Search Results (39,811)

Continuous spatial reconstruction in highly fragmented landscapes remains a persistent challenge in remote sensing and geographic information systems. Standardized products such as MODIS Net Primary Productivity (NPP) provide temporally consistent ecological baselines, but their moderate spatial resolution can obscure abrupt transitions in disturbed environments. This study develops a biophysical index-guided 1 × 1 Convolutional Neural Network (CNN) framework for NPP reconstruction over a mega-scale open-pit mining landscape. The framework uses five Landsat-derived biophysical tensors—Vegetation Moisture Stress Index (VMSI), Anti-Vegetation Environment Index (AVEI), Soil Adjusted Vegetation Environment Index (SAVEI), AAI-VHI, and Tasseled Cap Wetness (WET)—as point-wise predictors aligned to the MODIS NPP baseline grid. By restricting convolutional kernels to 1 × 1, the model performs nonlinear channel-wise mapping without incorporating neighboring grid cells, thereby reducing boundary mixing that can occur in conventional multi-pixel CNNs. Benchmark comparisons with Random Forest and a standard 3 × 3 CNN showed that the 3 × 3 CNN achieved slightly higher global accuracy, whereas the 1 × 1 CNN provided stronger gradient correspondence and lower full-domain spatial error in the 2020 spatial fidelity assessment. The results indicate that point-wise convolution guided by physically interpretable indices provides a conservative and interpretable option for standardized ecological reconstruction at the MODIS baseline grid scale. Full article

Transformative therapeutic innovation should not begin with a molecule—or even a molecular target. It should begin with a clearly defined unmet clinical need. Here, we present a seven-step Translational Therapeutic Development Roadmap that systematically connects an unmet medical need to a developable drug candidate through the disciplined sequence of (i) defining the need, (ii) understanding disease and resistance biology, (iii) building a mechanistic hypothesis, (iv) defining a target product profile (TPP), (v) molecular design and experimental validation, (vi) developability and manufacturability assessment, and (vii) clinical translation. A central conclusion emerging from this review is that resistance biology should be viewed not merely as a cause of therapeutic failure, but as a primary design input for next-generation therapeutic innovation. Our analysis identifies continuous alignment among unmet clinical needs, resistance biology, mechanistic hypothesis, molecular design, developability, and clinical translation as the defining characteristic of successful therapeutic development. We use dual-payload antibody–drug conjugates (ADCs) as a contemporary and highly illustrative case study of this resistance-informed therapeutic development approach. Single-payload ADCs such as trastuzumab deruxtecan and sacituzumab govitecan have transformed treatment across multiple solid tumors, yet most patients ultimately relapse through antigen loss, defective intracellular trafficking, drug efflux, payload-target alterations, and tumor heterogeneity, creating an emerging post-ADC treatment gap. Dual-payload ADCs, which deliver two mechanistically distinct warheads from a single antibody, represent a form of molecular combination therapy designed to increase the barrier to resistance and address multiple escape pathways simultaneously, as well as provide a clinically relevant model for resistance-informed therapeutic design. Using dual-payload ADCs as a worked example, we demonstrate how resistance biology directly informs payload pairing, molecular architecture, conjugation strategy, experimental validation, and developability. Our analysis indicates that successful dual-payload ADC design depends not simply on combining two cytotoxic payloads, but on selecting complementary mechanisms with non-overlapping resistance liabilities while satisfying predefined target product profiles and manufacturability requirements. We further summarize resistance-guided payload pairing strategies, including topoisomerase I plus tubulin inhibitors, topoisomerase I plus DNA-damage-response inhibitors, cytotoxic plus immunomodulatory payloads, and cell-permeable plus non-permeable combinations; the conjugation chemistries that enable defined dual-payload products; the preclinical validation, pharmacological optimization, and developability hurdles that separate promising biology from viable therapeutics; and the rapidly expanding clinical landscape, including the first-in-human program KH815 and emerging bispecific dual-payload constructs. Finally, we demonstrate that the same translational roadmap extends beyond ADCs to radiopharmaceutical conjugates, multispecific antibodies, targeted protein degraders, and cell and gene therapies, indicating that it represents a general framework for therapeutic innovation rather than an ADC-specific strategy. Collectively, this review supports the concept that therapeutic innovation is most successful when unmet clinical needs, resistance biology, molecular design, developability, and clinical translation are considered as an integrated continuum rather than as independent stages of drug discovery. This Translational Therapeutic Development Roadmap provides an organizing framework for guiding the rational development of next-generation targeted therapeutics across diverse therapeutic modalities. Full article

Mitochondria coordinate cellular energy production, metabolism, and signalling through the organization of the electron transport chain (ETC) and formation of respiratory supercomplexes. These structures facilitate efficient electron transfer and enable coenzyme Q (CoQ) channelling, allowing differential regulation of NADH- and succinate-driven respiration while modulating reactive oxygen species (ROS) production. Beyond their damaging potential, ROS act as key signalling molecules that regulate mitochondrial function through redox-sensitive modifications. Mitochondrial protein kinases add an additional layer of control, with Src-family kinases playing a central role. In particular, the mitochondrial tyrosine-kinase Fgr is activated by H₂O₂ and promotes phosphorylation of succinate dehydrogenase, boosting complex II activity, delivering more electrons to CoQ and inducing reverse electron transfer (RET) through CI, in a ROS-induced ROS generation amplification cycle. This induces a metabolic rewiring aimed at supporting stress adaptation, immune cell activation, and macrophage polarization. Overall, the interplay between supercomplex organization, ROS signalling, and kinase activity is critical for metabolic flexibility and represents a promising target for therapeutic intervention. Full article

Bamboo leaf flavonoids (BLFs) possess antioxidant and anti-inflammatory activities; however, their effects in aged laying hens remain unclear. This study investigated the effects of dietary BLF supplementation on production performance, egg quality, and liver health in aged laying hens. The results showed that compared with the control group, BLF significantly improved albumen height, yolk weight, and Haugh units. Histological examination showed that aged laying hens exhibited hepatic steatosis and vacuolar degeneration, whereas BLF supplementation alleviated these pathological changes. In addition, serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were significantly reduced in hens fed BLF, indicating that liver cell damage had been alleviated. BLF supplementation increased the hepatic glutathione peroxidase (GSH-Px) and total superoxide dismutase (T-SOD) activities while decreasing the malondialdehyde (MDA) levels, suggesting enhanced antioxidant capacity. Network pharmacology analysis identified major flavonoid components (quercetin, kaempferol, and luteolin) and inflammation-related targets, including IL-6, TNF, and IL-1β. Molecular docking analysis demonstrated strong binding affinities between BLF active components and these key inflammatory targets. Consistently, Western blot analysis showed that BLF reduced the expression of NF-κB, IL-6, and TNF-α in the liver. In conclusion, dietary BLF supplementation improved egg quality, enhanced hepatic antioxidant capacity, and alleviated liver inflammation in aged laying hens. These beneficial effects may be associated with the regulation of inflammatory signaling pathways, highlighting the potential of BLF as a functional feed additive. Full article

Chimeric antigen receptor (CAR)-T cell therapy has demonstrated remarkable efficacy in hematologic malignancies; however, durable responses remain limited by tumor microenvironment (TME)-mediated immunosuppression. Galectin-3 (Gal-3), a β-galactoside-binding lectin enriched in the TME, contributes to CAR-T cell dysfunction by impairing cytotoxicity, promoting apoptosis, and altering cellular signaling. While we previously demonstrated that enforced expression of the α2,6 sialyltransferase ST6GAL1 reduces galectin binding and improves CAR-T cell function, the mechanistic basis underlying this protection remains unclear. Here, we report that Gal-3 induced a hypometabolic state in CAR-T cells characterized by reduced mitochondrial function, ATP production, and glucose utilization. In contrast, ST6GAL1-overexpressing CAR-T cells preserved metabolic fitness and functional resilience under Gal-3 stress. Additionally, Gal-3 rewired cytokine signaling by increasing IL-5 expression and dysregulating downstream pathways, whereas enforced ST6GAL1 expressing CAR-T cells exhibited increased SOCS1 and SOCS3 expression and attenuated STAT5 activation. Transcriptomic analysis of CAR-T cells from diffuse large B-cell lymphoma patients further revealed enrichment of STAT5-associated signaling and SOCS1 expression in complete responders compared to partial responders. Collectively, these findings identify glycoengineering as a promising strategy to enhance CAR-T cell persistence and function under Gal-3-mediated immunosuppressive stress. Full article

Alpha-enolase (ENO1) is a multifunctional protein frequently overexpressed in solid tumors, where elevated levels are associated with aggressive behavior and poor prognosis. Beyond its canonical glycolytic role, ENO1 participates in immunoregulatory processes through distinct subcellular pools. Intracellular ENO1 shapes tumor-associated metabolic programs, while surface-exposed ENO1 functions as a plasminogen receptor and can engage innate immune signaling pathways. Post-translational modifications—particularly citrullination and phosphorylation—generate structurally altered epitopes that expand ENO1 antigenicity and enable adaptive immune recognition, including coordinated humoral and T-cell responses in cancer patients. These determinants of ENO1 immunogenicity have downstream consequences within the tumor microenvironment: immune-accessible ENO1 modulates myeloid cell recruitment, dendritic cell maturation, and macrophage polarization, while ENO1-dependent metabolic and signaling programs contribute to immune suppression and escape through multiple interconnected axes. Together, these mechanisms position ENO1 at the interface between tumor metabolism and immune regulation. Preclinical evidence demonstrates that ENO1-directed strategies—including antibody-based targeting, DNA vaccination, and vaccines incorporating post-translationally modified ENO1 peptides—can generate productive antitumor immunity and synergize with checkpoint blockade, supporting the rationale for ENO1 as an immunotherapeutic target. This review synthesizes current evidence within an integrated framework linking ENO1 dysregulation to its immunological consequences in cancer and discusses translational implications for ENO1-centered immunotherapy and immunoprevention. Full article

In the fields of dermatology and skin biomaterials, polynucleotides (PN) and polydeoxyribonucleotides (PDRN) typically refer to deoxyribonucleic acid (DNA)-based polymers or heterogeneous DNA-fragment mixtures rather than ribonucleic acid (RNA) polynucleotides. Recently, plant-derived PN/PDRN preparations, sourced from callus, adventitious roots, and plant cell culture systems, have emerged as a promising animal-free material class. However, current evidence remains predominantly preclinical and should not be construed as demonstrating clinical equivalence to conventional animal-derived PDRN. This review synthesizes recent reports on plant-derived and other non-animal PN/PDRN and integrates them with delivery platform evidence relevant to skin biomaterials. We distinguish directly demonstrated findings from plant-derived preparations from inferences drawn from animal-derived PDRN, synthetic sequence-defined nucleic acids, or broader biomaterial delivery literature. The review further emphasizes operational molecular definitions, polymer length and fragment distribution reporting, DNA purity and integrity, RNA carryover, residual nucleoproteins and plant-derived macromolecules, free nucleotide/nucleoside or degradation product fractions, enzymatic degradation, delivery matrices, and hypothesis-matched controls. Available data suggest overlapping biological signatures with classical PDRN, including keratinocyte repair, fibroblast extracellular matrix (ECM) remodeling, and A2A receptor-associated readouts; however, A2A receptor dependency has not been directly established for most plant-derived PN/PDRN preparations and should be interpreted as a working mechanistic hypothesis unless perturbation experiments demonstrate pathway dependence. Direct head-to-head studies using matched DNA dose, molecular weight distribution, purity, delivery platform, and exposure conditions remain limited. Accordingly, plant-derived PN/PDRN should be evaluated as a source–process–structure–platform–function system rather than as a DNA fraction alone. Full article

Background/Objectives: Gouty arthritis (GA) is an inflammatory disease caused by increased purine metabolism. The limitations of current anti-GA therapies remain a major challenge. Astilbin, the main flavonoid in Smilax glabra Roxb., was found to exert potential anti-GA effects in our previous study. Methods: In this study, a mouse model of monosodium urate (MSU)-induced arthritis and an inflammatory model using mouse bone marrow-derived macrophages (BMDMs) were established. Results: Our data showed that astilbin reduced MSU-induced joint swelling and inflammatory infiltration in mice, restored lipopolysaccharide (LPS)/MSU-induced reductions in cell viability, and inhibited the expression levels of inflammatory factors IL-1β, IL-6 and TNF-α. Further studies showed that astilbin significantly reduced MSU-induced increases in NLRP3 and P-p65 protein levels, as well as the expression of ASC, P-IKKα, P-IκBα, and cleaved-caspase-1. Conclusions: This study suggests that astilbin may be a promising natural product for the treatment of GA by inhibiting the activation of the NLRP3 inflammasome and NF-κB signaling pathway. Full article

Neonates and infants exhibit fundamentally distinct immune responses compared to adults, resulting in increased susceptibility to infectious diseases and reduced vaccine efficacy. These age-specific responses are characterized by developmental constraints affecting both adaptive and innate immunity. T cell-independent (TI) responses to polysaccharide vaccines are severely impaired due to reduced transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI) expression on neonatal B cells, while T cell-dependent (TD) responses are compromised by Th2 bias in the CD4+ T cell compartment, and by restricted T follicular helper (Tfh) cell development. Emerging data suggest that cytokines such as IL-6 have completely opposite effects on Tfh cell development between adults and neonates. Germinal center (GC) B cell responses are further constrained by delayed follicular dendritic cell (FDC) maturation, impaired B cell receptor (BCR) signaling, and elevated frequencies of IL-10-producing regulatory B cells. The overall immunosuppressive phenotype associated with early age extends to the neonatal innate immune system as exhibited by altered dendritic cell (DC) subset distribution, decreased IL-12p70 production, lower expression of MHC class II and co-stimulatory molecules, and increased IL-10 secretion. To overcome these immune constraints, various adjuvants that are shown to enhance immune response to vaccines in adults are considered for early age vaccines. Although some of these adjuvants show promising results in animal experiments, mechanistic studies need to be conducted in detail since adult and neonatal in vivo environments may dictate different outcomes between the two age groups, especially because early-life adjuvant exposure may have long-lasting effects on immune system programming. Elucidation of age-specific immune responses to vaccines and adjuvants will help develop age-tailored strategies to develop safe and effective pediatric vaccines. Full article

Algorithm-aversion research predicts that consumers prefer human curators to algorithmic ones in subjective decision domains, including taste-based hedonic recommendation. Drawing on the algorithmic-symbiosis paradigm and on assortment-perception theory, this paper identifies a boundary condition on that prediction: disclosing that recommendations are AI-curated rather than human-curated lifts purchase intention in hedonic e-commerce but not in utilitarian e-commerce. The mechanism is a search-side option-breadth inference—the consumer’s attribution about the size of the option pool the curator considered upstream—which is diagnostic in preference-formative consumption categories where consumers build, rather than match, a preference. Three online experiments deployed through a Chinese consumer panel test the framework. Study 1 ($N=228$) finds the predicted Disclosure × Product-type interaction (${\eta }_p^2=0.025$) with the AI-versus-human lift confined to the hedonic cell ($d=0.65$). Study 2 ($N=257$) isolates the option-breadth pathway against trust and competence as competing mediators. Study 3 ($N=519$) extends the design to a second hedonic category, decomposes option breadth into search-side and display-side subdimensions through an eight-item bi-factor scale, tests mentalizing alongside option breadth as a competing mediator, and brings the moderated-mediation test by consumer AI familiarity to conventional statistical power (index of moderated mediation $=+0.065$, 95% CI $[+0.014,+0.118]$). Implications for interactive-marketing practice and algorithmic-disclosure regulation are discussed. Full article

Waterlogging-induced hypoxic stress severely impairs vegetative growth and crop yield of melon (Cucumis melo L.). The formation of adventitious roots represents a critical morphological adaptive strategy for melon seedlings to alleviate hypoxic damage and maintain viability under waterlogging conditions. Nevertheless, the synergistic molecular regulatory mechanisms governing waterlogging-triggered adventitious root development in melon remain largely uncharacterized at the proteomic and metabolomic layers. In this study, the waterlogging-tolerant melon line ‘L8’ with superior adventitious root production capacity was exposed to waterlogging treatment, and hypocotyl tissues were harvested at 0, 24, 48 and 72 h post-waterlogging for untargeted metabolomic and proteomic analyses. A total of 1337 differentially accumulated metabolites (DAMs) and 2898 differentially expressed proteins (DEPs) were identified across the pairwise comparisons. Functional enrichment analyses of DAMs and DEPs indicated that pathways related to linoleic acid metabolism, α-linolenic acid metabolism, phenylpropanoid biosynthesis, biosynthesis of secondary metabolites, and glutathione metabolism were centrally implicated in adventitious rooting induced by waterlogging. At the protein level, pivotal functional proteins associated with anaerobic respiration (pyruvate decarboxylase, alcohol dehydrogenase), ethylene biosynthesis (1-aminocyclopropane- 1-carboxylate oxidase), cell wall remodeling and antioxidant defense were significantly up-regulated throughout adventitious root development. In addition, three transcription factors, namely the GRAS family protein MELO3C025904.1, MYB-related protein MELO3C007640.1, and ZF-HD protein MELO3C022921.1, exhibited differential expression across different time points compared to the control. Moreover, metabolomic profiling identified three prominent metabolites with regulatory functions, encompassing the terpenoid acorusnol, the piperidine alkaloid 1,4′-bipiperidine- 1′-carboxylic acid, and the flavonoid 4′,7-dihydroxy-2′-methoxy-3′-prenylisoflavan. Omics correlation analysis revealed extensive concordance between metabolomic and proteomic profiles. Nine core DAMs, including N-methylserotonin, Val-Val and glyuranolide, were tightly correlated with hundreds of DEPs and key transcription factors, constructing a complex regulatory network governing waterlogging stress acclimation and adventitious root morphogenesis. This study systematically characterizes the coordinated proteomic and metabolomic reprogramming underlying waterlogging-induced adventitious root formation in melon. These findings deepen our understanding of the molecular mechanism of waterlogging tolerance and provide valuable candidate genes and metabolic targets for genetic improvement of waterlogging resistance in melon. Full article

Cellular manufacturing (CM) has been extensively studied and is widely recognized as a resilient and effective production system. With respect to labor-intensive cells, recent studies have primarily concentrated on mixed-integer programming (MIP) models, often embedded within multi-phase solution frameworks. However, the computational complexity of such models remains a significant challenge. To address this issue, several studies have adopted hierarchical, multi-phase approaches that decompose the problem into more tractable subproblems, thereby significantly reducing computation time and enhancing their applicability in real-world environments, albeit at the cost of potential optimality. Considering the improvement in computer processing power in recent years, a new integrated mixed-integer programming model without phases is proposed and compared with the two-phase model via numerical experiments in this paper. In addition, considering unique multi-objective optimization models using integer and fractional parts without Pareto solutions, the newly proposed model is subjected to a comprehensive comparison with the two-phase model. As a result, it is demonstrated that, in the reported experimental setting and under the tested configuration of the two-phase procedure, the proposed model can lead to more feasible solutions that require fewer operators than the two-phase model under variable demand across 100 weeks. These findings pertain to the tested setting rather than representing a general property of the method. In addition, in the same setting, the proposed model can also lead to a smaller cumulative value of the secondary assignment-count metric than the two-phase model. Full article

Cultured meat aims to manufacture genuine animal tissue from cells in vitro, displacing the environmental and ethical liabilities of livestock slaughter. Because the final product must reproduce the fibre architecture, fat marbling, and nutrition of conventional meat, the cell—its identity, proliferative ceiling, and differentiation fidelity—is the central determinant of feasibility. This review consolidates the stem cell biology of cultured meat from a tissue engineering perspective. We first compare the principal cell sources: muscle satellite cells, which offer authentic myogenicity but limited expansion; pluripotent stem cells, which are effectively immortal but require directed differentiation; and mesenchymal, adipogenic, and fibro-adipogenic progenitors that supply fat and connective tissue. We then examine how myogenic and adipogenic commitment is controlled through growth-factor and small-molecule signalling, serum-free medium design, and co-culture strategies that recreate the multicellular composition of meat. We next survey biomaterial scaffolds—edible microcarriers, hydrogels, and decellularized plant matrices—that organize stem cells into anisotropic, perfusable, macroscale constructs, drawing on scaffold-design principles from regenerative medicine. Finally, we address bioreactor scale-up, medium cost, cell-line stability, and regulatory translation. We argue that cultured meat will advance fastest when cell source, differentiation protocol, and scaffold architecture are co-designed rather than optimized in isolation. Full article

Background: Danshen–Gegen is a classic herb pair in traditional Chinese medicine, which has been used to treat cardiovascular and cerebrovascular diseases. Ischemic stroke (IS) is a prevalent cerebrovascular condition; ferroptosis is one of the contributing factors driving the progression of IS. This study aims to determine the underlying mechanism and examine if Danshen–Gegen (DG) extract may prevent cerebral ischemia–reperfusion injury by preventing ferroptosis. Methods: The comprehensive compositional characterization of DG was analyzed by ultra-high-performance liquid chromatography coupled with hybrid quadrupole-orbitrap high-resolution mass spectrometry (UPLC-Q-orbitrap MS). The experiments were conducted in middle cerebral artery occlusion/reperfusion (MCAO/R) rats and oxygen-glucose deprivation/re-oxygenation (OGD/R) cells. The neuroprotective effects of DG on IS were assessed by examining rat survival rates, infarct volume, behavioral scores, and cerebral water content. Then, we tested the accumulation of Fe²⁺ and lipid peroxidation products such as reactive oxygen species (ROS), glutathione (GSH), malondialdehyde (MDA), myeloperoxidase (MPO), and 4-hydroxynonenal (4-HNE) in rats and cells. The expression of nuclear factor erythroid-derived 2-like 2 (Nrf2), Solute Carrier Family 7 Member 11 (-xCT), Glutathione peroxidase 4 (GPX4), Cyclooxygenase-2 (COX-2), Transferrin Receptor 1 (TFR1), and Long-chain-fatty-acid–CoA ligase 4 (ACSL4) was also assessed in vivo and in vitro. Results: UPLC-Q-orbitrap MS analysis was performed to characterize the chemical profile of DG, and a total of 33 chemical constituents were successfully identified. DG significantly alleviated the ischemic damage to brain tissue, reduced infarct volume, and improved neurological dysfunction. The content of Fe²⁺ and lipid peroxidation products was markedly decreased. Furthermore, DG could restore the expression of Nrf2, -xCT, and GPX4 with the inhibition of COX-2, TFR1, and ACSL4, thus achieving a suppressive effect on ferroptosis. Conclusions: The regulatory influence of DG via the Nrf2/System xc-/GPX4 axis may play a crucial role in alleviating ferroptosis and enhancing recovery from cerebral ischemia injury. Full article

No previous studies have characterized testicular polyamine metabolism across specific cell populations, including Sertoli cells, testicular peritubular cells, Leydig cells, germ cells, and testicular macrophages, during testicular maturation and aging. Here, we used immature, young adult, and aged adult Syrian hamsters as an animal model to quantify the main polyamines (PA) and their monoacetylated derivatives at the tissue and cellular levels by thin-layer chromatography and to assess the expression profiles of key genes involved in polyamine metabolism by RT-qPCR. At the tissue level, total PA concentration increased with age. During testicular maturation, putrescine increased and spermine decreased, whereas aged testes showed spermidine predominance. Testicular cell populations contributed unequally to PA production and release, and these contributions changed markedly with age. At the cellular level, aging was associated with a shift toward spermine- and N¹-spermine-rich profiles, suggesting enhanced PA catabolism, likely supported by Sat1/Paox up-regulation. Thus, PA catabolic enzymes represent potential therapeutic targets for aging-associated or even idiopathic infertility-related testicular alterations. Full article