Search Results (2,202)

Six different twin boundary interface models were constructed by molecular dynamics simulations to investigate the effect of biaxial load ratio on the fracture behavior of titanium twin boundaries. Analysis of microstructural evolution indicates that twin boundaries exhibit a dual role during crack propagation. On one hand, they serve as preferential sites for void nucleation, promoting crack propagation along the twin boundary; on the other hand, they provide favorable sites for dislocation nucleation, inducing local plastic deformation at the crack tip, altering the crack path, and thereby hindering crack propagation. The crack propagation behavior in the ($\overline{1}0$11) and ($\overline{1}0$13) twin boundary models shows evident asymmetry: the crack on the left side mainly propagates through the void nucleation mechanism and exhibits a faster growth rate, while the right-side twin boundary inhibits crack propagation by favoring dislocation nucleation. In contrast, the crack propagation behavior in the ($\overline{1}0$12), ($\overline{2}1$11), ($\overline{2}1$12) and ($\overline{2}1$14) twin boundary models is largely symmetric on both sides, showing no significant difference in propagation rate. Stress field analysis further reveals that the differences in crack propagation behavior among the various twin boundary models mainly originate from the disparity in dislocation activity on both sides of the crack, resulting in different levels of stress concentration at the crack tip. When void nucleation occurs at the twin boundary interface, the stress concentration between the main crack and the void intensifies, promoting their coalescence and further propagation. Meanwhile, with an increase in biaxial load ratio, the stress concentration at the crack tip becomes more pronounced, further accelerating crack propagation. Full article

The gut microbiota is recognized as a programmable metabolic organ that governs systemic homeostasis. Recent advances (2023–2025) have pivoted Type 2 Diabetes Mellitus (T2DM) research from a host-centric perspective toward a failure of bidirectional host–microbe metabolic flux. This review evaluates the molecular mechanisms underpinning this shift, focusing on microbial metabolite signaling, virome-mediated modulation, and the emergence of drug–microbiome interactions as critical therapeutic variables. We highlight the transformative role of AI-guided mapping and digital twin simulations in modeling high-resolution metabolic flux and predicting the stability of engineered microbial consortia. By integrating meta-transcriptomics and epigenomics, we characterize the functional plasticity of the microbiome under therapeutic stress. We argue that framing the microbiota as a programmable infrastructure—integrated with AI analytics and metabolic engineering—enables adaptive, real-time interventions. This synthesis offers a blueprint for transitioning from correlative observations toward precision microbiome engineering to achieve sustained metabolic resilience. Full article

Background/Objectives: Only substantial quantities of xeno-free human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CMs) (hiPSC-CMs) with stable quality and structural and functional maturity can meet the demand for cardiac cell therapy. The use of xeno-free microcarriers can significantly increase cell yield. Co-culturing with hematopoietic stem cells (HSCs) simulates the environment in vivo and has a necessary impact on the development of CMs. However, no microcarrier-based protocol for xeno-free hiPSC-CM culture has yet been established, and the effects of HSCs on CM development and their underlying mechanisms remain unclear. Therefore, this study aims to investigate these issues. Methods: We used a xeno-free microcarrier (plastic) culture system coated by a defined xeno-free matrix (MatriClone) to expand hiPSCs and hiPSC-CMs with human hematopoietic stem cells (hHSCs). Using RNA sequencing (RNA-seq), cytokine assay, and various cellular molecular techniques, we investigated the role of hHSCs in cardiac differentiation and maturation, and underlying mechanisms. Results: hiPSCs were evenly distributed on the surface of plastic coated with 1 μg/cm² MatriClone (MatriClone-Plastic), increasing and sustaining pluripotency marker levels. Directed differentiation of hiPSCs on 1 μg/cm² MatriClone-Plastic induced a larger number of CMs, and the level of cardiac differentiation was also significantly improved. When hHSCs were co-cultured with cells at the cardiac progenitor cell stage, results from electron microscopy, electrophysiology, and qPCR showed that hiPSC-CMs significantly promoted cardiac structural and functional maturation. The co-cultured hHSCs released multiple cytokines that were changed dynamically at different time points, and that were highly likely to activate the epidermal growth factor receptor (EGFR)/mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling pathway to promote cardiac development and maturation. Conclusions: hHSCs can efficiently promote differentiation and maturation of xeno-free hiPSC-CMs on MatriClone-Plastic via the EGFR/MAPK/ERK signaling pathway. Full article

Introduction: The discharge of treated wastewater into coastal and marine environments represents a continuous source of pollutants, including pharmaceuticals and plastic additives with endocrine-disrupting (ED) potential. These compounds are of increasing concern for the European Union due to their capacity to interfere with hormonal systems and their inclusion in current environmental monitoring priorities. ED compounds may induce sublethal effects in aquatic organisms, particularly in vertebrates, where endocrine pathways are highly conserved. In this context, the use of Cyprinodon variegatus, a euryhaline fish species, provides a suitable model to assess potential risks in marine ecosystems. Despite advances in wastewater treatment technologies, the persistence of biologically active substances in treated effluents remains a concern. Objective: This study aims to evaluate whether treated effluent water still contains compounds with endocrine-disrupting activity and to assess their potential effects on marine organisms. Methodology: Larvae of C. variegatus from a laboratory stock maintained at ECIMAT (University of Vigo), one of the few available stocks of this species in Europe, were exposed for 48 h to environmentally relevant dilutions (1:10, 1:30, and 1:100) of wastewater treatment plant effluent collected after UV disinfection as the final treatment step. Pools of 10 larvae were used for each condition. Sublethal effects were assessed through gene expression analysis using quantitative PCR (qPCR), targeting biomarkers involved in endocrine regulation. Two housekeeping genes (tbp and hprt) were used for normalization. Estrogenic responses were evaluated through vtgab and zp2, while androgenic responses were assessed using 17hsd and 11hsd. Results: Preliminary results indicate significant alterations in estrogen-related gene expression, particularly in vitellogenin (vtgab) and zona pellucida (zp2), highlighting the activation of estrogenic pathways and supporting the presence of endocrine-disrupting activity in treated effluent water. Conclusions: This study highlights the relevance of assessing endocrine disrupting activity in treated effluents and supports the use of molecular biomarkers as sensitive tools for evaluating their potential impact on marine ecosystems, contributing to the improvement of wastewater monitoring and management strategies. 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

The pyrolysis of polypropylene (PP) microplastics offers a potential route to convert plastic waste into fuel-range hydrocarbon mixtures and chemical feedstocks. However, the elementary radical pathways underlying the formation of medium-chain hydrocarbon fragments remain insufficiently resolved. In this study, a representative isotactic PP oligomer model (C₄₅H₉₂) was evaluated using a comparative density functional theory (DFT) framework. The main mechanistic analysis was based on M06-2X, ωB97X-D, and M11 calculations combined with the def2-TZVP basis set, whereas LANL2DZ was retained only as a lower-cost comparative level during reaction-pathway exploration. Thermochemical profiles were evaluated over a temperature range of 298–923 K. Three selected pathways involving mid-chain homolytic cleavage, intramolecular hydrogen transfer (backbiting), radical rearrangement, and β-scission were examined. Within the selected reaction set, Route 1 exhibited a comparatively more favorable thermochemical profile than Routes 2 and 3 and provided a mechanistically plausible sequence toward medium-chain hydrocarbon fragments. The −TΔS contribution strongly influenced the calculated Gibbs free-energy profiles because fragmentation increases the number of molecular species under the ideal-gas thermochemical approximation. Accordingly, the ΔG values were interpreted comparatively and were not treated as direct evidence of spontaneous fragmentation under condensed-phase pyrolysis conditions or as quantitative predictions of experimental product selectivity. Differences among the evaluated functionals further indicate that the relative description of radical intermediates and transition-state regions is method-dependent. These results provide a molecular-level framework for future studies integrating quantum-chemical calculations, microkinetic modeling, and experimental product characterization. Full article

The dopamine D₃ receptor (D₃R) has long been considered a secondary target in the treatment of Parkinson’s disease (PD), with therapeutic strategies primarily focused on D₂ receptor–mediated motor control. However, accumulating evidence now supports D₃R as a functionally distinct dopaminergic receptor subtype with specific relevance to non-motor symptom domains and dopaminergic signaling under hypodopaminergic conditions. Recent advances in high-resolution structural biology have elucidated the molecular basis of D₃R/D₂R discrimination, revealing how subtle residue-level and microstructural differences within a conserved G protein–coupled receptor framework shape ligand recognition and receptor activation. In parallel, the emergence of ligand-dependent biased signaling has refined current understanding of D₃R pharmacology. Selected ligands can preferentially engage Gα_i/o-mediated pathways while limiting β-arrestin recruitment and associated regulatory processes, providing a mechanistic rationale for more stable modulation of mesolimbic dopaminergic circuits involved in affective and motivational regulation. Beyond symptomatic modulation, preclinical studies suggest that D₃R signaling may influence neuronal resilience, synaptic plasticity, and adaptive responses to dopaminergic injury; however, such effects remain experimental and have not been demonstrated in clinical PD. This review integrates recent structural, signaling, and functional insights into D₃R biology, with particular emphasis on biased agonism and emerging therapeutic concepts. Although D₃R-targeted strategies do not currently represent disease-modifying interventions, they offer a rational framework for the development of next-generation dopaminergic therapies aimed at improving precision, tolerability, and long-term signaling stability in Parkinson’s disease. Full article

Brain-derived neurotrophic factor (BDNF) is a key regulator of neural development, plasticity, and behaviour. Recent work has enabled the generation of a viable adult bdnf^−/− zebrafish line, which provides a unique opportunity to investigate how complete loss of bdnf affects social behaviour. Here, we examined three-dimensional shoaling behaviour in adult male and female AB wild-type and bdnf^−/− knock-out zebrafish to determine whether the extensive molecular and behavioural alterations previously observed in individual-based assays extend to collective contexts. The bdnf^−/− shoals showed no differences in group structure, as inter-fish distance, shoal volume, shoal area, distance to the centroid, and homogeneity index were comparable to wild-type groups. Vertical spatial distribution was also largely preserved, although bdnf^−/− fish shifted toward the upper regions of the tank earlier during the trial. By contrast, horizontal distribution revealed a clear genotype effect: bdnf^−/− shoals spent more time in peripheral regions and displayed a pronounced early peak in peripheral occupancy. These findings indicate that bdnf loss does not impair shoal formation or cohesion but selectively modulates specific components of spatial exploration. The results also highlight a dissociation between the vertical and horizontal axes of behaviour, as well as between individual- and group-based phenotypes, underscoring the importance of social context in shaping the behavioural consequences of BDNF deficiency. Full article

Phosphoric acid-doped polybenzimidazole membranes are a leading fluorine-free electrolyte platform for high-temperature proton exchange membrane fuel cells, enabling proton transport under anhydrous conditions. However, recent evidence shows that conductivity, mechanical stability, and acid retention are intrinsically coupled, preventing independent optimization of these properties. This review establishes a unified framework in which membrane performance is governed by a multidimensional design space defined by acid doping level, activation energy (E_a), hydrogen-bond network topology, and mechanical confinement. Conductivity is shown to scale with both carrier density and hopping energetics, while mechanical stability decays with increasing ADL due to acid-induced plasticization, described through a semi-empirical relationship. Analysis across molecular architectures, including molecular weight control, crosslinking, backbone modification, topological design, and free-volume engineering, demonstrates that performance emerges from a balance between transport efficiency and structural stability. Device-level benchmarking further reveals that similar conductivity values can correspond to orders-of-magnitude differences in voltage decay rate, confirming that durability is governed primarily by mechanical confinement and acid mobility rather than σ alone. A multivariate stability corridor is identified, within which phosphoric acid-doped polybenzimidazole membranes achieve σ ≈ 0.14–0.20 S·cm⁻¹ while maintaining low degradation rates under realistic high temperature proton exchange membrane conditions. Based on this framework, quantitative design rules are derived linking acid doping level, activation, topology, and mechanical properties. This work shifts membrane design from conductivity-driven optimization toward predictive structure–property–durability engineering, providing a basis for the development of next-generation HT-PEM fuel cells with sustained long-term performance. Full article

The nanoindentation analysis of zirconium carbide (ZrC) has been studied through molecular dynamics simulations, focusing on various factors such as temperature, stoichiometric ratio, and crystal orientation. The findings show that as temperature increases, both the critical pop-in load and the maximum load decrease, while atomic strain, von Mises stress, and residual indentation depth increase. High temperatures facilitate the nucleation and propagation of 1/2<110> dislocations, which enhance the material’s ability to undergo plastic deformation. Both indentation hardness and Young’s modulus decrease linearly as temperature rises or the concentration of C vacancy increases. For stoichiometric ZrC, as the temperature rises from 10 K to 2100 K, the hardness decreases from 45.04 GPa to 20.36 GPa, and Young’s modulus drops from 396.28 GPa to 254.45 GPa. At 10 K, when the C/Zr ratio is reduced to 0.5, the hardness and Young modulus decrease to 25.32 GPa and 192.09 GPa, respectively. This reduction is attributed to the weakening of Zr-C bonds, which also reduces stress concentration. At elevated temperatures, the impact of C vacancies on the nanoindentation process diminishes due to the thermal softening of the substrate, which lessens the effects of vacancy-induced softening. Regarding anisotropy, Young’s modulus at room temperature decreases from 383.39 GPa on the (001) plane to 335.93 GPa on the $(1\stackrel{\mathrm{-}}{1}0)$ plane, and it reduces further to 303.31 GPa on the $(1\stackrel{\mathrm{-}}{1}1)$ plane; hardness shows a similar decreasing trend. This trend is primarily due to differences in slip systems, surface energies, and the angles between the plane normal and the Zr-C bond axis located directly beneath the surface atoms. Overall, these results may provide theoretical support for the processing and application of ZrC. Full article

The molecular coordination between the central nervous system and peripheral organs is fundamental to euryhalinity. This study elucidates the distinct adaptive strategies of the brain and gills in the four-finger threadfin (Eleutheronema tetradactylum), an aquaculture species of growing importance, during long-term (30-day) acclimation to low salinity (5 versus 25 control). A profound dichotomy in tissue-specific plasticity was uncovered: while the brain maintained remarkable transcriptional stability with only 10 differentially expressed genes (DEGs), the gills underwent extensive remodeling with 702 DEGs. Gill DEGs were functionally enriched in ion transport and metabolic remodeling, highlighted by the significant upregulation of the Na⁺-Cl⁻ cotransporter (slc12a10) and the prolactin receptor (prlr), coupled with a profound downregulation (log2FC = −5.97) of aquaporin-1 (aqp1). This indicates a concerted strategy to enhance ion uptake while minimizing water permeability. In contrast, the brain’s subtle response was dominated by the upregulation of key neuroendocrine hormones, including growth hormone (gh), prolactin (prl), and pro-opiomelanocortin (pomc). This suggests a top-down regulatory cascade. Integrative pathway analysis identified the PI3K-Akt and JAK-STAT signaling pathways as the primary conduits linking central hormonal signals to peripheral physiological adjustments. These results demonstrate that the euryhalinity of E. tetradactylum is achieved through a highly efficient strategy: a transcriptionally stable brain provides precise endocrine commands that orchestrate robust peripheral remodeling in the gills. This study deciphers the molecular basis of the brain–gill axis in osmoregulation and provides a rich repository of candidate genes for the genetic improvement of low salinity tolerance in aquaculture. Full article

SYNGAP1-related intellectual disability presents a therapeutic paradox where genetic rescue is highly effective in neonates but limited in adults, suggesting that deficiency represents a developmental trajectory violation rather than a static biochemical defect. By synthesizing molecular, biophysical, and clinical evidence, this review proposes the “Synaptic Clock” framework, redefining SynGAP1 as a critical developmental regulator. We hypothesize that SynGAP1 operates through a strictly ordered temporal sequence: Phase I (Scaffold Assembly) utilizes the α1 isoform and phase separation to establish the structural postsynaptic density, while Phase II (Catalytic Refinement) involves isoform switching to enable activity-dependent plasticity and homeostatic scaling. This model characterizes synaptic maturation as a biophysical transition from a fluid scaffold to a consolidated gel, potentially marking the biological closure of structural rescue windows. Based on this hypothesized temporal mapping, we establish a phase-stratified therapeutic roadmap—transitioning from early-stage “reset” strategies like gene replacement to late-stage “refinement” and “compensation” via pharmacological and neuromodulatory interventions. Ultimately, validating phase-specific biomarkers, including gamma oscillations and isoform stoichiometry, is essential for shifting from generic interventions toward precision, phase-matched medicine for neurodevelopmental timing. Full article

This study investigates the application of polymer inclusion membranes (PIMs) for the removal/recovery of 1H-benzotriazole from aqueous solutions, via facilitated transport mechanism, using tri-n-octylamine as a carrier and NaOH as a stripping agent. The process efficiency was analyzed using 1H-benzotriazole flux and permeability through the membrane, its recovery percentage, and the transport process kinetic constant. PIM containing 40% cellulose triacetate, 30% o-nitrophenyl octyl ether and 30% tri-n-octylamine yielded the best results for all four parameters studied due to the role of o-nitrophenyl octyl ether and tri-n-octylamine in reducing the cellulose triacetate polarity, which leads to carrier solubilization on the plasticizer, creating continuous pathways within the membrane and facilitating 1H-benzotriazole transport. Reduced graphene oxide inclusion as the fourth PIM component increases its hydrophobicity, promoting continuous pathway formation and enhancing 1H-benzotriazole transport, which leads to an increase of 10% to 20% in the values of the four parameters analyzed. Ultrasound use in membrane preparation leads to a further increase of 9% to 20% in the values of the four parameters analyzed because the cavitation effect improves the molecular mixing of membrane components and results in a less ordered configuration of cellulose triacetate molecules, thereby reducing their crystallinity degree. All of this significantly improves the interaction between the membrane components and pathway formation, enhancing 1H-benzotriazole transport through the membrane. Full article

Osteosarcoma (OS) is the most common primary bone cancer in adolescents and young adults. Despite tremendous preclinical and clinical efforts to advance therapy for OS, the standard of care, consisting of surgical resection and pre- and postoperative chemotherapy, has remained unchanged for over 40 years. Growing molecular understanding of OS highlights tumor heterogeneity as a major obstacle to therapeutic advances. In this narrative review, we comprehensively discuss current evidence of OS heterogeneity and strategies to overcome the barrier. Evidence shows that OS heterogeneity is multifactorial: it retains complex and dynamic somatic genomics, including genomic instability, alterations in tumor suppressors, and amplification/overexpression of oncogenes such as MYC. The tumor is associated with various germline vulnerabilities. OS’s tumor microenvironment has intense cellular and spatial diversity, which significantly shapes its heterogeneity. The effects of lineage plasticity, as well as epigenetic and metabolomic mechanisms, on OS heterogeneity are under study. To overcome this extreme heterogeneity, the therapeutic strategies for OS must be comprehensive and diversified. While surgical resection remains a mainstay of treatment, efforts to identify actionable biomarkers that guide risk stratification and therapy are ongoing. Diverse preclinical models offer insights into OS biology and novel therapeutics. To enhance combinational therapy for OS, various agents, including multi-targeted receptor tyrosine kinase inhibitors, immunotherapies, and epigenetic and metabolic modifiers, are being investigated. Distinctive efforts are continuing to establish maintenance therapy for OS. In summary, elucidating the complex drivers of OS heterogeneity, together with the development of multifaceted strategies to address them, is critical to accelerating therapeutic progress in OS. Full article

The pearlitic microstructure, comprising alternating lamellae of ferrite and cementite, provides a favorable combination of strength, toughness, and wear resistance. Consequently, pearlitic steels have been widely utilized in pipeline systems due to their advantageous mechanical properties and cost-effectiveness. These characteristics also render pearlitic steel pipelines promising candidates for hydrogen transport infrastructure, particularly in the context of repurposing existing natural gas networks. However, interactions between hydrogen and the pearlitic microstructure raise significant concerns regarding hydrogen embrittlement, a phenomenon that can substantially degrade mechanical performance and compromise long-term structural integrity. Experimental observations indicate that pearlitic microstructures are particularly susceptible to hydrogen embrittlement, largely due to the high density of ferrite–cementite interfaces, which act as effective hydrogen trapping sites. These detrimental effects motivate the present study, which aims to develop a deeper understanding of nanoscale mechanisms of hydrogen-assisted crack initiation and propagation in pearlitic microstructures. In this work, molecular dynamics simulations are employed to investigate the initiation and propagation of hydrogen-affected cracks in pearlitic microstructures, considering lamellar orientations both parallel and perpendicular to the applied tensile loading direction. The analysis focuses on the synergistic interaction between hydrogen-enhanced decohesion (HEDE), which promotes interfacial separation due to hydrogen segregation, and hydrogen-enhanced localized plasticity (HELP). Full article