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BRD4, a Bromodomain and Extraterminal (BET) protein family member, is a promising anti-cancer drug target. However, resistance to BET inhibitors targeting BRD4 is common in solid tumors. Here, we show that cancer-associated fibroblast (CAF)-activated stromal signaling, interleukin-6/8-JAK2, induces BRD4 phosphorylation at tyrosine 97/98 in colorectal cancer, resulting in BRD4 stabilization due to interaction with the deubiquitinase UCHL3. BRD4 phosphorylation at tyrosine 97/98 also displays increased binding to chromatin but reduced binding to BET inhibitors, resulting in resistance to BET inhibitors. We further show that BRD4 phosphorylation promotes interaction with STAT3 to induce chromatin remodeling through concurrent binding to enhancers and super-enhancers, supporting a tumor-promoting transcriptional program. Inhibition of IL6/IL8-JAK2 signaling abolishes BRD4 phosphorylation and sensitizes BET inhibitors in vitro and in vivo. Our study reveals a stromal mechanism for BRD4 activation and BET inhibitor resistance, which provides a rationale for developing strategies to treat CRC more effectively. BRD4 has a pro-tumorigenic role but non-cell-autonomous mechanisms of BRD4 activation need to be elucidated. Here the authors unravel a mechanism by which CAFs activate BRD4 and induce resistance to BET inhibitors in cancer cells through IL6/IL8 signaling.

The hypoxic tumor microenvironment has been implicated in immune escape, but the underlying mechanism remains elusive. Using an in vitro culture system modeling human T cell dysfunction and exhaustion in triple-negative breast cancer (TNBC), we find that hypoxia suppresses immune effector gene expression, including in T and NK cells, resulting in immune effector cell dysfunction and resistance to immunotherapy. We demonstrate that hypoxia-induced factor 1α (HIF1α) interaction with HDAC1 and concurrent PRC2 dependency causes chromatin remolding resulting in epigenetic suppression of effector genes and subsequent immune dysfunction. Targeting HIF1α and the associated epigenetic machinery can reverse the immune effector dysfunction and overcome resistance to PD-1 blockade, as demonstrated both in vitro and in vivo using syngeneic and humanized mice models. These findings identify a HIF1α-mediated epigenetic mechanism in immune dysfunction and provide a potential strategy to overcome immune resistance in TNBC. Hypoxia can promote tumor escape from immune surveillance and immunotherapy. Here, the authors show that hypoxia induces T and NK cell dysfunction through HIF1α-mediated epigenetic suppression of effector gene expression, conferring resistance to anti-PD1 blockade in triple negative breast cancer models.

Drones have rapidly emerged as transformative tools in landscape research, enabling high-resolution spatial data acquisition, real-time environmental monitoring, and advanced modelling that surpass the limitations of traditional methodologies. This scoping review systematically explores and synthesises the technological applications of drones within the context of landscape studies, addressing a significant gap in the integration of Uncrewed Aerial Systems (UASs) into environmental and spatial planning disciplines. The study investigates the typologies of drone platforms—including fixed-wing, rotary-wing, and hybrid systems—alongside a detailed examination of sensor technologies such as RGB, LiDAR, multispectral, and hyperspectral imaging. Following the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews) guidelines, a comprehensive literature search was conducted across Scopus, Web of Science, and Google Scholar, utilising predefined inclusion and exclusion criteria. The findings reveal that drone technologies are predominantly applied in mapping and modelling, vegetation and biodiversity analysis, water resource management, urban planning, cultural heritage documentation, and sustainable tourism development. Notably, vegetation analysis and water management have shown a remarkable surge in application over the past five years, highlighting global shifts towards sustainability-focused landscape interventions. These applications are critically evaluated in terms of spatial efficiency, operational flexibility, and interdisciplinary relevance. This review concludes that integrating drones with Geographic Information Systems (GISs), artificial intelligence (AI), and remote sensing frameworks substantially enhances analytical capacity, supports climate-resilient landscape planning, and offers novel pathways for multi-scalar environmental research and practice.

Owing to the development of technology, the majority of nations throughout the world now rely on fossil fuels and nuclear power plants to meet their energy needs. However, as academic research on this subject has shown, it has become clear that alternative energy uses are necessary due to the gradual depletion of these fuels and their significant negative effects on the environment. In order to ensure energy diversity and end the energy shortage, the development of renewable energy sources is crucial. The prediction of wind power is crucial for effectively utilizing the potential of wind energy. In this study, an adaptive neuro-fuzzy inference system (ANFIS) and an artificial neural network (ANN) have been developed for the prediction of wind power. In this study, data sets were created by taking the daily average wind speeds of the selected wind turbine, the daily average power values it produces, and the daily average wind speed values in the Velimese region. By creating single-hidden layer and multi-hidden layer ANN models, the network was trained multiple times with different activation functions and different numbers of neurons, and wind power prediction was performed. In the ANFIS model, the number of membership functions is kept constant, and wind power prediction is performed using different membership functions. With these ANFIS and ANN models developed with different parameter combinations, it is aimed to determine the most efficient model by performing daily average wind power prediction. Parameter combinations were tested to determine the appropriate models, and as a result, the ANN and ANFIS models were compared with each other.

Endothelial dysfunction is a systemic disorder that triggers vascular alterations, characterised by a reduction in nitric oxide (NO) synthesis and/or a defective vasodilatory response. Trimethylamine-N-oxide (TMAO) is a gut microbiota-derived dietary metabolite, while tumour necrosis factor alpha (TNF-α) functions as a pro-inflammatory cytokine. Both are known to induce inflammation, metabolic modulations, and endothelial dysfunction, contributing to cardiometabolic diseases. Nevertheless, the comparative effects of TMAO and TNF-α on inflammation and metabolic modulations have yet to be investigated. Here, using bulk RNA-sequencing (RNA-seq), real-time quantitative polymerase chain reaction (RT-qPCR) and interleukins/chemokines multiplex assays, we demonstrate significantly higher levels of inflammation, with a stronger cytokine response and activation of type I and II interferons, following TNF-α treatment compared to TMAO treatment in human dermal microvascular endothelial cells (HMEC-1). In addition, TNF-α upregulates the disassembly of the extracellular matrix (ECM), while ECM-related genes and pathways are either not modulated or down-regulated after TMAO treatment. Intriguingly, TMAO specifically induces a shift in energy metabolism (upregulation of OXPHOS (oxidative phosphorylation)), while TNF-α rather modulates lipid metabolism. In conclusion, this study reveals common pathways, but also key differences in molecular processes activated by TNF-α versus TMAO. These data are essential for identifying the most suitable in vitro human cellular models to study inflammation, as well as to discover novel targeted therapeutics to alleviate cardiometabolic conditions.

Amplification of chromosome 1q21.3 distinguishes cells with tumor-initiating capacity that drive tumor recurrence across different breast cancer subtypes. A droplet digital PCR assay in circulating free tumor DNA identifies patients with early-stage cancer at high risk of relapse and predicts response to therapy in the metastatic setting. Pharmacological blockade of targets within this amplicon using a clinically available compound prevents tumor recurrence, suggesting a potential therapeutic approach to improve the clinical management of patients harboring 1q21.3-amplified breast tumors. Tumor recurrence remains the main reason for breast cancer–associated mortality, and there are unmet clinical demands for the discovery of new biomarkers and development of treatment solutions to benefit patients with breast cancer at high risk of recurrence. Here we report the identification of chromosomal copy-number amplification at 1q21.3 that is enriched in subpopulations of breast cancer cells bearing characteristics of tumor-initiating cells (TICs) and that strongly associates with breast cancer recurrence. Amplification is present in ∼10–30% of primary tumors but in more than 70% of recurrent tumors, regardless of breast cancer subtype. Detection of amplification in cell-free DNA (cfDNA) from blood is strongly associated with early relapse in patients with breast cancer and could also be used to track the emergence of tumor resistance to chemotherapy. We further show that 1q21.3-encoded S100 calcium-binding protein (S100A) family members, mainly S100A7, S100A8, and S100A9 (S100A7/8/9), and IL-1 receptor–associated kinase 1 (IRAK1) establish a reciprocal feedback loop driving tumorsphere growth. Notably, this functional circuitry can be disrupted by the small-molecule kinase inhibitor pacritinib, leading to preferential impairment of the growth of 1q21.3-amplified breast tumors. Our study uncovers the 1q21.3-directed S100A7/8/9–IRAK1 feedback loop as a crucial component of breast cancer recurrence, serving as both a trackable biomarker and an actionable therapeutic target for breast cancer.

HER2-targeted therapy has yielded a significant clinical benefit in patients with HER2+ breast cancer, yet disease relapse due to intrinsic or acquired resistance remains a significant challenge in the clinic. Here, we show that the protein phosphatase 2A (PP2A) regulatory subunit PPP2R2B is a crucial determinant of anti-HER2 response. PPP2R2B is downregulated in a substantial subset of HER2+ breast cancers, which correlates with poor clinical outcome and resistance to HER2-targeted therapies. EZH2-mediated histone modification accounts for the PPP2R2B downregulation, resulting in sustained phosphorylation of PP2A targets p70S6K and 4EBP1 which leads to resistance to inhibition by anti-HER2 treatments. Genetic depletion or inhibition of EZH2 by a clinically-available EZH2 inhibitor restores PPP2R2B expression, abolishes the residual phosphorylation of p70S6K and 4EBP1, and resensitizes HER2+ breast cancer cells to anti-HER2 treatments both in vitro and in vivo. Furthermore, the same epigenetic mechanism also contributes to the development of acquired resistance through clonal selection. These findings identify EZH2-dependent PPP2R2B suppression as an epigenetic control of anti-HER2 resistance, potentially providing an opportunity to mitigate anti-HER2 resistance with EZH2 inhibitors. Resistance to anti-HER2 therapies in breast cancer remains a significant clinical challenge. Here, the authors demonstrate that EZH2 regulates response to HER2-targeting therapies in breast cancer, in part, by modulating the expression of PPP2R2B .

Agricultural terraces are critical landscape elements that promote sustainable rural development by enhancing water retention, mitigating soil erosion, and conserving cultural heritage. In northeastern Türkiye, particularly in the mountainous Erikli neighborhood of Uzundere, traditional terraces face growing threats due to land abandonment, topographic fragility, and socio–economic decline. This study applies a spatial–functional assessment framework that integrates UAV–based photogrammetry, GIS analysis, terrain modeling, and DBSCAN clustering to evaluate terrace conditions. UAVs provided high–resolution topographic data, which supported the delineation of terrace boundaries and morphometric classification using an adapted ALPTER model. A combined Terrace Density Index (TDI) and Functional Status Index (FSI) approach identified zones where terraces are structurally intact but functionally degraded. Results indicate that 76.4% of terraces fall within the meso and macro classes, yet 58% show partial or complete degradation. Cohesive terrace clusters are located near settlements, while isolated units in peripheral zones display higher vulnerability. This integrated approach demonstrates the analytical potential of drone–supported spatial diagnostics for monitoring landscape degradation. The method is scalable and adaptable to other terraced regions, offering practical tools for site–specific land use planning, heritage conservation, and resilience–based restoration strategies.

Background Xenopus has served as a valuable model system for biomedical research over the past decades. Notably, ADAR was first detected in frog oocytes and embryos as an activity that unwinds RNA duplexes. However, the scope of A-to-I RNA editing by the ADAR enzymes in Xenopus remains underexplored. Results Here, we identify millions of editing events in Xenopus with high accuracy and systematically map the editome across developmental stages, adult organs, and species. We report diverse spatiotemporal patterns of editing with deamination activity highest in early embryogenesis before zygotic genome activation and in the ovary. Strikingly, editing events are poorly conserved across different Xenopus species. Even sites that are detected in both X. laevis and X. tropicalis show largely divergent editing levels or developmental profiles. In protein-coding regions, only a small subset of sites that are found mostly in the brain are well conserved between frogs and mammals. Conclusions Collectively, our work provides fresh insights into ADAR activity in vertebrates and suggest that species-specific editing may play a role in each animal’s unique physiology or environmental adaptation.

Background Antenatal steroid therapy for fetal lung maturation is routinely administered to women at risk of preterm delivery. There is strong evidence to demonstrate benefit from antenatal steroids in terms of survival and respiratory disease, notably in infants delivered at or below 32 weeks’ gestation. However, dosing remains unoptimized and lung benefits are highly variable. Current treatment regimens generate high-concentration, pulsatile fetal steroid exposures now associated with increased risk of childhood neurodevelopmental diseases. We hypothesized that damage-associated changes in the fetal hippocampal transcriptome would be independent of preterm lung function. Methods Date-mated ewes carrying a single fetus at 122 ± 2dGA (term = 150dGA) were randomized into 4 groups: (i) Saline Control Group, 4×2ml maternal saline intramuscular(IM) injections at 12hr intervals ( n  = 11); or (ii) Dex High Group, 2×12mg maternal IM dexamethasone phosphate injections at 12hr intervals followed by 2×2ml IM saline injections at 12hr intervals ( n  = 12; representing a clinical regimen used in Singapore); or (iii) Dex Low Group, 4×1.5mg maternal IM dexamethasone phosphate injections 12hr intervals ( n  = 12); or (iv) Beta-Acetate Group, 1×0.125mg/kg maternal IM betamethasone acetate injection followed by 3×2ml IM sterile normal saline injections 12hr intervals ( n  = 8). Lambs were surgically delivered 48hr after first maternal injection at 122–125dGA, ventilated for 30min to establish lung function, and euthanised for necropsy and tissue collection. Results Preterm lambs from the Dex Low and Beta-Acetate Groups had statistically and biologically significant lung function improvements (measured by gas exchange, lung compliance). Compared to the Saline Control Group, hippocampal transcriptomic data identified 879 differentially significant expressed genes (at least 1.5-fold change and FDR < 5%) in the steroid-treated groups. Pulsatile dexamethasone-only exposed groups (Dex High and Dex Low) had three common positively enriched differentially expressed pathways related in part to neurodegeneration (“Prion Disease”, “Alzheimer’s Disease”, “Arachidonic Acid metabolism”). Adverse changes were independent of respiratory function during ventilation. Conclusions Our data suggests that exposure to antenatal steroid therapy is an independent cause of damage- associated transcriptomic changes in the brain of preterm, fetal sheep. These data highlight an urgent need for careful reconsideration and balancing of how antenatal steroids are used, both for patient selection and dosing regimens.