Yue Yu

Alternative lengthening of telomeres (ALT) is a telomerase-independent telomere maintenance mechanism active in a subset of aggressive cancers. Targeting ALT remains a therapeutic challenge due to its complexity and lack of clinically specific inhibitors. Here, we report that the natural compound Withaferin A (Wi-A) selectively impairs ALT cancer cell viability by disrupting Rad51-dependent homologous recombination (HR), a critical pathway for resolving telomeric replication stress and DNA damage in ALT cells. Comparative analysis using isogenic ALT and telomerase-positive cells revealed that Wi-A selectively downregulates PI3K/AKT signaling and induces replication stress, telomeric DNA damage, and DNA repair deficiency in ALT cells. Mechanistically, Wi-A destabilizes the Rad51 nucleoprotein filament and promotes Rad51 degradation via a RFWD3-dependent mechanism localized within ALT-associated PML bodies (APBs). Depletion of either PML or RFWD3 rescues Rad51 stability and reduces sensitivity of ALT cells to Wi-A. Together, these findings uncover a novel mechanism by which Wi-A selectively targets ALT cells through Rad51 destabilization within APBs, highlighting its potential to exploit ALT-specific vulnerabilities in telomere maintenance and DNA repair for therapeutic development.

Biothiol assays offer vital insights into health assessment and facilitate the early detection of potential health issues, thereby enabling timely and effective interventions. In this study, we developed ultrasmall CuMn-Histidine (His) nanozymes with multiple enzymatic activities. CuMn-His enhanced peroxidase (POD)-like activity at neutral pH was achieved through hydrogen bonding and electrostatic effects. In addition, CuMn-His possesses laccase (LAC)-like and superoxide dismutase (SOD)-like activities at neutral pH. Based on three different enzyme mimetic activities of CuMn-His at neutral pH, the colorimetric sensing array without changing the buffer solution was successfully constructed. The array was successfully used for the identification of three biothiols, glutathione (GSH), cysteine (Cys), and homocysteine (Hcy). Subsequently, excellent application results were shown in complex serum and cellular level analyses. This study provides an innovative strategy for the development of ultrasmall bimetallic nanozymes with multiple enzymatic activities and the construction of colorimetric sensing arrays.

The baculovirus expression vector system (BEVS) has been widely used for heterologous protein expression due to its powerful functionality and easy access to commercial expression vectors. Currently, most laboratories prefer two strategies for protein production using BEVS. One is recombinant bacmid based on transposition in Escherichia coli (e.g., Bac‐to‐Bac), and another is homologous recombination in insect cells (e.g., flashBac). In this manuscript, a rapid and simple YBac system was established. This novel system uses an Ac99KO bacmid as a virus vector and co‐transfected into Spodoptera frugiperda 9 (Sf9) cells with a donor plasmid capable of recombination into Ac42 loci that carry the genes of interest (GOIs) along with the complete Ac99 fragment. Based on the intracellular homologous recombination system, the production of foreign proteins was achieved by the complementation of the Ac99 gene together with the insertion of GOIs. In this study, the human thyroid peroxidase (hTPO) and porcine epidemic diarrhea virus‐like particles (PEDV VLPs) were successfully expressed using the YBac system. The entire process was shortened to 10 days, and the components involved in the system could be easily prepared in the laboratory, suggesting that the YBac system may have great potential in the production of heterologous proteins.

Developing agents that can accurately differentiate tumors from normal healthy tissues is of utmost importance for safe cancer therapy. Active targeting has been considered as an effective technique for tumor recognition. In this work, we demonstrate a folate-functionalized nanoscale covalent organic framework (FATD nCOF) highly specific to cancer cells through active targeting of their enriched folate receptors (FRs). The FATD nCOF prepared by simple post-synthetic modification of the COF surface defeats disperses well in water and exhibits a high loading capacity for various anticancer drugs. The biocompatible FATD nCOF is selectively internalized by FR-harboring cancer cells and consequently augments the efficacy of the loaded drug, Withaferin A (Wi-A), for targeted cancer cell killing. In biomolecular mechanism studies, Wi-A-loaded FATD (FATD@Wi-A) nanocomposites show remarkably a higher rate of apoptosis in FR-enriched cancer cells. Comparative analyses of FR-positive and FR-negative tumor xenografts reveal enhanced selective antitumor activity of FATD@Wi-A nanotherapeutics. Taken together, the study findings suggest that FATD nCOF holds great promise for active targeting of tumors in vivo. Our simple yet effective technology might be valuable for creating new state-of-the-art COFs for chemical and biomedical applications.

We present a data-driven workflow to biological tissue modeling, which aims to predict the displacement field based on digital image correlation (DIC) measurements under unseen loading scenarios, without postulating a specific constitutive model form nor possessing knowledge of the material microstructure. To this end, a material database is constructed from the DIC displacement tracking measurements of multiple biaxial stretching protocols on a porcine tricuspid valve anterior leaflet, with which we build a neural operator learning model. The material response is modeled as a solution operator from the loading to the resultant displacement field, with the material microstructure properties learned implicitly from the data and naturally embedded in the network parameters. Using various combinations of loading protocols, we compare the predictivity of this framework with finite element analysis based on three conventional constitutive models. From in-distribution tests, the predictivity of our approach presents good generalizability to different loading conditions and outperforms the conventional constitutive modeling at approximately one order of magnitude. When tested on out-of-distribution loading ratios, the neural operator learning approach becomes less effective. To improve the generalizability of our framework, we propose a physics-guided neural operator learning model via imposing partial physics knowledge. This method is shown to improve the model's extrapolative performance in the small-deformation regime. Our results demonstrate that with sufficient data coverage and/or guidance from partial physics constraints, the data-driven approach can be a more effective method for modeling biological materials than the traditional constitutive modeling.

Shengxian Decoction (SXT) is a traditional Chinese medicine prescription comprising several anti-cancer medicinal herbs. However, the anti-cancer effect of SXT has rarely been reported. Herein, we explored the therapeutic potential of SXT for the treatment of lung adenocarcinoma (LUAD). High-performance liquid chromatography analysis of crude SXT extract revealed the abundance of mangiferin, an established anti-cancer compound. The serum pharmacological evaluation revealed that serum SXT suppressed A549 lung cancer cell proliferation in vitro. The tumor-inhibitory activity of SXT was confirmed in vivo via tumor formation assays in nude mice. We applied biochemical, histopathological and imaging approaches to investigate the cellular targets of SXT. The results indicated that the treatment with SXT induced tumor necrosis, and downregulated hypoxia-inducible factor 1 alpha in the serum. In vivo biosafety assessment of SXT revealed low levels of toxicity in mouse models. Our study provides the first scientific evidence that SXT effectively represses cancer cell growth and, thus, may serve as a safe anti-cancer agent for LUAD treatment.

Conjugated organic polymers (COPs) have been excellent candidates because the conjugated structure occupied π structure that is useful to develop light‐emitting materials. However, most COPs emitt weak luminescence owing to the H‐aggregation effect. Light‐emitting conjugated organic polymers (LCOP‐1) possess rich butyl groups anchored in the skeleton to enhance light‐emitting activity via reducing the H‐aggregation effect. Owing to abundant hydroxyl and nitrogen atoms, LCOP‐1 exhibits high sensitivity, selectivity, and fast response to Cu²⁺ ions within 1 min in comparison with the cations of Na⁺, Mg²⁺, Al³⁺, Zn²⁺, Cd²⁺, Ni²⁺, Cr³⁺, Hg²⁺, Fe³⁺, Fe²⁺, Pb²⁺, Co²⁺, etc. The detection limit can be down to nanomolar. Moreover, the sensor exhibits detection toward Cu²⁺ ions via a naked eye colorful change from pale‐yellow to yellowish‐brown. Furthermore, the light‐emitting probe also successfully achieves the detection of Cu²⁺ ions in cells without cytotoxicity, indicating its great potentials in biological function.