Lumican promotes calcific aortic valve disease through H3 histone lactylation.

BACKGROUND AND AIMS: Valve interstitial cells (VICs) undergo a transition to intermediate state cells before ultimately transforming into the osteogenic cell population, which is a pivotal cellular process in calcific aortic valve disease (CAVD). Herein, this study successfully delineated the stages of VIC osteogenic transformation and elucidated a novel key regulatory role of lumican (LUM) in this process. METHODS: Single-cell RNA-sequencing (scRNA-seq) from nine human aortic valves was used to characterize the pathological switch process and identify key regulatory factors. The in vitro, ex vivo, in vivo, and double knockout mice were constructed to further unravel the calcification-promoting effect of LUM. Moreover, the multi-omic approaches were employed to analyse the molecular mechanism of LUM in CAVD. RESULTS: ScRNA-seq successfully delineated the process of VIC pathological transformation and highlighted the significance of LUM as a novel molecule in this process. The pro-calcification role of LUM is confirmed on the in vitro, ex vivo, in vivo level, and ApoE-/-//LUM-/- double knockout mice. The LUM induces osteogenesis in VICs via activation of inflammatory pathways and augmentation of cellular glycolysis, resulting in the accumulation of lactate. Subsequent investigation has unveiled a novel LUM driving histone modification, lactylation, which plays a role in facilitating valve calcification. More importantly, this study has identified two specific sites of histone lactylation, namely, H3K14la and H3K9la, which have been found to facilitate the process of calcification. The confirmation of these modification sites' association with the expression of calcific genes Runx2 and BMP2 has been achieved through ChIP-PCR analysis. CONCLUSIONS: The study presents novel findings, being the first to establish the involvement of lumican in mediating H3 histone lactylation, thus facilitating the development of aortic valve calcification. Consequently, lumican would be a promising therapeutic target for intervention in the treatment of CAVD.

Mechano Growth Factor Accelerates ACL Repair and Improves Cell Mobility of Mechanically Injured Human ACL Fibroblasts by Targeting Rac1-PAK1/2 and RhoA-ROCK1 Pathways.

Exceeded mechanical stress leads to a sublethal injury to anterior cruciate ligament (ACL) fibroblasts, and it will hinder cell mobility and ACL regeneration, and even induce osteoarthritis. The mechano growth factor (MGF) could be responsible for mechanical stress and weakening its negative effects on cell physiological behaviors. In this study, effects of MGF on cell mobility and relevant molecules expression in injured ACL fibroblasts were detected. After an injurious mechanical stretch, the analysis carried out, at 0 and 24 h, respectively, showed that the cell area, roundness, migration, and adhesion of ACL fibroblasts were reduced. MGF (10, 100 ng/mL) treatment could improve cell area, roundness and promote cell migration and adhesion capacity compared with the injured group without MGF. Further study indicated that cell mobility-relevant molecules (PAK1/2, Cdc42, Rac1, RhoA, and ROCK1) expression in ACL fibroblasts was down-regulated at 0 or 24 h after injurious stretch (except Rac1 and RhoA at 0 h). Similarly, MGF improved cell mobility-relevant molecule expression, especially the ROCK1 expression level in ACL fibroblasts at 0 or 24 h after injurious stretch. Protein expression of ROCK1 in injured ACL fibroblasts was also reduced and could be recovered by MGF treatment. In a rabbit partial ACL transection (ACLT) model, ACL exhibited poor regenerative capacity in collagen and extracellular matrix (ECM) synthesis after partial ACLT for 2 or 4 weeks, and MGF remarkably accelerated ACL regeneration and restored its mechanical loading capacity after partial ACLT for four weeks. Our findings suggest that MGF weakens the effects of pathological stress on cell mobility of ACL fibroblasts and accelerates ACL repair, and might be applied as a future treatment approach to ACL rupture in the clinic.

Hyperphosphorylation of Tau Due to the Interference of Protein Phosphatase Methylesterase-1 Overexpression by MiR-125b-5p in Melatonin Receptor Knockout Mice.

Melatonin has been indicated to ameliorate tau hyperphosphorylation in the pathogenesis of tau diseases, but the role of melatonin-receptor signal transduction has not been clearly discovered. In this study, we found intensive tau hyperphosphorylation in melatonin receptor knockout mice. Bielschowsky silver staining showed ghostlike neurofibrillary tangles in melatonin receptor-2 knockout (MT2KO) as well as melatonin receptors-1 and -2 knockout (DKO) mice, and an argyrophilic substance was deposited in melatonin receptor-1 knockout (MT1KO) mice. Furthermore, we found significantly decreased activity of protein phosphatase 2A (PP2A) by Western blot and enzyme-linked immunosorbent assay (ELISA), which was partly due to the overexpression of protein phosphatase methylesterase-1 (PME-1), but not glycogen synthase kinase-3ß (GSK-3ß), cyclin-dependent kinase 5 (CDK5) or protein kinase B (Akt). Finally, we observed a significant increase in cyclic adenosine monophosphate (cAMP) and a decrease in miR-125b-5p levels in MT1KO, MT2KO and DKO mice. Using a luciferase reporter assay, we discovered that miR-125b-5p largely decreased the expression of firefly luciferase by interfering with the 3'UTR of PME-1. Furthermore, miR-125b-5p mimics significantly decreased the expression of PME-1, while miR-125b-5p inhibitor induced tau hyperphosphorylation. These results show that melatonin-receptor signal transduction plays an important role in tau hyperphosphorylation and tangle formation.

Mechanical injury and IL-1ß regulated LOXs and MMP-1, 2, 3 expression in ACL fibroblasts co-cultured with synoviocytes.

OBJECTIVE: Interleukin (IL)-1ß in the joint cavity increases to promote healing after anterior cruciate ligament (ACL) injury. Synovial tissue is a major joint microenvironmental regulator after ACL injury. The purpose of this study was to investigate the effects of synovial cells (SCs) on lysyl oxidase (LOX) and matrix metalloproteinase (MMP) production by ACL fibroblasts (ACLfs) in the presence of IL-1ß. RESULTS: This study sheds light on the regulation of LOX and MMP-1, -2, -3 expression by ACLfs co-cultured with SCs and treated with IL-1ß. LOX and MMP-1, 2, 3 gene/protein expression in IL-1ß/stretch-stimulated ACLfs co-cultured with SCs were measured by real-time quantitative PCR and Western blot. Meanwhile, MMP-2 activity was analyzed by zymogram. The results showed that co-culture with SCs increased LOX and MMP-1, -2, -3 gene and protein expression in the presence of IL-1ß. Next, ACLfs were subjected to 12% mechanical stretch to simulate pathological injury. Under these conditions, SCs inhibited IL-1ß-mediated upregulation of LOXs. However, IL-1ß enhanced the expression of MMP-1, -2, -3 in injured ACLfs. CONCLUSIONS: SCs can either inhibit or increase LOX production in the presence of IL-1ß, while promoting the accumulation of MMP in injured ACLfs. These results may provide crucial insights into the mechanisms underlying ACL poor healing capacity after injury.

Smart hydrogels with high tunability of stiffness as a biomimetic cell carrier.

Human tissues are sophisticated ensembles of various distinct cell types encapsulated in the biomechanical cues of the extracellular matrix. It has been known matrix stiffness plays a pivot role in cellular events and tissue-scale biological processes. Thus, materials that can mimic mechanical environments of tissues in vitro and possess wide, physiologically relevant elasticity are highly desirable. Hydrogels provide a good cell platform to mimic native cellular environment. However, the limited stiffness tunability, and hinders the efforts to reproduce the biomechanical microenvironment of many in vivo progresses. These problems have been addressed by the recently emerged great quantity of exquisitely designed smart hydrogels. Smart hydrogels that respond sensitively to external stimuli are good choices due to the convenience in regulating their mechanical properties. In this review, we summarize the latest progress in the development of stimuli-responsive hydrogels as a cell carrier (platform for cell culture) which spans a wide range of stiffness. Different kinds of smart hydrogels corresponding to various stimuli, including pH, temperature, light, metal ions, and forces, are introduced and their stiffness modulation through physicochemical procedures are reported.

Nobiletin exhibits potent inhibition on tumor necrosis factor alpha-induced calcification of human aortic valve interstitial cells via targeting ABCG2 and AKR1B1.

Inflammation is considered to be one of the initial critical factors in the occurrence of calcific heart valve disease. This study was to prove Nobiletin (NBT) inhibits inflammation-caused calcification of human valve interstitial cells (hVICs) and to elucidate the involved molecular mechanisms. Tumor necrosis factor-alpha (TNF-α)-induced hVICs were treated with or without NBT. Cell growth and calcification of hVICs were assessed. RNA sequencing was utilized to investigate the gene expression changes. Molecular target prediction and docking assay were further performed. NBT interfered with hVIC growth under TNF-α condition in a dose-dependent manner also presented a gradual decrease of positive Alizarin Red S staining, down-regulation of BMP2, and RUNX2 gene expression. Based on the global gene expression cluster, control and TNF-α plus NBT group showed a high similarity versus TNF-α only group. After Venn interaction of differential expression genes (DEGs), 2,236 common DEGs were identified to display different biological functions and signaling pathways. ABCG2 and AKR1B1 were further selected as prediction targets of NBT involved in RELA, TNF, BMP2, RUNX2, etc. interactions in mediating hVIC calcification. The results show that NBT is a natural product to prevent the occurrence of heart valve calcification.

Smart mechanosensing machineries enable migration of vascular smooth muscle cells in atherosclerosis-relevant 3D matrices.

At the early stage of atherosclerosis, neointima is formed due to the migration of vascular smooth muscle cells (VSMCs) from the media to the intima. VSMCs are surrounded by highly adhesive 3D matrices. They take specific strategies to cross various 3D matrices in the media, including heterogeneous collagen and mechanically strong basement membrane. Migration of VSMCs is potentially caused by biomechanical mechanism. Most in vitro studies focus on cell migration on 2D substrates in response to biochemical factors. How the cells move through 3D matrices under the action of mechanosensing machineries remains unexplored. In this review, we propose that several interesting tension-dependent machineries act as "tractor"-posterior myosin II accumulation, and "wrecker"-anterior podosome maintaining, to power VSMCs ahead. VSMCs embedded in 3D matrices may accumulate a minor myosin II isoform, myosin IIB, at the cell rear. Anisotropic myosin IIB distribution creates cell rear, polarizes cell body, pushes the nucleus and reshapes the cell body, and cooperates with a uniformly distributed myosin IIA to propel the cell forward. On the other hand, matrix digestion by podosome further promote the migration when the matrix becomes denser. Actomyosin tension activates Src to induce podosome in soft 3D matrices and retain the podosome integrity to steadily digest the matrix.

[Research Progress of NOS3 Participation in Regulatory Mechanisms of Cardiovascular Diseases].

Cardiovascular disease has been a major threat to human's health and lives for many years. It is of great importance to explore the mechanisms and develop strategies to prevent the pathogenesis. Generally, cardiovascular disease is associated with endothelial dysfunction, which is closely related to the nitric oxide (NO)-mediated vasodilatation. The release of NO is regulated by NOS3 gene in mammals' vascular system. A great deal of evidences have shown that the polymorphism and epigenetic of NOS3 gene play vital roles in the pathological process of cardiovascular disease. To gain insights into the role of NOS3 in the cardiovascular diseases, we reviewed the molecular mechanisms underlying the development of cardiovascular diseases in this paper, including the uncoupling of NOS3 protein, epigenetic and polymorphism of NOS3 gene. The review can also offer possible strategies to prevent and treat cardiovascular diseases.

Mechanosensing of cells in 3D gel matrices based on natural and synthetic materials.

Cells in vivo typically are found in 3D matrices, the mechanical stiffness of which is important to the cell and tissue-scale biological processes. Although it is well characterized that as to how cells sense matrix stiffness in 2D substrates, the scenario in 3D matrices needs to be explored. Thus, materials that can mimic native 3D environments and possess wide, physiologically relevant elasticity are highly desirable. Natural polymer-based materials and synthetic hydrogels could provide an better 3D platforms to investigate the mechano-response of cells with stiffness comparable to their native environments. However, the limited stiffness range together with interdependence of matrix stiffness and adhesive ligand density are inherent in many kinds of materials, and hinder efforts to demonstrate the true effects contributed by matrix stiffness. These problems have been addressed by the recently emerging exquisitely designed materials based on native matrix components, designer matrices, and synthetic polymers. In this review, a variety of materials with a wide stiffness range that mimic the mechanical environment of native 3D matrices and the independent affection of stiffness for cellular behavior and tissue-level processes are discussed.

Single-cell RNA sequencing and spatial transcriptome reveal potential molecular mechanisms of lung cancer brain metastasis.

BACKGROUND: Lung cancer is a highly aggressive and prevalent disease worldwide. By the time it is first diagnosed, distant metastases have usually already occurred. Among them, the prognosis of patients with brain metastasis from lung cancer is very poor. Therefore, it is particularly important to identify the evolutionary status of tumor cells during lung cancer brain metastases and discover the underlying mechanisms of lung cancer brain metastases. METHODS: In this study, we analysed three types of data: single-cell RNA sequencing, bulk RNA sequencing, and spatial transcriptome. Firstly, we identified early metastatic epithelial cell clusters (EMEC) using CNV and trajectory analysis in scRNA-seq data. Secondly, we integrated scRNA-seq and spatial transcriptome data with the help of MIA (Multimodal intersection analysis) to explore the biological characteristics of EMEC. Finally, we used bulk RNA-seq data to validate the molecular characteristics of EMEC. RESULT: A total of 55,763 single cells were obtained and divided into 9 cell types. In brain metastasis, we found a significantly higher proportion of epithelial cells. In addition, we identified a specific subpopulation of epithelial cells, which was named as "early metastatic epithelial cell clusters (EMEC)". It is enriched in oxidative phosphorylation, coagulation, complement. Moreover, we also found that EMEC underwent cellular communication with other immune cells through ligand-receptor pairs such as MIF-(CD74 + CXCR4) and MIF-(CD74 + CD44). Next, we validated that EMEC were associated with poor clinical prognosis using three independent external datasets. Finally, spatial transcriptome analysis revealed specificity in the spatial distribution of EMEC, which shifted from the peripheral regions to the central regions of the tumour as the depth of tumor invasion progressed. CONCLUSION: This study reveals the potential molecular mechanisms of lung cancer brain metastasis from both single-cell and spatial transcriptomic perspectives, providing biological insights and clinical reference value for detecting patients suffering from lung cancer brain metastasis.

Natural product fargesin interferes with H3 histone lactylation via targeting PKM2 to inhibit non-small cell lung cancer tumorigenesis.

Non-small cell lung cancer (NSCLC) is one of the most common malignant tumors. There is an urgent need to find more effective drugs that inhibit NSCLC. Fargesin (FGS) has demonstrated anti-tumor effects; however, its efficacy and the molecular mechanism of inhibiting NSCLC are unclear. Herein, we investigated FGS' inhibitory effects on NSCLC by CCK8 and EdU assays and cell cycle analysis of A549 cells in vitro and in a nude mouse tumor transplantation model in vivo. FGS (10-50 µM) significantly inhibited cell proliferation and down-regulated expression levels of CDK1 and CCND1. Transcriptomic analysis showed that FGS regulated the cell metabolic process pathway. Differential metabolites with FGS treatment were enriched in glycolysis and pyruvate pathways. Cell metabolism assay were used to evaluate the oxygen consumption rate (OCR), Extracellular acidification rate (ECAR) in A549 cells. FGS also inhibited the production of cellular lactate and the expression of LDHA, LDHB, PKM2, and SLC2A1. These genes were identified as important oncogenes in lung cancer, and their binding to FGS was confirmed by molecular docking simulation. Notably, the over-expression and gene silencing experiments signified PKM2 as the molecular target of FGS for anti-tumorigenesis. Moreover, the H3 histone lactylation, were correlated with tumorigenesis, were inhibited with FGS treatment. Conclusively, FGS inhibited the aerobic glycolytic and H3 histone lactylation signaling pathways in A549 NSCLC cells by targeting PKM2. These findings provide evidence of the therapeutic potential of FGS in NSCLC.

Lactylome Analysis Unveils Lactylation-Dependent Mechanisms of Stemness Remodeling in the Liver Cancer Stem Cells.

Lactate plays a critical role as an energy substrate, metabolite, and signaling molecule in hepatocellular carcinoma (HCC). Intracellular lactate-derived protein lysine lactylation (Kla) is identified as a contributor to the progression of HCC. Liver cancer stem cells (LCSCs) are believed to be the root cause of phenotypic and functional heterogeneity in HCC. However, the impact of Kla on the biological processes of LCSCs remains poorly understood. Here enhanced glycolytic metabolism, lactate accumulation, and elevated levels of lactylation are observed in LCSCs compared to HCC cells. H3K56la was found to be closely associated with tumourigenesis and stemness of LCSCs. Notably, a comprehensive examination of the lactylome and proteome of LCSCs and HCC cells identified the ALDOA K230/322 lactylation, which plays a critical role in promoting the stemness of LCSCs. Furthermore, this study demonstrated the tight binding between aldolase A (ALDOA) and dead box deconjugate enzyme 17 (DDX17), which is attenuated by ALDOA lactylation, ultimately enhancing the regulatory function of DDX17 in maintaining the stemness of LCSCs. This investigation highlights the significance of Kla in modulating the stemness of LCSCs and its impact on the progression of HCC. Targeting lactylation in LCSCs may offer a promising therapeutic approach for treating HCC.

Non-targeted metabolomics and explainable artificial intelligence: Effects of processing and color on coniferyl aldehyde levels in Eucommiae cortex.

Eucommia ulmoides, a plant native to China, is valued for its medicinal properties and has applications in food, health products, and traditional Chinese medicine. Processed Eucommiae Cortex (EC) has historically been a highly valued medicine. Ancient doctors had ample experience processing EC, especially with ginger juice, as documented in traditional Chinese medical texts. The combination of EC and ginger juice helps release and transform the active ingredients, strengthening the medicine's effectiveness and improving its taste and shelf life. However, the lack of quality control standards for Ginger-Eucommiae Cortex (G-EC), processed from EC and ginger, presents challenges for its industrial and clinical use. This study optimized G-EC processing using the CRITIC and Box-Behnken methods. Metabolomics showed 517 chemical changes between raw and processed G-EC, particularly an increase in coniferyl aldehyde (CFA). Explainable artificial intelligence techniques revealed the feasibility of using color to CFA content, providing insights into quality indicators.

Macrophage Membrane-Encapsulated Dopamine-Modified Poly Cyclodextrin Multifunctional Biomimetic Nanoparticles for Atherosclerosis Therapy.

Atherosclerotic plaques exhibit high cholesterol deposition and oxidative stress resulting from high reactive oxygen species (ROS). These are the major components in plaques and the main pro-inflammatory factor. Therefore, it is crucial to develop an effective therapeutic strategy that can simultaneously address the multiple pro-inflammatory factors via removing cholesterol and inhibiting the overaccumulated ROS. In this study, we constructed macrophage membrane-encapsulated biomimetic nanoparticles (MM@DA-pCD@MTX), which not only alleviate cholesterol deposition at the plaque lesion via reverse cholesterol transport but also scavenge the overaccumulated ROS. ß-Cyclodextrin (ß-CD) and the loaded methotrexate (MTX) act synergistically to induce cholesterol efflux for inhibiting the formation of foam cells. Among them, MTX up-regulated the expression of ABCA1, CYP27A1, and SR-B1. ß-CD increased the solubility of cholesterol crystals. In addition, the ROS scavenging property of dopamine (DA) was perfectly preserved in MM@DA-pCD@MTX, which could scavenge the overaccumulated ROS to alleviate the oxidative stress at the plaque lesion. Last but not least, MM-functionalized "homing" targeting of atherosclerotic plaques not only enables the targeted drug delivery but also prolongs in vivo circulation time and drug half-life. In summary, MM@DA-pCD@MTX emerges as a potent, multifunctional therapeutic platform for AS treatment, offering a high degree of biosafety and efficacy in addressing the complex pathophysiology of atherosclerosis.

Elevated expression of TNFRSF4 impacts immune cell infiltration and gene mutation in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is a highly heterogeneous disease, which makes prognostic prediction challenging.We aimed to investigate association of TNFRSF4 expression with the immune infiltration and gene mutation in HCC. METHODS: In this study, the expression profiles and corresponding clinical data of HCC patients were downloaded from the Cancer Genome Atlas (TCGA) database.Kaplan-Meier and Cox regression were used to evaluate the clinical value of TNFRSF4. ESTIMATE and CIBERSORT algorithms were applied to investigate the infiltration ratio of 22 immune cells. The WGCNA and LASSO COX algorithms were performed, establishing a prognostic risk model that was then validated by HCC samples from GEO. Finally, the effects on gene mutation occurring in HCC patients of TNFRSF4 expression and risk score were appraised. RESULTS: In HCC tissues, it was found the TNFRSF4 expression profile was significantly different with age, gender, tumor grade, disease stage, prominently affecting the survival outcome and prognosis of patients. Univariate and multivariate COX regression analysis suggested that TNFRSF4 was an independent prognostic marker. Samples of high/low expression of TNFRSF4 were screened for differential genes, and then the WGCNA and LASSO COX constructed a 13-gene signature, excellently dividing samples into hign/low risk groups. Compared with the low-risk group, the overall survival (OS) of high-risk group was markedly lower, with P< 0.0001. By ROC curve analysis, the predictive ability of the 13-gene signature was further confirmed. Both the high/low TNFRSF4 expression and the high/low risk score were demonstrated to exert effects on the frequency of gene mutation in HCC. CONCLUSIONS: As an independent prognostic marker of HCC, TNFRSF4 was found simultaneously to affect the immune infiltration of cells and the frequency of gene mutations.

Biomechanics Assist Measurement, Modeling, Engineering Applications, and Clinical Decision Making in Medicine.

Biomechanical studies of surgeries and medical devices are usually performed with human or animal models [...].

Integrated bioinformatical and in vitro study on drug targets for liver cirrhosis based on unsupervised consensus clustering and immune cell infiltration.

Liver cirrhosis is one of the most common cause of death in the world. The progress of liver cirrhosis involves health, liver cirrhosis and liver cancer, leading to great challenges in the diagnosis of the disease. Drug targets, which could be obtained conveniently, can help clinicians improve prognosis and treatment. Liver cirrhosis is associated with serum calcium levels. And studies reported Tanshinone IIA plays a therapeutic role in liver injury through activating calcium-dependent apoptosis. In this study, we explored the diagnostic key targets of Tanshinone IIA in liver cirrhosis through exploration of comprehensive dataset including health, liver cirrhosis and liver cancer patients. The unsupervised consensus clustering algorithm identified 3 novel subtypes in which differentially expressed genes (DEGs) between both subtypes were found by pairwise comparison. Then, 4 key drug targets of Tanshinone IIA were determined through the intersection of these DEGs. The diagnostic performance of target genes was assessed and further verified in the external dataset. We found that the 4 key drug targets could be used as effective diagnostic biomarkers. Then the immune scores in the high and low expression groups of target genes were estimated to identify significantly expressed immune cells. In addition, the immune infiltration of high and low target gene expression groups in several immune cells were significantly different. The findings suggest that 4 key drug targets may be a simple and useful diagnostic tool for predicting patients with cirrhosis. We further studied the carcinogenesis role of AKR1C3 and TPX2 in vitro. Both mRNA and protein expression in hepatoma carcinoma cells was detected using qRT-PCR and Western blot. And the knockdown of AKR1C3 and TPX2 significantly suppressed cell proliferation, migration and invasion.

Machine learning algorithm and deep neural networks identified a novel subtype in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors. Due to the lack of specific characteristics in the early stage of the disease, patients are usually diagnosed in the advanced stage of disease progression. OBJECTIVE: This study used machine learning algorithms to identify key genes in the progression of hepatocellular carcinoma and constructed a prediction model to predict the survival risk of HCC patients. METHODS: The transcriptome data and clinical information were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). The differential expression analysis and COX proportional-hazards model participated in the identification of survival-related genes. K-Means, Random forests, and LASSO regression are involved in identifying novel subtypes of HCC and screening key genes. The prediction model was constructed by deep neural networks (DNN), and Gene Set Enrichment Analysis (GSEA) reveals the metabolic pathways where key genes are located. RESULTS: Two subtypes were identified with significantly different survival rates (p< 0.0001, AUC = 0.720) and 17 key genes associated with the subtypes. The accuracy rate of the deep neural network prediction model is greater than 93.3%. The GSEA analysis found that the survival-related genes were significantly enriched in hallmark gene sets in the MSigDB database. CONCLUSIONS: In this study, we used machine learning algorithms to screen out 17 genes related to the survival risk of HCC patients, and trained a DNN model based on them to predict the survival risk of HCC patients. The genes that make up the model are all key genes that affect the formation and development of cancer.

A Transendothelial Leukocyte Transmigration Model Based on Computational Fluid Dynamics and BP Neural Network.

The mechanism of immune infiltration involving immune cells is closely related to various diseases. A key issue in immune infiltration is the transendothelial transmigration of leukocytes. Previous studies have primarily interpreted the leukocyte infiltration of from biomedical perspective. The physical mechanism of leukocyte infiltration remains to be explored. By integrating the immune cell transmigration computational fluid dynamics (CFD) data, the paper builds a time-dependent leukocyte transmigration prediction model based on the bio-inspired methods, namely back propagation neural networks (BPNN) model. The model can efficiently predict the immune cell transmigration in a special microvascular environment, and obtain good prediction accuracy. The model accurately predicted the cell movement and flow field changes during the transmigration. In the test data set, it has high prediction accuracy for cell deformation, motion velocity and flow lift forces during downstream motion, and maintains a good prediction accuracy for drag force. The two prediction models achieved the prediction of leukocyte transmigration in a specific microvascular environment and maintained a high prediction accuracy, indicating the feasibility and robustness of the BPNN model applied to the prediction of immune cell infiltration. Compared with traditional CFD simulations, BPNN models avoid complex and time-dependent physical modeling and computational processes.

Nonsense-Mediated Decay Targeted RNA (ntRNA): Proposal of a ntRNA-miRNA-lncRNA Triple Regulatory Network Usable as Biomarker of Prognostic Risk in Patients with Kidney Cancer.

The most prevalent subtype of renal cell carcinoma (RCC), kidney renal clear cell carcinoma (KIRC) may be associated with a poor prognosis in a high number of cases, with a stage-specific prognostic stratification currently in use. No reliable biomarkers have been utilized so far in clinical practice despite the efforts in biomarker research in the last years. Nonsense-mediated mRNA decay (NMD) is a critical safeguard against erroneous transcripts, particularly mRNA transcripts containing premature termination codons (called nonsense-mediated decay targeted RNA, ntRNA). In this study, we first characterized 296 differentially expressed ntRNAs that were independent of the corresponding gene, 261 differentially expressed miRNAs, and 4653 differentially expressed lncRNAs. Then, we constructed a hub ntRNA-miRNA-lncRNA triple regulatory network associated with the prognosis of KIRC. Moreover, the results of immune infiltration analysis indicated that this network may influence the changes of the tumor immune microenvironment. A prognostic model derived from the genes and immune cells associated with the network was developed to distinguish between high- and low-risk patients, which was a better prognostic than other models, constructed using different biomarkers. Additionally, correlation of methylation and ntRNAs in the network suggested that some ntRNAs were regulated by methylation, which is helpful to further study the causes of abnormal expression of ntRNAs. In conclusion, this study highlighted the possible clinical implications of ntRNA functions in KIRC, proposing potential significant biomarkers that could be utilized to define the prognosis and design personalized treatment plans in kidney cancer management in the next future.