 0.32-0.62, P < 0.00001 and HR = 0.37, 95%CI: 0.17-0.80, P = 0.01, respectively). However, en-bloc resection required longer operative times and was associated with a higher overall complication rate compared to debulking surgery (P = 0.0005 and P < 0.00001, respectively). CONCLUSION: The current evidence indicates that en-bloc surgical resection can effectively control tumor recurrence and mortality, as well as improve RFS and OS for patients with spinal tumors. However, it is crucial not to overlook the potential risks of perioperative complications. Ultimately, these findings should undergo additional validation through multi-center, double-blind, and large-scale randomized controlled trials (RCTs).

AI hybrid survival assessment for advanced heart failure patients with renal dysfunction.

Renal dysfunction (RD) often characterizes the worse course of patients with advanced heart failure (AHF). Many prognosis assessments are hindered by researcher biases, redundant predictors, and lack of clinical applicability. In this study, we enroll 1736 AHF/RD patients, including data from Henan Province Clinical Research Center for Cardiovascular Diseases (which encompasses 11 hospital subcenters), and Beth Israel Deaconess Medical Center. We developed an AI hybrid modeling framework, assembling 12 learners with different feature selection paradigms to expand modeling schemes. The optimized strategy is identified from 132 potential schemes to establish an explainable survival assessment system: AIHFLevel. The conditional inference survival tree determines a probability threshold for prognostic stratification. The evaluation confirmed the system's robustness in discrimination, calibration, generalization, and clinical implications. AIHFLevel outperforms existing models, clinical features, and biomarkers. We also launch an open and user-friendly website www.hf-ai-survival.com , empowering healthcare professionals with enhanced tools for continuous risk monitoring and precise risk profiling.

High energy density picoliter-scale zinc-air microbatteries for colloidal robotics.

The recent interest in microscopic autonomous systems, including microrobots, colloidal state machines, and smart dust, has created a need for microscale energy storage and harvesting. However, macroscopic materials for energy storage have noted incompatibilities with microfabrication techniques, creating substantial challenges to realizing microscale energy systems. Here, we photolithographically patterned a microscale zinc/platinum/SU-8 system to generate the highest energy density microbattery at the picoliter (10-12 liter) scale. The device scavenges ambient or solution-dissolved oxygen for a zinc oxidation reaction, achieving an energy density ranging from 760 to 1070 watt-hours per liter at scales below 100 micrometers lateral and 2 micrometers thickness in size. The parallel nature of photolithography processes allows 10,000 devices per wafer to be released into solution as colloids with energy stored on board. Within a volume of only 2 picoliters each, these primary microbatteries can deliver open circuit voltages of 1.05 ± 0.12 volts, with total energies ranging from 5.5 ± 0.3 to 7.7 ± 1.0 microjoules and a maximum power near 2.7 nanowatts. We demonstrated that such systems can reliably power a micrometer-sized memristor circuit, providing access to nonvolatile memory. We also cycled power to drive the reversible bending of microscale bimorph actuators at 0.05 hertz for mechanical functions of colloidal robots. Additional capabilities, such as powering two distinct nanosensor types and a clock circuit, were also demonstrated. The high energy density, low volume, and simple configuration promise the mass fabrication and adoption of such picoliter zinc-air batteries for micrometer-scale, colloidal robotics with autonomous functions.

Exploring the cationic surfactant adsorption efficiency at concentrations relative to the critical micelle concentration by SA/SiO2 microspheres.

Studying the adsorption behavior of cationic surfactants can help to develop more effective strategies to limit their dispersion in the environment. However, there have few studies on the adsorption of cationic surfactants from the perspective of critical micelle concentration (CMC). In this study, with cetyltrimethylammonium bromide (CTAB) and octadecyl trimethylammonium bromide (OTAB) serving as the model cationic surfactants, the effect of CMC on the adsorption behavior of cationic surfactant onto the surface of sodium alginate/silica (SA/SiO2) microspheres was systematically revealed. The adsorption mechanism relative to CMC was investigated under different conditions, including surfactant concentration, pH, temperature, and adsorption time. The results suggest that at identical concentrations, the smaller the CMC value of the cationic surfactants, the greater the adsorption amount (qt). qt for CTAB and OTAB were 583.2 and 678.0 mg/g respectively, with the concentration higher than their CMC value. When the concentration was lower than the CMC value of the cationic surfactants, qt for CTAB and OTAB were 123.2 and 138.7 mg/g, respectively. The CMC value of CTAB was lower than that of OTAB under identical conditions, suggesting that the adsorption of cationic surfactants is related to their CMC. These results are beneficial for the removal of cationic surfactants by adsorption methods.

Platelet count as a prognostic marker for acute respiratory distress syndrome.

BACKGROUND: This study aimed to evaluate the role of platelet count (PLT) in the prognosis of patients with acute respiratory distress syndrome (ARDS). METHODS: The data were extracted from the Medical Information Mart for Intensive Care database (version 2.2). Patients diagnosed with ARDS according to criteria from Berlin Definition and had the platelet count (PLT) measured within the first day after intensive care unit admission were analyzed. Based on PLT, ARDS patients were divided into four groups: PLT ≤ 100 × 109/L, PLT 101-200 × 109/L, PLT 201-300 × 109/L, and PLT > 300 × 109/L. The primary outcome was 28-day mortality. Survival probabilities were analyzed using Kaplan-Meier. Furthermore, the association between PLT and mortality in ARDS patients was assessed using a univariate and multivariable Cox proportional hazards model. RESULTS: Overall, the final analysis included 3,207 eligible participants with ARDS. According to the Kaplan-Meier curves for 28-day mortality of PLT, PLT ≤ 100 × 109/L was associated with a higher incidence of mortality (P = 0.001), the same trends were observed in the 60-day (P = 0.001) and 90-day mortality (P = 0.001). In the multivariate model adjusted for the potential factors, the adjusted hazard ratio at PLT 101-200 × 109/L group, PLT 201-300 × 109/L, and PLT > 300 × 109/L was 0.681 [95% confidence interval (CI): 0.576-0.805, P < 0.001], 0.733 (95% CI: 0.604-0.889, P = 0.002), and 0.787 (95% CI: 0.624-0.994, P = 0.044) compared to the reference group (PLT ≤ 100 × 109/L), respectively. Similar relationships between the PLT ≤ 100 × 109/L group and 28-day mortality were obtained in most subgroups. CONCLUSION: PLT appeared to be an independent predictor of mortality in critically ill patients with ARDS.

Effects of Lime Powder on the Properties of Portland Cement-Sulphoaluminate Cement Composite System at Low Temperature.

In order to reduce the risk of early freezing damage to cement-based materials in winter construction, lime powder was used to improve the properties of the Portland cement-sulphoaluminate cement (PC-CSA) composite system at low temperatures. In this study, the effects of lime powder dosage on the properties of a PC-CSA blended system with two proportions (PC:CSA = 9:1 and 7:3) at -10 °C were investigated, and the mechanisms of improvement were revealed. The results showed that the compressive strength of the PC-CSA composite system was effectively improved, and the setting time was shortened by the addition of lime powder. Lime powder could effectively act as an early heating source in the PC-CSA composite system, as the maximum temperature of samples exposed to sub-zero temperatures was increased and the time before dropping to 0 °C was prolonged by the addition of lime powder. The extra CH generated by the hydration of lime powder provided an added hydration path for C4A3S¯, which accelerated the formation of AFt at each stage. Frozen water as well as the early frost damage were effectively decreased by lime powder because of the faster consumption of free water at an early stage. The modification of the hydration products also contributed to the denseness of the microstructure.

MSFN: a multi-omics stacked fusion network for breast cancer survival prediction.

Introduction: Developing effective breast cancer survival prediction models is critical to breast cancer prognosis. With the widespread use of next-generation sequencing technologies, numerous studies have focused on survival prediction. However, previous methods predominantly relied on single-omics data, and survival prediction using multi-omics data remains a significant challenge. Methods: In this study, considering the similarity of patients and the relevance of multi-omics data, we propose a novel multi-omics stacked fusion network (MSFN) based on a stacking strategy to predict the survival of breast cancer patients. MSFN first constructs a patient similarity network (PSN) and employs a residual graph neural network (ResGCN) to obtain correlative prognostic information from PSN. Simultaneously, it employs convolutional neural networks (CNNs) to obtain specificity prognostic information from multi-omics data. Finally, MSFN stacks the prognostic information from these networks and feeds into AdaboostRF for survival prediction. Results: Experiments results demonstrated that our method outperformed several state-of-the-art methods, and biologically validated by Kaplan-Meier and t-SNE.

MLL-AF9 regulates transcriptional initiation in mixed lineage leukemic cells.

Mixed lineage leukemia-fusion proteins (MLL-FPs) are believed to maintain gene activation and induce MLL through aberrantly stimulating transcriptional elongation, but the underlying mechanisms are incompletely understood. Here, we show that both MLL1 and AF9, one of the major fusion partners of MLL1, mainly occupy promoters and distal intergenic regions, exhibiting chromatin occupancy patterns resembling that of RNA polymerase II in HEL, a human erythroleukemia cell line without MLL1 rearrangement. MLL1 and AF9 only coregulate over a dozen genes despite of their co-occupancy on thousands of genes. They do not interact with each other, and their chromatin occupancy is also independent of each other. Moreover, AF9 deficiency in HEL cells decreases global TBP occupancy while decreases CDK9 occupancy on a small number of genes, suggesting an accessory role of AF9 in CDK9 recruitment and a possible major role in transcriptional initiation via initiation factor recruitment. Importantly, MLL1 and MLL-AF9 occupy promoters and distal intergenic regions, exhibiting identical chromatin occupancy patterns in MLL cells, and MLL-AF9 deficiency decreased occupancy of TBP and TFIIE on major target genes of MLL-AF9 in iMA9, a murine acute myeloid leukemia cell line inducibly expressing MLL-AF9, suggesting that it can also regulate initiation. These results suggest that there is no difference between MLL1 and MLL-AF9 with respect to location and size of occupancy sites, contrary to what people have believed, and that MLL-AF9 may also regulate transcriptional initiation in addition to widely believed elongation.

Aptamer functionalized hypoxia-potentiating agent and hypoxia-inducible factor inhibitor combined with hypoxia-activated prodrug for enhanced tumor therapy.

Triple-negative breast cancer (TNBC) is the most lethal subtype of breast cancer. Hypoxia-activated prodrugs (HAPs) have shown promise as potential therapeutic agents for TNBC. While increasing hypoxia levels may promote the HAP activation, it raises concerns regarding HIF1α-dependent drug resistance. It is desirable to develop a targeted approach that enhances tumor hypoxia for HAP activation without promoting HIF1α-dependent drug resistance in TNBC treatment. Herein, we proposed a multi-responsive carrier-free self-assembled nanomedicine named AQ4N@CA4T1ASO. This nanomedicine first targeted tumors by the TNBC-targeting aptamers (T1), and then disassembled in the reductive and acidic conditions within tumors. The released Combretastatin 4 (CA4) could exacerbate hypoxia, thereby promoting the conversion of inactive Banoxantrone (AQ4N) to its active form, AQ4. Simultaneously, the released antisense oligonucleotide (ASO) could attenuate hypoxia-induced HIF1α mRNA expression, thereby sensitizing the tumor to chemotherapy. Overall, this smart nanomedicine represents a profound targeted therapy strategy, combining "hypoxia-potentiating, hypoxia-activated, chemo-sensitization" approaches for TNBC treatment. In vivo study demonstrated significant suppression of tumor growth, highlighting the promising potential of this nanomedicine for future clinical translation.

Novel PATL2 variants cause female infertility with oocyte maturation defect.

PURPOSE: Oocyte maturation defect (OOMD) is a rare cause of in vitro fertilization failure characterized by the production of immature oocytes. Compound heterozygous or homozygous PATL2 mutations have been associated with oocyte arrest at the germinal vesicle (GV), metaphase I (MI), and metaphase II (MII) stages, as well as morphological changes. METHODS: In this study, we recruited three OOMD cases and conducted a comprehensive multiplatform laboratory investigation. RESULTS: Whole exome sequence (WES) revealed four diagnostic variants in PATL2, nonsense mutation c.709C > T (p.R237*) and frameshift mutation c.1486_1487delinsT (p.A496Sfs*4) were novel mutations that have not been reported previously. Furthermore, the pathogenicity of these variants was predicted using in silico analysis, which indicated detrimental effects. Molecular dynamic analysis suggested that the A496S variant disrupted the hydrophobic segment, leading to structural changes that affected the overall protein folding and stability. Additionally, biochemical and molecular experiments were conducted on cells transfected with wild-type (WT) or mutant PATL2 (p.R237* and p.A496Sfs*4) plasmid vectors. CONCLUSIONS: The results demonstrated that PATL2A496Sfs*4 and PATL2R237* had impacts on protein size and expression level. Interestingly, expression levels of specific genes involved in oocyte maturation and early embryonic development were found to be simultaneously deregulated. The findings in our study expand the variation spectrum of the PATL2 gene, provide solid evidence for counseling on future pregnancies in affected families, strongly support the application of in the diagnosis of OOMD, and contribute to the understanding of PATL2 function.

Establishment of epidemiological cut-off values for eravacycline, against Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Acinetobacter baumannii and Staphylococcus aureus.

OBJECTIVES: To establish the epidemiology cut-off (ECOFF) values of eravacycline against Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Acinetobacter baumannii and Staphylococcus aureus, from a multi-centre study in China. METHODS: We collected 2500 clinical isolates from five hospitals in China from 2017 to 2020. The MICs of eravacycline were determined using broth microdilution. The ECOFF values of eravacycline against the five species commonly causing cIAIs were calculated using visual estimation and ECOFFinder following the EUCAST guideline. RESULTS: The MICs of eravacycline against all the strains were in the range of 0.004-16 mg/L. The ECOFF values of eravacycline were 0.5 mg/L for E. coli, 2 mg/L for K. pneumonia and E. cloacae, and 0.25 mg/L for A. baumannii and S. aureus, consistent with the newest EUCAST publication of eravacycline ECOFF values for the populations. No discrepancy was found between the visually estimated and 99.00% ECOFF values calculated using ECOFFinder. CONCLUSIONS: The determined ECOFF values of eravacycline against the five species can assist in distinguishing wild-type from non-wild-type strains. Given its promising activity, eravacycline may represent a member of the tetracycline class in treating cIAIs caused by commonly encountered Gram-negative and Gram-positive pathogens.

Integrated analysis of miRNAome and transcriptome reveals that microgravity induces the alterations of critical functional gene modules via the regulation of miRNAs in short-term space-flown C. elegans.

Microgravity, as a unique hazardous factor encountered in space, can induce a series of harmful effects on living organisms. The impact of microgravity on the pivotal functional gene modules stemming from gene enrichment analysis via the regulation of miRNAs is not fully illustrated. To explore the microgravity-induced alterations in critical functional gene modules via the regulation of miRNAs, in the present study, we proposed a novel bioinformatics algorithm for the integrated analysis of miRNAome and transcriptome from short-term space-flown C. elegans. The samples of C. elegans were exposed to two space conditions, namely spaceflight (SF) and spaceflight control (SC) onboard the International Space Station for 4 days. Additionally, the samples of ground control (GC) were included for comparative analysis. Using the present algorithm, we constructed regulatory networks of functional gene modules annotated from differentially expressed genes (DEGs) and their associated regulatory differentially expressed miRNAs (DEmiRNAs). The results showed that functional gene modules of molting cycle, defense response, fatty acid metabolism, lysosome, and longevity regulating pathway were facilitated by 25 down-regulated DEmiRNAs (e.g., cel-miR-792, cel-miR-65, cel-miR-70, cel-lsy-6, cel-miR-796, etc.) in the SC vs. GC groups, whereas these modules were inhibited by 13 up-regulated DEmiRNAs (e.g., cel-miR-74, cel-miR-229, cel-miR-70, cel-miR-249, cel-miR-85, etc.) in the SF vs. GC groups. These findings indicated that microgravity could significantly alter gene expression patterns and their associated functional gene modules in short-term space-flown C. elegans. Additionally, we identified 34 miRNAs as post-transcriptional regulators that modulated these functional gene modules under microgravity conditions. Through the experimental verification, our results demonstrated that microgravity could induce the down-regulation of five critical functional gene modules (i.e., molting cycle, defense response, fatty acid metabolism, lysosome, and longevity regulating pathways) via the regulation of miRNAs in short-term space-flown C. elegans.

Identification of diagnostic signature and immune infiltration for ischemic cardiomyopathy based on cuproptosis-related genes through bioinformatics analysis and experimental validation.

BACKGROUND: Ischemic cardiomyopathy (IC) is primarily due to long-term ischemia/hypoxia of the coronary arteries, leading to impaired cardiac contractile or diastolic function. A new form of cell death induced by copper, called "cuproptosis" is related to the development and progression of multiple diseases. The cuproptosis-related gene (CuGs) plays an important role in acute myocardial infarction, while the specific mechanisms of CuGs in ischemic cardiomyopathy remain unclear. METHODS: The expressions of CuGs and their immune characteristics were analyzed with the IC datasets obtained from the Gene Expression Omnibus, namely GSE5406 and GSE57338, identifying core genes associated with IC development. By comparing RF, SVM, GLM and XGB models, the optimal machine learning model was selected. The expression of marker genes was validated based on the GSE57345, GSE48166 and GSE42955 datasets. Construct a CeRNA network based on core genes. Therapeutic chemiacals targeting core genes were acquired using the CTD database, and molecular docking was performed using Autodock vina software. By ligating the left anterior descending (LAD) coronary artery, an IC mouse model is established, and core genes were experimentally validated using Western blot (WB) and immunohistochemistry (IHC) methods. RESULTS: We identified 14 CuGs closely associated with the onset of IC. The SVM model exhibited superior discriminative power (AUC = 0.914), with core genes being DLST, ATP7B, FDX1, SLC31A1 and DLAT. Core genes were validated on the GSE42955, GSE48166 and GSE57345 datasets, showing excellent performance (AUC = 0.943, AUC = 0.800, and AUC = 0.932). The CeRNA network consists of 218 nodes and 264 lines, including 5 core diagnostic genes, 52 miRNAs, and 161 lncRNAs. Chemicals predictions indicated 8 chemicals have therapeutic effects on the core diagnostic genes, with benzo(a)pyrene molecular docking showing the highest affinity (-11.3 kcal/mol). Compared to the normal group, the IC group,which was established by LAD ligation, showed a significant decrease in LVEF as indicated by cardiac ultrasound, and increased fibrosis as shown by MASSON staining, WB results suggest increased expression of DLST and ATP7B, and decreased expression of FDX1, SLC31A1 and DLAT in the myocardial ischemic area (p < 0.05), which was also confirmed by IHC in tissue sections. CONCLUSION: In summary, this study comprehensively revealed that DLST, ATP7B, FDX1, SLC31A1 and DLAT could be identified as potential immunological biomarkers in IC, and validated through an IC mouse model, providing valuable insights for future research into the mechanisms of CuGs and its diagnostic value to IC.

Spatial-temporal patterns of fish trophic guilds in a freshwater river wetland ecosystem of northeastern China.

Muling River, situated amidst cultivated lands in Heilongjiang Province, northeastern China, has long been subjected to sand-digging activities, resulting in severe damage to its riverbed. However, little research has been conducted on the impact of this disturbance on the status of fish community structure and trophic guilds in this river. In this study, environmental factors, fish community structure, and fish trophic guild biomass distribution patterns from the Muling River basin were investigated among seasons (spring, summer, and autumn) and sections (upper, middle, and lower stream) in 2015 and 2017. During the six sampling times periods, 46 species of five orders and 12 families of fish were classified into seven trophic guilds. Fish species number and biomass were higher upper reaches of the watershed. The insectivores (16.26%), phytoplanktivores (10.09%), benthivores (40.17%), and omnivores (11.86%) were the dominant trophic guilds. We found that fish trophic guilds biomass and environmental factors such as transparency, water depth, pH value, total phosphorus, and chemical oxygen demand were highest in the upper section compared to other sections. Variation partitioning revealed that fish trophic guilds biomass was influenced more by environmental factors (61.2%), followed by section (0.7%) and season (0.1%). Partial RDA ordination showed that fish trophic guilds were positively correlated with water depth and transparency, while negative with turbidity. This study underscores the importance of considering trophic guilds of freshwater fishes to inform management strategies in regions experiencing significant environmental change.