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PubMed2026

Algae-to-host horizontal gene transfer in Paramecium bursaria is associated with host adaptation during endosymbiosis.

Paramecium bursaria maintains a stable endosymbiosis with green algae, yet the evolutionary consequences of this association remain unclear. Here, we screened the host genome for algal-derived horizontally transferred genes (HTGs) using a lineage-aware workflow designed to detect horizontal gene transfer (HGT) between two defined lineages. We identified 16 candidate HTGs, including four putative newly transferred genes and 12 homologous transferred genes, most of which were functionally associated with redox homeostasis and metabolism. Five HTGs showed symbiosis-dependent expression. RNAi knockdown of GH32s and SATs reduced host proliferation, total cell area, and motility, while GH32s knockdown also reduced endosymbiont load. Duplication patterns suggest that most transfers may have occurred after the P. bursaria lineage diverged from the sampled Paramecium species but before its lineage-specific whole-genome duplication (WGD). The HTGs also showed host-associated shifts in GC content and gene length, while representative HTGs retained conserved domains and functional motifs. Together, our results support algae-to-host HGT in P. bursaria and suggest that some transferred genes may contribute to metabolic integration during endosymbiosis.

Gene Transfer, Horizontal↗

PubMed2026

Stroke risk following BNT162b2 vaccination: a systematic review and meta-analysis of self-controlled case series studies.

INTRODUCTION: Whether BNT162b2 (Pfizer-BioNTech) vaccination increases stroke risk remains a public health concern. This is the first meta-analysis to synthesize self-controlled case series (SCCS)-derived stroke risk estimates specifically for BNT162b2 vaccination. METHODS: PubMed and Embase were searched from inception through 9 May 2026, following PRISMA 2020 guidelines. Eight eligible SCCS studies were pooled using a random-effects model with restricted maximum likelihood (REML) estimation and the Knapp-Hartung adjustment. RESULTS: Eight studies across six countries encompassing several million vaccinated individuals were included. The pooled incidence rate ratio (IRR) was 0.967 (95% CI 0.892-1.049; I2 = 69.2%), indicating no statistically significant increase in stroke risk. Subgroup analyses showed no evidence of effect modification across continent, risk-window length, dose category, SCCS variant, or age group. CONCLUSIONS: These findings provide no evidence of increased short-term stroke risk following BNT162b2 vaccination at the population level. The observed heterogeneity appeared to be partly driven by methodological differences rather than true biological variation in vaccine effect.

Humans↗

PubMed2026

Morphology-Encoded Colorimetric Hydrogen Sensing Using Embedded Reactive Pd Absorbers in Fabry-Perot Cavities.

Chemical reactions offer a powerful strategy for generating visible optical responses through localized changes in absorption, dielectric environment, and interfacial wetting. A palladium (Pd)-embedded Fabry-Perot cavity is introduced as a reaction-active optical platform in which structural color is governed by intracavity absorption coupled with reaction-induced dielectric perturbation. Positioning Pd within the dielectric spacer creates a spatially controllable reactive absorber whose vertical location relative to the standing-wave field dictates wavelength-selective absorption within the cavity. The morphology of the embedded Pd layer provides an additional design parameter by modulating both optical loss and interfacial wetting. Under hydrogen exposure in the presence of oxygen, catalytic water formation at the Pd/polymer interface generates localized dielectric heterogeneity and interfacial water droplets, thereby perturbing the optical path length and amplifying the visible response. As a result, the cavity exhibits pronounced, morphology-dependent color transitions that are inaccessible through dielectric-layer engineering or Pd/PdH refractive-index changes alone, enabling direct visual hydrogen sensing under ambient light, as well as flexible optical devices capable of large-area patterning. These findings establish a design framework for reaction-active optical cavities that translate localized chemistry into a colorimetric hydrogen sensing mechanism.

Fabry–Perot resonator↗

PubMed2026

A full review of online education resources available on antifungal stewardship.

BACKGROUND AND OBJECTIVES: Antifungal resistance represents an increasing global threat, driven by the rising burden of fungal disease. Antifungal stewardship (AFS) is a critical component of broader antimicrobial resistance (AMR) efforts, but education in this area remains less established than antibacterial stewardship initiatives. The scope and characteristics of the current landscape of online AFS resources have not yet been systematically described. To identify and evaluate online educational resources focused on fungal disease management and AFS, and assess their accessibility, format, educational design and implementation focus. METHODS: A structured search of internet search engines, distribution platforms and organizational websites was conducted to identify English-language web-based resources related to fungal disease management and stewardship. Resources were evaluated using predefined criteria including access model, format, length, educational design, interactivity and AFS content. An overall educational value score (1-10) was assigned. RESULTS: Twenty-three educational resources were identified. Most were delivered as online unfacilitated courses (11, 48%) and were short (<4 h) (12, 52%). Most focused on guidelines and syndromic management (18, 78%) and targeted doctors and/or nurses/midwives (22, 96%). Limited interactivity was reported in nine (39%) courses. Five courses (22%) had either a substantial or comprehensive focus on AFS. CONCLUSIONS: Online AFS educational resources are available and support awareness and knowledge development. However, they remain relatively few in number. Greater emphasis on implementation-focused learning, behaviour change components and broader global representation may enhance their impact.

Journal Article↗

PubMed2026

Transcriptomic analysis reveals the molecular mechanisms underlying the inhibition of Mytilus edulis attachment by biofouling control agents.

This study combined acute toxicity assays, phenotypic quantification, and transcriptomic profiling to systematically investigate the inhibitory effects and molecular regulatory mechanisms of a novel alkylamine-based antifouling agent on survival, byssus secretion, and attachment behavior of juvenile Mytilus edulis. The 96 h-LC50 of the agent to juvenile M. edulis was 8.84 mg/L, and 10 mg/L of the agent completely inhibited mussel attachment within 24 h, significantly reducing byssal thread number, length, and diameter while increasing detachment frequency, resulting in irreversible attachment failure. Transcriptomic analysis identified 2746 differentially expressed genes, which were mainly enriched in pathways including signal transduction, immune defense, stress response, cytoskeleton organization, and protein binding. KEGG and GSEA enrichment revealed that the antifouling agent activated the MAPK stress signaling pathway, disturbed transcriptional regulation, and impaired intracellular homeostasis and cytoskeletal stability, thereby synergistically suppressing the expression of key byssal protein genes including mfp-1 and mfp-3 and ultimately blocking byssus synthesis and adhesion. This study clarifies the multi-pathway molecular mechanism underlying antifouling agent-induced attachment inhibition in M. edulis, and provides core molecular targets and theoretical support for developing efficient, specific antifouling activity, and potentially applicable marine antifouling technologies.

Animals↗

PubMed2026

Complete mitochondrial genomes of eight cyclophyllidean tapeworms: genome pattern and phylogenetic analysis.

Cyclophyllidean tapeworms are widespread parasites of significant medical and veterinary importance. However, mitochondrial (mt) genomic resources for cyclophyllideans from China, particularly those recovered from wildlife hosts, remain comparatively limited. In this study, we sequenced and characterized the complete mt genomes of eight cyclophyllidean isolates collected from diverse wild and domestic hosts in China, including two Hymenolepis sp. isolates and two Raillietina sp. isolates from China, and four additional isolates of previously sequenced Taenia species. The circular mt genomes ranged from 13,387 to 14,021 bp in length, encoding 36 typical genes with variable non-coding regions. Comparative analysis revealed highly conserved gene composition and mostly conserved mt architecture, with localized rearrangement patterns detected among the cyclophyllidean lineages examined. In particular, all sampled Taeniidae exhibited a consistent trnL1-trnS2 arrangement, whereas the examined non-Taeniidae families showed the trnS2-trnL1 arrangement, confirming and extending, across additional wildlife-associated isolates, a previously proposed family-associated gene-order marker within Cyclophyllidea. Phylogenetic analyses based on concatenated amino acid sequences of the 12 protein-coding genes placed the eight isolates within their expected families, in topologies broadly consistent with previous mitogenomic studies. These data provide additional Chinese mitogenomic references, especially for underrepresented wildlife-associated isolates, and support family-associated gene-order patterns in Cyclophyllidea.

Animals↗

PubMed2026

Molecular Determinants and Therapeutic Targeting of Stop Codon Readthrough in Eukaryotic Translation.

Accurate translation termination is essential for proteome integrity and in eukaryotes is primarily governed by the release factors eRF1 and eRF3, which ensure precise recognition of stop codons and efficient release of nascent polypeptides. However, proteome integrity is challenged by mutations that generate premature termination codons (PTCs), leading to truncated, nonfunctional proteins and degradation of the aberrant transcript via nonsense-mediated mRNA decay (NMD). Collectively, these events account for ∼1800 human genetic diseases. Translational readthrough, the process by which near-cognate tRNAs decode stop codons and allow ribosomes to continue elongation beyond the stop codon, represents a possibility to suppress PTCs and restore full-length protein synthesis. Initially discovered in viruses as a mechanism to expand coding capacity, readthrough is now recognized as a regulated feature of eukaryotic gene expression influenced by both cis-acting sequence elements and trans-acting factors. Recent evidence highlights the remarkable context dependence of readthrough, revealing variation across transcripts, tissues, and developmental stages. In this review, we examine the molecular determinants that define stop codon recognition and readthrough efficiency, with particular emphasis on nucleotide context. We further discuss the mechanisms and binding sites of small molecules that promote PTC readthrough, and summarize the clinical development landscape of readthrough-inducing compounds for the treatment of diseases caused by nonsense mutations.

Humans↗

PubMed2026

Uncovering hidden complexity in the Apis mellifera mitotranscriptome: a polyadenylation-centered perspective.

Mitochondrial transcription is gaining increasing attention as researchers seek to better understand the full coding potential of mitochondrial DNA (mtDNA). Emerging evidence suggests that mtDNA may encode additional elements beyond classical oxidative phosphorylation genes, pointing to a more complex transcriptional architecture than previously recognized. In this study, we explored the mitochondrial transcriptome of Apis mellifera (Insecta: Hymenoptera), with a particular focus on polyadenylation-associated features. Our analysis revealed that both sense and antisense transcripts undergo polyadenylation, although transcript abundance and poly(A) tail lengths varied markedly across mitochondrial genes. Several transcripts exhibited alternative isoforms, either extended or truncated, frequently including intergenic regions. These regions may represent functional non-coding elements or structural variants rather than conventional untranslated regions (UTRs). Interestingly, some transcripts also contained non-templated nucleotide additions particularly cytosine residues immediately upstream of the poly(A) tails. Monocistronic units that included portions of downstream intergenic regions were among the most abundantly represented, suggesting a possible regulatory role for these sequences. To experimentally validate our in silico findings, we performed RT-qPCR to assess relative gene expression and applied 3' RACE-PCR to define transcript boundaries. These approaches confirmed the presence of multiple transcript isoforms and supported the involvement of polyadenylation in shaping mitochondrial RNA diversity. Together, our findings reveal a previously underappreciated level of complexity in the A. mellifera mitochondrial transcriptome and highlight the potential regulatory significance of polyadenylation dynamics and intergenic region transcription.

Animals↗

PubMed2026

The circadian clock proteins PRR modulate root hair development via the RHD6/RSL module in Arabidopsis.

Root hairs, derived from trichoblasts, are critical for plant growth and environmental adaptation. Although environmental cues are known to influence root hair development, how endogenous timing systems such as the circadian clock integrate into the core transcriptional network governing root hair formation remains unclear. Here, we show that the circadian clock-associated protein PSEUDO-RESPONSE REGULATOR5 (PRR5) physically interacts with ROOT HAIR DEFECTIVE6 (RHD6) and RHD6 LIKE1 (RSL1), two basic helix-loop-helix transcription factors essential for root hair initiation. Genetic analyses suggest that PRR proteins contribute to root hair development under long-day conditions in Arabidopsis thaliana. Simultaneous disruption of PRR5, PRR7, and PRR9 results in defective root hairs, whereas PRR5 overexpression markedly increases root hair density and length. Transcriptomic and RT-qPCR analyses reveal that PRRs enhance the expression of RHD6, RSL1, and multiple downstream root hair-responsive genes, while modulating their temporal expression patterns. Furthermore, PRR5-mediated root hair promotion requires RHD6/RSL1, and PRR proteins enhance RHD6-dependent activation of the RSL4 promoter. PRRs also contribute to root hair development under phosphate-deficient and salt-stress conditions. Together, these findings establish a molecular framework in which PRR proteins regulate the RHD6/RSL network to coordinate root hair development and environmental responses.

Arabidopsis↗

PubMed2026

Effects of Vacuum Compression Therapy on Healing of Chronic Lower Limb Ulcers: A Randomised Controlled Study.

Chronic lower limb ulcers remain difficult to manage when unresponsive to conventional treatment. This study evaluated the clinical and physiological effects of vacuum compression therapy on wound healing and quality of life. Fifty patients with chronic lower limb ulcers were randomised to receive 12 sessions of vacuum compression therapy plus standard care or standard care alone over 4 weeks. Wound dimensions, exudate, pain intensity and quality of life were assessed at baseline and post-treatment. Estimated wound volume was calculated as length × width × depth. Tissue oxygenation was measured at the dorsum of the foot in the experimental group. The vacuum compression therapy group showed greater improvements in wound width, depth, volume and quality of life. Estimated wound volume decreased by 61% in the intervention group, whereas no statistically significant volume reduction was observed in controls. Local tissue oxygenation in the experimental group increased by 43%. Baseline wound size was associated with poorer quality of life. Vacuum compression therapy may enhance wound healing and quality of life in patients with chronic lower limb ulcers. Observed increases in local tissue oxygenation represent exploratory physiological findings within the treated cohort that warrant controlled comparative evaluation. Trial Registration: ClinicalTrials.gov identifier: NCT07737184.

Humans↗

PubMed2026

The Complete Mitochondrial Genome of a Newly Recorded Chinese Species of Diglyphus sabulosus (Hymenoptera: Eulophidae) and Insights into Its Phylogenetic Position.

Diglyphus Walker, 1844 is an economically important genus which many species acting as biocontrol agents against agromyzid leafminer pests, but there is a lack of mitogenomic data on the evolutionary relationships within this genus, hindering a comprehensive understanding of its evolutionary history. We used traditional morphological methods to identify species, and present the first complete mitochondrial genome sequence and characterization of features of Diglyphus sabulosus and further infer its phylogenetic position based on the amino acid sequences of 13 protein-coding genes (PCGs). The complete mitochondrial genome of D. sabulosus is 15,690 bp in length, including 13 PCGs, 22 transfer RNA genes, 2 ribosomal RNA genes and a control region. The AT content of the whole genome sequence was 81.0%, indicating a significant AT bias. All protein-coding genes have the typical ATN as the start codon and TAA as the stop codon. Phylogenetic analysis inferred from the amino acid sequences of 13 PCGs revealed that all species within the family Eulophidae constituted a monophyletic clade, supporting the monophyly of this family. D. sabulosus and D. poppoea form a well-supported sister group, representing the species with the closest phylogenetic relationship within the analyzed taxa. In this study, the mitogenome structure was analyzed and the taxonomic status of D. sabulosus was clarified, thus providing a theoretical basis for understanding the phylogenetic relationships of Diglyphus.

Animals↗

PubMed2026

Exploratory identification and cellular functional characterization of ppiabl as a candidate gene associated with growth traits in Paralichthys olivaceus.

The Japanese flounder (Paralichthys olivaceus) is an important mariculture species. However, the genetic mechanisms underlying its growth traits remain poorly understood. To explore the genetic basis of growth variation, whole-genome resequencing was performed in a cultured cohort of 60 individuals, followed by exploratory genome-wide association analysis and candidate-gene prioritization. The results revealed heritability estimates of 0.40 for body weight and 0.24 for body length, with substantial overlap in associated loci between the two traits. Exploratory association and variant-annotation analyses prioritized ppiabl, which carries a nonconservative missense variant, as a candidate gene for further investigation. Tissue expression analysis showed that ppiabl was highly expressed in muscle tissue. This gene encodes a protein belonging to the conserved peptidyl-prolyl cis-trans isomerase family. In Japanese flounder primary muscle cells, ppiabl knockdown was associated with altered expression of growth-related genes and an increased G1-phase fraction, whereas overexpression produced changes in the opposite direction. In line with this, fast-growing individuals were found to have significantly larger muscle fiber areas than slow-growing ones. These findings suggest that ppiabl may be involved in muscle-related cellular processes associated with growth variation in Japanese flounder, although its contribution to whole-animal growth requires further validation. Overall, this exploratory study prioritizes ppiabl as a candidate gene potentially associated with growth-related cellular processes in Japanese flounder, although validation in larger independent populations and in vivo models is required.

Animals↗

PubMed2026

Genome-wide identification of the peanut HD-Zip gene family and AhHDZ15 positively regulating salt and drought stress in heterologously overexpressed Arabidopsis.

Homeodomain-leucine zipper (HD-Zip) transcription factors play important roles in plant growth, development, and abiotic stress responses. However, bioinformatic analyses and functional studies of HD-Zip family in peanut are scarce. In this study, 128 AhHDZ genes were identified and classified into four subfamilies in the phylogenetic analysis. Transcriptomic data and RT-qPCR analysis indicated the expression levels of AhHDZ4 and AhHDZ15 were significantly elevated in response to 12 h of salt stress, while AhHDZ4/15/60/69/126 all showed a progressive increase over time in response to drought stress. AhHDZ15 protein was localized in the nucleus. Under salt and drought stress, the germination rates of AhHDZ15-overexpressing in Arabidopsis were significantly higher than wild-type (WT), and root lengths were also significantly longer than WT. In addition, the SOD, CAT, chlorophyll content, and Relative Leaf Water Content (RLWC) value of leaves in AhHDZ15-overexpressing lines were significantly higher than WT, while the MDA content was significantly lower than WT. The above results indicate that heterologous overexpression of AhHDZ15 enhanced salt and drought tolerance in Arabidopsis. Furthermore, AhHDZ15 could bind to the L1-box element of the AhVNI2 promoter, thereby activating AhVNI2 transcription and enhancing the expression of downstream salt stress-responsive genes. These findings implies a potential function of AhHDZ15 in peanut that requires further validation.

Arabidopsis↗

PubMed2026

Distinct cell morphotypes of Aureobasidium melanogenum ZN exhibit differential functional profiles in promoting maize growth.

Black yeast-like fungi of the genus Aureobasidium exhibit morphological plasticity, but whether distinct cellular states within the same genetic background are associated with different plant growth-promoting functions remains unclear. Here, yeast-like cells (YL), swollen cells (SC), and chlamydospores (CH) of Aureobasidium melanogenum ZN were characterized. YL was associated mainly with siderophore production and laccase activity, SC with extracellular polysaccharide accumulation, and CH with phosphate mobilization and higher ammonia and IAA production. Whole-genome and comparative genomic analyses revealed a shared repertoire related to nutrient acquisition, auxin-associated metabolism, extracellular oxidation, and carbohydrate remodeling, with expansions in nutrient- and cell-surface-related gene families. Transcriptomic and metabolomic analyses showed distinct deployment of these capacities, with CH exhibiting broad reprogramming of tryptophan-associated, nitrogen, phosphate, central-carbon, and amino-acid metabolism. In maize, CH at the optimal inoculation concentration of 105 CFU·mL-1 produced the strongest growth promotion, increasing plant height, dry biomass, root length, root surface area, and root volume by 58.6%, 365.1%, 191.0%, 194.3%, and 222.4%, respectively. Consistent with this pronounced growth phenotype, maize root transcriptomics showed coordinated CH-induced responses involving root development, nutrient transport, redox regulation, and root-interface remodeling. Root-zone tracking showed greater short-term stability and persistence of CH. These findings identify cellular state as an important functional dimension of Aureobasidium-plant interactions and provide a basis for developing fungal inoculants with defined beneficial cellular states.

Zea mays↗

PubMed2026

Muscular fiber properties and multi-omics investigation of larval and adult locomotor muscle in Microhyla fissipes.

During metamorphosis, Microhyla fissipes undergoes a critical transition from an aquatic to a terrestrial lifestyle, accompanied by significant remodeling of skeletal muscle. Notably, larval tail muscle degenerates, while adult hindlimb muscle develops. However, the molecular mechanisms that orchestrate these muscle type-specific adaptations to the changing environment remain unclear. In this study, histological observation, transcriptomics, and metabolomics were integrated to compare locomotor muscles from two stages: larval muscle from tail versus adult muscle from hindlimb. Our results revealed that adult muscle fibers exhibited reduced diameter and shorter sarcomere length compared to those of tadpoles. Transcriptomic analysis identified 4103 differentially expressed genes (DEGs), including 2182 up-regulated and 1921 down-regulated genes. Up-regulated genes were mainly involved in energy metabolism and cellular homeostasis pathways, including PPAR signaling and oxidative phosphorylation, whereas down-regulated genes were associated with carbohydrate metabolism and cell proliferation pathways, such as glycolysis/gluconeogenesis and PI3K-Akt signaling. Metabolic profiling indicated a metabolic shift from anaerobic to aerobic energy production, with 57 differential metabolites identified, mainly involved in protein metabolism and insulin-related pathways. Integrated multi-omics analysis further highlighted the AMPK and FoxO signaling pathways play key roles in this process. In conclusion, our findings demonstrate that the metabolic and structural differences between larval and adult skeletal muscles are mediated by AMPK- and FoxO-dependent signaling pathways, providing novel insights into the molecular mechanisms underlying adaptive development and locomotor transition in anuran amphibians.

Animals↗

PubMed2026

Barefoot ambulation following partial foot amputation: A systematic review of biomechanical outcomes.

BACKGROUND: Partial foot amputation (PFA) is increasingly performed due to rising prevalence of diabetes and peripheral vascular disease. While PFA may preserve gait and reduce energy expenditure compared with transtibial amputation, biomechanical deficits are common. This review aimed to evaluate biomechanical outcomes during baref following PFA. METHODS: A systematic review was conducted. MEDLINE, Embase, CINAHL, SCOPUS and Web of Science databases were searched for studies reporting biomechanical outcomes in adults with PFA without prosthesis. Eligible outcomes included spatiotemporal metrics, joint kinematics and kinetics, plantar pressures, and ground reaction forces. FINDINGS: Twelve studies including a total of 101 participants met inclusion criteria. Across studies, PFA was associated with impaired barefoot gait. This included spatiotemporal changes, such as reduced walking speed and shorter step length, and kinetic changes, such as reduced ankle power. Elevated plantar pressures were commonly reported, particularly in the forefoot and midfoot, highlighting loading abnormalities in the residuum. Several studies also described proximal compensatory strategies at the knee and hip, suggesting that biomechanical consequences extend beyond the foot and ankle. However, the evidence base was limited by small sample sizes, inconsistent protocols, and substantial heterogeneity. INTERPRETATION: Barefoot walking is impaired after partial foot amputation and the degree of dysfunction may vary by amputation level. Abnormal loading and compensatory changes may extend beyond the foot and ankle to the knee and hip. Given the limited and methodologically heterogeneous evidence, larger prospective studies with standardised biomechanical outcomes are needed to clarify the effects of amputation level and aetiology. This standardisation is important to inform surgical planning, rehabilitation, and prosthetic device design.

Humans↗

PubMed2026

Continuous Ultrasound-guided Erector Spinae Plane Block Versus Thoracic Paravertebral Block for Postoperative Analgesia in Patients Undergoing Thoracotomy.

OBJECTIVES: To compare postoperative analgesia using continuous ultrasound-guided erector spinae plane block (ESPB) versus thoracic paravertebral block (TPVB), with dynamic visual analog scale (VAS) during coughing as the primary outcome. Secondary outcomes included static VAS (at rest), hemodynamic changes, side effects, total opioid consumption, time of first rescue analgesia, length of hospitalization, anesthesia recovery time, postanesthesia care unit stay, time to first ambulation, and patient satisfaction. METHODS: The study included 40 cases scheduled for elective thoracotomy admitted to the cardiothoracic surgery unit of Menoufia University Hospital. Patients were equally randomized into 2 groups, 20 patients each receiving either ultrasound-guided ESPB or TPVB (control group). Both groups received 20 mL of 0.25% bupivacaine as a loading dose followed by continuous infusion of 0.125% bupivacaine at 5 mL/h, with patient-controlled boluses of 20 mL on demand. RESULTS: Dynamic visual analogue pain scale scores were significantly lower in the ESPB group at 6, 9, 12, and 24 hours ( P =0.008, 0.035, 0.001, 0.006). Morphine consumption was significantly reduced in the ESPB group ( P < 0.001). Hypotension was more frequent in TPVB (40% vs. 10%, P =0.028). No significant differences were observed in hospital stay or patient satisfaction. DISCUSSION: The utilization of continuous ultrasound-guided ESPB demonstrated better postoperative visual analogue pain scale scores and a significant decrease in opioid consumption, with fewer side effects than TPVB.

Humans↗

PubMed2026

Genetic regulation of CPEB3-mediated alternative polyadenylation associated with survival of patients with hepatocellular carcinoma.

BACKGROUND: Alternative polyadenylation (APA) is a key post-transcriptional mechanism that regulates gene expression by modulating 3'UTR length, its dysregulation has been implicated in carcinogenesis. How genetic variants influence APA to affect hepatocellular carcinoma (HCC) prognosis remains unclear. METHODS: Prognosis-APA quantitative trait loci (apaQTL) were performed using genotype and APA profiling from TCGA data. A two-stage survival analysis in 848 Chinese and 369 TCGA LIHC patients and functional validation were used to identify prognostic apaQTL in HCC progression. RESULTS: A total of 2,025 and 817 significant APA events were identified in Chinese and TCGA cohort, respectively. Besides, 859 events were associated with poor prognosis in HCC and enriched in RNA splicing / metabolism pathways. We detected 32,034 significant apaQTLs, predominantly enriched in 3'UTRs and RBP-binding regions. CPEB3 was prioritized as a key APA regulator RBP; its low expression correlated with poor patient survival and promoted proliferation, migration, and invasion in HCC cells. Notably, a functional apaQTL variant rs2037547, located in GSK3B and mediated by CPEB3, demonstrated a poor survival of HCC patients in both cohort (pooled HR=1.29, p=0.016). Mechanistically, rs2037547 promoted aberrant APA at proximal poly(A) sites of GSK3B through CPEB3, leading to increased expression of short 3'UTR isoform. This regulatory alteration enhanced HCC cell proliferation, invasion, and migration, and contributed to HCC progression. CONCLUSION: These findings elucidated the distinct role of apaQTL-mediated APA dysregulation in HCC prognosis, providing insights for prognostic stratification and potential targets for personalized therapy in HCC.

RNA-binding proteins↗