Machine learning-based algorithm identifies key mitochondria-related genes in non-alcoholic steatohepatitis.

BACKGROUND: Evidence suggests that hepatocyte mitochondrial dysfunction leads to abnormal lipid metabolism, redox imbalance, and programmed cell death, driving the onset and progression of non-alcoholic steatohepatitis (NASH). Identifying hub mitochondrial genes linked to NASH may unveil potential therapeutic targets. METHODS: Mitochondrial hub genes implicated in NASH were identified via analysis using 134 algorithms. RESULTS: The Random Forest algorithm (RF), the most effective among the 134 algorithms, identified three genes: Aldo-keto reductase family 1 member B10 (AKR1B10), thymidylate synthase (TYMS), and triggering receptor expressed in myeloid cell 2 (TREM2). They were upregulated and positively associated with genes promoting inflammation, genes involved in lipid synthesis, fibrosis, and nonalcoholic steatohepatitis activity scores in patients with NASH. Moreover, using these three genes, patients with NASH were accurately categorized into cluster 1, exhibiting heightened disease severity, and cluster 2, distinguished by milder disease activity. CONCLUSION: These three genes are pivotal mitochondrial genes implicated in NASH progression.

Machine learning-based integration identifies the ferroptosis hub genes in nonalcoholic steatohepatitis.

BACKGROUND: Ferroptosis, is characterized by lipid peroxidation of fatty acids in the presence of iron ions, which leads to cell apoptosis. This leads to the disruption of metabolic pathways, ultimately resulting in liver dysfunction. Although ferroptosis is linked to nonalcoholic steatohepatitis (NASH), understanding the key ferroptosis-related genes (FRGs) involved in NASH remains incomplete. NASH may be targeted therapeutically by identifying the genes responsible for ferroptosis. METHODS: To identify ferroptosis-related genes and develop a ferroptosis-related signature (FeRS), 113 machine-learning algorithm combinations were used. RESULTS: The FeRS constructed using the Generalized Linear Model Boosting algorithm and Gradient Boosting Machine algorithms exhibited the best prediction performance for NASH. Eight FRGs, with ZFP36 identified by the algorithms as the most crucial, were incorporated into in FeRS. ZFP36 is significantly enriched in various immune cell types and exhibits significant positive correlations with most immune signatures. CONCLUSION: ZFP36 is a key FRG involved in NASH pathogenesis.

Systematic fine-mapping and functional studies of prostate cancer risk variants.

To date, genome-wide association studies (GWAS) have revealed over 200 genetic risk loci associated with prostate cancer; yet, true disease-causing variants remain elusive. Identification of causal variants and their targets from association signals is complicated by high linkage disequilibrium and limited availability of functional genomics data for specific tissue/cell types. Here, we integrated statistical fine-mapping and functional annotation from prostate-specific epigenomic profiles, 3D genome features, and quantitative trait loci data to distinguish causal variants from associations and identify target genes. Our fine-mapping analysis yielded 3,395 likely causal variants, and multiscale functional annotation linked them to 487 target genes. We prioritized rs10486567 as a genome-wide top-ranked SNP and predicted HOTTIP as its target. Deletion of the rs10486567-associated enhancer in prostate cancer cells decreased their capacity for invasive migration. HOTTIP overexpression in enhancer-KO cell lines rescued defective invasive migration. Furthermore, we found that rs10486567 regulates HOTTIP through allele-specific long-range chromatin interaction.

Field-Induced Wettability Gradients for No-Loss Transport of Oil Droplets on Slippery Surfaces.

Transporting oil droplets is crucial for a wide range of industrial and biomedical applications but remains highly challenging due to the large contact angle hysteresis on most solid surfaces. A liquid-infused slippery surface has a low hysteresis contact angle and is a highly promising platform if sufficient wettability gradient can be created. Current strategies used to create wettability gradient typically rely on the engineering of the chemical composition or geometrical structure. However, these strategies are inefficient on a slippery surface because the infused liquid tends to conceal the gradient in the chemical composition and small-scale geometrical structure. Magnifying the structure, on the other hand, will significantly distort the surface topography, which is unwanted in practice. In this study, we address this challenge by introducing a field-induced wettability gradient on a flat slippery surface. By printing radial electrodes array, we can pattern the electric field, which induces gradient contact angles. Theoretical analysis and experimental results reveal that the droplet transport behavior can be captured by a nondimensional electric Bond number. Our surface enables no-loss transport of various types of droplets, which we expect to find important applications such as heat transfer, anticontamination, microfluidics, and biochemical analysis.

A HOTAIR regulatory element modulates glioma cell sensitivity to temozolomide through long-range regulation of multiple target genes.

Temozolomide (TMZ) is a frequently used chemotherapy for glioma; however, chemoresistance is a major problem limiting its effectiveness. Thus, knowledge of mechanisms underlying this outcome could improve patient prognosis. Here, we report that deletion of a regulatory element in the HOTAIR locus increases glioma cell sensitivity to TMZ and alters transcription of multiple genes. Analysis of a combination of RNA-seq, Capture Hi-C, and patient survival data suggests that CALCOCO1 and ZC3H10 are target genes repressed by the HOTAIR regulatory element and that both function in regulating glioma cell sensitivity to TMZ. Rescue experiments and 3C data confirmed this hypothesis. We propose a new regulatory mechanism governing glioma cell TMZ sensitivity.

Local Dynamic Stability of Self-Paced Treadmill Walking Versus Fixed-Speed Treadmill Walking.

The purpose of this study was to assess the influence of gait stability induced by treadmill accelerations during self-paced treadmill walking (SPW). Local dynamic stability of three-dimensional (3D) upper body accelerations and hip angles were quantified. The results demonstrated that SPW was more unstable and had higher risk of falling than fixed-speed treadmill walking (FSW) under the impact of treadmill accelerations. The frequency domain analysis of treadmill speed indicated that intrastride treadmill speed variation was the dominating cause of the instability, and self-paced control strategies which can reduce the intrastride variation may achieve higher gait stability during SPW.

The prostate cancer risk variant rs55958994 regulates multiple gene expression through extreme long-range chromatin interaction to control tumor progression.

Genome-wide association studies identified single-nucleotide polymorphism (SNP) rs55958994 as a significant variant associated with increased susceptibility to prostate cancer. However, the mechanisms by which this SNP mediates increased risk to cancer are still unknown. In this study, we show that this variant is located in an enhancer active in prostate cancer cells. Deletion of this enhancer from prostate tumor cells resulted in decreased tumor initiation, tumor growth, and invasive migration, as well as a loss of stem-like cells. Using a combination of capture chromosome conformation capture (Capture-C) and RNA sequencing, we identified genes on the same and different chromosomes as targets regulated by the enhancer. Furthermore, we show that expression of individual candidate target genes in an enhancer-deleted cell line rescued different aspects of tumorigenesis. Our data suggest that the rs55958994-associated enhancer affects prostate cancer progression by influencing expression of multiple genes via long-range chromatin interactions.