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PubMed2026

SWI/SNF Alterations Define a Chromatin-Dependent Subtype of Urothelial Carcinoma.

PURPOSE: SWI/SNF (BAF) chromatin remodeling complex alterations are common in urothelial carcinoma, yet no biomarker-directed therapeutic strategies have been established for this population. We investigated whether BAF alterations delineate a biologically distinct, therapeutically actionable urothelial carcinoma subtype. EXPERIMENTAL DESIGN: We performed integrative genomic and transcriptomic analyses of 792 urothelial carcinoma tumors from the Oncology Research Information Exchange Network (ORIEN) and validated findings in the TCGA-BLCA cohort. Mechanistic studies incorporated RNA sequencing and ATAC-seq following histone deacetylase (HDAC) inhibition. Functional dependencies were assessed using patient-derived xenograft organoids and cell line models. Clinical relevance was explored in a biomarker-enriched investigator-initiated trial. RESULTS: Approximately half of urothelial carcinoma tumors exhibited BAF alterations, defining a previously unrecognized chromatin-altered molecular subtype characterized by activation of proliferative programs, loss of lineage identity, and altered metabolic signaling. This subtype was enriched for transcriptomic programs associated with HDAC inhibitor sensitivity and depleted of HDAC inhibitor resistance signatures. Mechanistically, HDAC inhibition induced widespread chromatin remodeling with reduced accessibility at AP-1 and TEAD-associated regions, and downregulation of E2F- and MYC-driven transcriptional networks. Functional studies confirmed enhanced HDAC inhibition sensitivity in ARID1A -mutated cell lines and a patient-derived organoid model. Early clinical observations demonstrated a durable responder treated with HDAC inhibitors and immunotherapy. CONCLUSIONS: BAF alterations define a chromatin-dependent tumor state in urothelial carcinoma that is selectively vulnerable to HDAC inhibition. Integrating genomic, epigenomic, functional, and early clinical evidence, these findings provide a rationale for biomarker-enriched clinical trials and HDAC inhibitor-based combination strategies in urothelial carcinoma.

Journal Article↗

PubMed2025

Revealing cancer driver genes through integrative transcriptomic and epigenomic analyses with Moonlight.

Cancer involves dynamic changes caused by (epi)genetic alterations such as mutations or abnormal DNA methylation patterns which occur in cancer driver genes. These driver genes are divided into oncogenes and tumor suppressors depending on their function and mechanism of action. Discovering driver genes in different cancer (sub)types is important not only for increasing current understanding of carcinogenesis but also from prognostic and therapeutic perspectives. We have previously developed a framework called Moonlight which uses a systems biology multi-omics approach for prediction of driver genes. Here, we present an important development in Moonlight2 by incorporating a DNA methylation layer which provides epigenetic evidence for deregulated expression profiles of driver genes. To this end, we present a novel functionality called Gene Methylation Analysis (GMA) which investigates abnormal DNA methylation patterns to predict driver genes. This is achieved by integrating the tool EpiMix which is designed to detect such aberrant DNA methylation patterns in a cohort of patients and further couples these patterns with gene expression changes. To showcase GMA, we applied it to three cancer (sub)types (basal-like breast cancer, lung adenocarcinoma, and thyroid carcinoma) where we discovered 33, 190, and 263 epigenetically driven genes, respectively. A subset of these driver genes had prognostic effects with expression levels significantly affecting survival of the patients. Moreover, a subset of the driver genes demonstrated therapeutic potential as drug targets. This study provides a framework for exploring the driving forces behind cancer and provides novel insights into the landscape of three cancer sub(types) by integrating gene expression and methylation data.

Humans↗

PubMed2025

Altered histone modifications in Aedes aegypti following Rift Valley fever virus exposure.

When arthropod-borne viruses (arboviruses) are delivered to vector mosquitoes in an infectious bloodmeal, viral components interact with host proteins to hijack cells and initiate replication. The extent to which arbovirus infection alters mosquito host transcriptional and genomic regulatory processes is currently unknown. We hypothesized that histone modifications would be altered in mosquitoes exposed to Rift Valley fever virus (RVFV MP12, Phlebovirus riftense, family Phleboviridae). We interrogated transcriptome and chromatin landscapes in Aedes aegypti midguts by performing Cleavage Under Targets and Release Using Nuclease (CUT&RUN), using H3K27ac and H3K9me3 marks. Altered H3K27ac marks were identified following RVFV MP12 exposure, as well as upon bloodfeeding alone. It took several days for differential H3K27ac marks to be associated with differentially expressed genes (DEGs) in RVFV-exposed midguts. H3K27ac peaks showed progressive depletion as infection progressed. Gene set enrichment analysis revealed that immune response transcripts were enriched at 1 and 3 dpf (days post-feeding) but depleted by 7 dpf. Hedgehog/Gli (glioma-associated oncogene homolog) signaling pathway transcripts were depleted, indicating possible viral manipulation of cellular polarization. Moreover, at 7 dpf, 7 of 102 DEGs were proximal to differentially acetylated sites in a pattern expected to favor viral propagation. However, one transcript coding for an antiviral effector (LysM-TLDc domain protein) showed significant depletion of both H3K9me3 and H3K27ac marks. Analysis of midguts after a non-infectious bloodmeal versus sugar-fed controls revealed global changes to H3K27ac and H3K9me3 marks during and following the period of bloodmeal digestion. Differential H3K27ac marks were proximal to one quarter of all DEGs at 1 dpf, consistent with an important role of H3K27ac in bloodmeal digestion. These results demonstrate that H3K27ac and H3K9me3 patterns are altered upon virus exposure in a complex interplay that favors viral replication but is also countered by host responses to limit replication.

ChIP-Seq↗

PubMed2026

Exploring the impact of syndecans in prostate cancer: Stage-specific roles and therapeutic implications.

Syndecans (SDCs) 1-4 are a family of transmembrane heparan sulfate proteoglycans (HSPGs) that regulate cell-cell communication, adhesion, extracellular matrix organization, and signaling pathways involved in tumor biology. In prostate cancer (PCa), accumulating evidence suggests that SDCs contribute to tumor progression, therapeutic resistance, and interactions within the tumor microenvironment. However, their specific, stage-dependent roles remain incompletely understood. This review provides an integrated synthesis of current experimental and clinical evidence on SDC1-SDC4 in PCa, complemented by exploratory analyses of publicly available transcriptomic, genomic, and proteomic datasets. In contrast, copy-number alteration (CNA) strata dichotomized by the mean for SDC1, SDC2, and SDC4 showed differences in progression-free interval. Specific CNA subclasses and relationships between CNA values and SDC mRNA or protein abundance could not be determined. Proteomic pseudotime analysis further suggested that SDC4 expression increases during PCa progression, supporting its potential involvement in advanced disease. We discuss the regulation and modulation of SDCs by androgen deprivation therapy (ADT), enzymatic shedding, integrin-mediated signaling, extracellular matrix interactions, lipid signaling pathways, and microRNA networks. In particular, SDC1-microRNA interactions may influence PCa cell proliferation, cellular senescence, epithelial-mesenchymal transition (EMT), and intracellular signaling pathways. Overall, this review highlights SDCs as context-dependent regulators of PCa biology with potential relevance as biomarkers or therapeutic targets. However, clinical translation will require independent validation, standardized assays, compartment-resolved analyses, and mechanistic confirmation.

Prognosis↗

PubMed2022

Lipid hydroperoxides and oxylipins are mediators of denervation induced muscle atrophy.

Loss of innervation is a key driver of age associated muscle atrophy and weakness (sarcopenia). Our laboratory has previously shown that denervation induced atrophy is associated with the generation of mitochondrial hydroperoxides and lipid mediators produced downstream of cPLA2 and 12/15 lipoxygenase (12/15-LOX). To define the pathological impact of lipid hydroperoxides generated in denervation-induced atrophy in vivo, we treated mice with liproxstatin-1, a lipid hydroperoxide scavenger. We treated adult male mice with 5 mg/kg liproxstain-1 or vehicle one day prior to sciatic nerve transection and daily for 7 days post-denervation before tissue analysis. Liproxstatin-1 treatment protected gastrocnemius mass and fiber cross sectional area (∼40% less atrophy post-denervation in treated versus untreated mice). Mitochondrial hydroperoxide generation was reduced 80% in vitro and by over 65% in vivo by liproxstatin-1 treatment in denervated permeabilized muscle fibers and decreased the content of 4-HNE by ∼25% post-denervation. Lipidomic analysis revealed detectable levels of 25 oxylipins in denervated gastrocnemius muscle and significantly increased levels for eight oxylipins that are generated by metabolism of fatty acids through 12/15-LOX. Liproxstatin-1 treatment reduced the level of three of the eight denervation-induced oxylipins, specifically 15-HEPE, 13-HOTrE and 17-HDOHE. Denervation elevated protein degradation rates in muscle and treatment with liproxstatin-1 reduced rates of protein breakdown in denervated muscle. In contrast, protein synthesis rates were unchanged by denervation. Targeted proteomics revealed a number of proteins with altered expression after denervation but no effect of liproxstain-1. Transcriptomic analysis revealed 203 differentially expressed genes in denervated muscle from vehicle or liproxstatin-1 treated mice, including ER stress, nitric oxide signaling, Gαi signaling, glucocorticoid receptor signaling, and other pathways. Overall, these data suggest lipid hydroperoxides and oxylipins are key drivers of increased protein breakdown and muscle loss associated with denervation induced atrophy and a potential target for sarcopenia intervention.

Male↗

PubMed2024

Progressive cardiomyopathy with intercalated disc disorganization in a rat model of Becker dystrophy.

Becker muscular dystrophy (BMD) is an X-linked disorder due to in-frame mutations in the DMD gene, leading to a less abundant and truncated dystrophin. BMD is less common and severe than Duchenne muscular dystrophy (DMD) as well as less investigated. To accelerate the search for innovative treatments, we developed a rat model of BMD by deleting the exons 45-47 of the Dmd gene. Here, we report a functional and histopathological evaluation of these rats during their first year of life, compared to DMD and control littermates. BMD rats exhibit moderate damage to locomotor and diaphragmatic muscles but suffer from a progressive cardiomyopathy. Single nuclei RNA-seq analysis of cardiac samples revealed shared transcriptomic abnormalities in BMD and DMD rats and highlighted an altered end-addressing of TMEM65 and Connexin-43 at the intercalated disc, along with electrocardiographic abnormalities. Our study documents the natural history of a translational preclinical model of BMD and reports a cellular mechanism for the cardiac dysfunction in BMD and DMD offering opportunities to further investigate the organization role of dystrophin in intercellular communication.

Animals↗

PubMed2025

Evolutionary engineering and molecular characterization of an antimycin A-resistant Saccharomyces cerevisiae strain: the key role of pleiotropic drug resistance (PDR1).

Antimycin A, an antifungal agent that inhibits mitochondrial respiration, provides a useful model for studying resistance mechanisms. Antifungal resistance is an escalating clinical concern with limited treatment options available. To understand the molecular mechanisms of antimycin A resistance, a genetically stable, antimycin A-resistant Saccharomyces cerevisiae strain was successfully developed for the first time through an evolutionary engineering strategy, based on long-term systematic application of gradually increasing antimycin A stress in repetitive batch cultures without prior chemical mutagenesis. Comparative whole genome resequencing analysis of the evolved strain ant905-9 revealed two missense mutations in PDR1 and PRP8 genes involved in pleiotropic drug resistance and RNA splicing, respectively. Using CRISPR/Cas9 genome editing tools, the identified mutations were introduced individually and together into the reference strain, and it was confirmed that the Pdr1p.M732R mutation alone confers antimycin A-resistance in S. cerevisiae. Comparative transcriptomic analysis of the reverse-engineered Pdr1p.M732R strain showed alterations in PDR (pleiotropic drug resistance), transmembrane transport, vesicular trafficking, and autophagy pathways. Our results highlight the potential key role of PDR1 in antifungal drug resistance. This study provides new insights into mitochondrial drug resistance and the adaptive potential of yeast under respiratory stress.

Saccharomyces cerevisiae↗

PubMed2025

Gfa1 (glutamine fructose-6-phosphate aminotransferase) is essential for Aspergillus fumigatus growth and virulence.

BACKGROUND: Aspergillus fumigatus, the primary etiological agent of invasive aspergillosis, causes over 1.8 million deaths annually. Targeting cell wall biosynthetic pathways offers a promising antifungal strategy. Gfa1, a rate-limiting enzyme in UDP-GlcNAc synthesis, plays a pivotal role in the hexosamine biosynthetic pathway (HBP). RESULTS: Deletion of gfa1 (Δgfa1) results in auxotrophy for glucosamine (GlcN) or N-acetylglucosamine (GlcNAc). Under full recovery (FR) conditions, where minimal medium is supplemented with 5 mM GlcN as the sole carbon source, the Δgfa1 mutant shows growth comparable to the wild-type (WT). However, when supplemented with 5 mM GlcN and 55 mM glucose, growth is partially repressed, likely due to carbon catabolite repression, a condition termed partial repression (PR). Under PR conditions, Δgfa1 exhibits compromised growth, reduced conidiation, defective germination, impaired cell wall integrity, and increased sensitivity to endoplasmic reticulum (ER) stress and high temperatures. Additionally, Δgfa1 demonstrates disruptions in protein homeostasis and iron metabolism. Transcriptomic analysis of the mutant under PR conditions reveals significant alterations in carbohydrate and amino acid metabolism, unfolded protein response (UPR) processes, and iron assimilation. Importantly, Gfa1 is essential for A. fumigatus virulence, as demonstrated in Caenorhabditis elegans and Galleria mellonella infection models. CONCLUSIONS: These findings underscore the critical role of Gfa1 in fungal pathogenicity and suggest its potential as a therapeutic target for combating A. fumigatus infections.

Aspergillus fumigatus↗

PubMed2026

Integrated multi-omics profiling identifies aging-related molecular signatures and convergent interferon signaling in systemic lupus erythematosus.

BACKGROUND: Systemic lupus erythematosus (SLE) is characterized by chronic immune activation and molecular alterations that overlap with aging-related biological processes. However, how these alterations are organized across molecular layers and whether they converge on shared regulatory networks remain incompletely understood. METHODS: We performed an integrative multi-omics analysis combining in-house proteomic and phosphoproteomic data from 130 patients with SLE and 90 healthy controls (HCs) and publicly available transcriptomic datasets comprising 1,461 SLE patients. Proteins and phosphorylation sites were annotated using established aging-related gene resources. Differential protein abundance and phosphorylation changes were analyzed across disease-status and disease-activity comparisons. Nominal P-value thresholds were used for exploratory feature selection, whereas FDR-adjusted P values were used to assess robustness after multiple-testing correction. Kinase-substrate enrichment, transcription factor annotation, and cell-type-resolved transcriptomic comparison were used to explore potential regulatory programs. RESULTS: We identified 128 nominally altered proteins annotated to aging-related biological processes, including genomic instability, mitochondrial dysfunction, and epigenetic alterations. Phosphoproteomic analysis revealed 36 nominally altered phosphorylation sites, including previously unreported sites in IFI16 (S153, S780) and PKCδ (S507, S664). Clustering analysis demonstrated heterogeneous protein co-regulation patterns across disease states. Kinase activity inference suggested altered activity of TBK1 and IKKβ. TF analysis further highlighted STAT1, RELA, and PML as potential central nodes within the inferred regulatory network. Notably, these multi-omic alterations were not randomly distributed but showed convergence toward shared signaling pathways, particularly those related to interferon responses. CONCLUSIONS: This integrative multi-omics study identifies inflammatory and interferon-dominated molecular alterations in SLE PBMCs that overlap with aging-related biological processes and converge on shared regulatory networks. These findings provide a hypothesis-generating framework for investigating the intersection between chronic immune activation and aging-related molecular remodeling in SLE.

Humans↗

PubMed2026

Multimodal Analysis Reveals Aberrant Expression of SUMO2 and Its Significant Association With Key Mechanisms of Metabolic Pathways in Hepatocellular Carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. However, the role of small ubiquitin-like modifier 2 (SUMO2), a core member of the small ubiquitin-like modifier (SUMO) family, regarding its expression patterns and metabolism-related functions in HCC remains inadequately understood. METHODS: A multidimensional analytical framework was applied, integrating immunohistochemistry (153 HCC vs. 21 non-HCC samples), proteomics (159 paired samples), bulk transcriptomics (3240 HCC vs. 2267 non-HCC samples), single-cell RNA sequencing (RNA-seq) (10 HCC vs. 8 non-HCC samples), spatial transcriptomics, and external CRISPR/Cas9 functional genomics data. Systematic analyses included standardized mean difference (SMD), pathway enrichment, pseudotime trajectory inference, in silico knockout, cell-cell communication, metabolic flux scoring, immune infiltration, clinical correlation, drug sensitivity prediction, and molecular docking. RESULTS: At the protein level, immunohistochemistry (nuclear positivity) and external proteomic data collectively demonstrated consistent SUMO2 overexpression in HCC. Consistent upregulation was also observed at the mRNA level across large-scale cohorts. Single-cell RNA-seq and spatial transcriptomics localized SUMO2 enrichment to malignant hepatocytes and tumor-dominant regions. CRISPR-mediated SUMO2 knockout suppressed proliferation in multiple HCC cell lines. Mechanistically, high SUMO2 expression was significantly associated with metabolic reprogramming involving glycolysis/gluconeogenesis, pyruvate metabolism, and the tricarboxylic acid cycle. SUMO2-high malignant hepatocyte subpopulations exhibited enhanced activity of the macrophage migration inhibitory factor signaling axis and enhanced iron-sensor interactions. Further, the immune infiltration analysis revealed a negative correlation between SUMO2 expression and M1 macrophages and a positive correlation between follicular helper T cells and regulatory T cells. Clinically, elevated SUMO2 levels were found to be associated with adverse prognostic features. Furthermore, high SUMO2 expression was associated with increased sensitivity to dasatinib, and molecular docking simulations predicted potential binding between SUMO2 and dasatinib, with a Vina score of -8.5 kcal/mol. CONCLUSIONS: SUMO2 is aberrantly expressed at the protein, mRNA, single-cell, and spatial transcriptomic levels in HCC and is significantly associated with metabolic reprogramming and altered migration inhibitory factor (MIF)-mediated intercellular communication, suggesting its potential as a novel biomarker for diagnosis and treatment.

Humans↗

PubMed2026

Transcriptional and histopathological profiling of skeletal muscle in Bla/J mice at the stage of dysferlinopathy manifestation.

Dysferlinopathy is a rare muscular dystrophy characterized by chronic muscle damage and ineffective regeneration. While late-stage morphological changes, such as fibroadipose replacement, are well described, the early molecular mechanisms driving muscle fiber loss and regenerative failure at the onset of the disease remain largely uncharacterized. To address this gap, we investigated the skeletal muscles of dysferlin-deficient Bla/J mice during the early manifestation stage (3 months of age). This exploratory study aimed to identify primary pathomorphogenetic events by correlating the transcriptomic profile of the tissue with its specific histopathological and ultrastructural alterations. We performed a comparative analysis of the m. gastrocnemius in 3-month-old Bla/J mice versus wild-type controls using RNA sequencing, RT-qPCR, histomorphometry and transmission electron microscopy. The results revealed atrophy and muscle fiber necrosis without the expected induction of Fbxo32 and Trim63 ubiquitin ligases, suggesting ubiquitin-proteasome system-independent muscle mass loss. Furthermore, the absence of Casp3, Bak1, and Bad induction, confirmed by the lack of active caspase-3, excluded apoptosis as the primary death mechanism. A differentiation block in satellite cells was confirmed by the lack of Myf5, Myod1, and Myog induction and a trend toward Tead4 suppression, pointing to an early failure of the reparative program. Exploratory RNA sequencing also identified a suppression of Prkn expression accompanied by LC3B-II-positive autophagosome accumulation. Immunohistochemical and immunofluorescent evaluation of the mitochondrial network (TOMM20) revealed abnormal accumulations and dense clumping, indicating impaired organelle clearance. Furthermore, ultrastructural analysis demonstrated internal organelle damage and the presence of myelin-like structures, consistent with a state of stalled mitophagy. Collectively, this exploratory study demonstrates that early muscle atrophy and myofiber necrosis in dysferlinopathy occur independently of canonical ubiquitin-proteasome and apoptotic pathways. Instead, the disease manifestation stage is structurally characterized by stalled mitochondrial clearance and a delayed regenerative response.

Animals↗

PubMed2026

Thyroid-stimulating hormone receptor mediates peripheral-central neuroimmune crosstalk in autoimmune thyroid diseases.

BACKGROUND: Organ-specific autoimmune diseases, particularly Graves' disease (GD) and its extrathyroidal manifestation, Graves' orbitopathy (GO), are characterized by systemic autoimmunity that may extend its impact to the central nervous system (CNS). While thyroid-stimulating hormone receptor (TSHR) is the primary driver of pathological remodeling in the thyroid and orbital tissues, emerging evidence suggests it is also expressed in the brain and may participate in neuroimmune signaling. However, the molecular mechanisms linking peripheral TSHR-driven autoimmunity to these extended systemic features remain unclear. Thus, GD and GO provide a unique window to investigate how peripheral autoantibodies influence CNS involvement as part of its broader pathological spectrum. METHODS: Genome-wide association studies (GWAS) and post-GWAS analyses were integrated with bulk RNA sequencing, single-cell and spatial transcriptomics, and brain imaging phenotypes to comprehensively characterize peripheral and central alterations in GD and GO. Mendelian randomization was applied to test causal relationships between genetic variants and brain signatures. Structural biology analyses were further conducted including protein-protein docking, small-molecule docking, and normal mode dynamics to identify prospective modulators of TSHR. Immunofluorescence staining was performed in a GO mouse model to validate the colocalization of potential interacted proteins in the specific brain region. RESULTS: Brain imaging-derived phenotypes (IDPs) alterations in GO and GO were systematically analyzed to identify neuroanatomical and functional alterations. TSHR was further identified as a shared genetic driver across peripheral and central compartments. TSHR was expressed in spiny projection neurons, microglia, and peripheral T cells, with cell-cell communication analyses highlighting TSHR-mediated interactions among neurons, endothelial cells, and microglia. Immunofluorescence staining in a GO mouse model confirmed the colocalization of TSHR with FN1 and GNAS in the basal ganglia, providing tissue-level validation of the computationally predicted ligand-receptor interactions. Immune profiling further showed immune alterations in GD and GO. Structural modeling supported plausible physical interfaces between TSHR and interacting proteins, and small-molecule screening identified three repurposable compounds - venetoclax, irinotecan, and dutasteride - with predicted favorable docking scores and stable binding poses in our simulations. CONCLUSIONS: These findings demonstrate that TSHR acts as a molecular hub mediating peripheral-central neuroimmune crosstalk in GD and GO. The results support a broader "disease-molecule axis" framework that links genetic susceptibility with multi-level immune and neural mechanisms. This work provides mechanistic insights relevant to the development of TSHR-targeted therapies, with implications for both peripheral immune modulation and central regulation. However, the limited sample size, lack of longitudinal follow-up, and absence of in vivo validation warrant cautious interpretation and further investigation.

Receptors, Thyrotropin↗

PubMed2026

Fetal hypoxia causes oocyte oxidative stress damage via the Sirt3/Sod2 pathway and can be alleviated by nicotinamide mononucleotide.

Environmental hypoxia exerts detrimental effects on the reproductive capabilities of both humans and animals. A fetal hypoxia model was established in which fetal mice were kept in a high-plateau hypoxic setting from embryonic day (E) 0 to 16.5. In our previous research, we found that fetal hypoxia exposure perturbs the methylation of imprinted genes in adult sperm and causes intergenerational placental impairments in male offspring. However, the specific impacts of fetal hypoxia on the female reproductive system, particularly regarding oocyte maturation, remain poorly understood. First, we found that fetal hypoxia mice exhibited a significant reduction in the average number of pups per litter. We conducted a comprehensive analysis of the transcriptome in oocytes from the hypoxic group and investigated the metabolic alterations within the follicular microenvironment. Fetal hypoxic stress contributed to cleavage and blastocyst rate reduction and induced early apoptosis and DNA damage triggered by mitochondrial dysfunction, oxidative stress aggravation and Sirt3/Sod2 downregulation. Additionally, administration of nicotinamide mononucleotide (NMN) has been shown to prevent oocytes from mitochondrial dysfunction and developmental impairment by increasing the expression of Sirt3/Sod2 and autophagy. The number of pups per litter in fetal hypoxia mice was reduced by 57.7% compared to the control group, while NMN intervention could restore it to 73.1% of the control group. These results indicate that fetal hypoxia exposure exerts multiple potential damages to adult female reproduction, while highlighting the clinical potential of NMN supplementation as a targeted intervention to alleviate such hypoxia-associated female reproductive impairment.

Animals↗

PubMed2026

Zea mays Drought-Overly Sensitive1/TUBA4 Is Wilty3, and Transcriptome Co-Expression Analysis of Shoot Meristem Mutant Tissues Reveals Wilty2/TUB6:Wi3 Interactions Associated With Stem Vascular Bundle Development.

Plant vasculature is essential for the transport of water, nutrients, and signaling molecules across organs, while also providing critical mechanical support for growth and development. Disruptions in vascular bundle formation can therefore lead to severe physiological and developmental defects. In maize, ethyl methanesulfonate (EMS)-induced dominant nonallelic Wilty mutants exhibit a pronounced wilting phenotype even under well-watered conditions, indicating underlying defects in vascular function. In this study, we characterized the Wi3 mutant, identified as ZmDrought-Overly-Sensitive1/DOS1, and compared it with the previously described Wi2 mutant to uncover shared mechanisms underlying their phenotypes. We provide evidence, by bulk segregant resequencing linkage disequilibrium of SNPs adjacent to the causal Wilty SNPs in respective ß- and α-tubulin genes, for the personal communication from Gerry Neuffer that Wi2/ß-tub6 provenance is from ACR-related stock, whereas Wi3/α-tub4 allele is from Mo17, not B73 as claimed by the authors who cloned Dos1. Histochemical staining and Fourier-transform infrared (FTIR) spectroscopy of vascular bundles in Wi3 indicated apparent alterations in cellulose and lignin content consistent with those observed in Wi2. Transcriptome analysis of shoot meristems further indicated that similar sets of genes and pathways are differentially expressed in both mutants, suggesting convergence on common biological pathways. Using bulk-segregant whole-genome resequencing, we identified alpha-tubulin4 (TUA4) as the causal gene in Wi3 (ZmDOS1), harboring a C-to-T substitution within the N-terminal GTPase-binding domain. This mutation results in a glutamic acid196-to-lysine substitution. Given that α- and β-tubulin subunits heterodimerize, and in many plants and animal mutant alleles are dominant-negative gains-of-function, we infer Wi2, Wi3, and likely Wi4, based on very similar FTIR biophysical difference spectra, may act as effectors of vascular bundle cell wall deposition, potentially involving vesicle trafficking as recently shown for asymmetric cell divisions in maize stomatal development. Together, these findings highlight the functional interdependence of tubulin subunits and provide a plausible mechanistic framework for the striking biophysical, transcriptomic, and phenotypic similarities observed between Wi2, Wi3/ZmDOS1, and Wi4 mutants.

bulk segregant analysis↗

PubMed2026

Lactylation-related immune-metabolic dysregulation defines prognostic and therapeutic stratification in lung adenocarcinoma.

BACKGROUND: Lactylation links lactate metabolism with inflammatory signaling and immune regulation in tumors. However, its cellular distribution and translational value in lung adenocarcinoma (LUAD) remain unclear. METHODS: Single-cell RNA-sequencing datasets GSE189357 and GSE171145 were integrated to characterize lactylation-related activity, intercellular communication, and malignant epithelial cell states in LUAD. Single-cell-derived lactylation-related differentially expressed genes were mapped to TCGA-LUAD and multiple GEO cohorts. Univariate Cox regression and machine learning algorithms were used to construct a lactylation-related prognostic signature (LRPS). The associations of LRPS with prognosis, immunotherapy response, drug sensitivity, genomic alterations, immune infiltration, and inflammation- and metabolism-related pathways were evaluated. KRT7 was further validated using virtual knockout analysis, spatial transcriptomics, and in vitro and in vivo experiments. RESULTS: lactylation-related transcriptional activity showed heterogeneous distribution across LUAD cell populations and was associated with altered cell-cell communication. In malignant epithelial cells, LRTS-high and LRTS-low states exhibited distinct metabolic, inflammatory, and tumor-related pathway activities. LRPS showed stable prognostic performance in TCGA-LUAD and multiple GEO cohorts and remained an independent prognostic factor. Low LRPS was associated with greater potential benefit from immunotherapy, whereas different LRPS groups displayed distinct drug sensitivity, genomic alteration, and immune microenvironment patterns. KRT7 was highly expressed in LUAD and associated with poor prognosis. KRT7 knockdown suppressed LUAD cell proliferation, migration, invasion, colony formation, and tumor growth in vivo. CONCLUSIONS: This study identifies lactylation-related immune-metabolic dysregulation as a clinically relevant feature of LUAD and develops a single-cell-guided LRPS for prognosis and therapeutic stratification. KRT7 emerged as an LRPS-related functional candidate with experimentally supported roles in malignant LUAD phenotypes.

Immunotherapy↗

PubMed2026

From transcriptomic profiling to precision oncology: a bibliometric analysis of RNA sequencing in acute myeloid leukemia.

BACKGROUND: RNA sequencing (RNA-seq) has become an important tool for investigating the molecular heterogeneity of acute myeloid leukemia (AML); however, the global development and thematic evolution of this field remain inadequately characterized. OBJECTIVE: To map the global landscape of AML RNA-seq research and identify major knowledge domains, emerging themes, and temporal changes in research priorities. METHODS: Publications indexed in the Web of Science Core Collection and Scopus between January 1, 2007, and August 18, 2025, were retrieved. After database filtering, merging, and deduplication, 3,460 articles and reviews were included. CiteSpace, VOSviewer, the bibliometrix R package, and Microsoft Excel were used to analyze publication trends, collaboration networks, co-citation structures, keyword evolution, and citation bursts. RESULTS: Publication output increased steadily, accelerating after 2014. China contributed the largest number of publications (n = 547, 15.8%), whereas the United States had the highest total citation count. Major publication outlets spanned hematology, oncology, genomics, and molecular biology. Co-citation analysis identified prominent themes involving next-generation sequencing, gene mutations, KMT2A rearrangements, epigenetic dysregulation, leukemia-initiating cells, drug resistance, biomarkers, T-cell biology, and single-cell sequencing. Earlier literature emphasized sequencing technologies, gene expression profiling, and molecular alterations, whereas recent publications show increasing representation of cellular heterogeneity, single-cell transcriptomics, drug resistance, biomarker applications, immune-related research, and computational interpretation. CONCLUSION: While molecular characterization remains foundational, AML RNA-seq research has broadened to encompass increasingly prominent cellular, functional, computational, and translational dimensions. This study provides a structured overview of the field; nevertheless, bibliometric prominence should not be interpreted as direct evidence of clinical utility.

RNA sequencing↗

PubMed2026

Convergent mitochondrial impairment and apoptosis driven by simultaneous down-regulation of multiple genes at 11p11.2 in Alzheimer's disease.

Genome-wide association studies (GWAS) and multi-omics analyses have identified numerous risk loci and thousands of potential causal genes associated with Alzheimer's disease (AD). However, the synergistic pathogenic contributions of multiple low-risk causal genes within a single locus remain poorly understood. Polygenic synergism at the 11p11.2 locus was systematically examined in AD pathogenesis. Three causal genes (MTCH2, NDUFS3, and PSMC3) exhibited coordinated down-regulation in both AD patients and AD mouse models. Individual knockdown in cultured cells altered mitochondrial function and disrupted AD-associated pathways, as revealed by transcriptomic profiling. Integrated RNA-seq analysis and experimental validation demonstrated that the concurrent down-regulation of all three genes synergistically enhanced mitochondrial reactive oxygen species (ROS) generation and activated the caspase-7-mediated apoptotic pathway. Notably, pharmacological caspase inhibition with Q-VD-OPh attenuated neuronal apoptosis, ameliorated memory deficits, and reduced Aβ plaque deposition in APP/PS1 mice. Simultaneous down-regulation of multiple genes at the 11p11.2 locus contributed to mitochondrial dysfunction and apoptosis in AD, highlighting polygenic synergism as a key pathogenic mechanism.

Animals↗

PubMed2026

Establishment and Characterization of Patient-Derived Xenograft Organoids for Personalized Treatment of Castration-Resistant Prostate Cancer.

BACKGROUND: Basic research on castration-resistant prostate cancer (CRPC) is limited by the lack of clinically relevant models. This study aimed to establish patient-derived xenografts (PDX) and PDX-derived organoids from clinical CRPC specimens to develop a bidirectional experimental platform for in vivo xenografts and ex vivo organoids. METHODS: We established a new PDX library (KUCaP PDX series) using CRPC clinical specimens and derived prostate cancer organoids. Comprehensive biological characterization of clinical specimens, PDXs, PDX-derived organoids, and organoid-derived xenografts (ODXs) was performed to confirm the preservation of the original tumor features. Using our PDX library, we conducted genetic engineering and drug testing to explore novel therapeutic approaches. RESULTS: PDX-derived organoids were successfully established from all eight KUCaP PDX lines (100%). Four of the eight lines (50%) were maintained during the long-term culture experiments for over ten passages. Key features observed in the original clinical specimens, including genetic alterations and castration responsiveness, were maintained across the PDX, PDX-derived organoid, and ODX models. RNA sequencing revealed that transcriptomic profiles were consistently maintained across clinical specimens, PDXs, PDX-derived organoids, and ODXs. One PDX and organoid (KUCaP19) which exhibited a high homologous recombination deficiency (HRD) score, without any pathogenic homologous recombination repair (HRR) gene alterations, showed sensitivity to a poly ADP-ribose polymerase (PARP) inhibitor. In contrast, KUCaP12, which had no HRR alterations and a low HRD score, did not respond to PARP inhibition. CONCLUSIONS: We developed the KUCaP library as a novel experimental platform for CRPC research by integrating clinical specimens with PDX, organoid, and ODX models along with their genomic and transcriptomic data. These models largely retained the genetic profiles and responses to castration observed in the original tumors. The bidirectional use of personalized PDX and organoids will facilitate the elucidation of the molecular mechanisms of CRPC.

Male↗