Genomics, Proteomics & Bioinformatics•2024•DOI: 10.1093/gpbjnl/qzad009
The high-fidelity (HiFi) long-read sequencing technology developed by PacBio has greatly improved the base-level accuracy of genome assemblies. However, these assemblies still contain base-level errors, particularly within the error-prone regions of HiFi long reads. Existing genome polishing tools usually introduce overcorrections and haplotype switch errors when correcting errors in genomes assembled from HiFi long reads. Here, we describe an upgraded genome polishing tool — NextPolish2, which can fix base errors remaining in those “highly accurate” genomes assembled from HiFi long reads without introducing excessive overcorrections and haplotype switch errors. We believe that NextPolish2 has a great significance to further improve the accuracy of telomere-to-telomere (T2T) genomes. NextPolish2 is freely available at https://github.com/Nextomics/NextPolish2.
Stem Cell Research & Therapy•2026•DOI: 10.1186/s13287-026-04903-y
Background Acute lung injury/Acute respiratory distress syndrome (ALI/ARDS) is a life-threatening inflammatory lung disorder characterized by high mortality rates and a lack of effective treatment options. Although mesenchymal stem cell (MSC)-based therapies have emerged as a promising approach for ARDS management, optimizing their therapeutic efficacy remains a significant challenge. Recent advances in gene modification techniques have opened new avenues for enhancing MSC functionality. Among these, Fibronectin type III domain-containing protein 5 (Fndc5)/irisin has attracted considerable attention due to its ability to improve endothelial function. This study aims to evaluate the therapeutic potential of Fndc5-modified MSCs in sepsis-induced ALI/ARDS and to elucidate the underlying molecular mechanisms driving their protective effects. Methods To comprehensively evaluate the therapeutic potential of Fndc5-modified MSCs (MSCs-Fndc5) in ARDS, we employed both in vivo and in vitro experimental models. In vivo, a mouse model of sepsis-induced ALI was established through intraperitoneal injection of lipopolysaccharide (LPS), and the protective effects of MSCs-Fndc5 were systematically assessed by analyzing lung histopathology, inflammatory cytokine levels, vascular endothelial integrity, lung wet-to-dry weight ratio, and MSC retention in lung tissue. In parallel, in vitro studies were conducted to investigate the role of MSCs-Fndc5 in mitigating LPS-induced endothelial cell (EC) injury, with a focus on EC proliferation, angiogenesis, barrier permeability, apoptosis, and the regulation of key signaling pathways. Results Fndc5 modification significantly increased the retention rate of MSCs in sepsis-induced ALI murine model while augmenting their in vitro proliferation and migration potential. In vivo, treatment with Fndc5-modified MSCs markedly attenuated lung inflammation, as evidenced by reduced levels of pro-inflammatory cytokines, decreased neutrophil infiltration, and improved lung histopathology. Additionally, MSCs-Fndc5 alleviated pulmonary edema, reduced fibrosis, lowered the lung wet-to-dry weight ratio, and preserved vascular endothelial integrity. In vitro, Fndc5 modification optimizes the therapeutic effect of rat MSCs on sepsis-induced ALI/ARDS via activating the PI3K/AKT signaling pathway.
Stem Cell Research & Therapy•2025•DOI: 10.1186/s13287-025-04229-1
Background Despite numerous studies addressing the molecular mechanisms by which pluripotent stem cells (PSCs) maintain self-renewal and pluripotency under normal culture conditions, the fundamental question of how PSCs manage to survive stressful conditions remains largely unresolved. Post-transcriptional/translational regulation emerges to be vital for PSCs, but how PSCs coordinate and balance their survival and differentiation at translational level under extrinsic and intrinsic stress conditions is unclear. Methods The high-throughput sequencing of cross-linking immunoprecipitation cDNA library (HITS-CLIP) was employed to decipher the genome-wide OCT4-RNA interactome in human PSCs, a combined RNC-seq/RNA-seq analysis to assess the role of OCT4 in translational regulation of hypoxic PSCs, and an OCT4-protein interactome to search for OCT4 binding partners that regulate cap-independent translation initiation. By taking the Heterozygous Knocking In N-terminal Tags (HKINT) approach that specifically disrupts the 5'-UTR secondary structure and tagging its protein product of the mRNA from one allele while leaving that from the other allele intact, we examined the effect of disrupting the OCT4/5'-UTR interaction on translation of AKT1 mRNA. Results We revealed OCT4 as a bona fide RNA-binding protein (RBP) in human PSCs that bound to the 5'-UTR, 3'-UTR and CDS regions of mRNAs. Multiple known proteins participating in IRES-mediated translation initiation were detected in the OCT4-protein interactome, and a combined RNC-seq/RNA-seq analysis further confirmed a crucial role of OCT4 in translational regulation of PSCs in response to hypoxic stress. Remarkably, OCT4 bound to the GC-rich elements in the 5'-UTR of AKT1 and multiple PI3K/AKT-pathway-gene mRNAs, and promoted their translation initiation via IRES-mediated pathways under stress conditions. Specifically disrupting the AKT1 mRNA 5'-UTR structure and the OCT4/5'-UTR interaction by the HKINT approach significantly reduced the translation level of AKT1 that led to a higher susceptibility of PSCs to oxidative stress-induced apoptotic death and prioritized differentiation toward ectoderm and endoderm. Conclusions Our results reveal OCT4 as an anti-stress RBP for translational regulation that critically coordinates the survival and differentiation of PSCs in response to various stressors.
Stem Cell Research & Therapy•2026•DOI: 10.1186/s13287-026-04903-y
Sepsis-induced acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) remain clinical syndromes with mortality exceeding 40% and no targeted pharmacotherapy. Mesenchymal stem cell (MSC) transplantation has shown promise, but poor pulmonary retention and limited endothelial repair capacity constrain therapeutic efficacy. This study evaluates fibronectin type III domain-containing protein 5 (Fndc5)/irisin-modified rat MSCs (MSCs-Fndc5) in lipopolysaccharide (LPS)-induced ALI. In vivo, MSCs-Fndc5 exhibited significantly elevated lung retention, reduced pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), diminished neutrophil infiltration, attenuated pulmonary edema (lower wet-to-dry weight ratio), and preserved vascular endothelial integrity. In vitro, Fndc5 modification enhanced MSC proliferation and migration, and co-culture with LPS-injured endothelial cells restored β-catenin and VE-cadherin expression, improved barrier function, and promoted angiogenesis. Mechanistically, MSCs-Fndc5 activated the PI3K/AKT pathway in endothelial cells, as evidenced by increased p-PI3K and p-AKT; the PI3K inhibitor LY294002 abolished these protective effects. These findings demonstrate that Fndc5 modification augments MSC retention and endothelial repair via partial PI3K/AKT activation, providing a rational strategy to enhance MSC-based therapy for ALI/ARDS.
Stem Cell Research & Therapy•2026•DOI: 10.1186/s13287-026-04903-y
Background: Acute lung injury/Acute respiratory distress syndrome (ALI/ARDS) is a life-threatening inflammatory lung disorder characterized by high mortality rates and a lack of effective treatment options. Although mesenchymal stem cell (MSC)-based therapies have emerged as a promising approach for ARDS management, optimizing their therapeutic efficacy remains a significant challenge. Recent advances in gene modification techniques have opened new avenues for enhancing MSC functionality. Among these, Fibronectin type III domain-containing protein 5 (Fndc5)/irisin has attracted considerable attention due to its ability to improve endothelial function. This study aims to evaluate the therapeutic potential of Fndc5-modified MSCs in sepsis-induced ALI/ARDS and to elucidate the underlying molecular mechanisms driving their protective effects. Methods: To comprehensively evaluate the therapeutic potential of Fndc5-modified MSCs (MSCs-Fndc5) in ARDS, we employed both in vivo and in vitro experimental models. In vivo, a mouse model of sepsis-induced ALI was established through intraperitoneal injection of lipopolysaccharide (LPS), and the protective effects of MSCs-Fndc5 were systematically assessed by analyzing lung histopathology, inflammatory cytokine levels, vascular endothelial integrity, lung wet-to-dry weight ratio, and MSC retention in lung tissue. In parallel, in vitro studies were conducted to investigate the role of MSCs-Fndc5 in mitigating LPS-induced endothelial cell (EC) injury, with a focus on EC proliferation, angiogenesis, barrier permeability, apoptosis, and the regulation of key signaling pathways. Results: Fndc5 modification significantly increased the retention rate of MSCs in sepsis-induced ALI murine model while augmenting their in vitro proliferation and migration potential. In vivo, treatment with Fndc5-modified MSCs markedly attenuated lung inflammation, as evidenced by reduced levels of pro-inflammatory cytokines, decreased neutrophil infiltration, and improved lung histopathology. Additionally, MSCs-Fndc5 alleviated pulmonary edema, reduced fibrosis, lowered the lung wet-to-dry weight ratio, and preserved vascular endothelial integrity. In vitro, MSCs-Fndc5 significantly enhanced cell proliferation, migration, angiogenesis, endothelial barrier function, apoptosis inhibition, likely via PI3K/AKT pathway activation. Conclusions: Fndc5 overexpression in MSCs augments their therapeutic efficacy in sepsis-induced ALI/ARDS, which may be achieved by activating the endothelial PI3K/AKT pathway and improving MSCs retention in vivo. These findings propose MSCs-Fndc5 as a promising therapeutic strategy for sepsis-induced ALI/ARDS by enhancing endothelial repair, curbing inflammation, and modulating pivotal signaling pathways.
Chinese Journal of Tissue Engineering Research•2026•DOI: 10.12307/2026.21263
BACKGROUND: Previous studies have linked immune cells to cardiovascular disease risk. As confounding factors are incompletely addressed, the causal relationship between them remains unclear. OBJECTIVE: To evaluate the potential causal relationship between immune cells and cardiovascular disease. METHODS: The source of research data mainly involves three databases: Genome-Wide Association Study (GWAS) database (GWAS Catalog, jointly maintained by the National Institute of Human Genomics and the European Institute of Bioinformatics), UK biobank (a database of British population genomics, health, and disease phenotypes supported by the UK government and the Wellcome Trust), and IEU OpenGWAS (a GWAS database developed by the MRC Epidemiology Unit at the University of Bristol, UK, primarily for European populations). All are open databases, and the study has been approved by the relevant institutional review boards. Using 731 immune cell phenotypes as exposures and 7 cardiovascular diseases (atrial fibrillation, dilated cardiomyopathy, coronary atherosclerotic heart disease, heart failure, hypertrophic cardiomyopathy, hypertension, and valvular heart disease) as outcomes, a two-sample Mendelian randomization analysis was performed. Inverse variance weighting and weighted median methods were mainly used for Mendelian randomization analysis and sensitivity analysis to assess heterogeneity and pleiotropy. RESULTS AND CONCLUSION: (1) After false discovery rate correction, immune phenotypes had statistically significant effects on atrial fibrillation and hypertension. Five cell types were associated with atrial fibrillation risk, including CD11c on monocytes (OR=0.917, 95%CI: 0.876-0.960), FSC-A on myeloid dendritic cells (OR=0.942, 95%CI: 0.910-0.974), CX3CR1 on CD14+ CD16- monocytes (OR=1.045, 95%CI: 1.022-1.070), CX3CR1 on monocytes (OR=1.050, 95%CI: 1.024-1.076), and CX3CR1 on CD14+ CD16+ monocytes (OR=1.050, 95%CI: 1.024-1.077). Three immune phenotypes with protective effects on hypertension were identified: CD19 on switched memory B cells (OR=0.986, 95%CI: 0.980-0.993), CD25++CD8+ T cells (OR=0.993, 95%CI: 0.990-0.997), and CD25++CD8+ T cells absolute count (OR=0.993, 95%CI: 0.989-0.996). No potential heterogeneity or horizontal pleiotropy was observed in sensitivity analyses. (2) The study found causal relationships between 4 monocyte types and 1 myeloid dendritic cell type and atrial fibrillation, and potential causal relationships between 1 memory B cell type and 2 T cell types and hypertension, suggesting the necessity of considering immune cell phenotypes when monitoring and treating atrial fibrillation and hypertension. This study used public databases for analysis, providing a reference for research on immune cell subsets and cardiovascular disease in the Chinese population, and offering insights for further prevention and treatment of atrial fibrillation and hypertension in Chinese people.
Chinese Journal of Tissue Engineering Research•2026•DOI: 10.12307/2026.21700
BACKGROUND: Some patients report dissatisfaction after total knee arthroplasty due to persistent issues like limited mobility, joint instability, and residual pain. To address these challenges, various osteotomy methods and alignment strategies have been proposed and clinically implemented. However, the optimal approach remains debated, with no clear consensus. OBJECTIVE: To comprehensively analyze global trends in alignment techniques for total knee arthroplasty and identify research hotspots through bibliometric and visual analysis, offering evidence-based insights to guide clinical decision-making. METHODS: We retrieved publications (articles and reviews) on total knee arthroplasty alignment techniques published between January 1, 2015 and December 31, 2024, from the Web of Science database (https://www.webofscience.com, developed by the Institute for Scientific Information, USA). Data on countries, institutions, publication years, authors, journals, mean citation rates, H-index, titles, keywords, and the top 25 most-cited articles were extracted and analyzed. VOSviewer and Citespace software were used to analyze keyword co-occurrence and predict research hotspots. RESULTS AND CONCLUSION: A total of 866 publications were identified, including 792 articles and 74 reviews. The United States had the highest number of publications, with the University of California being the most prolific institution and Howell, Stephen M being the most prolific author. The journal 'Knee Surgery Sports Traumatology Arthroscopy' had the highest publication and citation counts. Common keywords included total knee arthroplasty, alignment technique, arthroplasty, clinical outcomes, and survival rate. Keyword and reference burst detection indicated that kinematic alignment and robotic navigation are future research hotspots. The number of publications on total knee arthroplasty alignment techniques is increasing annually. The United States is currently the leading contributor, followed by the United Kingdom. Increasingly precise tools, such as computer-assisted navigation and patient-specific instrumentation, are being developed and applied to achieve alignment goals, but no optimal solution has yet been established. Future research frontiers may include 'robot-assisted navigation', 'patient satisfaction', 'long-term survival', 'indication range', and 'patient-specific alignment'.
Acta Biochimica et Biophysica Sinica•2026•DOI: 10.3724/abbs.2026020
The insulin receptor (IR) is central to the regulation of glucose and lipid metabolism. Although insulin is its primary ligand, insulin-like growth factors I and II (IGF-I and IGF-II) also engage IR, albeit with reduced affinity. The structural basis of cooperative ligand binding, however, has remained poorly understood. Here, we report cryo-Electron Microscopy (cryo-EM) structures of IR in complex with insulin, IGF-I, and IGF-II, revealing that all three ligands engage the receptor at overlapping binding sites and can induce a conserved T-shaped quaternary assembly involving four ligand molecules at site 1/1′ and site 2/2′. Despite this shared overall architecture, distinct ligand-specific conformational changes are observed. Notably, IGF-I and IGF-II adopt different binding sequence at site 1 and site 2 compared to insulin, suggesting unique interaction dynamics. These structural insights highlight divergent mechanisms of ligand recognition and cooperative binding, providing a deeper understanding of hormone-induced conformational modulation of the IR.