Advanced Science最新文献

Mitochondrial dysfunction plays a key role in the pathogenesis of metabolic dysfunction-associated steatohepatitis (MASH). As is known to play a key role in mitochondria, ECSIT, in relation to oxidized mitochondrial DNA is still unclear. This study examines mitochondrial ECSIT expression in MASH mouse models. Mitochondria-targeted ECSIT transgenic (ECSIT^MTG) mice and wild-type (WT) controls are fed a high-fat, high-cholesterol (HFHC) diet for 16 weeks or a methionine- and choline-deficient (MCD) diet for 8 weeks. Results demonstrate that mitochondrial ECSIT overexpression alleviates diet-induced MASH phenotypes. Mechanistically, we demonstrate that mitochondrial ECSIT promotes the localization of the deubiquitinase OTUD3 to mitochondria. OTUD3 then stabilizes SIRT3 via deubiquitination, thereby inhibiting mtDNA oxidation and alleviating steatosis-induced metabolic disorders. Overall, these findings indicate that mitochondrial ECSIT protects against MASH progression by stabilizing SIRT3, suggesting its potential as a therapeutic target.

Superlattices composed of nanometer-thick constituent layers with smooth interfaces exhibit a minimum in their cross-plane thermal conductivity as the period thickness is increased, marking a transition from coherent to incoherent phonon transport. Previous attempts to explain this minimum using the phonon Boltzmann transport equation (BTE) required an ad hoc diffuse interface scattering model due to the BTE's inherent particle-based framework. We apply the phonon Wigner transport equation (WTE) to study superlattices with smooth interfaces, a framework that inherently includes both the particle-like (i.e., population-channel) and wave-like (i.e., coherence-channel) contributions to thermal conductivity. Our results reveal that the WTE coherence channel is responsible for the thermal conductivity increase in the incoherent regime. The two distinct phonon wave effects in superlattices-the coherent transport induced by wave interference at the interfaces and the WTE coherence-channel transport enabled by tunneling between phonon modes-are examined in detail, along with their connection to the interfacial vibrational modes.

Bone metastasis is a devastating consequence of lung cancer. However, the key metabolic factors that determine the risk of bone metastasis remain unclear. Here, we show that glucose transporter type 3 (SLC2A3) is notably overexpressed by lung cancer bone metastatic cells and tissues, as a facilitator of lung cancer bone metastasis. Additionally, SLC2A3 promotes glucose metabolism, which promotes tumor cell proliferation and metastasis via lactate-mediated p53 lactylation. Within the tumor microenvironment, cancer cells serve as the primary source of secreted lactate, which induces protumor bone metastasis via osteoclast differentiation and suppresses the antitumor activity of CD8⁺ T cells. Subsequently, we developed Paris saponin VII, a SLC2A3 inhibitor that effectively suppressed bone metastasis in lung cancer bone metastasis mouse models and patient organoids. Notably, either inhibition of SLC2A3 or lactate limitation improved the tumor response and increased the sensitivity of lung cancer bone metastases to PD-1 treatment. Collectively, our findings highlight that targeting SLC2A3-mediated lactate metabolism, either alone or in combination with PD-1 inhibition, is a potential strategy for treating lung cancer bone metastasis.

Organ size homeostasis plays vital roles in maintaining the normal growth and development in both animals and plants. Grain size is an important agronomic trait for stable yield, quality, domestication, and breeding in crops, but the molecular mechanism underlying final size homeostasis remains unclear. Here, we identified three genes, OsGRX8, OsbZIP47 and OsbZIP08, underlying grain-length variation by genome-wide association study (GWAS) in rice. We confirmed that OsGRX8, OsbZIP47 and OsbZIP08 interact with each other and transcription factors OsbZIP47 negatively and OsbZIP08 positively regulate the expression of the downstream glutaredoxin-encoding gene OsGRX8. The binding ability of OsbZIP08 on the promoter of OsGRX8 in indica is higher than that in japonica, leading the differential expression of OsGRX8 between two subspecies. We further revealed a natural negative feedback regulatory mechanism for grain size homeostasis: OsGRX8 controls the reduction modification of OsbZIP47 thereby increasing OsbZIP47-OsbZIP08 interaction in a redox-dependent way or directly interacts with OsbZIP08 in a redox-independent way to inhibit the transcriptional activity of OsbZIP08 on OsGRX8. Finally, we revealed that two self-regulatory haplotypes (SRHs), caused by co-selected variations of the three genetically unlinked genes which formed the negative feedback loops, showed distinctive indica-japonica differentiation and large genetic contribution to key yield traits. Our findings provided the evolutional OsGRX8-(OsbZIP47)-OsbZIP08-OsGRX8 regulatory loops for synergistically controlling grain size homeostasis by fine-tuning OsGRX8 self-expression, offering a novel case for uncovering QTL interactions underlying genetic diversity of important traits in crops.

CuCrP₂S₆ is a van der Waals multiferroic where the tunable Cu⁺ sublattice underpins its exceptional ferroelectric and electronic switching properties. Yet, the microscopic mechanism governing Cu⁺ ordering has remained elusive. Here, we combine single-crystal X-ray and neutron diffraction with pair distribution function analysis to uncover a temperature-driven evolution of Cu⁺ ordering, giving rise to an incommensurate quasi-antipolar phase between the paraelectric and antiferroelectric states. The modulation originates from correlated Cu⁺ occupancy redistribution coupled to breathing distortion of surrounding S₃ triangles, establishing a symmetry-adapted lattice distortion mode. Diffuse scattering persisting over 35 K above the transition confirms that the structural instability follows an order-disorder mechanism. The spontaneous off-centering of Cu⁺ positions CuCrP₂S₆ as a model platform for correlated order-disorder phenomena in 2D layered ferroics, and provides design principles for next-generation memory and logic devices.

Liquid-liquid phase separation (LLPS) of polymers underlies the formation of biomolecular condensates and offers a versatile route to functional soft materials. Traditionally, LLPS is attributed to changes in solvent quality or associative coacervation, but here a purely entropic connectivity-driven mechanism is demonstrated: reversible crosslinking. Using coarse-grained simulations of a minimal bead-spring model in good solvent, it is shown that transient, pairwise crosslinks alone can drive phase separation at ultralow polymer densities, yielding highly swollen, water-rich condensates. The phase behavior exhibits closed-loop coexistence and re-entrant percolation. This is captured quantitatively by a mean-field Semenov-Rubinstein theory with a single fit parameter, the effective repulsion parameter. Notably, phase boundaries are largely robust to rearrangements of crosslinkable domains along the sequence; only highly blocky sequences appreciably reduce the phase separation region and can even convert condensates into micelles or connected micelle networks. These results establish an entropy-enabled mechanism for mesoscale organization and suggest routes to programmable, membraneless materials in synthetic and RNA-protein contexts.

Solution-processed metal halide perovskite transistors possess intrinsic characteristics that hold promise for integration with n-type semiconductors such as fullerene (C₆₀) in CMOS-like circuits. Yet, their performance and stability remain inferior to n-type counterparts due to inefficient in-plane charge transport and defect-induced instabilities. This study proposes a rational additive engineering strategy using 4,8-dihydrobenzo[1,2-b:4,5-b']dithiophen-4,8-dione (BDTD) to regulate nucleation and crystallization of MA_0.4FA_0.6Sn_0.5Pb_0.5I₃ films. BDTD alleviates microstrain, suppresses Sn⁴⁺-related defects, and passivates undercoordinated Sn and Pb ions, forming smoother films with enlarged grains. Compared to control devices, the optimized transistor achieves an increase by an order of magnitude in hole mobility (4.1 vs. 0.38 cm² V^-1 s^-1) and a substantially improved on/off ratio (1.8 × 10⁵ vs. 3.1 × 10⁴). Moreover, the BDTD-treated transistors exhibit excellent reproducibility and operational stability under inert conditions without encapsulation. Furthermore, surface passivation using tetrabutylammonium hexafluorophosphate (TBAPF6) reduces interfacial traps, improving reliability and lowering the threshold voltage from 9.89 to 3.6 V. Finally, integration with an n-type C60 transistor yields a functional perovskite-C60 inverter, demonstrating strong potential for complementary logic applications. This work highlights the synergistic role of additive and interfacial engineering in overcoming intrinsic limitations of Sn-Pb perovskites, offering a viable pathway toward practical perovskite-based complementary electronics.

Tumor metastasis represents a major determinant of prognosis in ovarian cancer. Accumulating evidence has demonstrated that the glycosylation of secretome proteins regulates cell communication in the tumor microenvironment, thereby affecting tumor metastasis; however, the underlying regulatory mechanisms remain unclear. In this study, we observed markedly elevated glycosylation levels in metastatic ovarian cancer and identified GALNT10 as a key glycosyltransferase that promotes EMT of ovarian cancer cells. Furthermore, GALNT10 enhances the extracellular secretion of IGFBP7 through O-GalNAc glycosylation modification at the T188 site. IGFBP7 subsequently interacts with the CD93 receptor on endothelial cells, leading to vascular remodeling characterized by abnormal vascular formation and impaired vascular maturity. Moreover, we identified the GALNT10 inhibitor Luteolin, which effectively suppresses ovarian cancer metastasis, modulates the immunosuppressive tumor microenvironment through tumor vascular-immune crosstalk, and exhibits synergistic effects with anti-PD1 therapy. Collectively, our findings indicate that GALNT10 facilitates ovarian cancer metastasis through the induction of tumor cell EMT and tumor vascular dysfunction, suggesting that GALNT10 inhibitors represent a promising avenue for the development of novel therapeutic strategies in ovarian cancer.

Pancreatic neuroendocrine neoplasms (pNEN) are rarely encountered, accounting for about 2% of all pancreatic neoplasms. Disease progression is frequently observed as recurrence or distal metastasis. Mechanisms underlying pNEN progression are still poorly investigated, and treatments against pNEN are challenging due to the pronounced neoplastic heterogeneity. Here, by performing clinicomolecular analysis, we report a novel mechanism of positive regulatory circuit between Cav1.2-mediated calcium signaling and epigenetic control by H3K27 acetylation (H3K27ac). Tumor-cell-specific expression of Cav1.2 strongly contributes to disease progression and correlates with malignant biological behaviors of pNEN. Moreover, we find calcium channel blockers (CCBs), especially amlodipine, remarkably inhibit pNEN progression in vitro and in vivo. Clinically, administration of CCBs correlates with better progression-free survival (PFS) and a lower rate of distal metastasis. Our work uncovers the novel mechanism of the Cav1.2-epigenetic circuit and expands the scope of therapeutic strategy for further investigation in pNEN.

2D Ti₃C₂T_x MXenes are of great potential in catalysis, energy storage, and conversion, yet the controlled tuning of their structure, intrinsic activity, and stability remains a challenge. Herein, we address this challenge through a dual-modification strategy, synthesizing a Cl-terminated MXene/MAX (Ti₃C₂Cl_x/Ti₃ZnC₂) heterostructure by a dynamic etching approach for efficient electrocatalytic nitrogen reduction reaction (NRR). This catalyst achieves an NH₃ yield of 20.1 µg h^-1 mg^-1 and a Faradaic efficiency of 38.1% at -0.2 V vs. RHE in 0.1 m KOH electrolyte, with high stability for over 70 h, positioning it among the top-performing MXene-based NRR electrocatalysts. Experimental and theoretical analyses demonstrate that the Ti₃C₂Cl_x/Ti₃ZnC₂ heterostructure modulates the electronic structure of Ti sites, thus optimizing the intermediate adsorption and reducing the energy barrier of *NH₂ → NH₃ conversion in the distal pathway to 0.7 eV. The Zn-N₂ battery assembled with Ti₃C₂Cl_x/Ti₃ZnC₂ can reach a peak power density of 36.5 µW cm^-2, with an NH₃ yield of 13.1 µg h^-1 mg^-1. This study has demonstrated that the dual modification strategy involving surface terminations regulation and heterostructure construction is effective to improve both NRR activity and stability of MXene-based electrocatalysts, which is crucial for efficient NH₃ production and energy generation. This improvement paves the way for efficient ammonia and energy co-generation, providing a viable materials design strategy and deeper mechanistic insights.