Search Results (22,259)

Background: The efficacy of chemotherapy in triple-negative breast cancer (TNBC) is limited by intrinsic resistance and the tumor microenvironment (TME). Accumulating evidence reveals a mechanistic connection between programmed death-ligand 1 (PD-L1) and c-x-c motif chemokine receptor 4 (CXCR4), which dominate stroma barriers, immune escape, and cancer metastasis. Earlier studies have shown that dual suppression of c-x-c motif ligand 12 (CXCL12)/CXCR4 and programmed cell death-1 (PD-1)/PD-L1 pathways regulates extracellular matrix (ECM) deposition, activation of cancer-associated fibroblasts (CAFs), and epithelial–mesenchymal transition (EMT) of pancreatic cancer cells. Methods: We combined BsNb PX4, a bispecific nanobody targeting PD-L1 and CXCR4, with paclitaxel or gemcitabine in multiple tumor cell lines and human peripheral blood mononuclear cell (hPBMC)-reconstituted xenograft mouse models. Antitumor activity was assessed by CCK-8, flow cytometry, and ELISA, and immune cell infiltration and TME remodeling were examined by immunofluorescence, immunohistochemistry, cytokine assays, and RNA-seq. Results: In MDA-MB-231 cells, BsNb PX4 synergistically enhanced paclitaxel-induced growth inhibition and apoptosis via G₂/M cycle arrest. This combinatorial strategy profoundly remodeled tumor immunity by expanding CD8⁺ T cells and depleting Foxp3⁺ CD4⁺ regulatory T cells (Tregs), while concurrently restoring T-cell cytotoxicity and skewing the cytokine balance toward an antitumor state, with elevated IFN-γ and reduced TGF-β1. Notably, compared with paclitaxel monotherapy, the combination significantly elevated intratumoral CD8⁺ T-cell infiltration, decreased Treg abundance, and exerted robust inhibitory effects on tumor growth and metastasis in humanized TNBC xenografts. Conclusions: These findings reveal that dual blockade of PD-L1 and CXCR4 acts synergistically with chemotherapy by triggering tumor cell apoptotic effects and reversing the immunosuppressive microenvironment, thereby emerging as a promising therapeutic strategy for TNBC. Full article

Metastasis-associated protein 1 (MTA1), an oncogenic transcriptional regulator, is overexpressed in canine urothelial carcinoma (UC) and is associated with aggressive clinicopathological features. However, its functional role and molecular mechanisms in canine UC remain poorly understood. Here, we investigated the contribution of MTA1 to epithelial-to-mesenchymal transition (EMT) and its interaction with BRAF signaling. MTA1 silencing in two canine UC cell lines significantly inhibited cell proliferation, cell survival, migration, and xenograft tumor growth. Mechanistically, MTA1 knockdown reduced the expression of MTA2, MTA3, and COX2, while producing unexpected changes in key EMT regulators, including Snail, Slug, and Cyclin D1, suggesting the activation of compensatory signaling pathways. MTA1 silencing also decreased mutant BRAF expression in AxA cells while increasing wild-type BRAF expression in SH cells, indicating context-dependent regulation of BRAF signaling. In AxA cells, reduced AKT phosphorylation following MTA1 knockdown further supports functional crosstalk between the BRAF and MTA1/AKT signaling pathways. Collectively, these findings identify MTA1 as a critical regulator of canine UC progression and reveal complex signaling interactions that support its potential as a therapeutic target for canine UC. Full article

Welan gum, a high-molecular-weight exopolysaccharide from Sphingomonas sp., exhibits exceptional rheological stability and robust hydrogel properties, emerging as a highly promising agricultural biomaterial. In this study, we show that the application of welan gum promotes maize seedling growth by enhancing nitrogen use efficiency via the coordinated transcriptional reprogramming of nitrogen regulators and transporters. Mechanistically, welan gum activates the TOR pathway and the MAPK cascade, leading to the phosphorylation of ZmS6K and the terminal MAPK ZmMPK3-1. Notably, TOR inhibition reduces ZmMPK3-1 phosphorylation, demonstrating that TOR activity is indispensable for MAPK activation. Furthermore, the TOR components ZmTOR and ZmLST8 physically interact with ZmMPK3-1, and ZmLST8 independently enhances ZmMPK3-1 kinase activity, revealing a multilayered regulatory mechanism triggered by welan gum. In addition, welan gum upregulates MPK3-targeted defense genes, effectively reconciling the plant growth–defense trade-off. Elucidating this TOR–MAPK crosstalk provides the mechanistic basis for translating welan gum into sustainable gel-based biofertilizers. Collectively, this study uncovers a cooperative signaling network that underpins welan gum-mediated growth promotion, establishing the strong potential of PGPR-derived polysaccharide hydrogels as sustainable, functional biofertilizers for modern agriculture. Full article

Legionella pneumophila (L. pneumophila) persists in engineered water systems and is the causative agent of Legionnaires’ disease. Despite its clinical importance, little is known about whether environmental populations are undergoing gradual changes in their antimicrobial susceptibility. Here, we compared the antimicrobial susceptibility of 95 environmental L. pneumophila isolates collected in 2013–2014 with those obtained in 2024–2025 from the same sites in a drinking water distribution system (DWDS) using Epsilometer (E-test). The analyses showed both temporal and spatial variation: Ciprofloxacin activity remained relatively stable, whereas levofloxacin exhibited a broader minimum inhibitory concentration (MIC) range among contemporary isolates, with the minimum inhibitory concentration required to inhibit the growth of 90% of isolates (MIC₉₀) doubling from 0.5 to 1.0 mg/L, suggesting increased variability and the emergence of less susceptible subpopulations. Tigecycline showed a marked site-specific increase in MIC values, with the mean MIC at site D increasing from 0.26 mg/L in the 2013–2014 isolates to 1.86 mg/L in the 2024–2025 isolates, indicating reduced susceptibility at this site. Among macrolides, erythromycin exhibited the lowest MIC values across both isolate collections, whereas azithromycin showed higher MIC values. Moreover, isolates recovered from adjacent sites within the same DWDS exhibited significantly different susceptibility profiles, possibly reflecting the influence of local environmental conditions. These findings emphasize that L. pneumophila susceptibility is not static but is likely shaped by ecological and temporal factors. The study underscores the importance of long-term environmental surveillance to track the evolution of this pathogen and provides new insights into how micro-scale dynamics within water systems can influence antimicrobial susceptibility patterns. Full article

This study evaluated the phytotoxicity of diesel oil (DO) using the green alga Pseudokirchneriella subcapitata and the aquatic plant Lemna minor. Toxic effects were assessed in 7-day Algaltoxkit and Lemna bioassays by measuring growth, chlorophyll fluorescence, and biogenic amine (BA) content. L. minor was less sensitive to DO in terms of growth than the alga. Toxicity thresholds (LOEC, 7 days) showed that DO concentrations above 0.11–0.12% significantly inhibited the growth and productivity of both model organisms. Chlorophyll fluorescence proved to be an early and sensitive indicator of DO toxicity. This study also provides the first characterization of BAs in P. subcapitata, identifying histamine, tyramine, putrescine, cadaverine, agmatine, spermidine, and spermine. Agmatine emerged as a common indicator of DO contamination in both species. Its content decreased in P. subcapitata (EC₅₀ = 0.85%) but increased in L. minor (EC₅₀ = 0.38%) under diesel exposure. The findings herein suggest that BA profiling, especially agmatine, can support early detection of hydrocarbon stress in aquatic organisms. Full article

Inflammation can either encourage or suppress tumor growth, thus having a two-sided effect on cancer development. This depends on the balance between pro-tumor and anti-tumor immune responses within the tumor microenvironment (TME). Pro-tumor inflammation, driven by specific immune cells, enhances blood flow and nutrient supply to tumors, promoting the activation of dormant cancer cells (DCCs). Conversely, antitumor inflammation hinders blood flow and can force active cancer cells into a state of dormancy. Tumors actively shift this balance towards pro-tumor inflammation to create a favorable environment for growth. Therefore, anti-inflammatory therapy may be an integral part of comprehensive cancer immunotherapy. This review explores how different anti-inflammatory medications, such as glucocorticoids, non-steroidal anti-inflammatory drugs (NSAIDs), antihistamines, anti-leukotrienes, statins, drugs that block pro-inflammatory cytokines, agents that inhibit oxidative phosphorylation, antioxidant vitamins, anti-angiogenic drugs, and low-dose chemotherapy, can be used to combat cancer. Granulocyte counts and erythrocyte sedimentation rate (ESR) can be used to assess inflammation levels and the effectiveness of anti-inflammatory treatments. We advocate for a paradigm shift in cancer treatment, moving away from aggressive tumor destruction, which triggers uncontrolled tumor regeneration, toward long-term immunological control of tumor growth while preserving the patient’s overall health. Full article

Auxin response factors (ARFs) are key transcription factors regulating plant growth and development, but their functions and molecular mechanisms in stem elongation of cucurbit crops remain unclear. In this study, we identified a nuclear-localized ARF member, ClARF4, in watermelon. ClARF4 knockout lines were generated using CRISPR-Cas9 technology and exhibited significant reductions in plant height, internode number, and internode length. Cytological analysis indicated that the dwarf phenotype resulted from inhibited longitudinal cell elongation in stems. Transcriptome analysis revealed that ClARF4 modulates cell size by regulating the expression of genes involved in auxin signaling and response pathways. Furthermore, using yeast two-hybrid screening, we identified ClPetC, a component of the photosynthetic electron transport chain, as an interacting protein of ClARF4; bimolecular fluorescence complementation (BiFC) assays further confirmed their direct interaction in the plant nucleus. This study not only reveals the key role of ClARF4 in regulating plant height in watermelon, but also provides important insights into the function of chloroplast–nucleus signaling crosstalk in plant architecture establishment by identifying the interaction between ClARF4 and the chloroplast protein ClPetC in the nucleus. Full article

Melanoma dissemination depends on tumor cell plasticity, extracellular matrix remodeling, and adaptive signaling pathways that promote survival, migration, invasion, and therapeutic resistance. In this study, we investigated the antitumor effects of the plant-derived Kunitz-type protease inhibitor EcTI using both in vitro B16F10-Nex2 melanoma cells and an in vivo murine melanoma model, focusing on adhesion-dependent signaling, autophagy, mitochondrial dysfunction, and regulated cell death. EcTI was efficiently internalized by melanoma cells and showed partial colocalization with lysosomal and mitochondrial compartments, suggesting intracellular trafficking toward these organelles. Treatment reduced cell adhesion to extracellular matrix proteins, particularly fibronectin and laminin, and inhibited migration, invasion, and angiogenic signaling. These effects were associated with modulation of the adhesion-dependent FAK/Src/ERK signaling axis and decreased MMP-9 activity. EcTI also disrupted autophagy, as indicated by accumulation of acidic vesicular organelles, increased LC3-II levels, and modulation of ULK1, Ambra1, and Beclin-1 signaling. In parallel, EcTI induced mitochondrial dysfunction, characterized by loss of mitochondrial membrane potential, intracellular Ca²⁺ dysregulation, and increased reactive oxygen species production. These alterations triggered regulated cell death involving apoptotic and necroptosis-like mechanisms. Importantly, EcTI significantly suppressed tumor growth in vivo without detectable systemic toxicity and modulated inflammatory mediators associated with tumor progression. Overall, these findings demonstrate that EcTI exerts broad antitumor activity by modulating multiple signaling pathways associated with melanoma progression and represents a promising therapeutic candidate for melanoma treatment. Full article

AI is currently shaping how people are being entrepreneurial by allowing the establishment of AI-native ventures. The creation of these new types of businesses builds off an infrastructure of data, computing power, and research that typically accompany advanced economies. In contrast, most developing economies are still experiencing institutional and structural barriers that inhibit the formation of new ventures and their subsequent growth. Despite the existence of research that explores some of the ways in which successful ecosystems from developed economies could be applied to developing ecosystems, there is little guidance on how to systematically adapt these successful practices in resource-constrained environments. This research uses a comparative, document-based study design to assess how to benchmark and configure AI-native entrepreneurship ecosystems across heterogeneous institutional environments. Using Switzerland and Jordan as two contrasting analytical cases, we define twelve dimensions of an ecosystem and then create comparative ecosystem profiles using a standardized coding and scoring framework. We combine dimension-level data on talent development, applied research, infrastructure, financing, governance and market access with baseline socio-economic indicators. Our results demonstrate a high level of structural asymmetry between the two ecosystems. Switzerland has a balanced and highly coordinated configuration, whereas there is a strong university anchor and demand for talent in Jordan, but there are also significant weaknesses in terms of infrastructure, financing, and industry linkages. Building from these results, we present the parameter re-weighting and the context-sensitive design model to encourage the emergence of AI-native entrepreneurship in Jordan through coordinated architecture, collaborative experimentation resources and internationalization at an early stage. This article advances both the fields of entrepreneurial ecosystems and digital entrepreneurship by framing AI-native entrepreneurship as a new form of knowledge-intensive venture creation and providing a context-sensitive approach for adapting entrepreneurial ecosystems. The results provide a document-informed basis for policymakers, academic institutions and other ecosystem actors seeking to develop AI-based innovation in resource-constrained economies. Full article

The scarcity of effective selective herbicides has made weed management a limiting factor for alfalfa yield and large-scale cultivation. This study aimed to preliminarily screen selective herbicides with acceptable safety to alfalfa and establish an effective weed management program based on sequential pre- and post-emergence herbicide applications through greenhouse screening and multi-year field trials. The greenhouse herbicide safety evaluation showed that, among the 22 herbicides tested, the post-application of 2 pre-emergence herbicides (s-metolachlor and prodiamine) and 5 post-emergence herbicides (benazolin, bentazon, fluazifop-p, imazethapyr, and nicosulfuron) showed a relatively higher survival rate (~4× the standard dose) on two alfalfa cultivars through assessing visual efficacy, plant height, and dry biomass per plant. However, even herbicides that result in relatively high plant survival can produce induce significant growth inhibition and biomass reduction when applied at high doses. Those herbicides were further tested under field conditions (2020–2023) for evaluation of weed control efficiency and alfalfa plant biomass yield potential and nutritive values. Among the herbicide application regimes, the pre-application of prodiamine followed by post-application of bentazon or fluazifop-p showed the most effective weed control efficacy (70–85% reduction of weed biomass in the alfalfa plot), which was greater than the reductions achieved with all single-herbicide applications (24–48%) and sequential application of s-metolachlor followed by the five post-emergence herbicides (25–46%). Additionally, the optimized combinations had no significant effect on the 1st and subsequent alfalfa plant height compared to that of alfalfa in weed-free control. No significant reductions in alfalfa yield or nutritive value were observed in the herbicide-treated plots treated with prodiamine followed by bentazon or fluazifop-p compared with the weed-free control. Collectively, sequential application combining pre- (prodiamine) and post-emergence (bentazon or fluazifop-p) herbicides shows effective weed control in alfalfa under the tested conditions, which provides a useful weed management program to enhance alfalfa forage production and nutritive values. Full article

Abelmoschus manihot (L.) flowers are widely used in traditional Chinese medicine, whereas the roots are often discarded as agricultural waste. The compact cellular and tissue architecture of the roots hinders the release of intracellular metabolites, thus impeding their reutilization. Here, enzyme-assisted ultrasonic extraction was developed to obtain a polysaccharide-rich crude extract from A. manihot roots. Orthogonal optimization identified pH 4.5, a temperature of 60 °C and a cellulase dosage of 6% (w/w) as the optimal extraction conditions, giving an extraction yield of 21.59%. The phenol–sulfuric acid assay indicated a total carbohydrate content of 75.09% (glucose equivalents). Structural analysis by Fourier transform infrared (FT−IR) confirmed the presence of characteristic polysaccharide functional groups, while monosaccharide composition analysis via high-performance liquid chromatography (HPLC) revealed the major components of glucose, glucuronic acid, rhamnose, galacturonic acid, etc. Inspired by the traditional use of A. manihot extract in papermaking, its preliminary hair care-related properties were further evaluated. At a concentration of 30 mg/mL, the extract solution inhibited Malassezia furfur growth by 84%, reduced wet and dry combing work by 16.93% and 30.86%, and increased tensile strength and tensile fracture energy by 13.04% and 14.84%, respectively. Scanning electron microscope (SEM) images suggested smoother hair fiber surfaces after treatment. These results highlight the extract’s great potential for hair care cosmetic products. Full article

Background/Objective: Niclosamide exhibits considerable potential for the treatment of drug-resistant cancers. However, its poor aqueous solubility substantially limits its oral bioavailability and therapeutic efficacy. To overcome this limitation, we developed a novel pharmaceutical supramolecular crystalline phase comprising niclosamide and nafamostat. Methods: In this study, we developed a niclosamide–nafamostat pharmaceutical supramolecular crystalline phase using a conventional solvent evaporation technique. Comprehensive solid-state characterization was carried out using X-ray powder diffraction (XRD), Fourier-transform infrared spectroscopy (FTIR), and differential scanning calorimetry (DSC). In vitro drug transport kinetics and barrier transport efficiency were evaluated across artificial transpermeable membranes using a diffusion cell setup. In vitro anticancer efficacy was systematically screened against human lung, breast, and pancreatic cancer cell lines. Finally, in vivo translation was established using female NOD/SCID mice tumor-bearing animal models; therapeutic efficacy and total tumor burden were evaluated. Results: Niclosamide–nafamostat cocrystal (NNC) was found to form a distinct crystalline phase, with characterization results supporting a unique crystal lattice stabilized through strong intermolecular hydrogen-bonding interactions and exhibiting high thermal purity. Crucially, the supramolecular crystalline phase considerably enhances membrane transport, yielding superior cumulative permeation and enhanced apparent permeability (Papp) values compared to those of pure niclosamide. In vitro evaluation across multiple cancer cell lines demonstrated a tenfold increase in antiproliferative potency compared to the parent compounds. Furthermore, in vivo studies revealed a twofold increase in tumor growth inhibition and a tenfold reduction in total tumor burden (p < 0.05). Conclusions: These findings demonstrate that the NNC supramolecular crystalline phase platform successfully optimizes membrane permeability and antitumor efficacy, highlighting its potential for treating advanced cancers. Full article

Celosia cristata is an important ornamental and medicinal plant widely cultivated in China. In July 2025, a severe black spot disease was observed on C. cristata in the Zhang Zhongjing Medicinal Plant Garden, Nanyang, Henan Province, China, resulting in substantial defoliation and yield loss. To identify the causal agent and provide a scientific basis for disease management, the pathogen was isolated and purified from diseased tissues using the tissue isolation method. The pathogen was identified based on morphological characteristics, multi-gene sequence analysis (ITS, RPB2, and TEF1-α), and pathogenicity tests conducted in accordance with Koch’s postulates. Seven isolates with uniform morphological features were obtained. Sequence analysis and multilocus phylogenetic reconstruction indicated that the isolates shared 99–100% identity with Alternaria alternata. Pathogenicity tests demonstrated that the isolates induced typical black spot symptoms on healthy plants. To our knowledge, this is the first report of A. alternata causing black spot disease on C. cristata in Henan Province. In vitro effective fungicides were screened, among which mancozeb demonstrated the strongest inhibitory activity against A. alternata, exhibiting an EC₅₀ value of 97.72 mg/L. Additionally, the biocontrol agent Trichoderma harzianum achieved a mycelial growth inhibition rate of 69.95% against the pathogen. These findings provide a scientific foundation for the future prevention and control of black spot disease in C. cristata. Full article

Lactic acid bacteria (LAB) from traditional foods are a useful source of natural biopreservatives. This study isolated and characterized indigenous LAB from goat meat produced in the argan grove ecosystem of the Souss-Massa region, Morocco, to identify strains that could improve food safety and shelf life. LAB were isolated under anaerobic conditions and screened by Gram staining, catalase test, growth profiling, and biochemical assays. Proteolytic, gelatinase, and hemolytic activity were assessed, together with antimicrobial activity against foodborne pathogens by agar well diffusion. The most promising strains were identified by 16S rRNA gene sequencing. The selected isolates belonged to Latilactobacillus and Enterococcus. Several isolates strongly inhibited Salmonella enterica, Listeria monocytogenes and Staphylococcus aureus, and none were hemolytic or gelatinase-positive. The sustained inhibition even after neutralization of pH suggested that the antimicrobial effects might be mediated by bacteriocin-like compounds or other non-acidic metabolites. In the strains tested, L. sakei MG4013 gave the best results because of its wide range of antimicrobial activity and absence of hemolytic, gelatinase, proteolytic and lipolytic activities. Goat meat from the Souss-Massa region therefore harbours LAB with biopreservative potential, with potential for use as natural preservatives in traditional meat products or as starter cultures in fermented foods. However, before being used as natural preservatives or starter cultures, they need to be further validated in food matrices. Full article

Plant pathogenic fungi pose a major threat to global crop production and food security, necessitating the development of sustainable control agents. This study investigated the antifungal potential of Pseudophaeolus soloniensis, a wood-decaying fungus. A wild strain was isolated from Hebei, China, and identified via morphology and ITS sequencing. A bioactive crude extract (P1) was obtained through optimized solid-state fermentation on A3M medium. Its antimicrobial spectrum was evaluated against major phytopathogenic fungi (e.g., Fusarium graminearum, Aspergillus flavus) and model bacteria (Staphylococcus aureus, Escherichia coli) using mycelial growth inhibition, Minimum Inhibitory Concentration (MIC), and agar diffusion assays. P1 exhibited strong, selective activity, showing significantly greater inhibition against S. aureus than E. coli and pronounced effects against F. graminearum (43.79% inhibition at 20 µg/mL) and A. flavus (73.5% at 0.2 mg/mL). A hormetic-like response was observed for F. oxysporum. Liquid Chromatography-Mass Spectrometry (LC-MS) analysis revealed a diverse secondary metabolome, including flavonoids, alkaloids, quinones, and saponins. These results establish P. soloniensis as a promising source of bioactive metabolites for developing eco-friendly fungicides. Full article