Search Results (367)

During protein synthesis, ribosome stalling, collision, and aberrant elongation can lead to the accumulation of defective nascent polypeptides and compromise cellular homeostasis. To counteract such translational disturbances, eukaryotic cells have evolved a highly conserved translational quality control network, in which the ribosome-associated quality control (RQC) pathway plays a central role in the recognition and elimination of aberrant translation complexes. Zinc Finger Protein 598 (ZNF598), a key E3 ubiquitin ligase in mammalian cells, functions as an essential factor in the early recognition and signal transduction steps of the RQC pathway. Accumulating evidence indicates that ZNF598 senses aberrant translational states, and particularly in the context of ribosome collision, mediates site-specific ubiquitination of 40S ribosomal proteins, thereby promoting ribosome splitting, nascent chain clearance, and subsequent processing of defective mRNAs. Beyond its canonical role in RQC, ZNF598 has also been implicated in the translational repression of defective mRNAs, regulation of inflammatory signaling, antiviral responses, and control of toxic translation products associated with neurodegenerative disorders. In this review, we summarize the structural features, molecular mechanisms, regulatory networks, and physiological as well as pathological functions of ZNF598. We also discuss current controversies and future directions in the field, with the aim of providing a broader framework for understanding translational quality control and its therapeutic potential. Full article

The epidermis is far more than a mechanical shield; it is a dynamic immunological interface whose structural integrity and immune homeostasis are co-regulated by interconnected transcriptional networks. This review examines how epidermal differentiation promoting transcription factors coordinate terminal keratinocyte maturation, skin barrier formation, immune suppression, lipid metabolism, and tissue repair. In particular, Zinc finger protein 750 (ZNF750), grainyhead-like transcription factor 3 (GRHL3), and ovo-like transcriptional repressor 1 (OVOL1) integrate epidermal differentiation with the suppression of inflammatory signaling by regulating lipid metabolism, innate immune sensors, stress-response pathways, and environmentally responsive transcriptional programs. Disruption of these regulatory nodes impairs barrier integrity, amplifies inflammatory signaling, and predisposes to chronic skin diseases, including psoriasis and atopic dermatitis. Full article

Background: Pathogenic variants in ZNF292 cause intellectual disability type 64 (MIM#619188), characterized by intellectual impairment ranging from mild to severe, speech delay, and autism spectrum disorder. However, reports of ZNF292-related neurodevelopmental disorders remain scarce, and most published studies are based on multi-center cohorts. Methods: We performed whole-exome sequencing in eight unrelated individuals presenting with unexplained neurodevelopmental disorders, including global developmental delay and/or intellectual disability. Detailed clinical characterization, neuroimaging, and developmental assessments were conducted. Results: Seven de novo variants in ZNF292 were identified, including two nonsense and five frameshift variants, namely, c.4189C>T (p.Arg1397Ter), c.6343C>T (p.Arg2115Ter), c.1533del (p.Ile511Metfs*11), c.3094dup (p.Ser1032Phefs*18), c.3997_3998del (p.Thr1333Glnfs*8), c.6028_6031del (p.Ala2010Ter) and c.6160_6161del (p.Glu2054Lysfs*14). Among these, c.1533del (p.Ile511Metfs11), c.3094dup (p.Ser1032Phefs18) and c.3997_3998del (p.Thr1333Glnfs*8) are reported here for the first time. All variants were classified as pathogenic. All individuals exhibited global developmental delay, intellectual disability, and short stature. The majority presented with language impairment, motor delays, autism spectrum features, and dysmorphic facial features, while brain magnetic resonance imaging revealed nonspecific abnormalities such as ventriculomegaly. Conclusions: This study contributes additional cases to the expanding phenotypic and mutational spectrum of ZNF292-related neurodevelopmental disorder. Growth retardation was observed in all eight individuals, but given the limitations of a single-center referral cohort, this observation should be interpreted with caution and requires validation in larger studies. Full article

Skeletal muscle is a continuously load-bearing tissue whose growth, repair, and age-related decline are governed by mechanical signals; failure of this mechano-regulation underlies disuse atrophy and sarcopenia. Piezo1, a mechanically activated cation channel, has emerged as a tractable transducer of these signals in muscle, contributing to satellite-cell quiescence and senescence, regenerative division, myoblast fusion, and the response to loading and unloading. In parallel, the myogenic noncoding RNA program is among the best defined in any lineage, with myomiRs miR-1/133/206, the long noncoding RNA LINC-MD1, and the circular RNA circ-ZNF609 being established regulators of the proliferation-to-differentiation transition. These layers are linked because Piezo1-evoked calcium influx feeds the RhoA/ROCK-actin-MRTFA-SRF and YAP/TAZ axis that drives myogenic transcription, yet no direct coupling between Piezo1 and noncoding RNAs has been demonstrated in skeletal myocytes. Drawing on validated precedents from vascular, cardiac, and tendon tissues, this review consolidates the two pillars, frames their convergence as a testable question, distinguishes validated relationships from hypotheses, and proposes three falsifiable predictions using an unbiased candidate selection strategy. The contribution of this review is this testable framework rather than any specific candidate list. Mechanically tunable noncoding RNAs may thus represent an underexplored node for counteracting disuse atrophy and sarcopenia. Full article

Enhancers regulate genes over long genomic distances by physically looping to interact with promoters, a process highly dependent on specific protein recruitment and local histone modifications. We identified 1399, 1394, and 4063 enhancer-associated chromatin loops in GM12878, K562, and HepG2 cell lines, respectively, and found that dual-function proteins, characterized by both activating and repressing activities, preferentially localized at loop-anchored enhancers. Although protein co-localization patterns varied among cell types, CTCF, RAD21, SMC3, and ZNF143 consistently co-localized with one another at these enhancers. Furthermore, enhancer-associated loops localized primarily to the A compartment. Enhancers anchored in A-A loops showed greater enrichment of H3K4me1, H3K4me2, H3K9ac, and H3K27ac than those anchored in B-B loops. However, in K562 cells, enhancers anchored in B-B loops exhibited minor changes in active histone modification enrichment compared to their A-A counterparts, and even showed higher proportions of H3K4me2 and H3K9ac enrichment for enhancer–promoter loops. Nevertheless, across all three cell lines, A-A enhancer–promoter loops with both active anchors exhibited significantly higher target gene expression than other A-A loops and B-B loops. Our study suggests that enhancer-associated loop formation correlates with dual-function protein co-localization and active histone modification enrichment, which may collectively contribute to target gene transcription. Full article

Heat stress limits dairy production. The temperature-humidity index (THI), combining temperature and relative humidity, is widely used to assess heat stress. However, in Chinese Holstein cattle, the phenotypic responses of milk traits and genotype-environment interaction mechanisms under different THI conditions are understudied. Based on 63,334 records from 7240 cows (milk yield, fat percentage, protein percentage), matched with meteorological data and 113,297 SNPs, we employed a random-effects GWAS to examine SNP effects across a continuous THI gradient, comparing results with conventional, temperature-, and humidity-interaction GWAS. As THI increased, all traits declined with distinct patterns. Random regression GWAS identified 149 significant SNP × THI interactions (5 for MY, 86 for FP, 58 for PP), distributed across BTA5, BTA6, BTA14, and BTA20. Candidate gene annotation identified 52 candidate genes near significant SNPs, of which 50 core candidate genes were supported in both temperature and humidity GWAS. The most robustly supported core candidate genes include DGAT1, CPSF1, ABCG2, MGST1, VPS28, PPP1R16A, ZNF250, GRID2, KCNC2, and LOC787350—of which DGAT1, ABCG2, and MGST1 have been functionally validated in milk production traits, whereas others represent novel candidates requiring further investigation. Temperature and THI-GWAS showed high consistency, while humidity-GWAS detected both overlapping and specific signals. Incorporating THI as a continuous environmental gradient identifies environment-dependent regulatory signals not captured by conventional GWAS, providing candidate genes that may contribute to future breeding strategies after further validation. Full article

Aqueous zinc metal batteries are promising for safe and cost-effective energy storage. However, their practical application is limited by the intrinsic instability of the Zn/electrolyte interface, including water-induced hydrogen evolution, Zn corrosion, and dendrite-prone Zn deposition. Herein, glutaronitrile (GLN) is introduced as a multifunctional dinitrile additive to stabilize Zn metal anodes through coupled regulation of solvation chemistry and interfacial evolution. The polar C≡N groups of GLN can coordinate with Zn²⁺, to replace part of the water molecules in the primary solvation shell, thereby suppressing the activity of coordinated water. Meanwhile, uncoordinated C≡N groups act as hydrogen-bond acceptors to reorganize the surrounding water network, further suppressing free-water participation in hydrogen evolution and corrosion. This dual regulation optimizes the Zn/electrolyte interfacial environment, improves electrolyte wettability on Zn, homogenizes Zn²⁺ flux, and promotes compact, dendrite-suppressed Zn deposition. Additionally, GLN promotes the formation of a chemically heterogeneous interfacial structure enriched with ZnF₂ in the inner region, which further protects the Zn surface and stabilizes the Zn plating/stripping process. The optimized ZHG6 electrolyte enables Zn||Zn symmetric cells to cycle stably for over 900 h at 1 mA cm⁻² and 1 mAh cm⁻², while Zn||Cu cells maintain high Coulombic efficiency during long-term cycling. Furthermore, Zn||V₆O₁₃ full cells exhibit enhanced cycling stability and rate capability, achieving stable operation for 3200 cycles at 5 A g⁻¹. As evidenced in this work, dinitrile-based molecular additives provide an effective and scalable strategy to fabricate durable aqueous zinc metal batteries. Full article

Background: Parkinson’s disease (PD) is a progressive neurodegenerative disorder with a well- documented prodromal phase during which non-motor symptoms appear years before motor onset. Seborrheic dermatitis (SD) is a chronic inflammatory skin disease that is significantly more prevalent in PD patients than in the general population. The biological mechanisms underlying this association have not been integrated into a single framework. Objectives: This narrative review aims to synthesise the available evidence on the molecular, genetic, and pathophysiological mechanisms linking SD and PD. Methods: A literature search was conducted across PubMed/MEDLINE, Scopus and ScienceDirect, supplemented by manual searches in OMIM and GeneCards. Results: Four major biological links between SD and PD have been proposed. First, alpha-synuclein deposits are detectable in cutaneous nerve fibres and autonomic fibres innervating sebaceous glands in PD patients and their pattern has been associated with disease subtype and progression. Second, dysfunction in ceramide and sphingolipid metabolism, associated with variants in GBA1, LRRK2, and ZNF750, has been linked to impaired lysosomal function and skin barrier integrity in both brain and skin tissue. Third, Malassezia, a commonly associated organism and possible trigger in susceptible hosts, produces metabolites that activate neuroinflammatory pathways relevant to PD and PD patients show altered Malassezia species composition on their skin. Fourth, NLRP3 inflammasome activation, which can be triggered by ceramide accumulation and fungal metabolites, has been proposed as a shared inflammatory mechanism that may operate in both keratinocytes and dopaminergic neurons. Conclusions: SD and PD appear to share overlapping genetic, lipidomic, microbial, and neuroinflammatory features. These associations are consistent with, but do not yet prove, a common pathological basis rather than a coincidental one. SD may therefore represent a potential prodromal feature or risk marker of PD. Future research should examine whether targeted intervention in high-risk SD patients can delay or modify PD onset. Full article

MicroRNAs (miRNAs) are conserved post-transcriptional regulators that play essential roles in cellular development and differentiation. Although miRNAs involved in oligodendrocyte lineage cell (OLLC) differentiation have been extensively studied in rodent models, their functions in human oligodendrocyte (OL) development remain poorly understood. To address this, we used a human embryonic stem cell (hESC) reporter system and an optimized differentiation protocol to generate and isolate well-characterized OLLCs at defined developmental stages. Next-generation sequencing-based miRNA profiling identified stage-specific miRNAs associated with OL lineage specification and maturation. In addition to canonical OL-associated miRNAs, we identified several previously uncharacterized oligodendrocyte progenitor cell (OPC)/oligodendrocyte (OL)-enriched miRNAs, including miR-3943, miR-4286, miR-1296-5p, miR-488-3p, miR-675-5p, and miR-128-3p, as potential novel regulators and molecular markers for human OLLC development. Computational target analysis further identified candidate regulatory genes, including ZNF488, DLX1, CSNK2B, and KCNJ1, and predicted their association with AKT, SMAD2/3, estrogen-receptor, and insulin-signaling pathways. Together, these findings provide a comprehensive stage-specific miRNA resource for human OL lineage development and provide insight into potential miRNA-mediated regulatory networks governing human OL development. Full article

Growth traits, as core economic indicators in pig breeding, are closely associated with production costs, rearing duration, and final carcass quality and have thus consistently been a major focus of genetic improvement. This study aimed to identify candidate genes affecting Age to 120 kg live weight (AGE120), Backfat thickness at 120 kg (BF120), and Loin muscle depth at 120 kg (LMD120) in pigs. Ear tissue samples were collected from 3364 healthy adult pigs (including 558 boars and 2805 sows) from three breeds: Large White, Landrace, and Duroc. Genotyping was performed using an 80 K functional site array, and quality-controlled SNP (Single-Nucleotide Polymorphism) loci were subjected to genotype imputation, resulting in 15,447,611 loci obtained. Genome-wide association studies (GWASs) for Age to 120 kg live weight, Back fat thickness at 120 kg, and Loin muscle depth at 120 kg were conducted using a mixed linear model in Genome-wide Complex Trait Analysis (GCTA). Genes located within 500 kb upstream and downstream of significant GWAS loci were extracted using the biomaRt package in R. Furthermore, colocalization analysis was performed using expression Quantitative Trait Locus (eQTL) data of 34 tissues from the PigGTEx database to identify genes that share the same causal variant as the GWAS signals. Through integrated GWAS and eQTL colocalization analysis, in addition to five previously reported genes associated with pig growth traits (TAF11, ZC3HAV1L, ANKS1A, USP20, and TBC1D1), a set of novel, high-confidence candidate genes was identified: ZNF215, UBE2Z, HOXB7, SARDH, ADAMTSL2, ATP6V0A4, RPL10A, PGM2, and RELL1. These findings enrich our understanding of the genetic architecture underlying growth traits in pigs at heavy body weights and provide an important foundation for subsequent functional validation and molecular breeding applications. Full article

In order to reveal the molecular response characteristics of different tissues of Megalobrama amblycephala under ammonia nitrogen stress, the liver, gill, muscle, kidney and brain tissues of juvenile Megalobrama amblycephala (12.05 ± 0.04 g) under 25 mg/L ammonium chloride stress were used as the research objects. The transcriptome sequencing technology was used to systematically analyze the transcriptional expression changes. A total of 204.42 Gb transcription data were obtained, and a total of 3039 DEGs were detected, of which 1331 genes were up-regulated and 1708 genes were down-regulated. Ten DEGs were randomly selected for quantitative qRT-PCR analysis, and the results confirmed that the transcriptome results were reliable. Multi-organ synergy analysis suggested that overlapping DEGs (e.g., ZNF239, DMBT1, NLRC3, MHC-I, and CCL8) may exhibit similar or opposing regulatory patterns across organs, potentially reflecting complementary and coordinated mechanisms in immune regulation, inflammatory responses, energy allocation, and detoxification strategies among organ systems. GO and KEGG pathway enrichment analysis of differentially expressed genes showed that ammonia nitrogen mainly affected immune inflammation-related processes, material transport and degradation, protein homeostasis maintenance, oxidative stress defense, membrane lipid metabolism remodeling, and energy metabolism regulation. In different tissues, genes related to specific functions are enriched according to their physiological roles: in the liver, genes related to detoxification and damage clearance are enriched; in the gill, genes related to barrier defense and antioxidant/detoxification are enriched; in the kidney, genes related to damage response and metabolic regulation are enriched; in the brain, genes related to membrane lipid homeostasis and protective stress are enriched; and in the muscle, genes related to energy metabolism and structural function adjustment are enriched. This study elucidated the multi-tissue response characteristics of Megalobrama amblycephala under ammonia nitrogen stress at the transcriptome level, providing fundamental data and references for further clarifying the mechanisms of ammonia nitrogen toxicity in fish and screening stress-responsive marker genes. Full article

The sheep Y chromosome encodes genes essential for testicular development and spermatogenesis, yet their transcriptional dynamics across developmental and pathological states remain largely uncharacterized. Here, we profiled Y-linked gene expression using RNA-seq datasets from Hu sheep testes across postnatal development (0, 3, 6, 12 months) and from divergent testicular (large, normal, small, cryptorchid) and epididymal (large, small) weights. Developmental trajectory analysis of 134 expressed Y-linked genes revealed three distinct patterns: progressive activation from birth to sexual maturity (dominated by multicopy families ZNF280BY, HSFY, PRAMEY, TSPY3), progressive decrease, and stage-specific expression. Differential expression identified 41 Y-linked genes consistently downregulated in small, cryptorchid, and pre-pubertal testes compared with normal or large mature testes. Hierarchical clustering showed that 6-month-old small testes transcriptionally clustered with cryptorchid testes, not with immature or normal testes. In the epididymis, only one Y-linked gene was differentially expressed between large and small groups. Among X–Y gametolog pairs, most showed positive expression correlations in testes, whereas DDX3X/DDX3Y exhibited a significant negative correlation (ρ = −0.450, p = 0.0185); strikingly, this pair reversed to a positive correlation in the epididymis (ρ = 0.607, p = 3.29 × 10⁻⁵). In conclusion, Y-linked transcriptional profiles distinguish testicular pathology from normal maturation, and DDX3X/DDX3Y regulation is strictly tissue-specific. Full article

Host genetic susceptibility to urogenital Chlamydia trachomatis (Ct) reinfection remains poorly understood. Coding variants identified in prior genome-wide association studies (GWAS) explained only a small fraction of the risk of reinfection. Our goal in this study was to characterize whether more risk would be captured by sequence variation that traditional GWAS insufficiently captures. Specifically, we evaluated the risk attributable to SNPs present in regulatory, non-coding regions; post-transcriptional regulation by microRNAs (miRNAs) that may depend on sequence variation in either the miRNA or the target mRNA; and copy number variants (CNVs). We analyzed GWAS data from African American women with or without documented urogenital Ct reinfection. Fine mapping and independent association analyses identified 30 unique index single-nucleotide polymorphisms (iSNPs), which were expanded to variants in linkage disequilibrium. Regulatory annotation was performed using HaploReg, RegulomeDB, FORGEdb, rSNPBase, and GTEx. We examined whether genes identified in the Ct reinfection GWAS are targeted by known Ct infection–associated microRNAs using curated databases. Genome-wide CNV calling was conducted using SNP intensity data, followed by stringent quality control and gene-level association testing. Functional annotation prioritized 7 SNPs with strong regulatory evidence, with stringent criteria for regulatory relevance, using HaploReg, RegulomeDB, FORGEdb, and rSNPBase. The strongest signals were observed at the CHIT1 locus, where multiple intronic variants (including rs2486963 and rs2244385) overlapped regulatory chromatin, altered transcription factor binding motifs, and acted as cis-expression quantitative trait loci for CHIT1 in whole blood. Additional regulatory variants were identified near TDRP, ERICH1, and DLGAP1, showing tissue-specific regulatory effects. MicroRNA analysis revealed extensive post-transcriptional targeting of SOCS6 and SULF1, while CHIT1 showed no curated Ct-associated miRNA interactions. CNV analysis identified 5775 high-confidence events, with nominal gene-level associations observed for ATAD3A, CARD14, TMEM240, and ZNF140. These results indicate that a greater fraction of the susceptibility to urogenital Ct reinfection may be driven by genetic variation affecting immune and epithelial pathways rather than protein-coding changes. Full article

Background: Gene fusions play a pivotal role in the pathogenesis and classification of hematologic malignancies. RNA sequencing (RNA-seq) has emerged as a powerful tool for detecting gene fusions; however, many clinical studies have focused on targeted RNA-seq, and optimal parameters for whole transcriptome RNA-seq remain uncertain. Methods: We retrospectively analyzed whole RNA-seq data from 301 patients diagnosed with acute leukemia between October 2022 and May 2025 to characterize the landscape of pathogenic gene fusions. Fusions were identified using the Arriba algorithm, and subsampling analyses were performed on cases with recurrent fusions to determine the minimum sequencing output required for reliable detection. Results: Pathogenic gene fusions were identified in 113 of 301 patients (37.5%). Whole RNA-seq detected fusions that were not identifiable by conventional assays, including UBTF::ATXN7L3, and highlighted frequent fusion events, such as ZNF384 rearrangements. Subsampling analysis demonstrated that a sequencing output ≥ 100 million reads (moderate confidence) or ≥300 million reads (high confidence) was sufficient for 100% detection of recurrent fusions. Conclusions: Whole RNA-seq reliably detects clinically relevant gene fusions in acute leukemia, aligns well with conventional karyotyping results, and surpasses targeted RNA-seq in comprehensiveness. A sequencing output of at least 100 million reads is recommended for clinical fusion detection. Full article

The aim of the work was to identify the features of associations of single nucleotide polymorphisms (SNPs) that determine the level of sex hormones in the body with simple endometrial hyperplasia without atypia (EnH_s) in women with different body mass index (BMI). Two groups of BMI-differing subjects (BMI < 25 [n = 766]: 196 EnH_s, 570 control and BMI ≥ 25 [n = 727]: 324 EnH_s, 403 control) with a total number of 1493 women were formed to conduct this study. Nine SNPs meaningful for the level of sex hormones (proven in genome-wide association studies [GWAS]) such as rs34670419 [G>T] ZKSCAN5, rs148982377 [T>C] ZNF789, rs11031002 [T>A] FSHB, rs11031005 [T>C] FSHB, rs112295236 [C>G] SLC22A10, rs117145500 [A>C] CHD9, rs727428 [C>T] SHBG, rs1641549 [C>T] TP53, rs117585797 [C>A] ANO2 were considered by us. In general, in the studied sample (EnH_s/control, n = 1493), an association of interactions of rs148982377 [T>C] ZNF789 × BMI with EnH_s (OR = 1.11) was revealed. As a result of a comparative analysis, we found that rs148982377 [T>C] ZNF789 was associated with EnH_s in women with a BMI ≥ 25 (OR = 1.77) and was not linked with the disease in women with a BMI < 25. Both common protective factors for EnH_s were also identified in women with BMI ≥ 25 and BMI < 25 (rs11031002 [T>A] FSHB (OR = 0.43 and OR = 0.46 respectively) and rs11031005 [T>C] FSHB (OR = 0.46 and OR = 0.58 respectively)). At the same time, in the BMI ≥ 25 cohort, the risk effect of the TT*rs11031002-rs11031005 haplotype (OR = 3.27) was more pronounced, and the contribution of interlocus interactions of sex hormone genes with EnH_s formation was more significant (7 SNPs in 12 models) than in the BMI < 25 group (OR = 2.31 and 4 SNPs in 3 models). In conclusion, the presented work is exploratory and demonstrates differences in the nature of the association with EnH_s in women with different BMI of the testosterone-determining polymorphism: SNP rs148982377 [T>C] ZNF789 was associated with EnH_s in women with a BMI ≥ 25 and was not linked with the disease in women with a BMI < 25. Full article