Advanced Science最新文献

Resolving the underlying mechanisms of complex brain functions and associated disorders remains a major challenge in neuroscience, largely due to the difficulty in mapping large-scale neural network dynamics with high spatiotemporal resolution. Multimodal neural platforms that integrate optical and electrical modalities offer a promising approach that surpasses resolution limits. Over the last decade, transparent graphene microelectrodes have been proposed as highly suitable multimodal neural interfaces. However, their fabrication commonly relies on the manual transfer process of pre-grown graphene sheets which introduces reliability and scalability issues. In this study, multilayer graphene microelectrode arrays (MEAs) with electrode sizes as small as 10-50 µm in diameter, are fabricated using a transfer-free process on a transparent substrate for in vitro multimodal platforms. For the first time, the capability of transparent graphene electrodes with a diameter of just 10 µm to reliably capture extracellular spiking activity with high signal-to-noise ratios (up to ∼25 dB) is demonstrated. The recorded signal quality is found to be more limited by the electrode-tissue coupling than the MEA technology itself. Overall, this study shows the potential of transfer-free multilayer graphene MEAs to interface with neural tissue, paving the way to advancing neuroscientific research through the next-generation of multimodal neural interfaces.

Major Innate Disordered Notch2-Associated Receptor 1 (MINAR1) is known to suppress angiogenesis and breast cancer cell growth and is associated with neurological disorders such as epilepsy. However, its neurobiological function remains unclear. Herein, we reveal the specific expression of MINAR1 in somatostatin (SST)- and parvalbumin (PV)-positive interneurons in the mouse forebrain. To explore its functional significance, MINAR1 conditional knockout (CKO) mice were generated from Nestin-Cre mice. During postnatal growth, gross brain morphology and cytoarchitecture were comparable between MINAR1 CKO mice and littermate controls; adult CKO mice exhibited increased vulnerability to pentylenetetrazole (PTZ)-induced seizures, and this phenotype was also present in SST-Cre-mediated CKO mice. Mechanistically, MINAR1 deficiency selectively impaired SST⁺ (but not PV⁺) interneuron excitability, reducing the inhibitory drive toward pyramidal neurons. This defect correlated with decreased G protein alpha S (Gαs) levels and disrupted Gαs-cAMP signaling. Notably, pharmacological activation of adenylate cyclase with forskolin rescued this inhibitory defect. Collectively, our results establish MINAR1 as a key regulator of seizure susceptibility, likely via Gαs-cAMP-dependent modulation of SST⁺ interneurons, offering a molecular framework for developing targeted epilepsy therapies.

Memristive devices are promising building blocks for next-generation memory and neuromorphic circuits in artificial intelligence. Among them, filamentary memristors offer great potential for high-performance and densely integrated systems. However, achieving both low-power operation and long-term cycling stability remains a key challenge. Here, we present a 2D AgCrS₂ volatile memristor that operates via a novel cation-driven valence change mechanism (CVCM). Unlike traditional filament-based conduction, this mechanism enables Ag⁺-driven switching without metal filament growth. The threshold switching process is governed by the reversible intercalation of highly mobile Ag⁺ ions into tetrahedral vacancies between CrS₂ layers, forming and rupturing the highly conductive Ag₂CrS₂ pathway and thus delivering an on/off ratio exceeding 10⁵ at 0.1 V. The AgCrS₂ memristor enables a reduced threshold voltage of 0.2 V and an ultralow power consumption down to 200 pW when the compliance current is further reduced to the nA level. Additionally, the absence of elemental Ag metallization in the switching layer prevents structural degradation, enabling stable operation for over 3 × 10⁵ switching cycles. These findings establish CVCM as a promising way for developing energy-efficient and reliable memristive technologies.

Triple-negative breast cancer (TNBC) remains a major clinical challenge, owing to its molecular complexity, therapeutic resistance, and lack of specific druggable targets. The herpes simplex virus thymidine kinase/ganciclovir (HSV-TK/GCV) suicide gene therapy system has shown promise in cancer treatment, but its clinical applicability is limited by off-target cytotoxicity. Here, we developed a breast cancer-specific suicide gene circuit (BRAS) that integrates the screened cancer-specific promoters RRM2 and MAFK with a microRNA specific to nontumor cells, utilizing the distinct molecular profiles of tumor and nontumor cells. This multi-input logic gate circuit enables precise, specific expression of HSV-TK in breast cancer cells with hardly expression in normal cell. We show that BRAS selectively induces apoptosis in patient-derived TNBC cells while sparing normal cells. In two orthotopic breast cancer models, BRAS significantly suppressed tumor growth without affecting body weight or general health, underscoring its therapeutic potential. This approach intelligently combines molecular signals from both cancerous and healthy cells to precisely regulate therapeutic gene expression, making it a promising platform for the next-generation cancer therapy.

Abdominal aortic aneurysm (AAA) is a life-threatening condition with limited pharmacological therapies. The pathological progression of AAA is closely attributed to the phenotypic switching of vascular smooth muscle cells (VSMCs). NFS1 is the rate-limiting enzyme for the synthesis of iron-sulfur proteins, and the roles of NFS1 in AAA initiation and development have not been explored. Angiotensin II (Ang II) infusion-induced AAA animal model with Apoe^-/- mice combined with human thoracic aorta samples are used to analyze the role of NFS1 in AAA development. Gain or loss-of-function studies are conducted to investigate the regulatory roles of NFS1 on SMC phenotypic switching at both cellular and animal levels. CUT&Tag is further performed for identifying the targets of NFS1 involved in AAA progression. NFS1 is downregulated in the abdominal aortic tissues from both patients and mice. Defects in NFS1 in VSMCs led to enhanced glycolysis and impaired mitochondrial function, contributing to the phenotypic transformation of VSMCs. Mechanistically, NFS1 functions as a transcriptional cofactor of SP2 for inducing the transcription of Idh2. Inhibition of IDH2 partially attenuated the protective effect of NFS1 on AAA. This study uncovers a crucial role for NFS1 in the development and progression of AAA, suggesting that NFS1 may serve as a novel therapeutic and prognostic marker for this condition.

Defensive behaviors against threatening situations are crucial for survival, and maladaptation of neural functions involved in defensive behavior may result in panic-like behavior. Defensive behaviors must be optimized for animals to efficiently avoid danger and maximize their chance of survival. The midbrain periaqueductal gray (PAG) controls defensive behaviors. However, the substrate of dysregulated panic-like defensive responses remains unknown. Using in vivo calcium imaging and recordings in mice, we found that PAG astrocytes are activated during threatening situations and trigger defensive behaviors. Using optogenetic astrocyte modulation and electrophysiological experiments, we provide evidence that PAG astrocyte activation and subsequent ATP release are required for optimal defensive behavior; aberrant activation of PAG astrocytes leads to maladaptive defensive behavior resembling panic-like behavior. Our results suggest that PAG astrocytes are neurobiological substrates underlying defensive dysregulation and might be an important cue in panic-related behaviors via increased calcium activity and ATP release.

Penile squamous cell carcinoma (PSCC) is a rare genitourinary malignancy, and factors of its tumor microenvironment (TME) could serve as prognostic indicators for tumor recurrence and metastasis. Here, we generated a comprehensive single-cell map of PSCC (66 421 cells) and identified 9 distinct cell populations with samples from nine tumor samples and six adjacent normal samples. Among the malignant cells, SEMA3C^high Mals was found to be associated with epithelial-mesenchymal transition. T cells in tumor tissues are in a highly exhausted state, while SPP1^high TAMs were observed to promote tumor progression. Cancer-associated fibroblasts were found to interact with malignant cells to facilitate EMT through several pathways. Notably, there is a specific type of pericyte called POSTN⁺ pericytes, which can promote angiogenesis and extracellular matrix remodeling in PSCC. Finally, SEMA3C was identified as an effective biomarker reflecting cancer stage and microvessel density. Overall, we investigated the heterogeneity of TME from a single-cell perspective and demonstrated that SEMA3C serve as an effective biomarker for predicting lymph node metastasis and prognosis in PSCC. These findings may offer valuable insights for future therapeutic strategies.

The growing demand for sustainable energy solutions has propelled organic solar cells (OSCs) into the spotlight as a promising alternative to traditional inorganic photovoltaics. Despite their advantages-such as lightweight, flexibility, and semitransparency-OSCs face significant challenges related to efficiency and stability. This review provides a comprehensive overview of OSC device fabrication, focusing on the critical roles of photoactive layers, transporting layers, and electrodes in influencing performance. We explore recent advancements in material processing techniques and scalable manufacturing methods, particularly for large-area devices, while addressing key issues like morphology optimization and charge carrier dynamics. By synthesizing current research trends and identifying areas for future investigation, this review aims to inform and inspire ongoing efforts in the field. The unique contribution of this manuscript lies in its detailed analysis of fabrication processes and the potential for enhanced efficiency and application in sustainable energy technologies, offering valuable insights for researchers and industry stakeholders alike.

Tumorigenesis and metastasis are frequently attributed to the intricate interplay between cancer cells and the tumor microenvironment (TME). Comprehending the mechanisms and key regulators of cancer-immune crosstalk in the TME is imperative for developing efficacious immunotherapy. Through a series of in vivo CRISPR screens, we identified tumor-intrinsic ITGB1 as a critical regulator of triple-negative breast cancer (TNBC) development and deciphered its underlying mechanisms. Tumoral ITGB1 facilitated the establishment of pro-tumorigenic TME by orchestrating tumor-associated myeloid populations. Suppressing ITGB1 favored the enrichment of anti-tumorigenic myeloid cells and enhanced infiltration of CD4 and CD8 T cells, culminating in superior antitumor effects. CRISPR scanning pinpointed a previously unrecognized functional domain essential for ITGB1's pro-tumorigenic activity. This domain is distinct from all known ligand-binding sites in ITGB1. An antibody capable of sterically blocking this domain significantly impaired TNBC progression. These findings position tumoral ITGB1 as a promising therapeutic target for reprogramming the TME from a pro- to an anti-tumorigenic state, thereby effectively inhibiting TNBC development. Our study uncovers a novel mechanism of TNBC development and provides a unique therapeutic strategy for targeting ITGB1 in TNBC treatment.

Cell therapy and oncolytic viruses have emerged as promising cancer treatments but face significant challenges in solid tumors due to immune suppression and gene-related toxicities. Here, we selected a probiotic Lactobacillus rhamnosus (LR) that appears to exert oncolytic activity by inducing massive calcium influx, which subsequently triggers a lethal ROS burst in tumor cells. To reduce systemic toxicity and enhance oncolytic efficacy at the tumor site, we designed molecular pili (MP) targeting collagen-rich solid tumors and modified them into LRs via chemical coupling (LR@MP). In mouse models of colorectal cancer and melanoma, LR@MP increased intratumoral accumulation by two times and enhanced bacterial clearance from peripheral tissues. At a safe dose of 4 × 10⁵ CFU, LR@MP inhibited 60%-80% of tumor growth. This dual-optimization strategy provides a new approach for next-generation in vivo therapies and warrants further preclinical evaluation.