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PubMed2026

A De Novo 16p13.3 Triplication Underlying Early-Onset Complex Neurodegeneration.

BACKGROUND: Neurodegenerative disorders are clinically and genetically heterogeneous, characterized by progressive neuronal loss and multidomain functional decline. Despite a presumed genetic etiology, a substantial proportion of cases remain molecularly undiagnosed. OBJECTIVE: The aim was to identify the genetic cause of an early-onset neurodegenerative disorder presenting with ataxia and cognitive impairment. METHODS: Rare copy-number variants were detected via short-read whole-genome sequencing (WGS), with candidate structural models inferred using long-read WGS. We performed transcriptomic profiling of peripheral blood leukocytes by RNA sequencing, with validation using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). RESULTS: We identified a de novo copy-number gain at 16p13.3. Combined copy-number profiling and long-read WGS suggested a candidate model comprising a triplicated segment in tandem with a proximal duplication, joined to a distal duplication via an inverted junction. Transcriptomic analysis demonstrated significant upregulation of ATP6V0C, AMDHD2, and PDPK1. CONCLUSIONS: These findings support a role for structural variation in early-onset neurodegeneration and highlight the value of combining short-read copy-number profiling with long-read WGS to detect and characterize complex genomic rearrangements. © 2026 International Parkinson and Movement Disorder Society.

16p13.3↗

PubMed2025

Cancer-associated fibroblast-derived SOD3 enhances lymphangiogenesis to drive metastasis in lung adenocarcinoma.

Despite advancements in diagnostic and therapeutic strategies, lung adenocarcinoma (LUAD) remains a leading cause of cancer-related mortality due to its aggressive metastatic potential. Extracellular superoxide dismutase (SOD3) is an antioxidant enzyme that regulates oxidative stress and is regarded as a tumor suppressor. However, studies have demonstrated that SOD3 can either promote or inhibit cell proliferation and survival in various cancers, and its molecular mechanisms within the tumor microenvironment are poorly understood. In this study, we report a breakthrough in uncovering the role of SOD3 derived from cancer-associated fibroblasts (CAFs) in LUAD. Using LUAD xenograft models co-implanted with SOD3-overexpressing CAFs (CAFSOD3), we observe an aggressive tumor phenotype characterized by increased lymphangiogenesis and lymphatic vessel invasion (LVI) of the tumor. Additionally, LUAD patients with elevated SOD3 levels exhibit a higher incidence of LVI and metastasis. Notably, RNA sequencing of CAFSOD3 reveals that SOD3-mediated VEGF-dependent tumor progression and lymphangiogenesis are up-regulated. Furthermore, single-cell transcriptomic analysis of LUAD clinical samples confirms a strong correlation between SOD3 expression in fibroblasts and characteristics of tumor exacerbation, such as lymphangiogenesis and metastasis. These findings underscore new insights into the role of CAF-derived SOD3 in LUAD progression and highlight its potential as a biomarker and therapeutic target.

Lymphangiogenesis↗

PubMed2025

Celastrol modulates IRS1 expression to alleviate ovarian aging and to enhance follicular development.

Ovarian aging significantly contributes to the decline of the female reproductive system, adversely affecting fertility and endocrine homeostasis. To address the challenges posed by reproductive aging, natural products have shown promising preventive and therapeutic effects. Here, we investigated the beneficial effects of natural compound celastrol on ovarian development and aging, together with its underlying mechanisms. We found that celastrol administration at a concentration of 3 mg/kg promoted follicle development in young mice and enhanced porcine oocyte maturation, while regulating granulosa cell proliferation and apoptosis. In 12-month-old mice (equivalent to middle-aged adults), celastrol exhibited similar beneficial effects. Transcriptomic analysis revealed that differentially expressed genes post-celastrol treatment were associated with steroid biosynthesis, estrogen signaling pathways, type 2 diabetes, insulin secretion, meiosis, and apoptosis. Additionally, insulin receptor substrate 1 (IRS1), an adapter protein in insulin signaling, was shown to advance puberty in young mice and to facilitate oocyte maturation. Overexpression of IRS1 in oocytes promoted follicular development and oocyte maturation, resulting in enhanced steroid hormone levels, whereas IRS1 knockdown inhibited these processes. Our findings indicate that celastrol may regulate ovarian development and aging by modulating IRS1 expression and its related pathways, suggesting celastrol as a novel small-molecule compound targeting IRS1, and offering new perspectives for potential therapeutic strategies against reproductive aging and infertility.

Animals↗

PubMed2025

Identification of Potential Therapeutic Agents for Type I Interferonopathy Using iPSC-Based Disease Modeling.

PURPOSE: Type I interferonopathy encompasses disorders marked by systemic inflammation and neurological involvement, arising from genetic mutations that result in the upregulation of type I IFN signaling through various mechanisms. Currently, therapeutic options are limited, and no standard therapy exists. This study aims to develop a strategy for identifying new therapeutic targets for type I interferonopathy using induced pluripotent stem cells (iPSCs). METHODS: The IFIH1 R779H variant was introduced into iPSCs through genome editing. RNA sequencing of iPSC-derived dendritic cells (DCs) was performed, and differentially expressed genes (DEGs) were identified. IFN-α secretion, reactive oxygen species (ROS), and mitochondrial oxygen consumption rate (OCR) were analyzed in iPSC-derived DCs. An in silico prediction of compounds binding to the OAS-like domain was conducted. Candidate compounds were evaluated for their ability to inhibit IFN secretion from IFIH1 R779H-mutated iPSC-derived DCs. RESULTS: Transcriptome analysis indicated upregulation of the IFN-related and metabolic pathways. IFIH1 R779H-mutated iPSC-derived DCs exhibited increased OCR and ROS generation, and blocking mitochondrial metabolism significantly reduced excessive IFN-α secretion. Among the DEGs, PML was upregulated, and targeting this gene with arsenic trioxide (ATO), a PML antagonist, suppressed IFN-α secretion from IFIH1 R779H-mutated iPSC-derived DCs. Additionally, bisantrene, phthalylsulfathiazole and ganaplacide were predicted to bind to the RNA binding groove of OAS-like domain of human OASL in silico, effectively inhibiting IFN-α secretion from IFIH1 R779H-mutated DCs. CONCLUSION: Our iPSC-based disease modeling and drug investigation approach provides a robust platform for validating the efficacy and toxicity of candidate therapeutic agents for rare and intractable human diseases such as type I interferonopathy.

Humans↗

PubMed2026

Synthesis of Padina boergesenii-Derived Zinc Oxide Nanoparticles and their Therapeutic Potential Against Oral Squamous Cell Carcinoma: A Transcriptomic and in Vitro Evaluation.

Cancer remains a major health challenge, with oral squamous cell carcinoma (OSCC) being an high aggressive subtype of head and neck squamous cell carcinoma that lacks effective therapeutic options. Current study integrates the synthesis of zinc oxide nanoparticles (ZnO-NPs) from the marine brown algae Padina boergesenii with the OSCC gene expression profile to evaluate their potential therapeutic effects against OSCC. Herein, the ZnO-NPs from Padina boergesenii were prepared through the green synthesis method. The obtained ZnO-NPs were characterized through spectroscopic methods, the UV spectrophotometer shows maximum absorbance at 372 nm, FT-IR presents Zn-O functional band at 516 cm- 1, HR-TEM confirms average particle size of 55.70 nm and the Zetasizer shows zeta potential of + 12.9 mV, indicating colloidal stability. The cytotoxicity assay with ZnO-NPs against oral cancer cell lines exhibited a reduction in cell viability at IC₅₀ value of 20 µg/mL. Meanwhile, the transcriptome analysis of OSCC highlights that MYC, STAT3, BRCA1, and AKT1 are the OSCC therapeutic targets involved in proliferation, immune evasion, genomic instability, and cancer signalling pathways. Further, qRT-PCR based gene expression analysis demonstrates significant down-regulation of these targets upon ZnO-NPs treatment in KB cell lines. Overall, this study emphasizes the anticancer potential of Padina boergesenii-derived ZnO-NPs that could effectively modulate the therapeutic targets and may benefit the treatment of OSCC cancer.

Cytotoxicity↗

PubMed2026

Selenium nanoparticle synthesis in Stenotrophomonas maltophilia: Mutagenesis and molecular mechanisms.

Biosynthetic selenium nanoparticles (SeNPs) exhibit superior bioavailability and detoxification potential compared to inorganic selenium forms. In this study, the strain Stenotrophomonas maltophilia SE5, isolated from the feces of piglets (Duroc × Large White × Landrace), was utilized as the wild-type strain and subjected to atmospheric and room temperature plasma (ARTP) mutagenesis. A high-yielding mutant, Mu537, was successfully obtained, which exhibited an enhanced tolerance to sodium selenite, with its maximum tolerable concentration increasing from 1.0 g/L to 1.5 g/L. After 48 h of cultivation, Mu537 achieved an approximate 35% increase in SeNPs conversion rate and a 40% increase in SeNPs concentration relative to the parental strain. Integrated whole-genome sequencing and transcriptomic analysis revealed that pivotal genes associated with efficient SeNPs biosynthesis, including cysB, trxA, and sufE, were significantly up-regulated. These findings provide a systematic understanding of the potential molecular mechanisms driving enhanced SeNPs biosynthesis, offering both high-quality microbial resources and theoretical support for the industrial production of SeNPs.

Stenotrophomonas maltophilia↗

PubMed2026

An allograft inflammatory factor enhances sperm viability by modulating intracellular calcium in oyster Crassostrea gigas.

As an important aquaculture bivalve, the Pacific oyster Crassostrea gigas faces severe constraints in artificial reproduction, where low sperm motility often leads to fertilization failure and limits the sustainable development of the oyster aquaculture industry. In the present study, the variation of sperm from different oyster individuals was observed, and high-quality sperm possessed intact, elongated flagella with no structural abnormalities, while low-quality sperm showed shortened flagella with frequent tangling or coiling defects. Transcriptomic analysis comparing high- and low-quality sperm revealed significantly reduced expression of genes associated with sperm motility and release (CgAIF1, CgAchR, CgSEX), sperm quality and development (CgEP4, CgIFi2b), and cryoprotection (CgISPs) in low-quality sperm. Notably, an allograft inflammatory factor (designed as CgAIF1) encoding EF-hand domain, known as Ca2+ binding activity, was among the most significantly downregulated in low-motility sperm. CgAIF1 is highly expressed in haemocytes, ganglia, and gonads of oysters. Incubation with the recombinant AIF1 protein (rCgAIF1) significantly improved sperm curvilinear velocity, thereby enhancing the overall motility of C. gigas sperm. Furthermore, rCgAIF1 incubation increased intracellular Ca2+ levels (2.13-fold at 30 min, 2.71-fold at 60 min) and superoxide dismutase (SOD) activity (1.44-fold at 30 min, 1.24-fold at 60 min) in sperm, suggesting potential roles in calcium homeostasis regulation and antioxidant defense. In conclusion, this study demonstrates that CgAIF1 significantly enhances motility of oyster sperm, providing a scientific basis for artificial breeding and seed production in oyster aquaculture.

Animals↗

PubMed2025

Liquid Biopsy-Multiomics Link Adhesion Pathway Dysregulation to Kidney Injury Severity.

INTRODUCTION: Severe acute kidney injury (AKI) is strongly associated with the risk of developing chronic kidney disease; however, little is known about the cell type-specific mechanisms driving kidney injury severity. METHODS: In this multicenter observational study, we used clinically obtained liquid biopsy proteomics and machine learning (ML) to predict severe outcomes in patients with COVID-associated and non-COVID AKI. Further, we orthogonally combined 169 urine proteomics with 437 plasma proteomics samples and 40 urine sediment single-cell transcriptomics samples to identify complementary dysregulated mechanisms. RESULTS: Using a 10-fold cross-validated random forest algorithm, we identified a set of urinary proteins that demonstrate predictive power for both discovery and validation set with AUC of 87% and 76%, respectively. These predictive proteomics features obtained demonstrate that cell adhesion and autophagy-associated pathways are uniquely impacted in severe AKI. Differentially abundant proteins (DAPSs) associated with these pathways are highly expressed in cells of the juxtamedullary nephron, endothelial cells (ECs), and podocytes, indicating that these kidney cell types could be potential targets. Single-cell transcriptomic analysis in the in vitro model of kidney organoids infected with SARS-CoV-2 reveal dysregulation of extracellular matrix (ECM) organization in multiple nephron segments, recapitulating the clinically observed fibrotic response across multiomics datasets. Ligand-receptor interaction analysis of the podocyte and tubule organoid clusters shows significant reduction and loss of interaction between integrins and basement membrane receptors in the infected kidney organoids. CONCLUSION: Collectively, these data suggest that ECM degradation and adhesion-associated mechanisms could be the main driver of severe kidney injury.

AKI↗

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↗

PubMed2026

Identification of tomato leaf miner secretory proteins and their roles in influencing plant defenses.

The tomato leaf miner (Tuta absoluta) is a globally destructive pest that cause extensive damage to tomato crops by chewing mouthparts, leading to severe necrosis, fruit abortion, and substantial yield losses. To date, the elicitors/effectors of T. absoluta have not been characterized. In this study, we combined proteomic profiling of T. absoluta-infested tomato leaves with transcriptomic analysis of salivary glands to identify candidate molecules involved in herbivory-driven plant responses. Bioinformatics analyses predicted 40 candidate elicitors and effectors, which were subsequently assessed through transient expression assays in Nicotiana benthamiana. The results demonstrated that the candidate number 33 (T. absoluta 33, Ta33) induced cell death in both the intracellular space and the apoplast, while Ta21 triggered a strong apoplastic reactive oxygen species (ROS) burst. Conversely, Ta38 effectively suppressed INF1-induced cell death. Quantitative real-time PCR analysis further showed that these genes were highly expressed during the feeding stage, supporting their involvement in plant-insect molecular dialogue. This study systematically identified and characterized elicitors and effectors of T. absoluta, providing a foundational framework for elucidating its herbivory mechanisms and developing targeted management strategies.

Moths↗

PubMed2026

Emergence of cefiderocol resistance in carbapenem-resistant Escherichia coli ST167 prior to clinical use: A multifactored resistance landscape.

OBJECTIVES: Cefiderocol is a novel siderophore cephalosporin with potent activity against multidrug-resistant Gram-negative bacteria. Here, we reported the prevalence and mechanisms of cefiderocol resistance in carbapenem-resistant Escherichia coli (CREC) in China before its clinical use. METHODS: A total of 443 non-duplicate CREC isolates collected from 67 hospitals in China (2013-2021) underwent antimicrobial susceptibility testing according to CLSI guidelines. Whole-genome sequencing, transcriptomic analysis, siderophore quantification, and targeted genetic manipulation were performed to investigate the underlying resistance mechanisms. RESULTS: Among the 443 CREC isolates, 102 (23.0%) were resistant to cefiderocol, and 34 (7.6%) showed intermediate susceptibility. Multivariable logistic regression identified ST167 lineage (OR, 3.05; 95% CI, 1.12-8.29; P = 0.028), blaNDM-5 carriage (OR, 9.04; 95% CI, 2.96-27.57; P < 0.001), and cirA truncation (OR, 49.56; 95% CI, 20.33-120.79; P < 0.001) as independent factors associated with cefiderocol resistance. Among ST167 isolates, cefiderocol-resistant isolates showed increased yersiniabactin carriage and siderophore production but comparable TonB-dependent transporter expression profiles. Phylogenetic analysis revealed that cefiderocol-resistant ST167 isolates clustered into a distinct subclade enriched with resistance-associated determinants, including a recurrent FhuA P50S substitution detected in 59/64 (92.2%) resistant isolates. Functional assays showed that the P50S substitution increased cefiderocol minimum inhibitory concentration (0.032-0.125 µg/mL), particularly in an NDM-5-producing background (0.032-0.5 µg/mL). CONCLUSIONS: Cefiderocol resistance is highly prevalent among high-risk ST167 CREC isolates before the clinical introduction of cefiderocol in China, highlighting the need for continued surveillance of this epidemic lineage. Cefiderocol resistance is mediated by multiple resistance determinants, and we identify the recurrent FhuA P50S substitution as a novel contributor to reduced cefiderocol susceptibility.

Antimicrobial resistance↗

PubMed2025

Reversible phenotypic resistance to phage infection via capsule downregulation in Klebsiella pneumoniae.

Capsule loss is a major mechanism by which bacteria evade phage infection. This has traditionally been attributed to mutations in capsule biosynthesis genes. Here, we investigated phage resistance in Klebsiella pneumoniae, a medically relevant encapsulated bacterium. Phage infection rapidly selected for resistant acapsular cells. As expected, transcriptomic analysis revealed a marked downregulation of capsule biosynthesis genes. However, full genome sequencing showed that capsule loss occurred without evidence of mutations, and acapsular phage-resistant cells were able to rapidly restore their capsule once phage pressure was removed. These findings highlight that phage-driven selective pressure can act on non-heritable variation in gene expression, providing a faster and more flexible resistance mechanism compared to the traditional mutation-selection process. This reversible resistance may complicate predictability and limit the long-term efficacy of phage therapy.

Cell biology↗

PubMed2026

Exercise-associated epigenetic remodeling and TCR repertoire dynamics in Lynch syndrome carriers.

Lynch syndrome (LS) carriers are at elevated cancer risk. Emerging evidence suggests that exercise may serve as a non-pharmacologic preventive strategy, yet the epigenetic and immunological mechanisms underlying its protective effects in this population remain unclear. Here, we perform integrative multi-omics profiling of DNA methylation, gene expression, and the T cell receptor (TCR) repertoire in LS carriers undergoing a 52-week aerobic cycling intervention. We identify compartment-specific DNA methylation changes, including innate immune activation in cfDNA and oncogenic pathway repression in tissue. Integrative transcriptomic analysis highlights ISL1 as a key exercise-repressed, epigenetically regulated gene, and identifies FLCN as a colorectal cancer (CRC)-associated methylation target. TCR analysis reveals an exercise-associated increase in systemic repertoire diversity and tissue-specific clonal convergence, thus suggesting antigen-driven recruitment. Collectively, these findings uncover epigenetic and immune remodeling as potential mechanisms of exercise-mediated protection in LS.

Lynch syndrome↗

PubMed2025

Targeting the bile acid receptor TGR5 with Gentiopicroside to activate Nrf2 antioxidant signaling and mitigate Parkinson's disease in an MPTP mouse model.

INTRODUCTION: Parkinson's disease (PD) is a common neurodegenerative disorder characterized by classical symptoms including bradykinesia, rest tremor and rigidity. Oxidative stress and mitochondrial dysfunction are recognized as pivotal factors in PD progression. Gentiopicroside (GPS), a secoiridoid derived from Gentiana manshurica Kitagawa, exhibits antioxidant and mitophagy induction properties. Nonetheless, the effects and mechanisms by which GPS mitigates neurodegeneration in PD remain to be thoroughly elucidated. OBJECTIVES: The goal of this study was to investigate the neuroprotective effects and mechanisms of GPS in PD models. METHODS: We established the MPTP/MPP+-induced PD models to measure the neuroprotection of GPS. Transcriptomic analysis, oxidative biochemical kits, western blot and cell immunofluorescence were conducted to elucidate the fundamental mechanisms at play. Subsequently, the targeting and activation of the transmembrane G protein-coupled receptor-5 (TGR5) by GPS were measured by molecular docking, cellular thermal shift assay, microscale thermophoresis (MST) and cyclic adenosine monophosphate (cAMP) quantitation. Finally, we verified whether the neuroprotective and antioxidant effects of GPS were dependent on TGR5 by using specific small interfering RNA (siRNA), pharmacological antagonist and knockout mice. RESULTS: GPS significantly attenuated dopaminergic (DAergic) neuron loss and restored motor function in the MPTP-induced PD mouse model. Whole-genome RNA sequencing and subsequent mechanistic investigations revealed that GPS enhanced the expression and facilitated nuclear entry of factor erythroid-related 2-factor 2 (Nrf2), and reduced oxidative stress and mitochondrial dysfunction stimulated by neurotoxin. Additionally, GPS could target TGR5 and prevent its downregulation in PD model. TGR5's silencing or inhibition weakened the neuroprotective effect of GPS and blocked GPS-mediated activation of Nrf2 antioxidant signaling in PD model. Moreover, the therapeutic effect of GPS in mitigating motor deficits and neurodegeneration was also abolished in Tgr5 knockout mice. CONCLUSION: These findings collectively indicated that GPS targeted TGR5 to activate Nrf2 antioxidant signaling and ultimately ameliorated the pathological progression of PD.

Animals↗

PubMed2026

Glial Connexin-43 Is a Pathogenic Mechanism Promoting Gut Inflammation in Postoperative Ileus Induced by Gut Surgical Manipulation With Potential Relevance to Humans.

BACKGROUND & AIMS: Abdominal surgery often precipitates postoperative ileus (POI), a frequent and severe gastrointestinal (GI) motility disorder, through mechanisms that involve intestinal inflammation. Emerging data show that enteric glia acquire a reactive phenotype that aggravates POI, but how glia exert this effect remains unclear. Enteric glia express connexin-43 hemichannels (gCx43), which are implicated in neurological and inflammatory disorders. Thus, we aimed to decipher contributions of glial connexin-43 (Cx43) in the pathophysiology of POI. METHODS: We induced POI in mice using in vivo intestinal manipulation and used glial Cx43cKO (Sox10CreERT2;Cx43fl/fl) or RiboTag (Sox10CreERT2/Rpl22HA/+) mice to evaluate Cx43-dependent signaling. Human enteric glial cultures (hEGC) and muscularis externa obtained during intestinal surgery translated findings to patients. Transcriptome analysis, immunofluorescence co-labeling, Western blots, and Cx43 hemichannel activation were used for quantitative analysis. RESULTS: Cx43 is the highest expressed connexin in enteric glia in mice and humans. Up-regulation of Cx43 occurs in various disease models linked to POI, GI surgical trauma, inflammation, immune cell activation, and enteric gliosis. In the mouse POI model, glial Cx43-deletion reduces glial reactivity, pro-inflammatory signals, upregulates host protection genes, regulates immune cell activation, and prevents enteric neuropathy. In hEGCs, interleukin (IL)-1β induction opens Cx43 and stimulates release of IL-6 and C-C motif ligand 2 (CCL2). The Cx43 peptide inhibitor, 43Gap26, inhibits glial Cx43 activation, reduces IL-6 release, and blocks upregulation of macrophage activation factors and immune cell regulation factors. Surgical intestinal trauma in patients upregulates Cx43 during inflammation and enteric gliosis in mouse POI. CONCLUSIONS: Glial Cx43 signaling promotes enteric gliosis, immune cell activation, inflammation, and enteric neuropathy in mice with potential translatability to humans after intestinal surgical trauma and mechanical stress in POI. Interventions that block glial Cx43 activation may be protective against POI development.

Animals↗

PubMed2026

Yorkie/Scalloped-OVOL-Rac1 axis controls insect wing development by promoting cell proliferation.

The regulation of organ size is a fundamental question in developmental biology, and insect wings provide a powerful model for elucidating the genetic mechanisms underlying morphogenesis. Although the conserved Hippo signaling pathway plays a central role in controlling tissue growth, its precise regulatory network during wing development remains incompletely understood. Here, we identify the zinc finger transcription factor OVOL as a critical mediator of Hippo signaling in insect wing development. We indicate that OVOL is essential for normal wing formation in both Locusta migratoria and Drosophila melanogaster, regulating cell proliferation and trichome patterning. Through transcriptomic analysis and functional validation, we further identify the small GTPase Rac1 as a key downstream effector of OVOL that promotes proliferative growth. Moreover, we find that OVOL expression is directly activated by the Yorkie/Scalloped (Yki/Sd) complex, the core transcriptional effector of the Hippo pathway, without forming a feedback loop. This regulation is mediated through a specific Sd-binding motif (GATAA) within the OVOL promoter. Importantly, Yki/Sd-induced Rac1 expression is dependent on OVOL. Collectively, our findings establish the Yorkie/Sd-OVOL-Rac1 pathway that governs insect wing development by promoting cell proliferation, providing mechanistic insights into organ size regulation in animals.

Cell proliferation↗

PubMed2026

Endobronchial Ultrasound-Guided Biopsy-Derived Lung Cancer Models: A Platform for Precision Therapy.

BACKGROUND: Endobronchial ultrasound-guided transbronchial needle aspiration is used for clinical diagnosis and staging in patients with lung cancer. Nevertheless, establishing patient-derived preclinical models using needle biopsy samples remains challenging. This study describes the establishment and utility of patient-derived organoid (PDO) from endobronchial ultrasound-guided (EBUS) specimens and EBUS patient-derived xenograft (PDX). METHODS: A total of 175 EBUS specimens were used to establish PDO and PDX. "Stable establishment" organoids with passage numbers of 10 or greater were used for genomic, transcriptome, and pathologic assessment. Drug sensitivity of EBUS organoids and PDX tumors were compared with those of the matched patient. Drug screening was performed using stably established organoid models. RESULTS: We successfully established a total of 20 EBUS organoids: six EBUS-PDOs and 14 EBUS-xenograft derived organoids. These stable cancer organoid models were validated for cancer cell enrichment and pathologic assessment. Pathologic findings, exome, and transcriptome analysis found a high correlation between EBUS organoids and parental samples. EBUS organoids and PDX indicated consistent drug response patterns with their corresponding patients. A drug screening conducted on an EBUS organoid led to the discovery of potent activity of trametinib to a rare MAP2K1 K57N mutation. CONCLUSIONS: EBUS-PDO and -xenograft‒derived organoids are good options to generate stable organoids in patients with advanced stage lung cancer. The models were consistent with the genetic and pathologic features of patient tumors, and the patient's responses to treatment, supporting their utility for novel therapeutic research.

Humans↗

PubMed2025

The Involvement of PI3K-Akt Signaling in the Clinical and Pathological Findings of Idiopathic Multicentric Castleman Disease-Thrombocytopenia, Anasarca, Fever, Reticulin Fibrosis, and Organomegaly and Not Otherwise Specified Subtypes.

Idiopathic multicentric Castleman disease is a rare lymphoproliferative disorder that is clinically classified into idiopathic plasmacytic lymphadenopathy (IPL); thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly (TAFRO); and not otherwise specified (NOS). Although each subtype shows varying degrees of hypervascularity, no statistical data on the degree of vascularization have been reported. Additionally, the mechanisms underlying vascularization in each clinical subtype are poorly understood. Here, we aimed to clarify these mechanisms by evaluating the histopathological characteristics of each clinical subtype across 37 patients and performing a whole-transcriptome analysis focusing on angiogenesis-related gene expression. Histologically, TAFRO and NOS exhibited a significantly higher degree of vascularization than IPL (IPL vs TAFRO, P < .001; IPL vs NOS, P = .002). In addition, the germinal centers (GCs) were significantly more atrophic in TAFRO than in IPL. In TAFRO and NOS, "whirlpool vessels" in GCs were seen in most cases (TAFRO, 9/9, 100%; NOS, 6/8, 75%) but not in IPL (IPL vs TAFRO, P < .001; IPL vs NOS, P = .007). Likewise, immunostaining for Ets-related gene revealed higher levels in endothelial cells of GCs in TAFRO than in IPL (P = .014), and TAFRO and NOS were associated with a significantly higher number of endothelial cells in interfollicular areas compared with that in IPL (TAFRO vs IPL, P < .001; NOS vs IPL, P = .002). Gene expression analysis revealed that the PI3K-Akt signaling pathway was significantly enriched in the TAFRO and NOS (TAFRO/NOS) groups. This pathway, which may be activated by vascular endothelial growth factor A and some integrins, is known to affect angiogenesis by increasing vascular permeability, which may explain the clinical manifestations of anasarca and/or fluid retention in TAFRO/NOS. These results suggest that the PI3K-Akt pathway plays an important role in the pathogenesis of TAFRO/NOS.

Humans↗