Advanced Science最新文献

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.

Ankylosing spondylitis (AS) is an osteoimmune disease characterized by pathological enthesitis related to mechanical strain. However, the cell interactions and molecular mechanisms of AS enthesitis are still unclear. Herein, we constructed a hind paw loading/unloading model using experimental spondyloarthritis SKG mice, and generated a single-cell RNA sequencing atlas of mechanical strain-related AS enthesitis. In this context, a disease-specific subpopulation of SDC1⁺ sheath fibroblasts was identified to arise under mechanical strain, and these cells secreted higher levels of CXCL5 to recruit and promote the activation of CXCR4^hi neutrophils, which exacerbated CXCR4^hi neutrophil-mediated enthesitis by increasing their neutrophil extracellular trap formation. Administering CXCL5 neutralizing antibody relieved disease progression in SKG mice. Additionally, computational trajectory analysis revealed a distinct fate branch of the mechanical strain-responding SDC1⁺ sheath fibroblasts under the control of SOX5-mediated enhancers and super-enhancers. Specifically inhibiting SOX5 in enthesis fibroblasts via rAAV9.HAP-1 carrying a shRNA targeting Sox5 blocked the generation of SDC1⁺ sheath fibroblasts in response to mechanical strain and markedly reversed the development of CXCR4^hi neutrophil-mediated enthesitis. This study identifies the specific cell interactions and molecular mechanisms involved in mechanical strain-related AS enthesitis, therefore contributing to the understanding of AS pathogenesis and providing insight into potential clinical treatments for AS.

Few nonhuman primates inhabit high-latitude regions that pose significant adaptive challenges. The Tibetan macaque (Macaca thibetana) represents a rare primate species entirely distributed north of the Tropic of Cancer. To investigate the genetic basis underlying its adaptation to high latitudes, we generated a refined Tibetan macaque reference genome (99.41% completeness). Genomic analyses identified a species-specific homozygous mutation (Pro71Thr) in the TBX6 gene, which potentially explains their characteristic shortened tail morphology. Functional validation using CRISPR-Cas9-edited mice demonstrated that this mutation reduces caudal vertebrae count, providing a mechanistic basis for the shortened tail. Quantitative CT revealed that Tibetan macaques accumulated approximately 9.3-fold more abdominal fat than rhesus macaques. Genomic analysis uncovered enhanced lipid metabolic capacity supported by multiple sources of evidence: (1) positive selection on genes associated with lipid storage (DGAT2, DYSF, CAV1), adipogenesis (PRKD1), and appetite regulation (LEPR); (2) a 390-bp deletion in CPE; (3) expansions of gene families on oxidative phosphorylation and gluconeogenesis/glycolysis. These genetic variations may account for the marked differences in adipose tissue gene expression between the two macaque species. The shortened tail and increased fat accumulation represent key adaptations for thermoregulation and energy conservation in high-latitude habitats. Notably, all Tibetan macaque populations experienced long-term selection pressures from cold at high latitudes, which have not only shaped distinctive adaptive traits, but may also render the species particularly vulnerable to contemporary climate warming, particularly for the eastern populations.

Solid-state nanopore arrays are emerging as powerful tools for label-free, ultrasensitive biosensing, yet their implementation has been constrained by inter-pore crosstalk and limited fabrication uniformity. A multilayer Al₂O₃/Au/Si₃N₄ nanopore architecture, produced via helium ion beam lithography, is introduced to address these limitations through structural and materials-level innovation. Finite-element analysis identifies a critical inter-pore spacing approximately 20 times the pore radius as necessary to minimize electric field coupling, enabling rational array design. The membrane structure incorporates a dielectric Al₂O₃ layer for electrical isolation and an intermediate gold layer for site-specific aptamer immobilization, confining molecular recognition to the nanopore interior. Arrays with ∼30 nm pores and <5% size variation achieve 300 nm spacing and support statistically independent, parallel signal acquisition. Diverse nanopore arrays with 75 nm pores and 800 nm spacing are utilized for the specific detection of alpha-fetoprotein. Detection of alpha-fetoprotein demonstrates label-free sensing at concentrations down to ∼3 fM across six orders of magnitude in dynamic range. This platform defines a closed-loop pathway from theoretical modeling to scalable fabrication, establishing a foundation for rational design and high-throughput deployment of solid-state nanopore biosensors.

Synthesizing MOF-derived carbons with not only tunable and uniform particle sizes but also ordered tubular mesoporous structures remains challenging. Moreover, the lack of precise morphological control makes it hard to clarify the relationships between structure and catalytic activity, limiting the rational design of MOF-derived electrocatalysts with breakthrough performance. This study successfully prepares ordered mesoporous Fe/MOF-545-x rod-shaped precursors with tunable lengths via a one-step modulation approach. After direct carbonization, Fe/MNC-x retains the rod-shape, mesoporous structures, and well-dispersed Fe-N_x active sites. Considering that the axis length is the most significant variable for the Fe/MNC-x series, they are promising model electrocatalysts to reveal the relationship between the particle size and utilization efficiency of electrocatalytic active sites in ORR. The electrochemical result shows that Fe/MNC-250 nm, which has the shortest length, displays a superior activity (E_1/2 = 0.917 V in alkaline and E_1/2 = 0.814 V in acidic electrolytes), due to the higher electrochemical surface area, lower charge transfer resistance, and a higher efficient active site density (1.27 ± 0.26 × 10^{1 9} sites g^{- 1}) estimated by in situ nitrite stripping technique. The fuel cell assembled using Fe/MNC-250 nm possesses an excellent power density of 521.16 mW cm^{- 2}. This work provides a simple strategy for regulating the particle sizes of ordered mesoporous MOF precursors and the derived carbon-based electrocatalysts for high-performance PEMFCs.

Liver fibrosis, driven by excessive collagen synthesis following hepatic injury, poses a significant health challenge. SLC39A13/ZIP13, a recently characterized intracellular iron transporter, is shown to provide iron to the ER/Golgi to help catalyze procollagen hydroxylation during collagen maturation. Here, we investigate whether ZIP13 plays a role during hepatic fibrogenesis modeled by CCl₄ stress or other inducers. ZIP13 expression is induced during liver fibrosis. Germline disruption of Zip13 dramatically reduces fibrosis. Surprisingly, these mice do not benefit from ZIP13 loss after CCl₄ challenge; instead, they are more susceptible to CCl₄ toxicity even with substantially less fibrosis development. This elevated vulnerability turns out to be a consequence of ferroptosis in the hepatocyte due to increased cytosolic iron after ZIP13 loss. Tissue-specific knockout (KO) reveals that hepatic stellate cell (HSC) KO of Zip13 attenuates liver fibrosis progression without adverse effects. Leveraging these findings, HSC-targeted delivery of Zip13-siRNA demonstrates robust efficacy and safety in preclinical fibrosis models. These results provide critical insights into the complex role of iron in liver fibrosis, and indicate that targeting iron homeostasis via ZIP13 in the HSC may be effective to mitigate fibrogenesis by simultaneously suppressing the synthesis of multiple kinds of collagen while minimizing possible side effects.

Proteolysis targeting chimeras (PROTACs) have emerged as an intriguing therapeutic strategy for targeted protein degradation (TPD), functioning as heterobifunctional compounds that induce the redirection of E3 ligases to ubiquitinate neo-substrates for proteasomal degradation. Despite the presence of over 600 E3 ligases, only a limited subset has been successfully harnessed for TPD. This study demonstrates that S-phase kinase-associated protein 2 (SKP2), the substrate receptor of the Cullin RING ligase 1 (CRL1) subfamily, can be employed for TPD using a selective, non-covalent SKP2 recruiter, SL1. We designed and synthesized SKP2-recruiting degraders by linking SL1 to the BRD4 inhibitor JQ1. These compounds effectively induce BRD4 degradation in MV-4-11 cells, with the most potent compound 2-1 exhibiting a half-maximal degradation (DC₅₀) of 298 nM, validating their potential as PROTACs. Mechanistic investigations show that 2-1 promotes BRD4 ubiquitination and subsequent degradation in a proteasome- and neddylation-dependent manner, which can be rescued by SKP2 knockdown and knockout. We further demonstrate that SKP2-directed PROTACs effectively degrade Androgen receptor (AR) in 22RV1 cells. These findings emphasize that SKP2, frequently overexpressed in various tumor cells, can be successfully exploited for TPD through non-covalent PROTACs, expanding the pool of E3 ligases available for potential therapeutic applications.