Search Results (2,978)

Cardiac fibrosis is a hallmark of cardiac aging and a major contributor to development of heart failure. However, therapeutic strategies that specifically target cardiac fibrosis remain limited. In this study, we demonstrate that small-molecule compound ML216 exerts protective effects against aging-associated or β-adrenoceptor agonist isoproterenol-induced cardiac fibrosis in vitro or in vivo. Mechanistically, ML216 inhibits transforming growth factor-β1 (TGF-β1) signaling by reducing TGF-β1 protein levels, thereby attenuating Mothers against decapentaplegic homolog (SMAD) phosphorylation and downstream induction of connective tissue growth factor (CTGF). This leads to a marked suppression of fibrotic genes Col1a1, Cnn2, and Acta2, ultimately resulting in reduced fibrosis. Additionally, the inhibition of the TGF-β1 pathway alleviates cardiomyocytes apoptosis, which may further limit inflammatory responses and contributes to the overall attenuation of cardiac fibrosis. Collectively, these findings demonstrate that ML216 mitigates cardiac fibrosis through the inhibition of TGF-β1 pathway-mediated fibrotic signaling and apoptosis, highlighting its potential as a therapeutic candidate for the treatment of cardiac fibrosis. Full article

Intensifying hydroclimatic extremes have heightened the need for basin-scale indicators of antecedent wetness that are relevant to flood responses. However, ground-based soil-moisture observations are spatially sparse, and satellite products frequently exhibit temporal gaps. To address this limitation, this study integrated satellite- and ground-soil-moisture observations, hydro-meteorological variables, and observed streamflow data from 2018 to 2024 across 26 standard basins (SBs) within three dam basin regions in South Korea: the Nam River Dam (NGD) and the upstream and downstream regions of the Seomjin River Dam (SJD). Using this integrated dataset, we quantified the relationships among precipitation, basin wetness, and rapid discharge increases, subsequently deriving composite thresholds for flood early warnings. For each SB, we trained a Random Forest regression model using satellite-soil-moisture and basin-representative hydro-meteorological inputs—including 1-day accumulated precipitation (P_1d), 7-day accumulated precipitation (P_7d), the antecedent precipitation index (API), and related meteorological variables—to estimate a continuous, daily basin-representative soil-moisture series (SM_RF). Validation results indicated that the coefficient of determination (R²) ranged from 0.6 to 0.7 for most SBs. Extreme event days were consistently associated with elevated values of SM_RF, P_1d, P_7d, and API, demonstrating that antecedent wetness significantly influences the likelihood of rapid discharge events. Finally, composite threshold scanning yielded candidate rules characterized by high precision, moderate hit rates, and low false-alarm rates, confirming the efficacy of the proposed framework for developing flash-flood early-warning thresholds in South Korean dam basins. Full article

Background/Objectives: Women and girls, particularly in sub-Saharan Africa, face high risks for both HIV and unintended pregnancy. Inconsistent condom use underscores the need for new multipurpose prevention technologies (MPTs) that combine HIV pre-exposure prophylaxis (PrEP) and contraception. Long-acting (LA) injectables are especially promising. To this end, an LA cabotegravir (CAB)/medroxyprogesterone acetate (MPA) in situ-forming implant (ISFI) has been developed. We report pharmacokinetic (PK) modeling to characterize CAB and MPA disposition and absorption to support the development of the MPT ISFI. Methods: Female BALB/c mice received single intravenous (IV) or subcutaneous (SQ) bolus doses of CAB or MPA. Sparse plasma samples were collected (~3 mice/timepoint) for PK analysis by LC-MS/MS. Noncompartmental analysis assessed SQ bioavailability. Macroparameterized compartmental PK models were fit to IV data to derive unit impulse responses (UIRs) for each drug. Results: CAB and MPA exhibited 61% and 42% bioavailability, respectively. CAB IV PK was best described by a two-compartment model with macroconstant parameters: A = 16,621 ng/mL, α = 4.52 h⁻¹, B = 30,206 ng/mL, and β = 0.053 h⁻¹. MPA IV PK was also best described by a two-compartment model, with A = 2506 ng/mL, α = 10.5 h⁻¹, B = 439 ng/mL, and β = 0.65 h⁻¹. These values define the UIR for CAB and MPA. Conclusions: Our IV PK modeling framework fully characterizes CAB/MPA disposition in mouse, enabling downstream deconvolution-based estimation of absorption from controlled-release formulations. This provides a foundation for in vitro–in vivo correlation, facilitating preclinical evaluation of long-acting formulations such as ISFIs. Full article

Wildfire impact on boreal watersheds was assessed across Alberta’s Regional Aquatics Monitoring Program (RAMP) domain by integrating multidecadal river, lake, and sediment physical–chemical data with historical wildfire perimeters, polycyclic aromatic hydrocarbon (PAH) indicators, continuous multiparameter sonde records, and pre-/post-fire hydrologic simulations. Site classification, distinguishing reference, industrial, wildfire, and combined influences, was used to enable spatial and temporal comparisons before, during, and after fires. Our synthesis indicated that wildfire acts as an important disturbance that alters watershed connectivity and transport pathways, resulting in shifts in water quality and quantity in surface waters and longer-term adjustments retained in sediments. The interpretation of chemical signatures, including PAHs, was complicated by overlap between areas with wildfire and industrial activities, highlighting cumulative effects and the importance of spatio–temporal context when assessing and quantifying source contributions for long-term resource sustainability. Hydrologic alteration emerged as the dominant downstream wildfire effect, emphasizing the need for long-term continuous monitoring of fire-responsive indicators, in addition to improved assessment of subsurface pathways in wildfire-prone boreal systems. Full article

The resource utilization of construction and demolition waste (CDW) is crucial for advancing the green transformation of the construction industry, but it faces challenges such as insufficient upstream R&D motivation and low downstream market acceptance. To investigate the impact of corporate social responsibility (CSR) and sales effort on the recycled cement supply chain, in this study, a Stackelberg game model of a two-tier supply chain comprising a single recycled cement manufacturer and retailers is constructed. Under government subsidy conditions, four CSR sharing modes are systematically compared: no CSR (NS), manufacturer-borne (MS), retailer-borne (RS), and shared by both (TS). The results indicate the following: (1) CSR implementation reduces wholesale and retail prices while increasing sales effort, the incorporation rate of recycled aggregates, and market demand, with retailers bearing CSR yielding the most significant pull effect; (2) heightened sensitivity to sales effort incentivizes retailers to increase sales investment and encourages manufacturers to increase the incorporation rate of recycled aggregates, thereby increasing overall supply chain profits and utility; and (3) when the CSR coefficient does not exceed the critical value of 0.97, both manufacturer profits and retailer profits increase as the CSR level increases under the TS model; under the RS model, total supply chain profits and total utility reach their maximum. Corporate social responsibility (CSR) undertaken or jointly undertaken by retailers can better align economic and social objectives. This study provides theoretical foundations and practical insights for policy formulation and corporate decision-making in construction waste resource management. Full article

Reconciling hydropower development with aquatic biodiversity conservation is a central challenge for sustainable river management worldwide. Cascade dam configurations, in which multiple impoundments are arranged in series along a single channel, impose longitudinal environmental gradients that restructure biological communities across trophic levels. Whether the resulting multi-trophic responses are independently driven by shared abiotic gradients (environmental filtering) or mechanistically coupled through direct food-web interactions (trophic cascading) remains unresolved. We surveyed phytoplankton, zooplankton, and benthic macroinvertebrates simultaneously at seven stations along a 430 km gradient downstream of Danjiangkou Dam in the Hanjiang River, the largest tributary of the Yangtze River and the source of China’s South-to-North Water Diversion Middle Route, over eight seasonal campaigns (2015–2017). Variance partitioning, piecewise structural equation modeling, Mantel tests, and co-occurrence network analysis were applied to partition environmental and trophic pathways. Environmental filtering dominated community restructuring at all three trophic levels, while the biotic proxy for direct trophic interactions explained less than 0.4% of community variation, consistent with weak detectable trophic coupling at seasonal resolution. Distance from Danjiangkou Dam shaped downstream transparency and turbidity gradients that mediated trophic-level-specific responses along distinct environmental axes (pH and water temperature for phytoplankton, conductivity for zooplankton, and transparency for benthic macroinvertebrates). Benthic macroinvertebrates were systematically decoupled from the pelagic analytical framework, absent from the cross-trophic co-occurrence network and structured more by spatial configuration than by water-column variables. Hub species in the network were associated with downstream mineralized conditions, confirming that network architecture reflects shared environmental preferences rather than biotic interactions. These findings support a management shift from single-dam mitigation toward cascade-scale coordination of environmental flow regimes, sediment connectivity, and substrate restoration as integrated strategies for sustaining multi-trophic biodiversity in regulated rivers. Full article

Cycloheptylprodigiosin is a promising anticancer candidate that induces cancer cell death accompanied by severe Golgi stress. Although the soybean oil-based optimized MB2216 medium produced a total prodiginine titer approximately three times that of the basal MB2216 medium, the overall production level remained limited. In addition, a substantial fraction of the pigments partitioned into floating oil droplets, hindering efficient recovery by simple centrifugation. In this study, a novel medium was rationally formulated based on genomic insights derived from homology analysis of conserved biosynthetic genes involved in cycloheptylprodigiosin production in Spartinivicinus ruber MCCC 1K03745^T. Sequential optimization through single-factor experiments, full factorial designs, steepest ascent experiments and response surface methodology identified an optimal medium consisting of peptone (5 g/L), yeast extract (1 g/L), peanut meal (7.611 g/L), and L-Proline (0.695 g/L) prepared in seawater at pH 7.6. Under the optimized conditions, the total prodiginine titer reached 53.33 mg/L, which was 11.37 times that of the basal MB2216 medium and 3.29 times that of the soybean oil-based MB2216 medium. Moreover, the pigment-associated biomass could be efficiently recovered by centrifugation. This study provides a genomics-informed strategy for improving prodiginine production in S. ruber and facilitates downstream pigment recovery. Full article

Lipopolysaccharide-induced tumor necrosis factor alpha factor (LITAF) as a crucial cytokine can mediate the inflammatory and immune regulatory responses of an organism. It plays a significant mediatory role in the innate immune system of insects. Firstly, the LITAF family of cotton bollworm (Helicoverpa armigera, Lepidoptera: Noctuidae) was analyzed, and the differentially expressed genes of HaLITAFs were screened from the 2-tridecanone-treated transcriptome. Subsequently, these two differentially expressed HaLITAF genes were cloned and analyzed, and the effect of different larval stages, tissues, and plant secondary metabolites on their gene expression were detected in H. armigera. The cotton bollworm contains 13 LITAF genes, and there are no repetitive sequences among them. Upon 2-tridecanone treatment, only HaLITAF5 and HaLITAF7 were significantly upregulated in the LITAF family of cotton bollworm larvae after 6 h. The HaLITAF5 and HaLITAF7 proteins, respectively, comprised 78 and 113 amino acids, and both contained a CXXC motif, hydrophobic amino acid region and HXCPXCXXXXG motif. Both of them belong to the LITAF analogues (zf-LITAF-like) superfamily. The expressions of HaLITAF5 and HaLITAF7 were both the lowest in fourth-instar larvae and the highest in sixth-instar larvae, and both were abundantly expressed in the midgut of sixth-instar larvae. Following a 28 h treatment with 2-tridecanone, the expression levels of HaLITAF5 and HaLITAF7 peaked. HaLITAF7 exhibited the highest expression level after a 4 h exposure to tannic acid, whereas HaLITAF5 reached its peak after 28 h of tannic acid treatment. The maximum expression levels of HaLITAF5 and HaLITAF7 were observed after 28 h and 4 h of quercetin treatment, respectively. Subsequent to ZQ-8 treatment, HaLITAF5 expression peaked at 28 h, while HaLITAF7 expression peaked at 8 h. Both HaLITAF5 and HaLITAF7 were overexpressed after different kinds of plant secondary metabolite stresses, and thereby, they may be regulated in the expression of genes related to downstream detoxification metabolic processes. This provides a theoretical foundation for further studies on the functional mechanism of the LITAF gene in H. armigera. Full article

Serglycin (SRGN) has been found overexpressed and secreted in glioblastoma (GBM), associated with tumorigenic signaling and poor prognosis. In this study, we aimed to elucidate the involvement of SRGN in the unfolded protein response (UPR), an oncogenic signaling pathway implicated in protein recycling and cell fate. Herein, we developed stably transduced LN-18^shSCR GBM cells, expressing high levels of SRGN, and SRGN-depleted LN-18^shSRGN cells. We observed significantly attenuated expression and activity of all UPR mediators upon SRGN suppression, in particular PERK, IRE1, ATF6 and downstream effectors. SRGN-expressing cells possessed a constitutively active UPR, as indicated by its active phosphorylation status and accumulated pool of nuclear ATF4 in LN-18^shSCR cells. Constitutive activation of the caspase-dependent apoptotic pathway was apparent in LN-18^shSRGN cells. Induction of endoplasmic reticulum (ER) stress pointed out that LN-18^shSRGN cells were predisposed to ER stress-associated cell death, whereas LN-18^shSCR cells activated adaptive UPR signaling and displayed resistance to apoptosis. The evaluation of TLRs, TNFRs, ILs and NF-kB also underscored that SRGN is essential for their expression and active inflammatory signaling. We concluded that SRGN-expressing cells acquire a pro-survival UPR mechanism, highlighting the novel regulatory role of SRGN in the adaptation and survival of GBM cells. Full article

Lung cancer remains the leading cause of cancer-related mortality worldwide, with non-small cell lung cancer accounting for the majority of cases and exhibiting persistent challenges related to therapy resistance and metastatic progression. Increasing evidence indicates that dysregulated G protein-coupled receptor signaling and ion channel activity function cooperatively as master regulators of tumor cell proliferation, migration, survival, and therapeutic response. Cannabinoids, including phytocannabinoids such as delta-9-tetrahydrocannabinol and cannabidiol, as well as endogenous endocannabinoids, are uniquely positioned to modulate both G protein-coupled receptors and ion channels, thereby influencing key oncogenic signaling networks. This review synthesizes current knowledge on the role of major ion channel families, including transient receptor potential channels, potassium channels, and sodium channels, and principal G protein-coupled receptor pathways involved in lung cancer progression. We further discuss how cannabinoids reprogram these interconnected signaling systems through canonical cannabinoid receptors, non-classical targets such as G protein-coupled receptor 55 and adenosine receptors, and direct modulation of ion channel activity. Special attention is given to G protein-coupled receptor–ion channel coupling within membrane microdomains and to the capacity of cannabinoids to act as biased ligands, redirecting downstream pathways, such as the phosphoinositide 3-kinase–protein kinase B–mechanistic target of rapamycin and epidermal growth factor receptor signaling, toward apoptosis and reduced metastatic potential. Emerging strategies, including cannabinoid-based combination therapies, selective receptor biasing, and targeted delivery systems, are also highlighted. Altogether, cannabinoid-driven rewiring of G protein-coupled receptor and ion channel signaling represents a promising mechanistic framework for developing innovative therapeutic approaches against lung cancer. Full article

Recombinogenic DNA damage can initiate chromosomal rearrangements that can alter gene expression or accelerate cancer progression in higher eukaryotes. Thus, there is a critical need to identify genes that suppress chromosomal rearrangements and environmental exposures that promote genetic instability. Cell cycle checkpoints modulate the cell cycle so that DNA repair occurs before the replication or segregation of damaged chromosomes. Saccharomyces cerevisiae (budding yeast) RAD9 was the first cell cycle checkpoint gene identified, which initiated intensive research studies into the mechanisms of checkpoint activation and the phenotypes of checkpoint mutants. The budding yeast Rad9 protein serves as both an adaptor and scaffold that facilitates downstream effector activation to orchestrate a DNA damage response at multiple stages of the cell cycle, which facilitates double-strand break (DSB) repair by sister chromatid recombination. However, the role of RAD9 in homologous recombination and in suppressing gross chromosomal rearrangements (GCRs) is not completely understood. In this review we discuss how RAD9 can promote genome instability resulting from aberrant DNA replication intermediates, while suppressing DSB-associated rearrangements. We also discuss possible mechanisms accounting for the synergistic increase in genomic instability in double mutants defective in both RAD9 and recombinational repair. We emphasize that while there is an overlap between checkpoint and recombinational repair pathways, RAD9 and checkpoint pathways can function independently to suppress chromosomal instability. These studies thus elucidate checkpoint mechanisms that control homologous recombination between repeated sequences. Full article

Human serum albumin (HSA) is the most abundant protein in plasma, and the redox state of circulating HSA has been used as a biomarker of systemic oxidative stress (OS) for decades. While informative, many traditional biomarkers of OS measure short-lived or downstream products of oxidative damage that offer limited perspectives on the dynamic and integrated processes that govern systemic redox biology within human populations. By moving beyond single-analyte damage markers and towards coordinated patterns of protein modifications, HSA-Cys³⁴ adductomics offers a systems-level approach that simultaneously captures change in multiple layers of OS. Because of its high abundance in plasma and HSA’s unique and highly reactive single free thiol (Cys³⁴), HSA-Cys³⁴ serves as an ideal sentinel target for monitoring reactions with reactive oxygen species (ROS), reactive nitrogen species (RNS), and electrophilic species produced by endogenous metabolism and responses to exogenous chemical exposures. The reaction of HSA with ROS, RNS, and reactive electrophiles yields a diverse array of protein modifications, including direct oxidation products (sulfenic, sulfinic, and sulfonic acid), low molecular weight thiol-disulfide exchange, and lipid peroxidation (LPO)-derived reactive aldehydes. With a mean residence time of about a month, these accumulated adducts serve as an integrated picture of oxidative and electrophilic stress that together function as a molecular record of systemic redox physiology. Previous studies using high-resolution mass spectrometry-based adductomics have enabled global untargeted analysis of HSA-Cys³⁴ modifications, yielding an expansive inventory of novel redox signatures of environmental stressors and disease states. In this paper we review the chemistry and biology underlying OS-related modifications of HSA-Cys³⁴ and highlight the important role of HSA-Cys³⁴ adducts as integrative biomarkers of OS at the interface of molecular biology, exposure assessment, and public health research. Full article

Tomato (Solanum lycopersicum) is a widely consumed vegetable crop and an established model system for plant functional genomics and genetic research in dicotyledons. Salt stress is a major abiotic factor limiting tomato productivity worldwide. The WRKY transcription factor family, one of the largest and most conserved plant-specific transcription factor families, plays pivotal roles in stress responses. This review summarizes recent advances in understanding the functions of tomato WRKY genes under salt stress, focusing on the genomic basis and evolutionary characteristics of the WRKY family, the roles of core WRKY members under salt stress, and the multi-layered regulatory networks mediating WRKY-dependent salt and alkali tolerance. To date, approximately 10 core SlWRKY genes have been functionally validated to regulate tomato salt tolerance, mainly by maintaining ion homeostasis, regulating reactive oxygen species (ROS) balance, facilitating osmotic adjustment, and integrating hormone signaling pathways. Despite this progress, systemic regulatory hierarchies and epigenetic modulation remain poorly resolved. Furthermore, we discuss how specific WRKY members directly regulate downstream effector genes, such as SlSOS1 and SlNHX4. However, direct experimental evidence for the coordination between tomato WRKYs and mitogen-activated protein kinase (MAPK) cascades, as well as epigenetic modifiers under salt stress, is still scarce in current studies. This review provides a theoretical framework and outlines potential technical pathways for translating fundamental insights into tomato salt tolerance into practical applications for sustainable agriculture. Full article

Global freshwater scarcity is a pressing environmental challenge, particularly in Egypt, which depends entirely on the Nile River and its tributaries. Rapid population growth, domestic wastes, agricultural runoff, and rapid industrial expansion exert highly anthropogenic stress on aquatic ecosystems, including Bahr Yusuf and Ibrahimia Canals in Upper Egypt. This study aimed to evaluate the ecological health and sustainability status of the two canals using an integrated multi-metric framework combining physicochemical variables, microbiological indicators, and community structures of zooplankton and benthic fauna. Multivariate statistical analyses (PCA, CCA), and ecological indices, including the water quality index (WQI), microbial assessment index (MAI), Rotifer-Based Index (TSI_Rot) and Hilsenhoff Biotic Index, were applied to determine pollution gradients. The results revealed that Bahr Yusuf suffers from higher pollution levels than the Ibrahimia Canal. Canonical correspondence analysis (CCA) showed that nutrient enrichment and elevated organic load are responsible for over 72% of the variance in zooplankton and benthic invertebrate assemblage in both water bodies. The dominance of pollution-tolerant species, Philodina roseola and B. calyciflorus of zooplankton and Limnodrilus udekemianus, Chironomidae larvae, Melanoides tuberculate and Cleopatra bulimoides of benthic taxa, further indicates a direct increase in organic loading and nutrient enrichment from agricultural and domestic sources. According to the Integrated Water Quality–Biotic Health Index (IWQ-BHI), the downstream stations of Bahr Yusuf are critical risk zones, with scores below 50.0, while the upstream stations of Ibrahimia Canal fell within the “good” category, with scores exceeding 70.0. Overall, both waterbodies are approaching a critical threshold of ecological instability and require urgent, integrated and sustainable management to restore and preserve these vital freshwater ecosystems. Full article

Background: A major technical challenge in single-cell transcriptomics is the absence of an integrative analytic pipeline that can simultaneously leverage gene regulatory network (GRN) architecture, AI-assisted gene panel discovery, and functional relevance analyses to generate coherent biological insights. Existing approaches often treat these components independently, focusing on clusters, marker genes, or predictive features without integrating them into a mechanistically grounded framework. Consequently, comprehensive screening that links regulatory association, gene signature screening, and functional interpretation within single-cell datasets remains limited, underscoring the need for an integrated strategy. Methods: We developed an integrative bioinformatics pipeline based on Gene regulatory network–AI–Functional Analysis (GAFA), combining latent-space integration, unsupervised clustering, diffusion pseudotime analysis, lineage-resolved generalized additive modeling, GRN inference, and machine learning-based gene panel discovery. This framework enables systematic mapping of cell-state structure, reconstruction of differentiation and effector trajectories, and identification of transcriptional and regulatory features strongly associated with clinical outcomes. As a case study, we applied the pipeline to NK cell transcriptomes from six CML patients (two early relapse, two late relapse, two durable treatment-free remission—TFR; 15 samples) collected at TKI discontinuation and 6–12 months after therapy cessation. Results: We reanalyzed publicly available scRNA-seq data from a previously published CML cohort to evaluate NK-cell transcriptional programs associated with treatment-free remission and relapse. We resolved six transcriptionally distinct NK cell states spanning CD56^bright-like cytokine-responsive, early activated, terminally mature, cytotoxic, lymphoid trafficking, and HLA-DR⁺ immunoregulatory populations, each exhibiting outcome-specific compositional differences. Pseudotime analysis revealed two major NK cell lineages—a maturation trajectory and a cytotoxic effector trajectory. TFR samples displayed balanced occupancy of both lineages, whereas early relapse samples showed marked depletion of the maturation branch and preferential accumulation in cytotoxic end states. AI-guided feature selection and random forest modeling identified an 18-gene panel that distinguished NK cells from TFR and relapse samples in an exploratory manner. Among them, CST7, FCER1G, GNLY, GZMA, and HLA-C were conventional NK-associated genes, whereas ACTB, CYBA, IFITM2, IFITM3, LYZ, MALAT1, MT2A, MYOM2, NFKBIA, PIM1, S100A8, S100B, and TSC22D3 were novel. The GRN inference further uncovered outcome-specific regulatory modules, with RUNX3, EOMES, ELK4, and REL regulons enriched in TFR, whereas FOSL2 and MAF regulons were enriched in relapse, and their downstream targets linked to IFN-γ signaling, metabolic reprogramming, and immunoregulatory feedback circuits. Conclusions: This AI-enabled single-cell analysis demonstrates how NK cell state composition, differentiation trajectories, and regulatory network rewiring collectively shape TFR versus relapse following TKI discontinuation in CML. The integrative pipeline provides a modular framework that could be extended to additional datasets for data-driven biomarker discovery and mechanistic stratification, and highlights candidate transcriptional regulators and NK cell programs that may be leveraged to improve remission durability, pending validation in larger patient cohorts. Full article