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We develop a trajectory-resolved extension of the thermo-field entanglement description for a minimal dissipative two-spin system. For the isolated exchange-coupled model, the intrinsic thermo-field entanglement coefficient is b_0(t)=1/4sin^2(ωt). We promote the corresponding open-system coefficient to a stochastic trajectory observable, b_qe^(ξ)(t)=b_0(t)X_t, where the binary variable X_t specifies whether the trajectory occupies the one-excitation entangling sector or the decayed sector. For a bidirectional time-local jump process 10 and 01, we derive an exact two-time connected correlation function, C_qe(t,s)=b_0(t)b_0(s)S(s)[1-S(s)] exp[-∫_s^t(a(u)+b(u)) du], t≥ s, where S(t)=⟨ X_t⟩. The one-time mean determines the net probability current, Ṡ=J_R-J_F, whereas the normalized two-time correlation determines the rate sum, a+b. Combining the two quantities yields an exact reconstruction of the forward and reverse currents, J_F=S(1-S)q-SṠ, J_R=S(1-S)q+(1-S)Ṡ, with q=-∂_tln[C_qe(t,s)/b_0(t)]. This leads to a three-current decomposition of the mean thermo-field entanglement dynamics into coherent generation, dissipative loss, and memory-induced return. For Markovian amplitude damping the reconstruction gives J_R=0, while in a pure non-Markovian revival interval it gives J_F=0 and J_R=Ṡ>0. The result shows that the mean alone measures only net backflow, whereas mean plus two-time fluctuations resolves hidden bidirectional traffic between system and environment.
Small-molecule drug candidates often encounter challenges related to physicochemical properties, such as poor solubility and stability. Modifying the crystal form of these compounds is a promising approach to overcoming these challenges. Herein, trimethoprim (TMP), a biopharmaceutics classification system (BCS) class II drug with low water solubility, and sulfathiazole (STZ), a polymorphic sulfa drug, were selected as model active pharmaceutical ingredients. A TMP-STZ complex was prepared using liquid-assisted grinding, yielding anhydrous and ethanol-solvated forms. Physicochemical analyses confirmed that the complexes formed stable salt crystals, reducing hygroscopicity and improving thermal stability. An ethanol solvate demonstrated enhanced stability but exhibited a decreased melting point due to desolvation. Single-crystal structure analysis revealed strong hydrogen-bonding interactions between TMP and STZ, contributing to the stability of the crystal. Structural analysis confirmed proton transfer between TMP and STZ, forming a stable salt. Reduced hygroscopicity and improved thermal stability indicate enhanced solid-state robustness of TMP. These results provide a structural basis for controlling the solid-state stability of TMP by salt formation.
We investigate periodically impulsive fractional relaxation as a minimal model of nonlocal dissipative dynamics under repeated external stimulation. The free relaxation law is classical, but the driven problem introduces an additional timescale whose competition with the intrinsic fractional-memory scale generates nontrivial accumulation and crossover behavior. We derive the exact Laplace-domain and time-domain responses, establish the sparse-forcing scaling of the long-time averaged response, and obtain an analytical crossover interval proportional to the inverse fractional power of the relaxation coefficient. To separate established properties of Mittag–Leffler relaxation from the new effects of forcing, we explicitly compare the unforced, impulsive, and periodically driven settings. Extended long-time simulations verify the algebraic tail, while an independent L1 discretization provides a numerical benchmark for the exact solution. We further connect the relaxation kernel to measurable frequency-domain quantities through the Cole–Cole complex susceptibility and discuss interpretations in dielectric and viscoelastic relaxation, anomalous transport, non-Markovian open systems, and intermittent reinforcement. The resulting framework supplies an analytically solvable reference model for memory accumulation under repeated driving. The present analytical framework therefore provides a bridge between fractional relaxation theory and experimentally accessible time- and frequency-domain observables.
Overcoming resistance to immune checkpoint blockade (ICB) therapy in gastric cancer (GC) remains a major clinical challenge. Here, we apply multi-omics profiling, including single-cell RNA sequencing and spatial transcriptomics, to GC tissues from patients receiving neoadjuvant ICB therapy to identify drivers of resistance. We identify tumor-intrinsic Yes-associated protein 1 (YAP1) as a key regulator of immunosuppressive cellular communities that contribute to ICB non-responsiveness. To mitigate the off-target toxicity of verteporfin, a YAP1 inhibitor, we develop macrophage-membrane-camouflaged hollow mesoporous silica nanoparticles (M@O-VNPs) co-loaded with verteporfin and oxaliplatin. This nanoplatform selectively inhibits YAP1, suppresses the CXCL5-CXCR2 axis, and reduces the activity of SPP1+ macrophages. By inducing immunogenic cell death, M@O-VNPs remodel the tumor microenvironment and enhance ICB efficacy while minimizing systemic toxicity. The therapeutic potential of this strategy is supported by synergistic antitumor effects of M@O-VNPs combined with anti-PD-1 therapy in genetically engineered and syngeneic GC models.
This study developed a homogeneous ADC via site-specific conjugation of a potent antitumor agent, a camptothecin derivative, to the N-glycan in the Fc domain of an antibody, achieving a drug-to-antibody ratio (DAR) of 4. The resulting glycan-conjugated ADC exhibited improved thermal stability, reduced aggregation, and reduced premature payload release in human plasma. Despite utilizing the same antibody and payload, this glycan-linked ADC outperformed a clinically approved cysteine-conjugated homogeneous ADC (DAR 8) in vivo.
