Genes&Diseases

语种：英文出版周期：双月刊

E-ISSN：2352-3042P-ISSN：2352-4820

主管单位：重庆市教育委员会主办单位：重庆医科大学

Genes and Diseases是本由重庆医科大学于2014年创办的双月刊，也是国内第一本分子医学与转化医学相结合的全英文综合期刊，并入选“中国科技期刊卓越行动计划”高起点新刊项目。

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VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is an adult-onset and treatment-refractory inflammatory disease, caused by acquired mutations in UBA1 (ubiquitin-like modifier activating enzyme 1), an X-linked gene encoding an E1 enzyme of the ubiquitin-proteasome system.1 The disease occurs predominantly in elderly male patients and has heterogeneous but expanding clinical features that include fever, characteristic vacuoles in hematopoietic precursors, cytopenias, and chondritis. As such, VEXAS patients may be initially diagnosed with relapsing polychondritis, myelodysplastic syndrome, and other syndromes.

Chlorpyrifos (CPF), a widely used organophosphate pesticide, accumulates in the environment and affects human health. Its neurotoxicity has been extensively studied, and recent research has revealed that it can also lead to abnormal spermatogenesis. However, the factors and molecular mechanisms involved remain unclear. In this study, male Sprague–Dawley rats were gavaged with different concentrations of CPF for 30 days, resulting in a disrupted blood-testis barrier (BTB) and abnormal spermatogenesis. RNA sequencing analysis of Sertoli cells, the primary components of the BTB and key targets of environmental toxins, revealed that ferroptosis-related genes were predominantly among the differentially expressed genes. The expression of ferroptosis-related markers was up-regulated, malondialdehyde and Fe2+ levels were elevated, and glutathione levels were reduced in CPF-exposed testicular tissue and its metabolite TCP-exposed Sertoli cells, confirming that CPF exposure triggered ferroptosis in testes and Sertoli cells. Moreover, treatment with ferrostatin-1, a ferroptosis inhibitor, restored Sertoli cell junctional function. Given the important roles of clockophagy and the HIF-1α pathway in ferroptosis, we investigated the activity of clockophagy in testes and Sertoli cells. Unexpectedly, clockophagy activity was found to be enhanced by the significantly reduced expression levels of ARNTL and HIF-1α following CPF and TCP exposure. Notably, Arntl knockdown impaired Sertoli cell junctional function. Collectively, these findings strongly indicate that CPF induces ferroptosis in Sertoli cells through activating clockophagy, resulting in the decreased expression of HIF-1α and BTB-associated proteins; this ultimately leads to the disruption of BTB integrity and spermatogenesis dysfunction.

Dysfunctional inhibitor of nuclear factor-κB (NF-κB) kinase regulatory subunit gamma (IKBKG) is known to trigger incontinentia pigmenti (IP), anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID), immunodeficiency (ID), and IKBKG deleted exon 5 autoinflammatory syndrome (NDAS). The correlation between genotype and phenotype remains elusive because of the considerable variability in IKBKG genes. This study aimed to systematically describe IKBKG gene mutations and clinical characteristics. Cases with IKBKG mutations and thorough clinical features were gathered using PubMed, Web of Science, EMBASE, Scopus, and Cochrane databases, with a publication deadline of February 12, 2023. The Newcastle-Ottawa scale and its modified version were used to assess the quality of each study. Gene mutations and clinical manifestation data were analyzed and reviewed. 144 publications with 564 patients were included in the analysis. IP, EDA-ID, ID, and NDAS accounted for 78.0%, 15.8%, 5.0%, and 1.2% of IKBKG mutations, respectively. Skin abnormalities (89.5%), dental abnormalities (68.5%), infection (100%), and non-infectious inflammation (100%) were the most common manifestations of IP, EDA-ID, ID, and NDAS, respectively. Mutations related to EDA-ID and ID are concentrated in the zinc finger region and characterized by the most severe clinical symptoms. E390RfsX5 can cause IP, EDA-ID, and ID. c.1182_1183delTT and H413R caused the most clinical manifestations. Mycobacterium (22.7%) and Streptococcus (17.5%) were the most common pathogens. Almost all cases of hyper-IgM occurred in patients with EDA-ID. Different structural domains correspond to symptoms with varying degrees of severity. Certain mutations may correspond to unique manifestations, providing insight into disease progression.

Left ventricular non-compaction (LVNC), is a hereditary cardiomyopathy with limited treatments. Our previous study linked phosphodiesterase 4D interacting protein (PDE4DIP) to LVNC development. To explore the functional role of PDE4DIP activation in regulating cell polarity, skeleton, and energy metabolism, and to elucidate its mechanisms driving LVNC development, bioinformatics analysis was performed to compare its expression in LVNC patients and normal subjects. Overexpression and knockdown of PDE4DIP were constructed in H9C2 cells and neonatal Sprague–Dawley rat primary cardiomyocytes, respectively. Electron microscopy, MitoTracker-Green staining, and an ATP kit were employed to assess mitochondria's morphology and functional status. Real-time quantitative PCR, western blotting, and immunofluorescence assays were employed to detect the expression of cell polarity-, skeleton-, and Rho-ROCK signaling-related genes and proteins. Cell scratching and CCK-8 assays were employed to detect cell migration and proliferation abilities of H9C2, respectively. We found that PDE4DIP expression was increased in the LVNC-derived human-induced pluripotent stem cell-derived cardiomyocytes compared with normal subjects. Furthermore, overexpression of PDE4DIP induced cytoskeletal disorganization, decreased ATP content and cell migration, and increased cell proliferation and mitochondrial vacuolation. Moreover, the knockdown of PDE4DIP promoted cytoskeleton formation and contributed to increased ATP content and elevated cell migration. Mechanically, overexpression of PDE4DIP inhibited cell polarity-, skeleton-, and Rho-ROCK signaling-related genes and proteins, which could be increased by knockdown of PDE4DIP, suggesting that a critical regulation of PDE4DIP to Rho-ROCK pathway. This discovery suggests that PDE4DIP contributes to the development of LVNC by regulating cell polarity, skeleton, and energy metabolism through the Rho-ROCK pathway.

Neuropathic pain (NP) is a chronic debilitating disease caused by nerve damage or various diseases, significantly impairs patients’ quality of life. Super-enhancers (SEs) are important cis-regulatory elements, but how they affect NP remains elusive. Therefore, we aim to explore the molecular mechanism by which SEs are involved in NP progression and identify potential drug candidate targets. We first established a NP model in rats, and subsequently performed H3K27ac ChIP-Seq and RNA-Seq on their spinal cord tissues to analyze the active enhancers. By integrated analysis of ChIP-seq data and RNA-seq data, we clarified a series of SE-associated genes involved in NP progression. qPCR and double immunofluorescence staining results suggested that Jmjd1c mRNA and protein levels were significantly down-regulated in the NP model. In addition, a dual-luciferase reporter assay showed that KLF15 could activate Jmjd1c transcription by binding to the SE of Jmjd1c. Functionally, enhanced Jmjd1c can inhibit the levels of inflammatory cytokines such as IL-6, TNF-α, IL-1β, and inhibited the progression of NP, whereas silencing Jmjd1c had the opposite effect. Mechanistic exploration identified Jmjd1c exerted its anti-NP effect via positively regulating Socs3 expression by increasing the activity of H3K9 demethylation, and the Jmjd1c/Socs3/JAK/STAT3 regulatory pathway was finally validated as downstream effectors. In conclusion, our study suggests that SE-associated Jmjd1c was suppressed during NP progression due to the decreased recruitment of KLF15. The reduction of Jmjd1c downregulated Socs3 through the demethylation of H3K9 at Socs3 promoter region, leading to NP progression.

Ulcerative colitis is an idiopathic, chronic inflammatory bowel disease. Its pathogenesis is multifactorial involving inflammation and immune dysregulation. Proinflammatory TNFα/NFκB signaling is believed to play a cardinal role in ulcerative colitis. Growing evidence indicates the molecular interactions between the cellular metabolites and different phases of inflammation. This study aims to identify the metabolites that can inhibit TNFα/NFκB signaling and are potentially therapeutic against various TNFα-associated inflammatory diseases, particularly inflammatory bowel diseases. We performed in vitro and in vivo screening of cellular metabolites to inhibit TNFα/NFκB signaling. Multiple confirmation assays, including NFκB translocation, quantitative real-time PCR, ELISA, immunofluorescence staining, and RNA sequencing analysis were executed. Drug affinity-responsive target stability assay with proteomics was utilized for target identification. cPLA2 ablated mice with dextran sodium sulfate-induced colitis were employed to assess pyruvate's dependence on its molecular target in attenuating ulcerative colitis pathogenesis. Metabolite screening and subsequent validation with multiple approaches led to the isolation of pyruvate, a glycolytic metabolite, and a critical node in several metabolic pathways, as a novel inhibitor of TNFα/NFκB signaling. Importantly, pyruvate suppressed inflammation, preserved colonic histology, maintained tight junction proteins, and regulated permeability in the ulcerative colitis model. Additionally, cPLA2 was identified as a previously unknown target of pyruvate and pyruvate largely lost its therapeutic effects against ulcerative colitis in cPLA2-deficient mice. Conclusively, this study not only unveils pyruvate as an antagonist of TNFα/NFκB signaling and therapeutic intervention against colitis but also provides mechanistic insight into the mode of action of pyruvate.

Galectin-3 (Gal-3) plays a multifaceted role in the development and progression of pancreatic adenocarcinoma (PAAD), which is associated with a poor prognosis. Its interaction with tumor microenvironment cells has been reported. However, the Gal-3-mediated tumor–stromal interaction and induced energy metabolism associated with drug resistance remain unknown. Our previous study has reported that Gal-3 secretion from tumor cells and inflammatory cytokine dependency are therapeutic targets. In this study, we revealed that the expression of Gal-3 was not only remarkably up-regulated in tumors but also significantly associated with the tumor-associated fibroblasts of PAAD patients. A coculture model of PAAD cells and pancreatic stellate cells revealed that Gal-3 mediated the Ca2+/−calcineurin–NFAT pathway to increase the transcription of CCL2 and BSG in tumor-associated fibroblasts. These findings ultimately lead to the observation of low energy metabolism in tumor cells. Particularly, mitochondrial oxidative phosphorylation was functionally arrested in Gal-3-high tumor cells, as demonstrated by a lower oxygen consumption rate and mitochondrial ATP production through abnormal mitochondrial morphology. The inhibition of the CCL2-CCR2 and PPIA-BSG pathways indicated the restoration of gemcitabine sensitivity when drug resistance was elicited by Gal-3. Oral administration of the natural Gal-3 inhibitor modified citrus pectin extract (MCP) showed therapeutic effect for Gal-3-activated tumors and stromal cells in orthotopic pancreatic xenograft models. Hence, our findings offer insights into the fact that low mitochondrial metabolism is dependent on Gal-3 activation-mediated gemcitabine resistance through tumor–stromal interactions.

Urolithiasis, a disease characterized by the formation of urinary stones, is influenced by immune system dysregulation and metabolic factors. This study investigated the interplay between specific immune cell characteristics and blood metabolites in urolithiasis based on Mendelian randomization. We further explored the potential mediating effects of genetically predicted blood metabolites based on mediation analysis. We employed a two-sample Mendelian randomization analysis to examine the association between immune cell properties, blood metabolites, and urolithiasis risk. Genetic instruments for immune cell characteristics and blood metabolites were used to assess causal relationships and mediating pathways. Our results indicate that 10 immune cell characteristics had a unidirectional causal association with urolithiasis risk. We also detected 13 blood metabolites associated with urolithiasis. We identified 4 pathways through which genetically predicted blood metabolites partly mediated the association between specific immune cell characteristics and urolithiasis risk. This suggests potential mechanistic links where altered blood metabolites may play a role in developing urolithiasis through immune system modulation. This Mendelian randomization study highlights the complex relationship between immune responses, blood metabolites, and urolithiasis. The findings underscore the importance of considering both immune cell features and metabolic factors in understanding the pathogenesis of urolithiasis, offering insights into novel therapeutic targets and diagnostic strategies for this disorder.

The major histocompatibility complex (MHC) region plays a crucial role in immune function and is implicated in various diseases and cancer immunoediting. However, its high polymorphism poses challenges for accurate genetic profiling using conventional reference genomes. Here, we present high-quality, haplotype-resolved assemblies of the MHC region in five widely used tumor cell lines: A549, HeLa, HepG2, K562, and U2OS. Numerous oncological studies extensively employ these cell lines, ranging from basic molecular research to drug discovery and personalized medicine approaches. By integrating CRISPR-based targeted enrichment with 10 × Genomics linked-read and PacBio HiFi long-read sequencing, we constructed MHC haplotypes for each cell line, providing a valuable resource for the research community. Using these assembled haplotypes as references, we characterize the aneuploidy of the MHC region in these cell lines, offering insights into the genetic landscape of this critical immunological locus. Our work addresses the urgent need for accurate MHC profiling in these widely used cell line models, enabling more precise interpretation of existing and future genomic and epigenomic data. This resource is expected to significantly enhance our understanding of tumor biology, immune responses, and the development of targeted therapies.

We evaluated the potential mechanisms responsible for inducing beta-cell decline during the progression of obesity to type 2 diabetes mellitus (T2DM). Between February 2021 and February 2022, 25 subjects with non-diabetic obesity, 20 subjects with obesity and new-onset T2DM, and 25 healthy volunteers were recruited. Circulating exosome-contained miRNA expression profiling was performed by miRNA sequencing. The role of specific miRNA was analyzed by a gain-of-function approach in Min6 beta-cells, mouse islets, and human islets. Expression of 83 exosomal miRNAs was differently regulated in the circulation of subjects with non-diabetic obesity. We focused on miR-146b, which was mildly up-regulated in non-diabetic obesity and dramatically up-regulated in obese new-onset T2DM. Using an obese diabetic db/db mouse model, we found the expression of miR-146b to be mainly increased in islets. Overexpression of miR-146b in mouse beta-cells, mouse islets, and human islets in vitro facilitated beta-cell apoptosis yet inhibited its proliferation and insulin synthesis, leading to impaired insulin secretion. Eventually, miR-146b directly targeted the B cell translocation gene 2 (Btg2), an antiapoptotic transcriptional factor. Overexpression of Btg2 reversed miR-146b-induced apoptosis and -suppressed proliferation in beta-cells. miR-146b that targets Btg2 might be a predictive biomarker and an inducer of beta-cell decline.

Non-small cell lung cancer (NSCLC) remains a leading cause of mortality in the clinic. Previous studies have demonstrated that the NF-kappa-B activating protein like (NKAPL) is positively correlated with prognosis in several types of cancers. However, the role of NKAPL in the progression of NSCLC remains unclear. The expression and promoter methylation of NKAPL were examined by real-time PCR, quantitative PCR, and methylation-specific PCR. The functional impacts of NKAPL on NSCLC proliferation were explored by CCK8 assay and colony formation assay. Transwell assay was conducted to investigate the role of NKAPL in NSCLC cell migration and invasion, and the influence on metastasis was verified in vivo. Flow cytometry was exploited to analyze the influence on the cell cycle and apoptosis. The regulatory mechanism of NKAPL was investigated by immunoprecipitation-mass spectrometry, western blotting, immunofluorescence, and immunohistochemistry. NKAPL was down-regulated due to promoter methylation, which was associated with poor prognosis in NSCLC patients, while the up-regulation of NKAPL suppressed NSCLC cell proliferation and metastasis both in vitro and in vivo. Mechanistically, the NF-κB signaling pathway was inhibited because the up-regulation of NKAPL increased the stability and expression of TRIM21. NKAPL suppressed NSCLC cell proliferation and metastasis both in vitro and in vivo by increasing the stability and expression of TRIM21 and subsequently inhibiting the NF-κB signaling pathway.

Ovarian cancer (OC) peritoneal metastasis (OCPM) is a major cause of high mortality of OC, in which cancer cells incubated in ascites evolve various mechanisms to survive. Hippo/YAP singling plays multiple roles in carcinogenesis, however, its roles in OCPM have remained elusive. Here, we report that restriction of YWHAB-mediated YAP cytoplasmic retention is a critical mechanism underlying OCPM stemness maintenance. Combined tandem mass tag- and tissue microarray-based proteomic studies revealed YWHAB down-regulation in post-neoadjuvant chemotherapy OCPM tissues, which was confirmed in no-neoadjuvant-chemotherapy-response tissues, isolated OCPM stem cells, and induced cisplatin-resistant cells. Knockdown of YWHAB promoted stemness and resistance in parental complete or near-complete primary OCPM and OVCAR3 cells in vitro and in vivo. Mechanistic study showed that YWHAB directly bound to YAP and promoted YAP cytoplasmic retention and thus YWHAB restriction promoted YAP activity and stemness in OCPM in the cells in which the Hippo/YAP signaling was constitutively activated by overloaded constitutively active YAP (YAP5SA), and the effect of YWHAB knockdown was significantly abolished. The SH3 binding domain in YAP is critical for YWHAB-YAP binding. Alteration in the 5mc methylation level in the YWHAB promoter was observed in OCPM stem cells. In summary, our results reveal that restriction of YWHAB-mediated YAP cytoplasmic retention is a critical mechanism underlying OCPM stemness maintenance. Our findings suggest that YAP would be a therapeutic target for suppressing OCPM stemness caused by YWHAB restriction.

The study aimed to analyze the single-cell transcriptomes of immune cells in juvenile idiopathic arthritis (JIA) patients to understand the cellular heterogeneity within the immune system. Peripheral blood samples from fourteen JIA patients and four healthy individuals were subjected to single-cell RNA sequencing. Various subtypes of JIA were included in the patient cohort. Functional analyses, such as pseudotime trajectories and cell communication studies, were conducted to uncover immune cell changes in JIA patients. Results showed disrupted interferon and acute inflammatory responses in most cell types of JIA patients, with particularly intense responses in systemic JIA (sJIA) patients versus non-sJIA patients. Pseudotime analysis of CD4+ T, CD8+ T, B, and myeloid cells revealed that the functions of each cytokine production, cytotoxicity, and the processing and presentation of antigens were progressively strengthened, while the regulation of nuclear factor kappa B (NF-κB)-related pathways was weaker in CD4+ T and CD8+ T cells than in non-JIA. Reclustering analysis of myeloid cells highlighted interferon-related functions predominantly in non-classical monocytes of sJIA patients. Additionally, cell communication analysis identified unique ligand–receptor pairs in sJIA, suggesting potential roles in disease progression. In conclusion, interferon disorders are evident across various immune cell types in JIA patients, with stronger responses observed in sJIA patients. The ligand–receptor pairs involving migration inhibitory factor (MIF) and CXCR7/CD44 may contribute to differing joint symptoms between sJIA and non-sJIA patients. Moreover, non-classical monocytes and the CXCR2 receptor in MIF signaling may play crucial roles in sJIA progression.

The immune microenvironment plays an important role in leukemia treatment. However, a specific single-cell profiling of the immune alteration in bone marrow of chronic myeloid leukemia (CML) patients is still lacking. We performed multi-level single-cell sequencing to systematically decipher the bone marrow T cell atlas of CML patients. The results exhibited extensive changes of T cells, including the decreased CD4 T cells and increased CD8 T cells in the CML bone marrow. Subpopulation analysis revealed a significant increase of CD8 terminal effector (TE) cells and a significant decrease of CD4 naïve T cells. T cell receptor sequencing showed that the overall diversity of the T cell receptor repertoire was reduced in CML, with the exception of the CD8 TE cell. In addition, CD8 TE cells were the main source of gene expression differences in CD8 T cells. Intercellular communication analysis revealed the altered interaction between CD8 TE and other non-T cells in CML, including neutrophil subtype, indicating the potential regulation of bone marrow microenvironment cells on CD8 TE dynamics. Collectively, our work characterises the alteration of T cell subsets in CML patients at multiple single-cell levels, providing a valuable resource for understanding the immune microenvironment and developing new immune strategies for CML therapy.

Pancreatic cancer (PC) is a highly malignant neoplasm of the digestive system. The primary objective of this investigation is to elucidate the intricate mechanisms underlying the role of the aging process and the related factor Epithelial membrane protein 1 (EMP1) in PC progression. We established a prognostic model pertinent to the aging process that could be applied in postoperative PC patients. In vitro assays were employed to elucidate the impact of EMP1 on PC cell function. We employed lentiviral vectors for both knockdown and overexpression of EMP1 in Panc02 cells, followed by the establishment of subcutaneous, pulmonary metastasis, and orthotopic pancreatic liver metastasis models in mice. Using tissue microarrays, we evaluated the expression of EMP1 and its downstream entities, and then conducted clinical correlation analysis. A predictive Age-Related Score (ARS) system based on age-associated prognostic genes was developed, offering precise prognostic predictions for postoperative PC patients, which could be applied well at the single-cell level, showing diverse aging, epithelial–mesenchymal transition (EMT), cell migration, cell proliferation, and PI3K/AKT signaling activity in high and low ARS risk cells. EMP1 was identified as a pivotal molecule in the ARS system and is associated with poor prognosis. Besides, EMP1 could enhance the proliferation, migration, and invasion of PC cells both in vitro and in vivo by augmenting the PI3K/AKT signaling cascade. In essence, this research formulated an aging-centric prognostic model for postoperative PC and pinpointed EMP1 as an oncogenic factor facilitating tumor cell EMT during the aging trajectory in resectable PC patients.

Several factors during pregnancy, such as changes in serotonin (5-HT) levels, can affect intestinal function in offspring mice. The role of 5-HT in regulating intestinal motility after lipopolysaccharide (LPS) exposure during pregnancy is unclear. In this study, Tlr4fl/fl and Tlr4▵IEC mice were injected with LPS or phosphate-buffered saline during pregnancy to obtain prenatal LPS-exposed or non-exposed offspring mice. Changes in intestinal morphology, motility, and the TLR4 and 5-HT signaling pathways were examined in male offspring mice. The role of TLR4 in regulating 5-HT secretion was investigated in the BON-1 enterochromaffin cell line. In the prenatal LPS-exposed Tlr4fl/fl group, offspring mice exhibited colonic mucosal injury and faster intestinal motility, but these effects were absent when TLR4 was knocked out in intestinal epithelial cells. The TLR4 and 5-HT signaling pathways were activated in the colon of prenatal LPS-exposed Tlr4fl/fl offspring mice but were inactivated in prenatal LPS-exposed Tlr4 knockout offspring mice. In BON-1 cells, TLR4 interacted with the calcium ion channel PIEZO1, causing calcium influx and promoting 5-HT secretion. This process was disrupted by the TLR4 inhibitor TAK242. LPS exposure during pregnancy affected intestinal motility in offspring mice by activating TLR4 pathways in the colon and increasing 5-HT secretion from enterochromaffin cells. The effects of LPS on the intestine might be explained by the interaction between TLR4 and PIEZO1, suggesting that TLR4 is related to abnormal intestinal motility in offspring mice exposed to LPS during pregnancy.

Immune checkpoint inhibitors have a poor effect in treating ovarian cancer, and the specific mechanism is unknown. The purpose of this research was to investigate the impact of XPR1 on controlling autophagy in ovarian cancer. The findings suggested an increase in XPR1 expression in ovarian cancer tissues. The elevated level of its expression was linked to the stage of ovarian cancer, as well as overall survival and progression-free survival. XPR1 enhanced the growth and spread of ovarian cancer while suppressing autophagy. Moreover, XPR1 suppressed autophagy flux by interacting with LAMP1 and the PI3K/Akt/mTOR pathway. XPR1 controlled the positioning and production of MHC-I molecules on the surfaces of ovarian cancer cells via autophagy. Silencing XPR1 combined with the autophagy inhibitor chloroquine significantly inhibited tumor growth in mouse ovarian cancer models. In conclusion, the findings indicate that XPR1 could serve as a promising target for the diagnosis and treatment of ovarian cancer. Combined autophagy inhibitors may improve the sensitivity of ovarian cancer immunotherapy.

The aggregation of the peptide hormone amylin in the pancreas is a pathological hallmark of type-2 diabetes. Additionally, amylin can form aggregates in the brain, promoting β-amyloid deposition and tau phosphorylation in Alzheimer's disease. The cross-seeding between amylin and tau exacerbates tau pathology spread and synaptic loss, leading to neurodegeneration and cognitive deficits. Given the link between lysosomal dysfunction and tauopathy in the brain and amylin aggregation in the pancreas, we hypothesized that amylin could potentially worsen tau pathology in diabetic mice. We administered streptozotocin and/or amylin peripherally to the PS19 model of tauopathy at 3 months and characterized them at 6 months of age. We found that streptozotocin diminished body weight gain, increased blood glucose levels, worsened motor performance, and improved fear-conditioned memory in PS19 mice. Both amylin and streptozotocin administration prompted the emergence of tau pathology in the pancreas, which coincided with a decrease in the number of lysosomes in pancreatic islets. Mice treated with amylin and streptozotocin also developed robust tau pathology concomitant with lowering lysosomal cathepsin D levels in the visual cortex. These findings suggest that in diabetic mice, amylin administration diminished pancreatic lysosomes, possibly increasing the number of amylin aggregates that reached the brain and contributing to the worsening of tau pathology due to lysosomal impairment in the visual cortex. The outcome of our research enhances the understanding of the cellular pathways by which amylin may serve as a link between the pancreas-brain axis during diabetes, influencing the risk of developing tau pathology.

Cataracts, a widely prevalent ocular pathology, engender visual impairment and emerge as a primary etiological factor contributing to ocular blindness. Substantial evidence substantiates that epithelial–mesenchymal transition stands prominently among the pivotal causative factors associated with this debilitating condition. However, the underlying mechanism remains unclear. In the present study, we analyzed the single-cell data and found that the mRNA expression of nuclear receptor subfamily 2 group F member 1 (NR2F1/COUP-TFI) was notably decreased in fibrocytes compared with epithelium. Interestingly, we observed a significant up-regulation of NR2F1 protein in the anterior subcapsular cataract mice model and transforming growth factor-β1 (TGF-β1)-treated SRA01/04 cells. Furthermore, we found that TGF-β1 stimulation disrupted the balance of autophagy, leading to impaired degradation and increased protein levels of NR2F1 in SRA01/04 cells. Subsequently, after anterior chamber injection of NR2F1 adeno-associated virus in anterior subcapsular cataract mice, the development of fibrosis was alleviated. In vitro, the knockdown of NR2F1 in SRA01/04 also mitigated the TGF-β1-induced epithelial–mesenchymal transition. Mechanically, NR2F1 proteins directly interacted with the promoter region of STAT3 and orchestrated the up-regulation of phosphorylated STAT3 (p-STAT3), thereby facilitating the apoptosis and migration of SRA01/04 cells via the JAK1/STAT3 pathway, resulting in epithelium fibrosis and cataracts. Furthermore, inhibition of p-STAT3 obviously attenuated apoptosis and fibrosis of SRA01/04 cells. Collectively, our study provides a novel therapeutic target for cataracts and offers insight into the underlying mechanism of the epithelial–mesenchymal transition of cataracts.

The processes of tumorigenesis and development are intricate, involving numerous genes and molecular pathways. Fusion genes, direct products of abnormal chromosomal rearrangements, are key factors in the formation of many types of tumors. In recent years, the advent of sequencing technology and bioinformatics has led to the discovery of more fusion genes associated with specific types of tumors. The objective of this review is to undertake a comprehensive examination of the discovery and functional mechanisms of fusion genes present in a range of cancers. This will include an analysis of their impact on the biological properties of tumor cells. This review will examine the most prevalent types of fusion genes observed in representative tumor types, including hematological tumors, lung cancer, soft tissue sarcomas, thyroid cancer, and prostate cancer. We provide an overview of the roles and clinical significance of fusion genes, as well as a summarization of the therapeutic strategies for fusion genes, including the application of targeted drugs and related studies. This review presents a comprehensive analysis of the function of fusion genes in the development and treatment of tumors, providing guidance and insights for future research and clinical practice.

Ribonucleases (RNases), essential for RNA metabolism, are implicated in human diseases, including neurodevelopmental, developmental, hematopoietic and other dysfunctions through mutations that disrupt their enzymatic functions. Exploring RNase mutations across organisms offers insights into Mendelian diseases, facilitating molecular dissection of pathological pathways and therapeutic development. By employing model organisms, our analysis underscores the evolutionary conservation of RNase genes, facilitating deeper insights into disease mechanisms. These models are vital for uncovering rare molecular dysfunctions and potential therapeutic targets, demonstrating the effectiveness of integrated research approaches in addressing complex genetic disorders. Drawing from phylogenetic analyses, literature survey, and databases documenting the effects of human disease-causing mutations, the review highlights the significance and advantages of employing model organisms to study specific Mendelian disorders.

Osteosarcoma, a prevalent primary malignant bone tumor, predominantly affects both elderly and adolescent populations and usually has an unfavorable prognosis. The specific mechanisms underlying its invasive progression remain unclear. The tumor microenvironment includes not only cancer cells but also bone-related cells, immune cells, tumor-associated nerve cells, and cell-secreted factors. The cooperative and competitive interactions among these cellular components contribute to the proliferation, progression, metastasis, and immune evasion of osteosarcoma. Alterations in bone-related cells, resulting from oncogenic changes, can rapidly increase bone density or aggravate bone loss, thereby promoting the survival of osteosarcoma cells. During the progression of osteosarcoma, genetic alterations in tumor cells lead to changes in extracellular matrix components, influencing the variation in cell-secreted factors, promoting immunosuppression within the tumor microenvironment, and consequently affecting tumor proliferation and progression. This review summarizes the roles of tumor microenvironment components in the pathogenesis of osteosarcoma and discusses existing therapeutic targets. The findings suggest potential research directions for further investigation of osteosarcoma, provide novel insights into the development of osteosarcoma, and may guide the development of more effective anti-tumor strategies.

Older age is one of the leading risk indicators for advanced breast cancer. It is critical to extensively investigate how aging affects breast cancer, considering the increasing rate of population aging. Human body aging and death are caused by cellular senescence and alterations in the aging microenvironment in vivo. Breast cancer cells may invade more easily with age due to the stiff extracellular matrix of the breast. Furthermore, growing evidence suggests that the massive release of inflammatory immune mediators, such as cytokines (interleukins) or CXC chemokines (CXCs), and their receptors (CXCRs), including interleukin (IL)-6, IL-8/CXCL8, tumor necrosis factor (TNF), interferon (INF), transforming growth factor (TGF), CXCL1, CXCL9, CXCL10, CXCL11/CXCR3, and CXCL12/CXCR4, plays a critical role in the development of breast cancer in elderly patients. Researchers are particularly interested in obesity-induced inflammation because it has been shown to raise the risk of breast cancer in postmenopausal women with higher body mass index. Obesity-triggered inflammation causes increased infiltration of proinflammatory cytokines, adipokines, immune cells, and tumor cells in the enlarged adipose tissue of postmenopausal women with breast cancer, thereby modulating the tumor's immune-mediated microenvironment. Therefore, in this review, we focus on the functional significance studies of proinflammatory cytokines, CXCs, and CXCRs and describe their roles in influencing breast cancer progression in older women and their factors, such as obesity in postmenopausal women. In addition, the current status and prospects of cytokine- and CXC-based theranostic interventions for breast cancer therapy in elderly and postmenopausal women are discussed.

Circular RNAs (circRNAs) are a class of stable and versatile non-coding RNAs that are pivotal in the occurrence and development of some diseases, particularly tumors. Hepatitis B virus (HBV)-induced hepatocellular carcinoma (HCC) is a liver disease with substantial global impact. Despite efforts towards adequate management, the survival of patients with HBV-induced HCC has been consistently low. circRNAs regulate various physiological activities of HBV-induced HCC. This review aims to elucidate the biogenesis of circRNAs and the pathophysiology of HBV-induced HCC and comprehensively analyze the applications of circRNAs in oncology and therapeutics. In addition, this review summarizes past research achievements on circRNAs in HBV-induced HCC. Finally, the limitations of existing methodologies and circRNA research in HBV-induced HCC have been discussed to provide a blueprint for future investigations.

Mammalian hair follicles undergo periodic regeneration, with recent research highlighting the immunological niche as a critical regulator of stem cell activity and hair follicle regeneration. Chemotactic signals from hair follicles attract macrophages and T cells, which, in turn, control the resting and differentiation of epithelial stem cells in both healthy and damaged conditions. T cells play a pivotal role in hair follicle regeneration, contributing to injury-induced hair neogenesis and physiologic hair cycling. However, disruption of this interaction can lead to clinically significant immune-mediated alopecia. Both scarring and non-scarring forms of alopecia arise from an imbalance in this dynamic system. In this review, we address the role of T cells in hair follicles, summarize related mechanisms, and highlight key genes involved in T cell differentiation and development. Our aim is to provide insights into the development of hair disorders linked to T cell immune homeostasis and hair follicle regeneration.

Transposable elements, long considered genomic intruders, have been found to play significant and intriguing roles during early embryonic development based on the paradigm shift that has undergone in recent years. Long interspersed element-1 (LINE-1) is the predominant class of retrotransposons with autonomous retrotransposition capabilities in mammals and has emerged as a crucial element of preimplantation development. In this review, we elucidate the expression dynamics of key transposable elements throughout preimplantation development and their contribution to the regulation of developmental progression and totipotency. We also explore the critical function of LINE-1 activation and its rich functional reservoir, which is exploited by the host to provide cis-regulatory elements and functional proteins. Particular highlights of the widespread activities in preimplantation development of LINE-1 during multiple epigenetic modifications such as DNA methylation, histone methylation, ubiquitination, and RNA methylation. The silencing complex and RNA exosome also coordinate with LINE-1 across distinct developmental stages. Accordingly, the up-regulated expression of LINE-1 retrotransposons and their protein products plays a key role in various processes, including the opening of chromatin architecture, zygotic genome activation, aging, and age-related disorders. It may reflect an effect on totipotency and pluripotency of mammalian development. Underscoring its pivotal significance, the nuanced regulation of LINE-1 illuminates its indispensable role in orchestrating the precise coordination essential for the regulation of cellular pluripotency and the intricate mechanisms of zygotic genome activation.

Fibroblast growth factor 8 (FGF8), a secreted signaling molecule, involves in regulating cell survival, proliferation, migration, and differentiation. It exhibits a highly dynamic gene expression pattern throughout embryonic development, participates in craniofacial structures, limbs, internal organs, brain development, and is crucial during organogenesis. The dysregulation of precise localization and dosage of FGF8 at distinct embryonic stages can lead to developmental multiorgan abnormalities. This comprehensive review explores the FGF8 expression in humans and mice, summarizes the involvement of FGF8 in various tissues including craniofacial, limbs, cardiovascular and urogenital system, nephrogenesis, lung, and brain development as well as developmental abnormalities resulting from the aberrant regulations of FGF8 such as skeletal abnormalities, ciliopathies, and holoprosencephaly.

Breast cancer, the most prevalent cancer in women, poses a significant threat to their health. One of the prominent characteristics of malignant transformation in breast cancer cells is metabolic reprogramming, which encompasses glucose, lipid, and amino acid metabolism. Notably, breast cancer cells exhibit augmented energy metabolism and heightened glycolysis. In addition, there is an escalated demand for glutamine, which is met through intrinsic synthesis, uptake from extracellular sources via membrane transport proteins, or up-regulation of key metabolic enzymes in the glutamine metabolism pathway. Lipids not only serve as an energy source for tumor cells but also function as signaling molecules for intercellular communication. Extensive research in recent years has focused on unraveling the intricate mechanisms underlying metabolic reprogramming. Consequently, genes implicated in these processes have emerged as clinical therapeutic targets for cancer treatment. This review provides a comprehensive summary of the common metabolic alterations observed in cancer cells, discusses the factors and regulatory mechanisms influencing these changes, and explores potential therapeutic targets and strategies within the realm of cancer metabolism.

Despite advancing therapeutic treatments, cancer remains the leading cause of death worldwide, with most of its patients developing drug resistance and recurrence after initial treatment. Therefore, incorporating preclinical models that mimic human cancer biology and drug responses is essential for improving treatment efficacy and prognosis. Patient-derived xenograft (PDX) models, as a promising and reliable preclinical trial platform, retain key features of the original tumor such as gene expression profiles, histopathological features, drug responses, and molecular signatures more faithfully compared with traditional tumor cell line models and cell line-derived xenograft models. Their significant advantages have been the preferred choice in cancer research, especially demonstrating remarkable potential in drug development, clinical combination therapy, and precision medicine. However, the successful construction and effective application of PDX models still face several challenges. In this review, we summarize the details of constructing PDX models and the drivers affecting their success rates, which will provide some theoretical basis for subsequent model optimization. In the meantime, we delineate the strengths and weaknesses of various mature PDX models and other developing preclinical models, including PDX-derived models, organoids, and genetically engineered models. Moreover, we highlight the challenges of newly developed technologies on the PDX models. Finally, we emphasize the innovative usage of PDX models in a variety of cancer studies and offer insights into their prospects.

Ribosome biogenesis is a multi-step process that initiates within the nucleolus, terminates in the cytoplasm, and determines the rate of protein synthesis. Ribosome biogenesis is essential for maintaining liver function. In eukaryotes, it involves producing and assembling approximately 200 factors and 80 ribosomal proteins. Mutations in ribosome proteins, ribosomal RNA processing, and ribosome assembly factors in the liver can result in liver disease. Hepatitis C virus causes acute or chronic infection and liver disease, which can progress to liver cirrhosis, cancer, and death. This review provides an overview of the effects of ribosomal biogenesis, including ribosomal RNA, ribosomal proteins, and ribosome biogenesis factors, on liver regeneration, hepatitis C virus, nonalcoholic fatty liver disease, liver fibrosis, cirrhosis, and liver cancer. It lists drugs that exploit ribosome biogenesis to treat liver cancer. Targeting ribosome biogenesis shows promise as a therapeutic approach. A better understanding of this process will contribute to developing effective and targeted therapeutic strategies for ribosome biogenesis disorders.

The ten-eleven translocation 1 (TET1) protein, a member of the human α-ketoglutarate-dependent dioxygenase TET family, functions as a 5-methylcytosine hydroxylase with a strong affinity for genomic regions enriched with 5′-CpG-3′ dinucleotides, particularly CpG islands. TET1 is critical in initiating DNA demethylation and maintaining a balanced interaction between demethylation and DNA methylation, which is essential for genomic methylation stability and precise epigenetic regulation. By removing methyl groups from specific tumor suppressor genes, TET1 can influence their expression. This review summarizes the latest advancements in TET1 research, emphasizing its role in demethylation mechanisms and its significance in regulatory processes related to clinical conditions. TET1 is a crucial mediator of demethylation, although the precise details of this mechanism are not yet fully understood. Additionally, TET1 plays a key role in inhibiting tumor progression, but its effects vary across different tumors. This variability arises from its interactions with diverse signaling pathways, where it can function either as an antagonist or a promoter. The role of TET1 remains controversial in certain cancer types, and its potential oncogenic functions have attracted growing interest, opening new avenues for investigation.

N6-methyladenosine (m6A) is the most abundant and well-investigated internal RNA modification in eukaryotic RNAs, affecting its target gene expression by controlling RNA localization, splicing, stability, and translation. m6A modifications are regulated by m6A methyltransferase complex, demethylase, and reading proteins. Insulin-like growth factor-2 mRNA-binding protein 1 (IGF2BP1), a member of a conserved family of single-stranded RNA-binding proteins, has recently been identified as a vital m6A reading protein. IGF2BP1 is highly expressed in various tumors and is associated with poor prognosis and treatment resistance. Furthermore, previous studies have shown that IGF2BP1 plays critical roles in regulating various cancer hallmarks, including sustained cell proliferation, cell death resistance, activation of invasion and metastasis, deregulated cellular energetics, immune evasion, and unlocking phenotypic plasticity. IGF2BP1 could promote the expression of cancer-related genes by recognizing their m6A sites, thereby altering cell characteristics, and eventually, malignancy. Therefore, IGF2BP1 might be a potential target for tumor diagnosis and anti-tumor therapeutic strategies. This review summarizes the current knowledge on the functional roles and underlying molecular mechanisms of IGF2BP1 in regulating cancer hallmarks. Moreover, we discuss the prospects of IGF2BP1 as a potential tumor diagnosis marker, as well as a potential target for an anti-tumor therapeutic strategy.

Long noncoding RNAs (lncRNAs) are endogenous noncoding RNAs exceeding 200 bases in length that are prevalent in malignant tumors and are closely associated with the onset and progression of hepatocellular carcinoma. The synthesis of lncRNAs exhibits similarities to that of protein-coding transcripts, which is regulated by epigenetic modifications. Recent research has highlighted the significant regulatory role of epigenetic modifications in the transcription of lncRNA genes in hepatocellular carcinoma. This review outlines the impact of epigenetic modifications, including DNA methylation, histone modification (methylation and acetylation), RNA modification, and microRNAs on the transcription of lncRNA genes in hepatocellular carcinoma and delves into the underlying mechanisms by summarizing how these lncRNA genes contribute to the development and progression of hepatocellular carcinoma.

Liquid biopsy has emerged as a valuable clinical tool due to its non-invasive nature and real-time molecular profiling capabilities. Transfer RNA-derived small RNAs (tsRNAs) are a group of small non-coding RNAs generated from mature tRNAs or tRNA precursors. Recently, increasing studies have reported tsRNAs' potential to serve as promising biomarkers in various diseases, especially cancers. Notably, tsRNAs can be detected in various kinds of body fluids, such as seminal fluid plasma, blood plasma, saliva, and urine, and have been demonstrated to exist stably in body fluids. In this mini-review, we will summarize the recent discoveries on the role of tsRNAs in body fluids as biomarkers, hoping to provide new insights for disease diagnosis and therapeutic strategies.

Kelch-like family member 17 (KLHL17) is predominantly expressed in the brain and plays a crucial role in neuronal development and function, deletions and/or mutations in KLHL17 have been linked to neurodevelopmental disorders in humans, e.g., intellectual disability, autism spectrum disorder, and infantile spasms, but the etiology and pathogenesis remain largely enigmatic.1,2 As a member of the family of the Kelch proteins, KLHL17 contains an N-terminal BTB/POZ domain followed by a BACK domain and four to six tandem Kelch motifs at the C-terminal region (Fig. S1A).1,3 Previously, we identified a novel de novo variant in KLHL17 (c.701C > T; p. P234L) in a cohort of 225 Chinese children with developmental delay/intellectual disability based on whole-exome sequencing (1/225), the mutation located in the BACK domain, a very high conversed region (Fig. S1B), and the affected boy presented with developmental delay, intellectual disability, hypotonia, and abnormal brainstem auditory evoked potential signal.4 The finding may offer a new clue to investigate the molecular pathogenesis of KLHL17 gene in neurodevelopmental disorders.

Breast cancer is one of the most common cancers and the leading cause of cancer-related deaths among women due to the diagnostic delay and failure of treatment.1 Despite the significant progress made in developing therapeutic strategies for breast cancer, effective treatment of breast cancer, particularly aggressive triple-negative breast cancer, remains lacking. Angiogenesis is a crucial risk factor for breast cancer metastasis and a predictor of poor prognosis. Thus, developing novel agents capable of suppressing tumor angiogenesis offers a promising approach for breast cancer treatment. Oridonin, the major active ingredient of the traditional Chinese medicinal herb, exhibits anti-cancer activity by inhibiting tumor-induced angiogenesis.2 Nevertheless, the therapeutic potential of oridonin is limited due to its rapid plasma clearance and limited potency. Various novel oridonin analogues have been designed and chemically synthesized by modifying their A, B, and D rings to achieve an agent with better anti-cancer efficacy and lower toxicity than oridonin.3 Chick embryo chorioallantoic membrane (CAM) and yolk sac membrane (YSM) models were commonly utilized to study tumor-induced angiogenesis. To discover the promising anti-angiogenic agents, we screened novel oridonin analogues synthesized in-house using the CAM and YSM models. Ultimately, four molecules were discovered to show the potential anti-angiogenic ability in the CAM (Table S1). Among them, CYD0682 was identified as a promising anti-angiogenic drug candidate in which a double bond was introduced at the 1,2-positions of the A-ring by removal of the hydroxy group on this ring to enhance the drug-like properties such as lipophilicity and cell permeability (Table S1).4 Angiopoietin-like protein 4 (ANGPTL4), a member of the ANGPTL family, is closely correlated with tumor growth, metastasis, and angiogenesis. Furthermore, ANGPTL4 down-regulation can promote the invasion and metastasis of colorectal cancer via the extracellular signal-regulated kinase (ERK) signaling pathway.5

With the development of the social economy and an increasingly aging population, cardiovascular diseases have become a severe threat to public health. Vascular aging is a primary risk factor for the development of cardiovascular diseases and it is associated with the cellular senescence of the vascular endothelium.1 Endothelial cell senescence leads to endothelial dysfunction that manifests as impaired endothelium-dependent vasorelaxation and vascular inflammation, ultimately predisposing individuals to atherosclerosis and other cardiovascular complications.2 By delaying senescence of vascular endothelial cells, it is possible to reduce or prevent the occurrence and development of atherosclerosis.

G protein subunit alpha O1 (GNAO1)-related disorders represent a broad spectrum of neurological diseases mainly caused by de novo mutations in GNAO1 encoding for G protein alpha subunit o (Gαo). As the major transducer of neuronal G protein-coupled receptors (GPCRs), Gαo is essential for the signaling involved in neuronal excitability and neurodevelopment. The most severe neomorphic GNAO1-mutations lead to developmental and epileptic encephalopathy-17 (DEE17; OMIM #615473) or neurodevelopmental disorder with involuntary movements (NEDIM; OMIM #617493), the latter with or without epileptic seizures.1 Movement disorders are present in almost all patients, with hypo/hyperkinetic features and profound impairment of postural development.2 Milder phenotypes including late-onset dystonia and parkinsonism with different extents of cognitive impairment have recently emerged from mutations leading to loss-of-function and haploinsufficiency.3 However, clear genotype–phenotype correlations and underlying pathogenic mechanisms are still poorly understood, limiting an accurate prediction of disease progression and the implementation of early therapeutic interventions. Here, we present two unrelated Italian patients carrying novel GNAO1 mutations with atypical phenotypes, thus expanding the phenotypic spectrum of GNAO1-related disorders. We additionally provide a deep molecular analysis of the pathogenic Gαo variants along with a discussion of potential treatment options.

Oral squamous cell carcinoma (OSCC) is one of the most common and aggressive types of oral cancer, accounting for over 90% of oral malignancies. Globally, the incidence of OSCC has been increasing, especially in regions with high rates of tobacco and alcohol consumption.1,2 In 2020, approximately 377,713 new cases of oral cancer were reported globally, with age-standardized incidence rates of 6.0 per 100,000 males and 2.3 per 100,000 females.3 Despite advances in treatment strategies, the prognosis for OSCC remains poor, as a significant proportion of cases are diagnosed at advanced stages, contributing to lower survival rates. Moreover, research on oral cancer lags behind that of other common cancer types globally.4 Consequently, the early detection and the identification of novel therapeutic targets are essential for improving clinical outcomes for OSCC patients.

Anterior segment dysgenesis (ASD) represents a complex spectrum of ocular disorders linked to various genetic mutations, including PITX3, FOXE3, BMP4, CHRDL1, LTBP2, and CYP1B1.1 This heterogeneity disrupts the anterior segment's structure, impacting components crucial for vision, including the cornea, iris, and lens, alongside the aqueous humor outflow system. Such disruptions account for the phenotypic diversity observed in ASD, underlining the importance of understanding the genotype-phenotype correlations within this syndrome.2,3

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder whose mechanisms underlying remain incompletely understood, particularly the role of glial cells. This study investigated the impact of ALS-associated genes on distinct glial populations in Drosophila. We assessed motor function and lifespan, revealing significant sexual dimorphism, with males generally showing greater declines. Our findings also underscore the importance of glial cells, particularly subperineurial glia (SPG) in the male leg femur, and provides valuable insights into the complex interplay between glial cells and ALS-associated genes.

Skin cutaneous melanoma (SKCM) is a malignancy arising from the transformation of melanocytes in the basal layer of the epidermis, which accounts for over 75% of skin cancer-related deaths.1 Homeodomain-only protein homeobox (HOPX) is the smallest member of the known homeodomain protein family in terms of relative molecular weight, and it was identified in 2002.2 Recently, it has been reported that HOPX can act as a tumor suppressor and is also able to participate in immune regulation,3,4 however, its role and mechanisms in SKCM and its modulation of immune cells remain unclear. Therefore, in this study, we aimed to investigate the role and mechanisms of HOPX on SKCM growth and its potential impact on macrophage polarization.

Interleukin 2 receptor gamma (IL2RG) is an important receptor component for interleukin-2 (IL2) family cytokines including IL2, IL4, IL7, IL9, IL15, and IL21.1 IL2RG is located on the X-chromosome q13.1, encoding a common gamma chain (γC) that is essential in lymphoid development, especially in the modulation of T cell and natural killer (NK) cell immune responses. Mutations in the IL2RG gene cause X-linked severe combined immunodeficiency (X-SCID), which is a life-threatening rare disease. In typical X-SCID, the disease is characterized by a nearly complete absence of T cells and NK cells, alongside normal or elevated counts of non-functional B cells (T– B+ NK− phenotype). Infants with X-SCID exhibit high susceptibility to bacterial and opportunistic infections. Here, we report a splice site mutation (c.924+5G > C) in the IL2RG gene in a 3-month-old boy presenting with a typical phenotype of X-SCID.

Globally, ovarian cancer (OvCa) is the deadliest gynecological malignancy, which threatens women's health.1 Despite innovations in cancer treatments, nearly 70% of OvCa patients still suffered tumor recurrence and poor survival after standard therapy.1 Therefore, further research is urgently needed to identify prognostic biomarkers and explore specific mechanisms for OvCa. Tertiary lymphoid structure (TLS), a newly acknowledged form of ectopic lymphoid tissues, plays a crucial role against cancer, though have not been validated in OvCa yet.2 Here, we developed and validated a TLS-related gene (TRG) signature to predict drug sensitivity and prognosis for OvCa patients via bioinformatics analysis. Moreover, through PCR and multiplex immunohistochemical analyses, we validated the importance of TLS and the related signature, particularly STAT5A (signal transducer and activator of transcription 5 A), thus assisting clinical decision-making for OvCa precision treatment.

There are similarities between rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) in terms of clinical manifestations, immune responses, and therapeutic strategies,1 and thus a joint analysis of the two diseases could contribute to a deeper understanding of the shared pathogenesis of autoimmune diseases. The subtype analysis of RA and SLE is currently understudied, and the marker genes used for subtype definition in most studies are derived from bulk RNA sequencing data or microarray data, which are underrepresentative of individual immune cell status.2 Therefore, we aimed to identify cell type-specific expressed genes as biomarkers based on single-cell RNA sequencing data and to explore the commonalities and differences between RA and SLE by a combined subtype analysis based on microarray data. Both the representativeness of the markers in terms of immune characteristics and the reproducibility of the results are ensured by the sufficient sample size. Immune infiltration analysis revealed the subtype heterogeneity and significant differences in clinical characteristics between different subtypes of RA patients, which verified the heterogeneity between different subtypes. Finally, we constructed subtype prediction models by machine learning algorithms further validating the heterogeneity among subtypes. Detailed methodology and the overall flowchart (Fig. S1) are provided in the supplementary material.

The pathogenesis of benign prostatic hyperplasia (BPH) is commonly regarded as androgen-dependent. The first FDA-approved androgen-targeted medication for BPH, finasteride, achieves its therapeutic effect by selectively inhibiting type II 5-alpha reductase (SRD5A2). This inhibition reduces the androgenic response by attenuating the interaction between dihydrotestosterone and androgen receptor (AR), ultimately leading to a reduction in prostate volume and alleviation of BPH-associated symptoms. However, it is noteworthy that non-response to finasteride may develop in certain BPH patients,1 indicating a potential inadvertent promotion of disease progression by this treatment. Nevertheless, the underlying mechanism remains elusive. Recent researches suggest that it may be associated with alterations within the prostate gland epithelia.2 Therefore, we designed this study to elucidate this phenomenon by employing spatial transcriptomic (ST) and single-cell RNA sequencing (scRNA-seq) (methods were described in Supplementary Materials in detail). Our findings will improve treatment adjustments by enabling a more accurate evaluation of patient's response to finasteride therapy, thus enhancing therapeutic outcomes.

Osteosarcoma (OS) is a highly aggressive bone tumor that predominantly affects teenagers and young adults, characterized by rapid growth and a high propensity for metastasis.1 Despite significant advancements in surgical techniques and chemotherapy, the survival rate for OS patients has plateaued over the past decades.2 Understanding the molecular mechanisms underlying OS progression and identifying new therapeutic targets remain critical for improving patient outcomes. Long non-coding RNAs (lncRNAs) are a class of functional RNA molecules that are typically over 200 nucleotides in length and cannot code for proteins.3 Initially considered as “junk DNA”, recent studies have revealed the crucial roles lncRNAs play in a wide range of biological processes, including cellular differentiation, apoptosis, inflammation, and cancer.4

Lung cancer is the leading cause of cancer-related mortality globally, including small-cell lung cancer and non-small-cell lung cancer. As the most prevalent histological subtype of non-small-cell lung cancer, lung adenocarcinoma (LUAD) accounts for approximately 40% of all lung cancer cases.1 Due to the heterogeneity of LUAD, accurate categorization is required to create a treatment plan for LUAD patients, while the existing paradigm does not adequately capture the enormously heterogeneous characteristics of LUAD. The rise of epigenetics has brought new perspectives for tumor heterogeneity exploration. Epigenetic modifications, such as aberrant DNA methylation and microRNA (miRNA), are essential in controlling gene expression, heterogeneity, and clinical implication.2 Meanwhile, epigenetic disruptions contribute to lung cancer tumorigenesis, the generation of a malignant phenotype and aggression, and chemoresistance, which could serve as credible biomarkers for lung cancer molecular categorization, early diagnosis, prognosis classification, and treatment efficacy prediction.3 Through integrative clustering of the gene expression profiles regulated by epigenetics, we determined and validated four lung adenocarcinoma epigenetic subtypes (LAESs) with distinct prognoses and biological peculiarities from four independent multi-center lung adenocarcinoma cohorts.

Duchenne muscular dystrophy (DMD) is a fatal X-chromosome-linked genetic disease caused by dystrophin gene mutations, including nonsense mutations.1 Nonsense mutations are caused by the introduction of premature termination codons, which prevent translation of full-length proteins. Read-through therapies show potential for addressing DMD's genetic basis; however, issues such as non-specific amino acid insertions, gene-editing delivery challenges, and clinical safety concerns have limited their progress.2,3 To address nonsense mutations, nonsense suppressor transfer RNAs (sup-tRNAs) have been proposed as a genetic therapy approach.3, 4, 5 In this study, we propose a new MyoAAV-delivered suppressor tRNA (sup-tRNA) strategy to restore dystrophin expression. Our approach specifically targets nonsense mutations in mdx mice and patient-derived myoblasts and cardiomyocytes, significantly increasing dystrophin levels, especially in the heart (up to 61.43% when combined with CC-90009). This combination alleviates dystrophic symptoms and improves read-through efficiency, likely by reducing translation termination factor activity. These findings highlight the potential of sup-tRNA in DMD and other nonsense mutation-related diseases.

HIV-associated neurocognitive disorder (HAND) is a central nervous system complication of HIV infection that affects cognitive, behavioral, and motor functions. The pathogenesis of HAND and its possible association with Alzheimer's disease (AD) remain unclear. This study used genomic data to reveal molecular mechanisms underlying HAND and key HAND biomarkers, with a focus on identifying new genetic variants, miRNAs, and transcription factors. We analyzed genomic studies, genome-wide association studies, and single-cell RNA sequencing datasets from cerebrospinal fluid and brain samples of individuals with HAND. Our objectives were to identify biomarkers associated with HAND and AD, validate them, and explore their interactions with genetic variants, miRNAs, and transcription factors. Our findings demonstrate significant decreases in synapse-related biomarkers and increases in immune system biomarkers in HAND. Key biomarkers, including APOE, RHOA, DLG4, APP, and GAPDH, were consistently altered across various datasets. Single nucleotide polymorphisms such as MTND4P3 [rs4718789-T], RNA5SP231 [rs4718789-T], and MSH6 [rs2098242-T] were identified as significant contributors to HAND pathogenesis, as were miRNAs hsa-miR-16-5p, hsa-miR-320a, and hsa-miR-335-5p. Transcription factors THRA and NEUROD6 were also implicated in HAND. Altered expression of synapse-related and immune system biomarkers underscores the complex interplay between neurodegeneration and inflammation in HAND. The identified biomarkers and genetic variants offer potential avenues for further research and therapeutic development.

Gene therapy has shown promise for treating sensorineural hearing loss, supported by numerous successful preclinical studies. From the perspective of translation to humans, researchers have focused more on the genetic causes of profound sensorineural hearing loss, where the sensory epithelium remains viable and intact for a considerable time after birth in humans. A key human deafness gene that best fits such a context is OTOF (GenBank AF183185.1), of which protein products, otoferlin, is essential for synaptic exocytosis and vesicle replenishment at the inner hair cell level in the cochlea.1 Several preclinical studies where Otof cDNA was transferred into the cochlea of adult Otof null allele mice, including both OtofΔ/Δ and Otofp.Q939∗/p.Q939∗, successfully achieved near-normal thresholds,2 and furthermore, relatively successful human clinical trials of gene therapy have been conducted for DFNB9 (OMIM 60381) patients showing auditory neuropathy.3,4 One important consideration is that, to date, there has not been a single case in any preclinical study or human clinical trial where both alleles of OTOF/Otof were non-truncating. However, many human patients with DFNB9 carry non-truncating missense variants in OTOF, indicating that their inner hair cells express some mutant RNA/proteins. This raises questions about how these mutant RNA/proteins might interact with exogenous transgene products, affect the function of newly expressed otoferlin, and influence the outcome of gene therapy. To address this, research on wild-type Otof cDNA transfer in mouse models with two copies of common founder missense variants, like p.Arg1939Glu (p.R1939Q), prevalent in Korean and Japanese populations,5 is essential.

Early studies utilized microarrays to identify liver-enriched genes, and the roles of some of these genes in liver development in mice and zebrafish were confirmed.1,2 However, many genes involved in liver growth regulation remained unidentified through this approach. Recently, bulk RNA sequencing or single-cell RNA sequencing has been used to study liver differentiation,3 but no study has screened genes highly expressed in hepatocytes during liver growth. Since rapid hepatocyte proliferation is a common characteristic of liver growth in early liver development and hepatocellular carcinoma (HCC) progression, identifying the genes being involved in regulating liver growth and clarifying how it works would benefit studying HCC progress.

Progressive familial intrahepatic cholestasis type 2 (PFIC2), also known as bile salt export pump (BSEP) deficiency disease, is a rare autosomal recessive inherited liver disease caused by mutations in the ABCB11 gene (located on chromosome 2q24-31), leading to impaired bile secretion.1 Over 200 distinct mutations in the ABCB11 gene have been identified, including missense, nonsense, insertion, deletion, and splice site mutations.1 Compared with other types of PFIC, patients with BSEP deficiency are at a higher risk of progressing to cirrhosis and liver failure. Current treatment options for PFIC2 remain limited and frustrating. Liver transplantation, the only effective intervention, remains the sole definitive treatment for PFIC2. Nevertheless, its application is severely limited by the prohibitive cost and the scarcity of suitable liver donors. Addressing the pathogenesis of PFIC2 poses a significant clinical challenge. However, a recent study has shown that sirolimus may partially restore the bile excretion ability of ABCB11 mutants in abcb11 knockout Zebrafish models.2 This case report describes a patient with BSEP deficiency disease who responded favorably to sirolimus treatment.

Knee osteoarthritis (OA) is extremely common and often complicated by loss of extension (flexion contracture or FC), associated with worse clinical outcomes.1, 2, 3 Once established, an FC is very difficult to reverse, leading to increased long-term morbidity.1, 2, 3 Whole-genome microarray studying posterior knee capsule biopsies in people with OA and knee FC reported an up-regulation in cellular and biological adhesion pathways consistent with an underlying activated connective tissue process, such as excess fibrous tissue production, limiting knee extension.3 Fibrous tissue is produced by fibroblasts, which in turn are derived from mesenchymal stromal cell precursors.4 Fibroblasts and mesenchymal stromal cells may therefore contribute to a pathologic tissue process in the posterior joint capsule in OA, such as capsular fibrosis, and could represent novel early targets for reducing OA morbidity. Therefore, the objectives of this study were to examine the whole-genome expression of fibroblasts and mesenchymal stromal cells within the posterior and anterior OA joint capsule and to identify genes and pathways associated with knee FC to better understand the pathophysiology of OA FC development and direct novel treatment avenues.

Among the most common malignancies, colorectal cancer (CRC) has a high incidence and mortality rate.1 Matrix metalloproteinase 2 (MMP2) plays an important role in the migration and invasion of malignant tumor cells.2 Although many trans-activating factors of MMP2 have been identified, relatively little is known about MMP2 transcriptional inhibition. In this study, we found that zinc finger transcription factor ZNF24 (zinc finger protein 24) may be a novel transcriptional repressor of MMP2 expression.

Previous studies have sought to classify bladder cancer (BLCA) into different molecular subtypes to understand its pathogenic pathways and uncover specific treatments.1 These subtypes, often based on genetic, transcriptomic, or proteomic profiles, aim to stratify patients for precision medicine and improve therapeutic outcomes. Despite these efforts, such classifications have rarely been applied in clinical practice due to challenges in standardization, reproducibility, and limited translational studies validating their utility.1 The treatment of BLCA predominantly relies on surgery, often combined with chemotherapy, immunotherapy, targeted therapy, or antibody-drug conjugates. Radical cystectomy remains the cornerstone for muscle-invasive bladder cancer (MIBC), while transurethral resection and intravesical therapy are common for non-muscle-invasive bladder cancer (NMIBC).2 However, the choice of its treatment modality still depends specifically on whether the disease is NMIBC or MIBC, rather than on the various molecular subtype classifications.3 Bridging the gap between molecular research and clinical application remains a significant challenge, highlighting the need for robust biomarker validation and the development of treatment algorithms that incorporate these subtypes to better guide personalized therapy.