Search Results (437)

Transboundary river basins face water stress exacerbated by data scarcity and political instability, and most allocation models require ideal conditions that ordinarily do not exist. This study operationalizes Water Diplomacy Theory (WDT) for data-scarce, conflict-prone basins through quantifiable allocation rules—a critical gap as 310 transboundary basins worldwide face similar challenges. We address: (1) How can a four-stage allocation framework reduce basin-wide water stress under varying Institutional Capacity (IC), Data Transparency (DT), and Stakeholder Inclusion (SI)? (2) What treaty provisions achieve bindingness under upstream-downstream power asymmetries? (3) How does this framework advance beyond existing models in equity, efficiency, and adaptive capacity? We synthesize Water Diplomacy Theory with Hydro-political Security Complex Theory to construct a novel four-stage framework: initial allocation with ecological floors, conditional reallocation triggers, interannual water banking, and satellite-verified compliance. Drawing on 14 treaty precedents and 30-year hydrological data for the Salween River, we embed these rules in an open-source water banking model. Results demonstrate that increasing IC from low to high reduces basin-wide water stress by 34% (±7%, 95% IC) under drought conditions. Stakeholder Inclusion decreases allocation conflicts by 52%. Water banking outperforms priority rules by 23% across climate scenarios. Cooperation becomes self-enforcing when IC exceeds 0.55. The novelty and contribution to existing literature our study provides are: (1) first operationalization of hybrid commons-to-treaty transition with 85.7% empirically grounded clauses; (2) evidence that binding cooperative treaty design is achievable in weak-state contexts through institutional design; and (3) a portable template for data-scarce conflict-affected basins. Full article

In complex ground environments, conventional RRT* often suffers from low planning efficiency and poor path quality for robot path planning. This paper proposes BGSE-RRT* (Bi-tree Cooperative, Goal-guided, low-discrepancy Sampling, multi-sector Expansion). First, BGSE-RRT* constructs a nonlinear switching probability via bi-tree cooperative adaptive switching, together with KD-Tree nearest-neighbor acceleration and multi-condition triggering, to adaptively balance global exploration and local convergence. Meanwhile, a goal-guided expansion with dynamic target binding and adaptive step size, under a multi-constraint feasibility check, accelerates the convergence of the two trees. When the goal-guided expansion becomes blocked, BGSE-RRT* generates candidate points in local multi-sector regions using a 2D Halton low-discrepancy sequence and selects the best candidate for expansion; if the multi-sector expansion still fails, a sampling-point-guided expansion is activated to continue advancing and search for a feasible path. Second, B-spline smoothing is applied to improve trajectory continuity. Finally, in five simulation environments and ROS/real-robot joint validation, compared with GB-RRT*, BI-RRT*, BI-APF-RRT*, and BAI-RRT*, BGSE-RRT* reduces planning time by up to 84.71%, shortens path length by 2.94–6.88%, and improves safety distance by 20.68–48.33%. In ROS/real-robot validation, the trajectory-tracking success rate reaches 100%. Full article

A high-risk infectious disease or a Category A pathogen, Lassa virus (LASV), requires strict containment, classified as biosafety level 4 (BSL-4) conditions, which restricts research on the virus due to the scarcity of BSL-4 facilities. Thus, replication-defective pseudotyped retroviral vectors have been widely used as safe materials for neutralizing activity assays of drugs and antibodies in BSL-2. Here, we established a novel retroviral vector system encoding LASV glycoprotein complex (GPC) that can exclusively replicate in cells expressing the Gag-Pol protein of murine leukemia virus (MLV) under BSL-2 conditions. Using this conditional replication system, we successfully isolated LASV GPC variants resistant to either an anti-LASV compound, lamellarin α 20-sulfate, or a neutralizing antibody derived from a Lassa fever survivor. In the lamellarin α 20-sulfate-resistant variants, K125E and H13R amino acid substitutions cooperatively conferred resistance. The K125E enhanced infectivity and simultaneously conferred a lethal effect on cells in the conditional replication system, while the H13R mitigated the latter effect, thereby enabling stable expression of LASV GPC in cells. In the neutralizing antibody-resistant variants, I403T substitution was responsible for the resistance by impairing antibody binding. This study provides a valuable BSL-2-based platform for isolating LASV GPC variants resistant to inhibitors and characterizing their mutations. Full article

Metal-free two-dimensional (2D) polymers built from open-shell π-conjugated units offer a promising platform for realizing correlation-driven magnetism without transition metal elements. Here, we present a systematic first-principles study of phenalenyl-based 2D polymers that elucidates how atomic-level chemical substitution controls magnetic order through the interplay of electronic correlation and sublattice symmetry. Combining density functional theory with an effective tight-binding and Hubbard model analysis, we show that atomic substitution with boron or nitrogen on phenalenyl building blocks acts as a sublattice-resolved tuning knob for both the ratio of on-site Coulomb interaction to inter-site hopping (U/t) and the relative on-site energies of the two sublattices. Sublattice-asymmetric substitution with boron or nitrogen breaks sublattice equivalence and drives the system from an antiferromagnetic Mott-insulating state into spin-polarized semiconducting phases with pronounced spin-dependent gaps. In contrast, uniform substitution on both sublattices preserves symmetry and yields nonmagnetic metallic states characterized by rigid band shifts rather than correlation-driven spin polarization. These results establish a unified microscopic framework in which electronic correlations and sublattice symmetry emerge as cooperative yet independently tunable parameters, providing general design principles for metal-free 2D π-conjugated materials with tailored magnetic and spintronic functionalities. Full article

The separation of xenon (Xe) and krypton (Kr) is very important for industrial applications and environmental protection. However, the lack of permanent dipoles, low polarizabilities arising from their spherical nature, and similar kinetic diameters make their efficient separation by porous adsorbents exceptionally challenging. This study explored the effects of pore geometry and surface polarity of a series of aluminum-based metal–organic frameworks (CAU-10-H, MIL-160, KMF-1, CAU-23) on Xe/Kr separation performance using a heteroatom engineering strategy. These MOFs are composed of AlO₆ clusters and bent dicarboxylic acid linkers, enabling us to systematically investigate the effects of pore size and heteroatom types on Xe/Kr separation performance. Among them, MIL-160 has a polar linker based on furan, showing the best balance performance. At 298 K and 1.0 bar, the uptake of Xe is 4.12 mmol g⁻¹ and the IAST selectivity is 7.63 for a Xe/Kr (20/80) mixture. The practical performance was verified by dynamic breakthrough experiments, which yielded a long Xe breakthrough time of 42.9 min g⁻¹. Grand Canonical Monte Carlo (GCMC) simulations and first-principles density functional theory (DFT) calculations revealed that the enhanced performance originates from cooperative confinement and polarization effects, with the furanyl oxygen atoms providing optimal Xe-binding sites. This work clarifies the structure–property relationships governing Xe/Kr separation in aluminum-based MOFs (Al-MOFs), highlighting the potential of heteroatom engineering for designing efficient noble gas adsorbents. Full article

Retromer is an evolutionarily conserved protein complex first identified in budding yeast. It was originally described for its essential role in endosome-to-Golgi retrieval of lysosomal hydrolase receptors. Retromer is now known to mediate trafficking of many endosomal cargoes. The mammalian retromer is constituted by a core heterotrimer encoded by the vacuolar protein sorting (VPS) gene products VPS26, VPS35, and VPS29. To mediate cargo recognition and endosomal sorting into various pathways, this trimer can cooperate with phosphoinositide-binding sorting nexin family members. Defective retromer functioning has been associated with alterations in cellular homeostasis, leading to disease. To gain insights into how it may mediate these broad processes, a proteomic strategy in polarized Madin-Darby canine kidney cells was devised to identify retromer-interacting proteins. Subsequent validation of one of the candidates, i.e., cytokeratin 19, led to the unexpected finding that retromer localizes to the pericentriolar region in dividing cells and subsequently translocates to the midbody during cytokinesis. Retromer was found interacting with CK19, and its antisense depletion led to delocalization from CK19. Subcellular fractionation and live cell monitoring of depleted cells provided evidence of a role by retromer in post-metaphase progression and in epithelial cell migration, thereby connecting retromer with key processes of cellular dynamics. Full article

Background/Objectives: Thrombin, a serine protease central to coagulation and platelet activation, remains an important target for the development of safer and more effective antithrombotic agents. Naturally derived pentacyclic triterpenoids, such as betulinic acid and its acetylated derivatives, 3β-acetoxybetulinic acid, exhibit promising antiplatelet aggregation activity in validated in vitro and ex vivo assays; however, the molecular determinants underlying their direct thrombin inhibition remain unexplored. Results: Docking and MM/GBSA analyses revealed that Baa exhibits the strongest binding affinity (ΔG = −29.58 ± 2.97 kcal/mol), exceeding those of Ba (−20.94 ± 5.81 kcal/mol) and Asp (−18.87 ± 4.18 kcal/mol). Baa forms a highly persistent hydrogen bond with Trp96 (95.5% occupancy) and extensive hydrophobic contacts with Trp215, Leu99, Ile174, and Tyr60A residues defining thrombin’s aryl-binding pocket. MD trajectories demonstrated that Baa binding reduced solvent-accessible surface area (SASA) and residue fluctuations, indicating enhanced structural compaction and stability. In contrast, Ba exhibited weaker, transient hydrogen bonding, while Asp bound primarily near the catalytic triad. The triterpenes exhibit limited oral bioavailability, free PAINS alerts, favourable permeability and metabolic stability. Conclusions: Acetylation at C-3 (acetoxy substitution) substantially enhances thrombin binding via cooperative hydrogen bonding and van der Waals stabilisation, explaining the superior experimental inhibitory potency of Baa. These findings provide a mechanistic framework for structure-guided optimisation of triterpenoid-based thrombin inhibitors and support their further experimental development. Methods: In this study, molecular docking, molecular dynamics (MD) simulations (400 ns), and MM/GBSA free energy analyses were employed to elucidate the binding mechanisms of 3β-acetoxybetulinic acid (Baa), betulinic acid (Ba), and aspirin (Asp) within the thrombin receptor active site. The simulations were explicitly grounded in previously reported chromogenic antithrombin assays and platelet aggregation studies and were designed to mechanistically rationalise the experimentally observed inhibitory potency. Full article

Human alpha-herpesvirus 1 (HSV-1) acute infection culminates in life-long latency in sensory neurons in trigeminal ganglia and certain neurons in the central nervous system. Previously, E2F family members and glucocorticoid receptor (GR) were shown to stimulate HSV-1 and bovine herpesvirus 1 (BoHV-1) replication. Consequently, we hypothesized GR and E2F family members activate certain HSV-l promoters. To test this hypothesis, we determined if four HSV-1 ICP0 cis-regulatory modules (CRM) upstream of the ICP0 promoter were activated by E2F. GR and E2F2, but not E2F1, E2F3a, or E2F3b, cooperatively transactivate the ICP0 CRM-C, but not CRM-A, -B, or -D fragments upstream of a minimal promoter in a luciferase reporter construct. CRM-C sequences contain two E2F consensus binding sites, a GC-rich motif that E2F2 can bind, and a consensus ½ GR response element (GRE) adjacent to the consensus E2F #2 binding site. Mutating the ½ GRE or the 3 E2F binding sites significantly reduced GR- and E2F2-mediated transactivation. Chromatin immunoprecipitation studies revealed E2F2 occupied ICP0 CRM-C sequences during productive infection and mutating the E2F binding sites prevented E2F2 binding. These studies reveal GR and E2F2 transactivate ICP0-promoter activity, which may enhance viral replication in certain cell types. Full article

Botulinum neurotoxins (BoNTs), among the most potent biological toxins, rely on co-produced nontoxic proteins to survive harsh gastrointestinal conditions and achieve efficient systemic dissemination after oral exposure. Recent structural and functional studies have revealed how BoNTs bind to the nontoxic non-hemagglutinin (NTNH) factors to engage in interactions with either OrfXs/P47 or hemagglutinins (HAs) components for systemic dissemination. This review synthesizes recent findings that elucidate the molecular basis of NTNH-specific anchoring to the HA70 triskelion-like element or to the host protease-activated form of OrfX2, thereby highlighting divergent pathways that enhance oral toxicity. We also discuss current perspectives on the molecular mechanisms through which BoNTs, in cooperation with associated nontoxic proteins, are absorbed from the intestine. Full article

Under binding resource constraints and rising environmental pressures, enabling poor smallholders to raise incomes while reducing chemical input use remains a key policy challenge in many developing economies. Drawing on two waves of household survey data from Guangxi, China, this study evaluates the impacts of small-scale beef cattle rearing promoted through an incentive-based subsidy scheme (Yijiang Daibu). Exploiting quasi-experimental variation in household participation, we combine Coarsened Exact Matching (CEM) with household fixed-effects models to address selection bias and time-invariant unobserved heterogeneity. The results show that participation in dispersed cattle rearing significantly increases household welfare (measured by per capita consumption expenditure) while simultaneously reducing chemical fertilizer application, indicating clear economic and environmental co-benefits. Mechanism evidence suggests that substituting cattle manure for chemical fertilizer plays a central role in driving fertilizer reduction. Moreover, access to credit, participation in farmer cooperatives, and internet access further reinforce both welfare gains and manure–fertilizer substitution effects. Overall, incentive-based support for small-scale livestock production, when aligned with local resource endowments, can deliver both welfare gains and greener production outcomes. This study provides micro-level evidence on how well-designed industrial support policies can jointly promote inclusive growth and agricultural sustainability in smallholder-dominated regions. Full article

This article examines in detail Advisory Opinion No. 32, issued by the International Court of Justice (ICJ) in July 2025. The analysis examines how the decision of the International Court of Justice establishes the principle of intergenerational equity as an interpretative criterion for climate obligations, consolidating specific duties of prevention, due diligence, cooperation, mitigation, and adaptation to the consequences of climate change that directly affect present and future generations. This Opinion also designates the 1.5 °C threshold as a central legal benchmark for assessing States’ due diligence in climate mitigation and adaptation and extends state obligations to the regulation of private actors, characterizing climate protection as an erga omnes duty based on human rights and customary international law. Through a doctrinal and institutional legal method, supported by systematic documentary analysis of treaties, case law and soft-law instruments, this study situates the ICJ’s reasoning within the broader evolution of intergenerational equity and explores its implications for state responsibility and climate litigation. It also analyzes the potential of the Advisory Opinion to foster new institutional mechanisms, such as ombudsmen, fiduciary management mechanisms, and intergenerational impact assessments, to represent future generations in climate governance. The main conclusion is that the Advisory Opinion inaugurates a new stage in global climate governance, in which intergenerational equity ceases to be a purely aspirational vision and instead operates as a binding interpretative standard guiding the interpretation and review of existing climate obligations, rather than serving as an autonomous source of new duties. However, its transformative effect will depend primarily on the political will and institutional capacity of states to implement effective mechanisms. Full article

Intracerebral hemorrhage (ICH) is the deadliest subtype of stroke, and its primary harm to the human body arises from the formation of brain hematomas. Promoting microglial-mediated endogenous hematoma clearance has become a key focus in current ICH treatment strategies. Semaphorin 3s (Sema3s) are molecular signals involved in the regulation of the central nervous system, angiogenesis, and microenvironment homeostasis, and they are closely associated with various central nervous system diseases. Hematoma clearance and inflammation regulation are crucial to the role of microglia, yet the mechanisms by which Sema3s regulate microglia after ICH remain unclear. Here, using high-throughput RNA sequencing of a mouse ICH model, we identified that neuron-derived Sema3B is downregulated after ICH. Further mechanistic studies revealed that Sema3B can bind to PlexinA1 on microglia, activating NRF2 to promote the expression of the phagocytic receptor TREM2 and the key hematoma clearance molecule HO-1. Furthermore, Sema3B enhances the interaction between PlexinA1 and TREM2, cooperatively boosting microglial phagocytosis of the hematoma after ICH. Furthermore, Sema3B regulates the M2 polarization of microglia, exerting an anti-inflammatory effect. Our findings suggest that manipulating microglial phagocytosis of hematoma and inflammation suppression via regulation of Sema3B may be a potential strategy for treating patients with ICH. Full article

Cyclic GMP-AMP synthase (cGAS) functions as a DNA sensor in the cytoplasm, triggering immune responses, but it is also translocated to the nucleus, where it is kept catalytically inactive. It consists of an unstructured N-terminal domain of around 160 amino acids, and a larger C-terminal fold comprising the catalytic and DNA-binding domains. Subcellular localization of cGAS is thought to play a key role in its regulation. Here, we make use of heterologous expression in the eukaryotic model Saccharomyces cerevisiae to study cGAS localization in a neutral cellular environment. cGAS-eGFP was mostly found in aggregates at the endoplasmic reticulum–mitochondria encounter structure (ERMES) and juxtanuclear protein quality compartments (JUNQs), although some cells displayed an association between cGAS-eGFP and the plasma membrane. The N-terminus of cGAS fused to eGFP was unable to associate with the plasma membrane by itself, but its deletion dramatically promoted nuclear localization of cGAS-eGFP and decreased cytoplasmic aggregates. A mutant in the DNA-binding Zn-thumb motif of cGAS also showed a more prominent nuclear localization. Thus, both the N-terminal and C-terminal domains of cGAS seem to cooperate to prevent nuclear localization and to maintain cytoplasmic reservoirs of the protein. Heterologous cGAS expression in yeast is a valuable tool for modeling aspects of its subcellular localization and aggregative features. Full article

The development of oxidation-resistant and regenerable materials remains a major challenge for mercury removal from contaminated waters and industrial effluents. In this study, a zwitterionic mesoporous silica gel functionalized with L-cysteine (SG-3PS-Cys) was synthesized, where the thiol group is covalently anchored to the silica framework, preventing oxidative degradation while preserving –NH₃⁺ and –COO⁻ groups for Hg(II) coordination. Spectroscopic analyses (FTIR, XPS, and ¹³C NMR) confirmed the formation of a stable, thiol-free binding environment in which mercury interacts through carboxylate oxygen atoms, electrostatically stabilized by neighboring ammonium groups. The material exhibited a high surface area (134 m² g⁻¹) and uniform mesoporosity (9.8 nm), achieving a maximum Hg(II) uptake of 82.7 mg g⁻¹ at pH 3 with rapid kinetics and cooperative S-type isotherms. The adsorbent retained 72% of its capacity after five regeneration cycles and maintained 38.7% selectivity toward Hg(II) in multicomponent solutions. DFT-based surface energy distribution analysis supported the zwitterionic coordination mechanism, revealing energetically homogeneous and high-affinity binding domains. Beyond its chemical stability, the material introduces a sustainable route for mercury remediation, linking surface energy, electrostatic effects, and porosity to achieve durable performance under acidic and complex aqueous conditions. These findings provide a mechanistic and design framework for the next generation of non-thiol adsorbents capable of selective and reusable Hg(II) removal in environmentally relevant scenarios. Full article

The targeting of cyclin dependent kinase 8 (CDK8) as a potential strategy for cancer treatment has been of interest since the identification of CDK8 as an oncogene product. In this report, we communicate the results of our continuing investigation into the effects of CDK8 inhibitor on triple-negative breast cancer cell line MDA-MB-468. Here, we demonstrate that inhibition of CDK8 decreases phosphorylation of CDK8 substrates E2 promoter binding factor 1 (E2F1) at serine 375 and signal transducer and activator of transcription 3 (STAT3) at serine 727 in these cells. Additionally, luciferase expression was increased in E2F1-responsive luciferase plasmid-transfected cells. Expression of E2F1 transcription target, the proapoptotic protein p73, was increased, and expression of antiapoptotic protein myeloid cell leukemia sequence 1 (Mcl-1) was decreased in CDK8 inhibitor-treated cells. We also demonstrate that knockdown of STAT3 or disruption of STAT3 function in MDA-MB-468 cells opposes the effects of CDK8 inhibition on Mcl-1. Together, these results suggest that CDK8 inhibitor treatment can modulate the expression of apoptosis-related proteins p73 and Mcl-1 and continues to highlight the potential cooperative effects of E2F1 and STAT3 in the activity of CDK8 inhibitor against MDA-MB-468 triple-negative breast cancer cells. Full article