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The aberrant changes of fussion/fission-related proteins can trigger mitochondrial dynamics imbalance, which cause mitochondrial dysfunctions and result insulin resistance (IR). However, the relationship between the inner mitochondrial membrane fusion protein optic atrophy 1 (Opa1) and hepatic IR as well as the specific molecular mechanisms of signal transduction has not been fully elucidated. In this study, we explore whether abnormalities in the Opa1 cause hepatic IR and whether berberine (BBR) can prevent hepatic IR through the SIRT1/Opa1 signalling pathway. High-fat diet (HFD)-fed mice and db/db mice are used as animal models to study hepatic IR in vivo. IR, morphological changes, and mitochondrial injury of the liver are examined to explore the effects of BBR. SIRT1/Opa1 protein expression is determined to confirm whether the signalling pathway is damaged in the model animals and is involved in BBR treatment-mediated mitigation of hepatic IR. A palmitate (PA)-induced hepatocyte IR model is established in HepG2 cells in vitro. Opa1 silencing and SIRT1 overexpression are induced to verify whether Opa1 deficiency causes hepatocyte IR and whether SIRT1 improves this dysfunction. BBR treatment and SIRT1 silencing are employed to confirm that BBR can prevent hepatic IR by activating the SIRT1/Opa1 signalling pathway. Western blot analysis and JC-1 fluorescent staining results show that Opa1 deficiency causes an imbalance in mitochondrial fusion/fission and impairs insulin signalling in HepG2 cells. SIRT1 and BBR overexpression ameliorates PA-induced IR, increases Opa1, and improves mitochondrial function. SIRT1 silencing partly reverses the effects of BBR on HepG2 cells. SIRT1 and Opa1 expressions are downregulated in the animal models. BBR attenuates hepatic IR and enhances SIRT1/Opa1 signalling in db/db mice. In summary, Opa1 silencing-mediated mitochondrial fusion/fission imbalance could lead to hepatocyte IR. BBR may improve hepatic IR by regulating the SIRT1/Opa1 signalling pathway, and thus, it may be used to treat type-2 diabetes.

Natural gas hydrates (NGH) are widely found in seafloor sediments. In engineering, it is usually necessary to inject 60% of thermodynamic inhibitors, which makes hydrate extraction costly and polluting. Currently, kinetic inhibitors have attracted much attention due to their low injection dose and environmental friendliness, but the research is costly and time-consuming. In this study, we investigated the interaction between winter flounder antifreeze proteins (AFPs) and methane hydrate growth using molecular dynamics simulations. AFPs adsorbed on the hydrate surface and hindered the mass transfer of methane molecules. At the same time, the water molecules around the AFP adsorption surface are in a quasi-liquid state, a structure that facilitates the binding of AFPs to the hydrate surface. Analysis of the probability of amino acid adsorption showed that AFP was adsorbed to the hydrate surface through a combination of hydrophobic and hydrogen bonding interactions. Subsequent directional mutagenesis experiments showed that increasing the hydrophobicity of AFP rather weakens its adsorption capacity. This suggests that excessive hydrophobicity of AFP may be counterproductive to its adsorption on the hydrate surface. These findings deepen the understanding of the AFP mechanism and its potential for the development of novel hydrate inhalants.

The problem of project portfolio selection considering risk propagation is a new research topic, but it overlooks the fact that the risk propagation process can be hindered by resource mobilization within candidate projects, which is defined as "risk absorption" in this paper. Neglecting this process may lead to the risk propagation process being overestimated, thereby resulting in the selection of suboptimal projects. Based on this, this article examines the risk absorption process in project portfolio selection problem, aiming to investigate its impact on project portfolio decision, ultimately resulting in the selection of more stable project portfolio. To address this issue, the article first examines the process of risk absorption among projects and calculates the amount of risk absorbed based on the strength of the interactions between the projects selected. Secondly, the total risk intensity of the project is given by calculating the risk propagation intensity and self-incurred risk intensity. Finally, a dual-objective project portfolio selection model considering risk absorption is developed by combining the risk intensity and net present value of the project. The analysis of a case study demonstrates that (1) considering risk absorption can reduce the probability of project risks occurring due to being propagated, (2) considering risk absorption will prioritize projects with higher returns, albeit accompanied by relatively higher risks. [ABSTRACT FROM AUTHOR]

B‐cell acute lymphoblastic leukaemia (B‐ALL) is the most prevalent hematologic malignancy in children and a leading cause of mortality. Managing B‐ALL remains challenging due to its heterogeneity and relapse risk. This study aimed to delineate the molecular features of paediatric B‐ALL and explore the clinical utility of circulating tumour DNA (ctDNA). We analysed 146 patients with paediatric B‐ALL who received systemic chemotherapy. The mutational landscape was profiled in bone marrow (BM) and plasma samples using next‐generation sequencing. Minimal residual disease (MRD) testing on day 19 of induction therapy evaluated treatment efficacy. RNA sequencing identified gene fusions in 61% of patients, including 37 novel fusions. Specifically, the KMT2A‐TRIM29 novel fusion was validated in a boy who responded well to initial therapy but relapsed after 1 year. Elevated mutation counts and maximum variant allele frequency in baseline BM were associated with significantly poorer chemotherapy response (p = 0.0012 and 0.028, respectively). MRD‐negative patients exhibited upregulation of immune‐related pathways (p < 0.01) and increased CD8+ T cell infiltration (p = 0.047). Baseline plasma ctDNA exhibited high mutational concordance with the paired BM samples and was significantly associated with chemotherapy efficacy. These findings suggest that ctDNA and BM profiling offer promising prognostic insights for paediatric B‐ALL management. [ABSTRACT FROM AUTHOR]

Background Hypertrophic scarring is a disease of abnormal skin fibrosis caused by excessive fibroblast proliferation. Existing drugs have not achieved satisfactory therapeutic effects. Objectives To explore the molecular pathogenesis of hypertrophic scars and screen effective drugs for their treatment. Methods Existing human hypertrophic scar RNA sequencing data were utilized to search for hypertrophic scar-related gene modules and key genes through weighted gene co-expression network analysis (WGCNA). Candidate compounds were screened in a compound library. Potential drugs were screened by molecular docking and verified in human hypertrophic scar fibroblasts and a mouse mechanical force hypertrophic scar model. Results WGCNA showed that hypertrophic scar-associated gene modules influence focal adhesion, the transforming growth factor (TGF)-β signalling pathway and other biologic pathways. Integrin β1 (ITGB1) is the hub protein. Among the candidate compounds obtained by computer virtual screening and molecular docking, crizotinib, sorafenib and SU11274 can inhibit the proliferation and migration of human hypertrophic scar fibroblasts and profibrotic gene expression. Crizotinib had the best effect on hypertrophic scar attenuation in mouse models. At the same time, mouse ITGB1 small interfering RNA can also inhibit mouse scar hyperplasia. Conclusions ITGB1 and TGF-β signalling pathways are important for hypertrophic scar formation. Crizotinib could be a potential treatment drug for hypertrophic scars. [ABSTRACT FROM AUTHOR]

Background and Objective: We explore molecular and metabolic pathways involved in interstitial cystitis (IC) with integrating multi‐omics analysis for identifying potential diagnostic and therapeutic targets. Methods: Mouse models of IC/bladder pain syndrome (BPS) were established by intraperitoneal injection of cyclophosphamide and bladder tissue samples were collected for metabolomics and transcriptome analysis. Results: We found a total of 82 and 145 differential metabolites in positive ion modes and negative ion modes, respectively. Glycerophospholipid metabolism, choline metabolism in cancer, and nucleotide metabolism pathways were significantly enriched in the IC/BPS group. Transcriptome analysis demonstrated that 1069 upregulated genes and 1087 downregulated genes were detected. Importantly, the stronger enrichment for cell cycle pathway was observed in IC/BPS than that in normal bladder tissue, which may be involved in the process of bladder remodeling. Moreover, the inflammatory response and inflammatory factors related pathways were enriched in the IC/BPS group. Conclusions: Our findings provide critical directions for further exploration of the molecular pathology underlying IC/BPS. [ABSTRACT FROM AUTHOR]