Search Results (1,835)

Background/Objectives: First-generation CDK4/6 inhibitors (palbociclib, ribociclib, abemaciclib) target the conserved ATP-binding pocket of CDK4 and, despite clinical success, are limited by acquired resistance and insufficient exploration of alternative regulatory sites. This study aimed to identify a putative allosteric small-molecule candidate at the CDK4 αE-helix–Cyclin D1 α1-helix protein–protein interaction (PPI) interface within the CDK4/Cyclin D1/p21 ternary complex using RapidFunnel-AI, a decision-interpretable virtual-screening pipeline. Methods: Starting from 50,000 ChEMBL 33 molecules, the pipeline sequentially applied a Q-Fold/RapidFunnel topological Tanimoto scan based on clinical CDK4/6 inhibitor motifs, fragment-level electronic-property enrichment, ADMET/PAINS filtering, dry Vina-GPU docking, hydration-mediated AutoDock-GPU (Version 1.6) docking, explicit-solvent molecular dynamics, contact-retention analysis, and MM-GBSA energy decomposition. The Q-Fold Thermo-Core surrogate model provided fragment-level enrichment, predicting the HOMO–LUMO gap (R² = 0.93) and isotropic polarizability (R² = 0.98) on QM9. Candidate selection did not rely on the lowest docking or MM-GBSA score alone, but on pose persistence, contact continuity, and energy-component consistency. Results: The workflow reduced the initial library to 43 topologically prioritized candidates, 25 ADMET/PAINS-filtered ligands, and 9 docking-derived complexes for MD validation. Ligand_020 emerged as the only candidate that preserved a persistent binding mode at Site 2 during a 500 ns simulation—an interface engagement reproduced across three independent 500 ns replicates with no full dissociation in any replicate—with a protein Cα RMSD of 2.88 ± 0.32 Å, a ligand heavy-atom RMSD of 3.56 ± 0.28 Å, and a van der Waals-dominated MM-GBSA profile (ΔGbind = −28.23 ± 3.57 kcal/mol). In contrast, palbociclib and ribociclib, forcibly placed at Site 2 as negative controls, lost most initial contacts within 5 ns and tended to detach despite more favorable MM-GBSA values. Conclusions: These results suggest that single-score docking or MM-GBSA ranking can generate false positives at shallow PPI interfaces. By integrating AI-assisted prioritization, multipocket docking, explicit-solvent MD, contact-retention analysis, and energy-component consistency, RapidFunnel-AI nominated Ligand_020 as an experimentally testable putative allosteric hit targeting the CDK4/Cyclin D1 interface, offering a reusable platform for PPI-focused oncological drug discovery. Full article

Schistosomiasis remains a major public health concern in Nigeria. We molecularly characterized Schistosoma eggs obtained from human urine to identify species and assess the presence of hybrid schistosomes in Abuja, Nigeria. Urine samples were collected from 1887 participants aged five years and above. Samples were examined for Schistosoma eggs using light microscopy. A total of 507 (26.9%) were positive for any form of Schistosoma while 91 (4.8%) had atypical Schistosoma eggs. DNA extracted from pooled ova was analyzed using metagenomic sequencing, read mapping, phylogenetic analysis, and BLASTn confirmation. Molecular analyses identified genetic signatures associated with both S. haematobium and S. bovis within pooled human urine samples, indicating the co-circulation of multiple schistosome species in the study area. Phylogenetic analyses based on trans-ITS and mitochondrial COX1 markers supported the presence of distinct nuclear and mitochondrial schistosome lineages. However, because sequencing was performed on pooled egg samples, the findings cannot distinguish between true recombinants and mixed infections involving co-circulating parental species. These findings highlight the potential complexity of schistosome transmission dynamics in endemic communities and underscore the need for enhanced molecular surveillance, especially single-parasite genomic approaches, and integrated One Health investigations to better understand schistosome transmission and its implications for control and elimination efforts in Nigeria. Full article

Abiotic stresses, including drought, salinity, alkalinity, temperature extremes, flooding, heavy metals, and emerging pollutants, challenge plant growth and productivity by disturbing water relations, ion balance, redox homeostasis, membrane stability, energy metabolism, and developmental progression. Although substantial progress has been made in the identification of stress-responsive hormones, second messengers, kinases, transcription factors, transporters, and metabolic regulators, plant stress adaptation cannot be fully explained by linear signaling cascades or single tolerance genes. A major unresolved question is how early molecular events are reorganized into coordinated physiological and developmental outputs that support survival, recovery, and productivity. In this review, we propose an intermolecular interaction-driven adaptive remodeling framework for plant abiotic stress responses. This framework emphasizes that stress tolerance emerges from dynamic changes in receptor–ligand recognition, protein–protein interactions, calcium decoding, redox-sensitive modification, phosphorylation networks, transcriptional regulation, chromatin-associated control, and metabolite-mediated feedback. We further emphasize ROS as integrative redox switches that connect stress sensing, defense activation, senescence-related transitions, and recovery, and chromatin-associated mechanisms as regulators that may stabilize primed or memory-like adaptive states. We discuss how these interaction networks converge on core signaling hubs, including abscisic acid, reactive oxygen species, Ca²⁺, and kinase/phosphatase systems, and how they remodel stomatal behavior, root architecture, ion and pH homeostasis, redox buffering, metabolism, development, and reproductive resilience. We further highlight how natural variation, multi-omics, genome editing, high-throughput phenotyping, and field validation can translate interaction-centered stress biology into crop resilience. This perspective provides a conceptual bridge between molecular stress perception, network behavior, physiological adaptation, and climate-resilient agriculture. Full article

Plants must continuously balance the trade-offs between growth and defense, a constraint that is exacerbated by biotic and abiotic stresses, particularly when they occur together. Ethylene (ET) serves as a central, integrative regulatory node controlling this by linking developmental programs to stress-responsive signaling networks. Advances at the molecular and systems levels have revealed that ET mediates the redistribution of metabolic resources via coordinated regulation of its synthesis, perception, and downstream signaling. The ETR (Ethylene Receptor)-CTR1 (Constitutive Triple Response 1)-EIN2 (Ethylene Insensitive 2)-EIN3(Ethylene Insensitive 3) signaling module lies at the core of this network, integrating multiple hormonal pathways. Through dynamic crosstalk with jasmonic acid (JA), salicylic acid (SA), abscisic acid (ABA), auxin (AUX), and gibberellins (GA), ET enables the fine-tuned coordination of growth inhibition, immune activation, and stress acclimation in response to environmental fluctuations. Processes such as induced systemic resistance, programmed cell death, and architectural plasticity further reinforce this regulatory framework, with ethylene-responsive transcription factors, including ERFs (ethylene responsive factor gene family) and WRKYs, acting as critical convergence points. Emerging insights into ACC (1-aminocyclopropane-1-carboxylic acid) -dependent signaling, chromatin remodeling, and tissue-specific regulation expand the functional scope of ET beyond traditional hormone paradigms. At the same time, the ability of pathogens to manipulate ET signaling underscores its dual role in both promoting immunity and facilitating susceptibility. By integrating molecular, physiological, and ecological perspectives, this review highlights ET as a central coordinator of plant stress resilience and growth optimization, providing a unifying framework for understanding how plants adapt to complex and dynamic environments. Full article

Prior to this study, knowledge on the evolutionary lineage of Garra remained inadequate, as previous phylogenetic investigations were primarily based on partial gene sequences. Although several mitogenomes of Garra species have been reported, their structural organization and comprehensive genomic characteristics have not been thoroughly evaluated. In this study, Garra manipurensis, endemic to the Indo-Burma biodiversity hotspot, was identified based on its detailed morphology and meristic counts. The circular mitogenome of G. manipurensis is 16,776 bp in length and contains the canonical set of 37 genes, along with duplicated control regions separated by tRNA-Proline. The comparative assessments across Garra species indicate predominantly conserved GTG start codons, occasional alternative ATA initiation codons, and incomplete stop codons. The selection pressure examinations within Garrini taxa reveal a purifying selection across all protein-coding genes. The control region comprises four conserved sequence blocks and species-specific tandem repeats, reflecting a balance between functional constraint and lineage-dependent evolutionary dynamics. The phylogenetic inference supports the monophyly of Garra and places G. manipurensis in close affinity with Garra flavatra, which is native to the western slope of Rakhine Yoma in Myanmar and Mizoram State in northeastern India. The genetic diversity analyses revealed haplotype differentiation, with shallow intraspecific genetic distances (0.000–0.011) observed samples between two distinct drainage systems in Manipur and Mizoram, northeastern India. The observed pattern of haplotype divergence in G. manipurensis may reflect the historical or seasonal hydrological connectivity among the western-slope drainages of the Chin Hills, with the subsequent geographic isolation potentially contributing to the emergence of distinct genetic lineages. Nevertheless, the extent and evolutionary significance of this differentiation remain uncertain and warrant further investigation through expanded geographic sampling and the incorporation of additional molecular data. Collectively, these findings provide in-depth insights into the mitogenomic architecture, comparative gene arrangements, phylogenetic patterns, and matrilineal evolutionary history of G. manipurensis and other congeners, thereby improving our understanding of the systematics and genetic diversity of this important cyprinid fish lineage. Full article

Autism spectrum disorder is increasingly linked to altered microglial biology. However, current research models are limited by outdated descriptions of microglial “activation”. Here, we propose that microglial involvement in ASD is best understood as a problem of state mismatch, in which temporally programmed and regionally specialized microglial states fail to align with local developmental demands. We synthesize evidence across genetic models, human transcriptomics, and experimental systems to examine three axes of misalignment: developmental timing, circuit specificity, and functional phenotype. These mismatches produce divergent outcomes, including both excessive and insufficient synaptic pruning, and reflect a decoupling between microglial activation markers and effector capacity. We further evaluate molecular recognition systems governing microglia–synapse interactions, with emphasis on complement signaling and glycan-mediated pathways such as sialic acid–Siglec signaling and polysialylation. While glycosylation is not a universal driver of ASD pathology, it represents a plausible regulatory layer controlling synapse visibility and microglial engagement. This framework reconciles conflicting findings in the literature and positions microglia as dynamic developmental effectors whose misaligned state trajectories contribute to circuit-level dysfunction in ASD. Full article

Dipeptidyl peptidase-4 (DPP-4) is a key therapeutic target for type 2 diabetes (T2D). Several synthetic anti-DPP-4 drugs are currently available for the treatment of T2D; however, the need for safe and effective therapies remains unmet due to the side effects associated with existing DPP-4 inhibitors. This study aimed to integrate structure-based and machine learning (ML)-based virtual high-throughput screening to identify natural DPP-4 inhibitors. Random forest, logistic regression, support vector machine (SVM), and multilayer perceptron (MLP) models were trained on DPP-4 IC₅₀ datasets. Among these, the SVM and MLP models achieved high predictive performance, with areas under the curve of 0.928 and 0.923, respectively. Screening of a natural compound database identified 107 compounds for further analysis. Subsequent structure-based screening, using sitagliptin as a positive control, identified sennidin B and doxorubicin hydrochloride as promising candidates with strong binding affinity for DPP-4. Molecular dynamics simulations (200 ns) and MM-PBSA calculations confirmed stable interactions with DPP-4. Further, sennidin B and doxorubicin hydrochloride inhibited DPP-4 activity in a concentration-dependent manner, with estimated IC₅₀ values of 39.39 and 19.78 μM, respectively. Sennidin B also reduced DPP-4 mRNA and protein expression levels in Caco-2 cells. Overall, sennidin B shows promise as a natural DPP-4 inhibitor and warrants further investigation as a potential antidiabetic agent. Full article

Northern pike (Esox lucius) myofibrillar protein (MP) forms inherently weak gels due to endogenous proteolytic activity and the low thermal stability of fish myosin, limiting its application in surimi products. This study investigated the reinforcing effect and underlying mechanism of rice protein amyloid fibrils (RFs) on pike MP gels. Dynamic rheology revealed that RFs increased both the storage and loss moduli in a concentration-dependent manner, with the 5% group exhibiting an approximately threefold increase in the G′ at 100 rad/s relative to the control. The gel strength, hardness, and chewiness increased progressively with the RF content, whereas the water-holding capacity peaked at 1–3% RFs and declined sharply at 5% RFs. Microstructural imaging showed that moderate RF levels promoted a dense, homogeneous network architecture, while excessive RFs induced phase separation and structural heterogeneity. Hydrophobic interactions and hydrogen bonds were strengthened via RF incorporation, while disulfide bonds decreased monotonically with the increasing fibril concentration. FTIR spectroscopy revealed an α-helix-to-β-sheet transition, with the β-sheet content reaching a maximum of 49.37% at 3% RFs, and SDS-PAGE confirmed that the RF–MP interactions were predominantly non-covalent in nature. These results demonstrate that RFs reinforce pike MP gels through a molecular mechanism involving rigid fibrils acting as structural scaffolds within the protein network and a progressive shift from disulfide-mediated covalent crosslinking toward non-covalent stabilization via hydrophobic interactions and hydrogen bonding. The 1–3% RF range delivers the most balanced gel properties, while excessive fibril loading at 5% induces over-aggregation and impairs water retention. These findings establish amyloid fibrils as effective structural modifiers for freshwater fish gel products and provide a mechanistic basis for their application in surimi processing. Full article

Background: Ferrocene-containing compounds have gained attention in medicinal chemistry due to their unique redox and structural properties. This study investigates ferrocene-based analogues of imatinib and nilotinib to define their binding determinants within the ABL1 kinase domain using an integrated in silico approach, in relation to their previously reported cytotoxic activity. Methods: Ligand geometries were optimized at the B3LYP/def2-TZVP level with D3(BJ) dispersion and SMD solvation. Molecular docking against ABL1 (PDB ID: 2HYY) was performed using Glide SP, validated by re-docking and enrichment screening. Docked poses were refined using MM-GBSA (Prime, VSGB 2.1/OPLS4). The most active compounds (9 and 15a), together with the inactive control 15e, were subjected to three independent 500 ns molecular dynamics simulations (Desmond, OPLS4), followed by trajectory analysis including RMSD, RMSF, radius of gyration, SASA, and polar surface area. Results: Compounds 9 and 15a maintained stable binding within the ATP-binding pocket despite lacking the canonical hinge interaction with Met318, indicating hinge-independent binding. Their binding was mainly driven by interactions with Asp381 (DFG motif) and cation–π contacts with Lys271. In contrast, the compound 15e showed unstable binding, increased conformational flexibility, reduced pocket burial, and loss of key stabilizing interactions. Active compounds also preserved stable P-loop dynamics, with Tyr253 engagement suggesting a role in loop stabilization. Compound 9 exhibited the most constrained and reproducible binding mode among all analogues. Conclusions: Ferrocene-based analogues can sustain stable ABL1 binding via non-classical interaction networks independent of hinge recognition. The clear distinction between active compounds and the inactive analogue 15e supports the robustness of the proposed binding mode and provides a structural basis for their reported cytotoxic activity. These findings support further experimental evaluation of ferrocene-containing scaffolds as potential BCR-ABL1 inhibitors. Full article

RelA/SpoT homologue family enzymes participate in controlling the cellular levels of the alarmone (p)ppGpp, thereby activating the stringent response and promoting survival under stress conditions. These proteins contain an N-terminal catalytic domain and a C-terminal regulatory domain. They catalyze both the synthesis of ppGpp/pppGpp from ATP and GDP/GTP and their hydrolysis to GDP/GTP and pyrophosphate. Here, we report the crystal structure of the N-terminal domain of Rel from Streptococcus equisimilis in complex with pppGpp at 3.2 Å resolution. The asymmetric unit contains a dimer with asymmetric ligation: pppGpp occupies only the synthetase site in one monomer, whereas in the other monomer, it is bound in both the hydrolase and synthetase sites. The two monomers exhibit distinct conformational states, with pronounced rearrangements of the flexible loops surrounding the binding pockets, including the α2/α3 and α8/α9 loops that act as steric gates. Molecular dynamics simulations support the dual binding arrangement and reveal additional probable transient binding sites, including a region in the linker between hydrolase and synthetase subdomains. These findings provide a structural framework for understanding how pppGpp binding modulates the opposing catalytic activities of bifunctional Rel enzymes and suggest possible mechanisms for (p)ppGpp-mediated autoregulation. Full article

Temperature and pressure are critical controlling parameters in the in situ conversion process (ICP) of oil shale. Clarifying the mechanisms governing organic matter pyrolysis is essential for reliably extrapolating laboratory findings to geological conditions. This review systematically summarizes the effects of temperature and pressure on shale pyrolysis and on hydrocarbon generation kinetics. Temperature is the primary factor controlling pyrolysis rates and product distribution, with an optimal temperature window enhancing shale oil yield while suppressing secondary cracking. Low heating rates favor thorough pyrolysis, although their influence on reaction pathways is generally overlooked in current kinetic models. Pressure effects are stage-dependent: during organic matter conversion, they are minor, whereas, in the product expulsion stage, high pressure inhibits hydrocarbon expulsion, prolongs residence time, and promotes secondary cracking, thereby reducing overall oil yield while increasing light fractions. Discrepancies in reported pressure effects arise from variations in experimental systems, sample forms, and medium conditions. The coupling of temperature and pressure is synergistic rather than additive. Given that current kinetic models largely neglect pressure and heating-rate effects, and that temperature–pressure coupling mechanisms remain unclear, future research should focus on thermal simulation experiments across wide ranges of pressures and heating rates, complemented by ReaxFF molecular dynamics to elucidate reaction pathways and guide kinetic model development. Further in situ experiments under high-temperature and high-pressure conditions are needed to characterize coupled pore evolution and fluid migration. Ultimately, integrated thermo-hydro-mechanical-chemical (THMC) models should be developed to capture hydrocarbon generation, retention, and expulsion, providing a robust theoretical framework for optimizing ICP technology. Full article

Despite technological advances in radiation therapy (RT), improvements in locoregional control of locally advanced disease remain limited, indicating a plateau in RT effectiveness. It is becoming increasingly clear that RT occurs within a dynamic metabolic microenvironment that merges oncogenic activity with metabolic and immune interactions. This includes responses to oxidative stress, regulation of cell death and survival signals, energy metabolism, protein synthesis, autophagy of molecules and organelles, and ultimately, the anti-tumor immune response. Each tumor, regardless of its histology, maintains a unique molecular and microenvironmental identity that influences its response to RT. Furthermore, RT acts as a cellular stressor that activates responses in cancer and stromal cells, impacting clinical outcomes. The concept of Metabolism and Immunity Adaptive Radiotherapy (M.I.A.R) recognizes that RT success depends not only on radiation dose and distribution but mainly on key interventions that alter and influence the biological environment before, during, and after therapy. It highlights the importance of an initial diagnostic workup, which is achievable with current tools, to identify tumor-specific oncogenes, metabolic, and immune profiles. Within the context of M.I.A.R., effective RT requires tumor preconditioning combined with concurrent use of drugs, including metabolism-targeting agents, to increase tumor sensitivity to radiation. Post-RT metabolic and immune interventions are essential for complete tumor eradication. This involves combining existing oncogene-targeting therapies with available immune treatments, supported by low-toxicity modulating drugs/agents with demonstrated preclinical activity against specific molecular and microenvironmental features. Overall, while MIAR remains a theoretical approach, existing preclinical and recent clinical data, e.g., those exploiting tumor hypoxia and re-oxygenation status, or post-RT immunotherapy, strongly support further dedicated investigation. Full article

Essential host functions are often maintained by conserved molecular systems, but in biological contexts shaped by evolutionary conflict, the genes that execute such functions may be unstable, replaceable, or repeatedly recruited from different evolutionary sources. Mammalian placentation provides a striking example of this principle. Trophoblast cell fusion is essential for placental development, yet this function is mediated in different mammalian lineages by distinct endogenous retrovirus-derived envelope proteins, including syncytin-1, syncytin-2, and other lineage-specific Env-derived fusogens. Here, I propose the Baton Pass model as a conceptual framework for explaining how host-level biological functions can be maintained despite turnover of the molecular agents that execute them. This model differs from conventional examples of antagonistic coevolution, which often emphasize recurrent mutations within the same interacting genes, and from non-orthologous gene displacement, which generally concerns replacement among cellular genes. In the syncytin paradigm, the molecular executors are repeatedly supplied by exogenous retroviral env genes that become endogenized, domesticated, and incorporated into host developmental programs. I further discuss how receptor compatibility, placental expression control, and host–virus evolutionary conflict may together destabilize individual Env–receptor systems while allowing the host-level function of trophoblast fusion to persist. Analogous functional reassignment is also observed in primate lentiviruses, where antagonism of BST-2 shifts among distinct viral genes. The Baton Pass model therefore describes a testable evolutionary principle: essential host functions can be preserved not only through conservation of specific genes, but also through dynamic succession of genes of distinct evolutionary origins. Full article

Banana Fusarium wilt, caused by Fusarium oxysporum f. sp. cubense tropical race 4 (Foc TR4), poses a significant threat to global banana production; however, effective and sustainable control strategies remain limited. Extracellular self-DNA (esDNA), which functions as a damage-associated molecular pattern (DAMP), has recently been identified as a crucial regulator of plant innate immunity. Nonetheless, it is unclear whether the immune regulatory function of esDNA varies with disease progression. In this study, we examined the effects of esDNA derived from banana leaves exhibiting different disease severities on plant resistance to Fusarium wilt. Hydroponic experiments revealed that esDNA displayed a distinct disease-stage-dependent regulatory pattern. EsDNA from mildly diseased tissues significantly suppressed Foc TR4 colonization, supported plant growth, and mitigated oxidative damage, whereas esDNA from severely dise ased tissues lost protective effects and even intensified cellular stress. Physiological analyses indicated that beneficial esDNA effectively reduced H₂O₂ and malondialdehyde accumulation while enhancing antioxidant enzyme activities and phenylpropanoid metabolism. Transcriptome profiling further demonstrated that esDNA extensively altered pathogen-induced gene expression, with enrichment of pathways involved in metabolic and redox homeostasis. These transcriptional changes correlate with the observed reduction in oxidative damage and improved plant growth, suggesting that restoration of homeostasis may contribute to esDNA-mediated resistance. Our findings collectively demonstrate that esDNA serves as a dynamic DAMP signal, exhibiting effects that depend on the disease stage. This study offers new insights into the role of plant self-DNA in mediating immunity and presents a promising strategy for developing environmentally sustainable control measures against banana Fusarium wilt. Full article

The subject of CO₂ subsurface storage security has never been more critical, and there is a need to explore the injection of functional materials that are capable of providing both conformance control and in situ CO₂ adsorption, thereby improving overall formation storage integrity. Herein, a molecular dynamics simulation method was used to investigate the adsorptive tendency of two variants of interpenetrating network (IPN) composite materials comprising amine-stabilized hydrophobically modified cellulose sulphates and methylene bisacrylamide crosslinked polyacrylamide. Using the COMPASS III force field and Metropolis Monte Carlo, the diffusivity and adsorption isotherms for CO₂ were determined in the IPN gels, respectively. The results indicate that the two interpenetrating networks D-I-AM-MBA-G-Cl and D-II-AM-MBA-G-Cl demonstrated reasonable CO₂ adsorption. In saline conditions, the adsorption was further enhanced with diffusion coefficients of 4.87 × 10⁻⁴ cm²/s and 2 × 10⁻⁶ cm²/s. The adsorption isotherm of D-I-AM-MBA-G-Cl closely fits the Sips equation, with a regression coefficient of 0.9996, while that of D-II-AM-MBA-G-Cl follows the Temkin isotherm with an R² value of 0.9885. This study revealed that carefully designed plugging agents with strong CO₂ adsorption tendencies can aid in the improvement of the geosequestration integrity of subsurface formations. Full article