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PubMed2026

Inheritance of the epigenetic signature and reduced intermuscular bone phenotype acquired via DNA methylation editing of the runx2 b promoter in zebrafish.

The presence of intermuscular bones (IBs) can directly affect the economic value of aquaculture fish. Although genome editing can create IB-free fish by knocking out key IB-related genes, such as runx2b, the associated DNA sequence alterations raise food safety and health concerns, limiting its breeding applications. In this study, we used CRISPR/dCas9-mediated epigenome-editing technology targeting the runx2 b promoter in zebrafish to alter DNA methylation patterns without changing the DNA sequence. Our results showed that higher runx2 b promoter methylation patterns significantly inhibited eGFP mRNA expression levels in the recombinant plasmid. Using the CRISPR/dCas9-Dnmt7 system to enhance methylation of the zebrafish runx2b promoter, we observed a significant decrease in runx2 b mRNA expression levels in the F0 generation. The IBs in the 11 th-16 th muscle segments of the adult F0 fish were significantly shorter compared with the controls. Inbreeding of fish was used to produce F1 and F2 offspring that retained these high promoter methylation levels, along with persistent runx2b expression suppression and IB development inhibition. Transcriptome sequencing analysis suggested that increasing runx2 b promoter methylation levels may synergistically induce additional epigenetic modifications, potentially affecting the PPAR signaling pathway and FoxO transcription factor regulation, which appears to inhibit osteoblast proliferation and differentiation. Overall, this study demonstrates an innovative application of epigenetic editing technology for aquaculture breeding. By precisely regulating the expression patterns of key genes for economically important traits while preserving genomic DNA integrity, this approach provides a theoretical foundation and technical support for improving fish economic traits.

Animals↗

PubMed2003

Interaction of soft condensed materials with living cells: phenotype/transcriptome correlations for the hydrophobic effect.

The assessment of biomaterial compatibility relies heavily on the analysis of macroscopic cellular responses to material interaction. However, new technologies have become available that permit a more profound understanding of the molecular basis of cell-biomaterial interaction. Here, both conventional phenotypic and contemporary transcriptomic (DNA microarray-based) analysis techniques were combined to examine the interaction of cells with a homologous series of copolymer films that subtly vary in terms of surface hydrophobicity. More specifically, we used differing combinations of N-isopropylacrylamide, which is presently used as an adaptive cell culture substrate, and the more hydrophobic, yet structurally similar, monomer N-tert-butylacrylamide. We show here that even discrete modifications with respect to the physiochemistry of soft amorphous materials can lead to significant impacts on the phenotype of interacting cells. Furthermore, we have elucidated putative links between phenotypic responses to cell-biomaterial interaction and global gene expression profile alterations. This case study indicates that high-throughput analysis of gene expression not only can greatly refine our knowledge of cell-biomaterial interaction, but also can yield novel biomarkers for potential use in biocompatibility assessment.

Cell Adhesion↗

PubMed2025

Genomic subtypes of non-muscle-invasive bladder cancer: guiding immunotherapy decision-making for patients exposed to aristolochic acid.

BACKGROUND: The limited genomic data on non-muscle-invasive bladder cancer (NMIBC) hampers our understanding of its carcinogenesis and development. Specifically, Aristolochic acid (AA), a potent human carcinogenic compound from aristolochia plants and commonly found in Chinese herbal medicine, has been extensively documented as being closely associated with the onset and progression of bladder cancer. However, the field of AA-induced NMIBC remains largely unexplored in terms of its genomic and molecular characteristics, as well as clinical therapeutic strategies. METHODS: To bridge this knowledge gap, we conducted a comprehensive study using a cohort of 81 NMIBC samples. We performed whole-exome sequencing (WES) and RNA sequencing (RNA-seq) to obtain detailed genomic and transcriptomic data. We subjected these datasets to genomic analysis and subtype analysis to gain valuable insights into NMIBC. RESULTS: By temporally dissecting mutations in NMIBC specimens, we identified a comprehensive mutational landscape of NMIBC and the associations of these mutations with recurrence-free survival. Additionally, we discerned four genomic subtypes of NMIBC: AA-like, FGFR3/HRAS, FGFR3 & chr9Del, and genome instability (GI). The AA-like subtype presented a high frequency of gene mutations along with a pronounced AA mutagenesis signature of SBS22 (Fisher test: P-value 3.5e-4, OR 25.25) even after temporal dissection. The FGFR3/HRAS subtype exhibited FGFR3 or HRAS mutations with few copy number alterations (CNAs). The FGFR3 & chr9Del subtype was characterized by the co-occurrence of chr9p and chr9q deletions as well as FGFR3 mutations, while the GI subtype showed a high frequency of CNAs. Notably, the AA-like and GI subtypes demonstrated better outcomes after immunotherapy, whereas the FGFR3/HRAS subtype showed poorer outcomes. CONCLUSIONS: Our findings provide novel perspectives on the genomics of NMIBC, unveiling four prominent genomic subtypes, each showing different outcomes following immunotherapy. TRIAL REGISTRATION: No. 2019PHB268-01 (retrospectively registered on February 14, 2020).

Humans↗

PubMed2003

Cardiac transcriptome analysis in obesity-related hypertension.

Obesity is associated with volumetric arterial hypertension and with early increase in heart rate and decreased heart rate variability. The consequences of obesity-related hypertension on heart gene regulation are poorly known and were investigated in a model of obesity-related hypertension induced by high fat diet in dogs. When compared with control animals (n=6), a 9-week high fat diet (n=6) provoked significant weight gain and increased blood pressure load and heart rate but failed to significantly change left ventricular mass assessed by echocardiography. Subtractive hybridization of dog heart cDNA libraries were used to generate sublibraries containing differentially expressed cDNAs that were in turn spotted onto membranes to create custom microarrays. Hybridizations of these microarrays with complex probes representing mRNAs expressed in right atria and left ventricles from obese hypertensive and control dogs were performed. Thirty-eight differentially expressed genes were identified; altered expression was confirmed by Northern blot analysis in 15. In addition, real-time quantitative polymerase chain reaction confirmed differential expression for 80% of the randomly chosen tested genes. Once identified, transcripts were categorized into groups involved in metabolism, cell signaling, ionic regulation, cell proliferation, protein synthesis, and tissue remodeling. In addition, we found a set of 11 cDNAs encoding proteins with unknown functions. This study clearly shows that obesity-related hypertension, lasting for only 9 weeks, causes marked changes in gene expression in right atrium as well as the left ventricle that may contribute to early functional changes in heart function and to long-term structural changes such as left ventricular hypertrophy and remodeling.

Animals↗

PubMed2026

FANCI promotes esophageal squamous cell carcinoma progression and cell cycle regulation and interacts with FANCD2.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is an aggressive malignancy with poor clinical outcomes, and reliable molecular biomarkers and therapeutic targets remain limited. Fanconi anemia group I protein (FANCI) is a core component of the Fanconi anemia (FA) pathway, but its expression pattern, clinical significance, and functional role in ESCC have not been comprehensively defined. This study aimed to investigate FANCI expression and prognostic value in ESCC, assess its effects on malignant cellular phenotypes and tumor growth, and explore its potential mechanistic relationship with Fanconi anemia group D2 protein (FANCD2) and cell-cycle regulation. METHODS: Multi-cohort analyses were performed using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets, together with ESCC single-cell RNA sequencing (RNA-seq) data. FANCI functions were assessed by bidirectional gain- and loss-of-function experiments in vitro (proliferation, colony formation, migration, invasion, apoptosis, and cell-cycle assays) and by xenograft models in vivo. Mechanistic studies included protein-protein interaction (PPI) analyses, co-immunoprecipitation (Co-IP), and immunofluorescence (IF) colocalization. RESULTS: FANCI was consistently upregulated in ESCC across bulk transcriptomic datasets and was further supported by quantitative polymerase chain reaction (qPCR), Western blotting, and immunohistochemistry (IHC). FANCI discriminated ESCC from normal tissues in TCGA-ESCC and was independently validated in GSE53624 [area under the curve (AUC) =0.940 and 0.975, respectively]. FANCI was associated with poorer overall survival (OS) and shorter disease-free interval (DFI), and these findings were validated in an independent GEO cohort. Functionally, FANCI promoted ESCC cell proliferation, migration, and invasion, while inhibiting apoptosis; FANCI knockdown suppressed tumor growth in vivo and induced G2/M cell-cycle arrest. Mechanistically, FANCI physically interacted with FANCD2, colocalized with FANCD2 in the nucleus, and was associated with altered FANCD2 protein abundance, consistent with cell-cycle and DNA repair-related programs. Single-cell analysis indicated that FANCI was enriched in epithelial cells and associated with higher activity of malignant functional programs. In TCGA-ESCC, FANCI-high tumors showed distinct mutation profiles, a trend toward increased tumor mutation burden (TMB), and altered immune-associated signatures. CONCLUSIONS: FANCI is upregulated in ESCC and is associated with diagnostic and prognostic value. It promotes malignant phenotypes and tumor growth, potentially through a FANCI-FANCD2-linked cell-cycle/DNA repair program, supporting FANCI as a candidate biomarker and therapeutic target in ESCC.

Esophageal squamous cell carcinoma (ESCC)↗

PubMed2026

Transposable Element Dynamics Drive the Genomic Evolution and Phenotypic Diversification of Allotetraploid Common Carp.

An important question in evolutionary biology is how polyploidization generates raw material for phenotypic diversification. Transposable elements (TEs) represent an underestimated source of genetic variation in eukaryotic genomes. By integrating 516 whole-genome resequencing datasets and 236 transcriptomes from common carp (Cyprinus carpio), a representative allotetraploid fish, we constructed the first population-scale landscape of TE insertions in teleosts. TE insertions are widespread in the carp genome and preferentially associated with stress-responsive genes, with DNA transposons as major contributors. Relaxed purifying selection and TE burst events coexist, generating abundant variation for subsequent subspecies differentiation. Compared with a closely related diploid species, carp exhibits more exonic TE insertions and shorter TE-gene distances, and multiple TE superfamilies expanded during tetraploidization. Genome-wide association analyses uncovered intragenic TE variants underlying domesticated traits missed by SNPs, including DNA transposon deletions associated with scale reduction and altered body shape. Notably, lighter-colored individuals harbor homozygous deletions of LTR and DNA transposons within mdfic2, whose knockout in zebrafish reduces pigmentation. Most trait-associated variants reflect lineage-specific loss of ancient TE insertions rather than recent transposition. Overall, these findings highlight the distinct role of TEs in polyploid genome evolution and phenotypic diversification, providing new insights into TE dynamics in vertebrates.

allotetraploidization↗

PubMed2026

Single-cell RNA sequencing reveals disease associated changes in brain endothelial cells in the 5XFAD mouse.

Vascular dysfunction is a key contributor to Alzheimer’s disease (AD) pathology, where changes to the endothelium and its crucial role in maintaining blood-brain barrier (BBB) integrity have been of particular emphasis. The transgenic 5XFAD (5X Familial Alzheimer’s Disease) mouse model, which exhibits AD-related amyloidosis through FAD associated mutations in amyloid precursor protein (APP) and presenilin-1 (PS1), has become a widely adopted preclinical model in AD-related research studies. The need for cross-study standardization, accessibility, and data reproducibility has led to the widespread implementation of the C57BL/6J genetic background for maintaining this model. However, its reliability for studying vascular dysfunction and BBB alterations has been questioned due to conflicting reports in the literature. This variation is often attributed to the previously documented protective nature of the C57BL/6J background and loss of genetic background diversity. Since prior studies have mostly relied on imaging or functional assays, we herein utilized single-cell RNA sequencing (scRNAseq) to investigate AD-related molecular changes to endothelial cell populations in the 5XFAD mouse model. To initially build this resource, we focused on 12-month-old male mice, which revealed differentially expressed genes between 5XFAD and wildtype animals that mapped to signaling pathways involved in DNA damage, immune reactivity, and inflammation, among others. Many of these transcriptomic changes were zonated along the arteriovenous axis and occurred in AD genome-wide association study (GWAS) risk-associated genes. Overall, we anticipate this resource will help clarify the use of the 5XFAD model for studying AD-associated vascular changes and provide the foundation for expanded molecular profiling of brain endothelial cells under AD-associated conditions.

Animals↗

PubMed2026

Oxidative Stress Associated LncRNAs as Potential Biomarkers for Prognosis and Immune Responses in Lung Squamous Cell Carcinoma Patients.

Long-chain non-coding RNA (lncRNA) significantly influences lung squamous cell carcinoma's (LUSC) prognostic value and immune infiltration. This study aimed to demonstrate how oxidative stress-related lncRNAs impact lung squamous cell carcinoma (SCC). The Cancer Genome Atlas (TCGA) dataset gathered transcriptome information and related clinical data for LUSC. To build a prognostic model, 10 prognostic-related genes were identified using a series of bioinformatics analyses that compared the OS gene's aberrant expression in tumor and healthy tissues, as well as its association with malignancy. Subjects were stratified into high- and low-risk groups based on the median risk score derived from the 10-gene signature. While the mathematical risk model demonstrated limited independent predictive performance in the validation cohort (AUC ~ 0.5), functional and immunological evaluations revealed significant differences in the tumor microenvironment (TME) across risk strata. Specifically, high-risk patients exhibited distinct immune infiltration profiles and altered immunological scores relative to their low-risk counterparts. Therefore, rather than serving as a direct clinical prediction tool, this oxidative stress-related lncRNA signature provides valuable biological insights into the immune landscape of LUSC and highlights potential therapeutic targets for further mechanistic investigation.

Humans↗

PubMed2025

Deleterious, protein-altering variants in GSPT2 are putatively associated with an X-linked neurodevelopmental disorder with intellectual disability, language impairment, autism, and epilepsy.

PURPOSE: Approximately 6% of individuals with neurodevelopmental disorders are predicted to be X-linked, and the GSPT2 gene, located at Xp11.22, has not yet been associated with any Mendelian disease. METHODS: To establish genotype-phenotype associations between GSPT2 and neurodevelopmental disorders, clinical investigations were performed in unrelated individuals, genomic and functional studies were conducted on the participants' blood and heterologous cell system. RESULTS: We described 6 individuals from 6 unrelated families carrying hemizygous variants in GSPT2 with intellectual disability, delayed speech and language development, autism spectrum disorder, epilepsy, or abnormal fetal neurodevelopment. Structural molecular modeling revealed significant deleterious effects of the identified variants. GSPT2 is preferentially enriched in the brain and cerebellum compared with other tissues. GSPT2-deficient H4 neuroglioma cells slow down the proliferation and downregulate the expression of cell-cycle-related genes. Transcriptomics revealed that GABAergic and calcium-signaling-related genes were significantly downregulated in GSPT2-deficient cells. Consistent with the transcriptomic data, RT-PCR analysis verified the marked downregulation of critical genes (CACNA1B, etc) in GSPT2-knockout cells and further confirmed these findings with proteomic profiling. CONCLUSION: Our data suggest a putative GSPT2-related X-linked neurodevelopmental disorders through dysregulation of cell-cycle progression and calcium/GABAergic signaling pathways.

Humans↗

PubMed2026

Host immunological response of Ross 308 broilers fed an anti-IL-10 antibody to Eimeria and Clostridium perfringens challenge.

Understanding host response mechanisms may lead to improved management of poultry diseases such as necrotic enteritis. Ross 308 broilers (20 birds/cage, 32 cages) received diets ± anti-interleukin-10 (IL-10) antibody, an intervention to improve immune activation, in three experimental replicates (R1, R2, R3). R1 and R2 received 1 × 108 colony forming units (CFU) Salmonella Typhimurium on day (d) 1. On d 14, birds were assigned to unchallenged control or 15,000 sporulated Eimeria maxima oocyst gavage challenge, with a subset receiving E. maxima + Clostridium perfringens (1 × 10⁸ CFU d 18-19) to induce necrotic enteritis. Intestinal tissue and digesta samples were collected from 6 birds/treatment at baseline (d 14), peak infection (d 21), and post-peak infection (d 25) to measure luminal IL-10 (ELISA), interferon gamma (IFNγ) via immunohistochemistry, and IL-10, CD4, CD8, CD25, and KUL01 via RNAscope. Data were analyzed via two-way ANOVA (P ≤ 0.05). In R3, baseline duodenal IL-10 was 458 ng/mg protein greater in birds fed the control diet, while E. maxima + C. perfringens inoculation increased jejunal and ileal IL-10 content by 528 and 649 ng/mg protein at peak infection (P < 0.05). In R2, peak jejunal tissue % IL-10 area increased during E. maxima + C. perfringens challenge (P < 0.05). Baseline and peak jejunal R3 RNA was sequenced on an Illumina NovaSeq 6000, mapped to the chicken genome, and differential expression identified with DESeq2 (|log₂ fold change| > 1; FDR ≤ 0.05). At peak, E. maxima challenge overrepresented genes involved in cell cycle, lipid metabolism, and B cell proliferation (P < 0.002), while E. maxima + C. perfringens overrepresented defense response and catabolic process terms (P < 0.0001). Sex altered the host immune response to challenge (P < 0.05), while E. maxima ± C. perfringens induced a similar host immune response regardless of dietary anti-IL-10. Overall, pathogenic challenge status was the primary driver of host immune response with the effect of anti-IL-10 antibody influenced by S. Typhimurium.

Clostridium perfringens↗

PubMed2025

Repression of CADM1 transcription by HPV type 18 is mediated by three-dimensional rearrangement of promoter-enhancer interactions.

Upon infection, human papillomavirus (HPV) manipulates host cell gene expression to create an environment that is supportive of a productive and persistent infection. The virus-induced changes to the host cell's transcriptome are thought to contribute to carcinogenesis. Here, we show by RNA-sequencing that oncogenic HPV18 episome replication in primary human foreskin keratinocytes (HFKs) drives host transcriptional changes that are consistent between multiple HFK donors. We have previously shown that HPV18 recruits the host protein CTCF to viral episomes to control the differentiation-dependent viral transcriptional programme. Since CTCF is an important regulator of host cell transcription via coordination of epigenetic boundaries and long-range chromosomal interactions, we hypothesised that HPV18 may also manipulate CTCF to contribute to host transcription reprogramming. Analysis of CTCF binding in the host cell genome by ChIP-Seq revealed that while the total number of CTCF binding sites is not altered by the virus, there are a sub-set of CTCF binding sites that are either enriched or depleted of CTCF. Many of these altered sites are clustered within regulatory elements of differentially expressed genes, including the tumour suppressor gene cell adhesion molecule 1 (CADM1), which supresses epithelial cell growth and invasion. We show that HPV18 establishment results in reduced CTCF binding at the CADM1 promoter and upstream enhancer. Loss of CTCF binding is coincident with epigenetic repression of CADM1, in the absence of CpG hypermethylation, while adjacent genes including the transcriptional regulator ZBTB16 are activated. These data indicate that the CADM1 locus is subject to topological rearrangement following HPV18 establishment. We tested this hypothesis using 4C-Seq (circular chromosome confirmation capture-sequencing) and show that HPV18 establishment causes a loss of long-range chromosomal interactions between the CADM1 transcriptional start site and the upstream transcriptional enhancer. These data show that HPV18 manipulates host cell promoter-enhancer interactions to drive transcriptional reprogramming that may contribute to HPV-induced disease progression.

Humans↗

PubMed2026

Molecular characterization of CD36 deficiency in blood donors of Middle Eastern and African origin reveals transcript-level defects beyond genomic variants.

BACKGROUND: The increasing diversity of blood donor populations has created new challenges for transfusion services worldwide. The identification of donors lacking relevant high-prevalence antigens is becoming increasingly important to ensure compatible blood products for alloimmunized patients and to support the development of rare donor registries. CD36 (ISBT 045) is a glycoprotein expressed on platelets, monocytes, and erythroid precursor cells. CD36 deficiency has been reported across multiple populations and is of relevance due to its association with anti-CD36 isoantibodies, which may cause platelet transfusion refractoriness and fetal/neonatal alloimmune thrombocytopenia. STUDY DESIGN AND METHODS: We analyzed CD36 expression in 1250 blood donors of diverse ancestry using flow cytometry. CD36-negative samples underwent molecular characterization using Sanger sequencing and next-generation sequencing of genomic DNA, complemented by cDNA analysis and cloning to investigate transcript-level alterations. RESULTS: We identified CD36 deficiency in 27 donors (2.16%). Genomic sequencing revealed 18 distinct coding variants, including three novel variants, most in the heterozygous state. In one CD36-negative donor, cDNA analysis demonstrated a 52-bp deletion in exon four and complete skipping of exon 9, despite the absence of splice-site variants in genomic DNA. Cloning confirmed coexistence of aberrant and wild-type transcripts in this individual. CONCLUSION: Our findings demonstrate that CD36 deficiency can arise from transcript-level defects in the absence of detectable coding or splice-site variants. These results indicate that genomic sequencing alone may be insufficient to fully resolve CD36-negative phenotypes and highlight the importance of integrating transcriptomic approaches to improve molecular diagnostics and transfusion support in increasingly diverse donor populations.

CD36 deficiency↗

PubMed2024

Machine learning algorithm-based biomarker exploration and validation of mitochondria-related diagnostic genes in osteoarthritis.

The role of mitochondria in the pathogenesis of osteoarthritis (OA) is significant. In this study, we aimed to identify diagnostic signature genes associated with OA from a set of mitochondria-related genes (MRGs). First, the gene expression profiles of OA cartilage GSE114007 and GSE57218 were obtained from the Gene Expression Omnibus. And the limma method was used to detect differentially expressed genes (DEGs). Second, the biological functions of the DEGs in OA were investigated using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Wayne plots were employed to visualize the differentially expressed mitochondrial genes (MDEGs) in OA. Subsequently, the LASSO and SVM-RFE algorithms were employed to elucidate potential OA signature genes within the set of MDEGs. As a result, GRPEL and MTFP1 were identified as signature genes. Notably, GRPEL1 exhibited low expression levels in OA samples from both experimental and test group datasets, demonstrating high diagnostic efficacy. Furthermore, RT-qPCR analysis confirmed the reduced expression of Grpel1 in an in vitro OA model. Lastly, ssGSEA analysis revealed alterations in the infiltration abundance of several immune cells in OA cartilage tissue, which exhibited correlation with GRPEL1 expression. Altogether, this study has revealed that GRPEL1 functions as a novel and significant diagnostic indicator for OA by employing two machine learning methodologies. Furthermore, these findings provide fresh perspectives on potential targeted therapeutic interventions in the future.

Humans↗

PubMed2003

Use of cDNA microarrays to monitor transcriptional responses of the chestnut blight fungus Cryphonectria parasitica to infection by virulence-attenuating hypoviruses.

Hypoviruses are a family of cytoplasmically replicating RNA viruses of the chestnut blight fungus Cryphonectria parasitica. Members of this mycovirus family persistently alter virulence (hypovirulence) and related fungal developmental processes, including asexual and sexual sporulation. In order to gain a better understanding of the molecular basis for these changes, we have developed a C. parasitica cDNA microarray to monitor global transcriptional responses to hypovirus infection. In this report, a spotted DNA microarray representing approximately 2,200 C. parasitica genes was used to monitor changes in the transcriptional profile after infection by the prototypic hypovirus CHV1-EP713. Altered transcript abundance was identified for 295 clones (13.4% of the 2,200 unique cDNAs) as a result of CHV1-EP713 infection-132 up-regulated and 163 down-regulated. In comparison, less than 20 specific C. parasitica genes were previously identified by Northern analysis and mRNA differential display as being responsive to hypovirus infection. A 93% validation rate was achieved between real-time reverse transcription-PCR results and microarray predictions. Differentially expressed genes represented a broad spectrum of biological functions, including stress responses, carbon metabolism, and transcriptional regulation. These findings are consistent with the view that infection by a 12.7-kbp hypovirus RNA results in a persistent reprogramming of a significant portion of the C. parasitica transcriptome. The potential impact of microarray studies on current and future efforts to establish links between hypovirus-mediated changes in cellular gene expression and phenotypes is discussed.

Ascomycota↗

PubMed2025

Multi-omics reveals an ecdysone-activated Eip75B-FABP signaling axis coordinating nutrient metabolism for development in Hermetia illucens.

INTRODUCTION: Efficient nutrient storage is essential for insect development and energy homeostasis; however, the mechanisms coordinating nutrient allocation during ontogeny are not well understood. Elucidating these systems may yield valuable insights to insect metabolic adaptation. OBJECTIVES: This study aimed to identify regulatory modules governing nutrient metabolism in insects, focusing on hormonal and metabolic interplay. METHODS: Multi-omics profiling (proteomics, phosphoproteomics, and transcriptomics) was conducted throughout the life cycle, from egg to adult, to identify metabolic regulators. RNAi was utilized for gene knockdown, followed by qRT-PCR and mitochondrial DNA quantification to evaluate knockdown efficiency and its metabolic implications. Assessments of nutrient metabolism were performed using assays for triglycerides, crude protein, and fatty acid synthase. EMSA and BODIPY staining examined transcriptional regulation and lipid droplet dynamics. RESULTS: Utilizing an integrative multi-omics approach, this study elucidates the temporal metabolic regulators in insects. A conserved regulatory module was identified in which the PPAR homolog, ecdysone-induced protein 75B (Eip75B), functions as a transcriptional activator of fatty acid binding protein (FABP), sustaining lipid metabolic homeostasis during the larval stage. PPARγ modulators (rosiglitazone and GW9662) alter lipid accumulation, along with the expression of Eip75B and FABP, which was measured by qRT-PCR. Furthermore, the deficiency of FABP may reprogram metabolic pathways by inhibiting lipid storage and promoting mitochondrial β-oxidation, as supported by increased mitochondrial DNA copy number, as well as enhancing protein synthesis. This metabolic change could be modulated by ecdysone signaling, as hormonal supplementation effectively rescued the lipid loss phenotype. Our results establish the ecdysone-Eip75B-FABP signaling axis as a central regulatory module that integrates hormonal and nutrient-sensing signals to control insect nutritional metabolism. CONCLUSION: The ecdysone-Eip75B-FABP axis integrates hormonal and nutrient signals to regulate metabolic plasticity, underscoring a universal strategy for developmental energy allocation. The data also offer potential implications for research on metabolic disorders and bioenergy applications.

Animals↗

PubMed2026

A targetable dependency on nonsense-mediated decay for cellular homeostasis and immune control in small cell lung cancer.

Small cell lung cancer (SCLC) is one of the most aggressive malignancies, characterized by rapid metastatic dissemination and poor overall survival. Despite harboring excessive alterations, expectedly resulting in immunogenic neoantigens, patients with SCLC remain largely refractory to immunotherapy. We found abundant frameshift mutations in SCLC, regarded as highly immunogenic, counterbalanced by a hyperactive nonsense-mediated decay (NMD) pathway, responsible for frameshift-mRNA degradation. NMD activity correlated with tumor mutational burden (TMB) across cancers, suggesting that SCLC and other TMBhigh cancers may depend on NMD to limit the accumulation of mutation-derived byproducts in order to maintain cellular homeostasis and evade immune recognition. In TMBhigh SCLC models, inhibition of NMD impaired cell proliferation and induced ER stress-dependent apoptosis due to the accumulation of misfolded proteins. Genetic and pharmacological NMD inhibition in vivo effectively controlled TMBhigh tumor growth without overt toxicity. By integrating genome and transcriptome sequencing with MHC-I immunopeptidomics and functional in vitro and in vivo assays, we identified that NMD inhibition boosted neoantigen expression and presentation by tumor cells and increased T cell recognition, thus enhancing overall tumor immunogenicity and further improving immunotherapy efficacy in vivo. Our work shows that SCLC - as a TMBhigh cancer - relies on NMD for survival and immune escape, uncovering a novel TMB-dependent tractable vulnerability for this devastating disease.

Humans↗

PubMed2026

Integrative multi-omics and single-cell analysis identifies EGFR pathway activation and metabolic reprogramming as potential synthetic lethal vulnerabilities in resistance to the FGFR inhibitor AZD4547.

BACKGROUND: Although fibroblast growth factor receptor (FGFR) inhibitors (FGFRi) have demonstrated clinical promise, the inevitable emergence of acquired resistance remains a critical bottleneck, severely compromising their long-term clinical efficacy. The pan-cancer molecular landscape and heterogeneous mechanisms driving this resistance, ranging from genetic alterations to dynamic network rewiring, remain poorly understood. METHODS: We integrated large-scale pharmacogenomic profiling of the FGFR inhibitor AZD4547 from the GDSC2 and PRISM databases with single-cell RNA sequencing to dissect the multi-omics landscape of FGFRi resistance across 312 cell lines from 8 cancer types. This multi-omics framework was further extended by machine learning modeling and systematic synthetic lethality screening to uncover actionable therapeutic targets. In vitro viability assays and western blot analysis were subsequently conducted to experimentally evaluate the predicted FGFR-EGFR synthetic lethality. RESULTS: Our dual-database analysis unveiled a multi-dimensional atlas of FGFRi resistance. We identified cancer-specific genomic drivers, such as ELF4 amplification in glioblastoma, alongside key transcriptomic markers including UCP2 and FSCN1, highlighting a shift towards metabolic reprogramming and epithelial-mesenchymal transition (EMT). Single-cell analysis unveiled that resistance is linked to the heterogeneous enrichment of baseline subpopulations characterized by distinct metaprograms, including cell-cycle dysregulation. Furthermore, a random forest model built on a LASSO-derived transcriptomic signature was constructed, demonstrating promising predictive capability for AZD4547 sensitivity (mean test-set AUC = 0.73, 95% CI [0.63, 0.80]); the signature generalized well to erdafitinib but showed limited transferability to some other FGFR inhibitors (e.g. pemigatinib, BGJ398). Most notably, our synthetic lethal screening revealed a convergent reliance on compensatory RTK signaling (specifically EGFR pathway enrichment) and downstream MAPK/PI3K cascades in resistant phenotypes, providing converging computational evidence for EGFR pathway activation as an adaptive bypass mechanism. This predicted synthetic lethality was experimentally supported in two FGFR-dependent cell line models (RT112 and CCLP1), in which combined FGFR-EGFR inhibition produced marked synergistic antiproliferative effects. CONCLUSIONS: This study establishes a comprehensive multi-omics atlas of resistance to the FGFR inhibitor AZD4547, delineating convergent mechanisms of metabolic reprogramming and EGFR-mediated bypass signaling. Our findings characterize the resistance as a dynamic network rewiring and nominate rational combination strategies to overcome this therapeutic bottleneck. While FGFR-EGFR co-inhibition is experimentally supported, metabolic co-targeting remains a computationally derived, hypothesis-generating strategy.

Benzamides↗

PubMed2024

Decoding the trajectory of antibiotic resistance genes in saline and alkaline soils: Insights from different fertilization regimes.

The soil salinity and alkalinity play an important role in the occurrence and proliferation of antibiotic resistance genes (ARGs). Yet, little is known the underlying mechanism by which soil salinity and alkalinity affect antibiotic resistance evolution. Here we investigated the ARGs variation in soil salinity and alkalinity environments created by different fertilization, and explored the biological mechanisms that salinity and alkalinity alter the evolutionary paradigm of antibiotic resistance. The results showed the soil treated by organic fertilizer exhibited a low salinity, neutral level (TSD 239.20 μS/cm, pH 7.17). The ARG abundance in the OF treatment was the highest, keeping an average of 67.83 TPM. Beside the effect of direct input of organic fertilizer at the beginning, it was important to note that, ARGs abundance during planting showed significant correlations with pH and electric conductivity. We observed that changes in microbial survival strategies under different salinity and alkalinity conditions further affected ARG hosts abundance. Indoor experiments demonstrated that there was a survival trade-off between the growth of resistant bacteria and the evolution of antibiotic resistance in salinity and alkalinity environments. Meta-genomic and Meta-transcriptomic analysis consistently demonstrated bacterial antibiotic resistance was primarily associated with pyruvate, energy and lipid metabolic pathways. The functional gene related to salinity and alkalinity, like cysH, cysK, plsB and plsC showed negative correlations with MDR. Prokaryotic transcription assays validated these relations. This study well explains the prevalence of soil ARGs after different fertilization regimes and will give a deeper understanding for the effect of soil salinity and alkalinity on antibiotic resistance evolution.

Soil↗