Background: Chimeric antigen receptor (CAR)-based immune cell therapies attack neighboring cancer cells after receptor recognition but are unable to directly affect distant tumor cells. This limitation may contribute to their inefficiency in treating solid tumors, given the restricted intratumoral infiltration and immunosuppressive tumor microenvironment. Therefore, cell–cell fusion as a cell-killing mechanism might develop a novel cytotherapy aimed at improving the efficacy against solid tumors. Methods: We constructed a fusogenic protein, fusion-associated small transmembrane (FAST) p14 of reptilian reovirus, into cancer cells and mesenchymal stem cells (MSCs), which cocultured with various colon cancer cells and melenoma cells to validate its ability to induce cell fusion and syncytia formation. RNA sequencing, quantitative reverse transcription polymerase chain reaction, and Western blot were performed to elucidate the mechanism of syncytia death. Cell viability assay was employed to assess the killing effects of MSCs carrying the p14 protein (MSCs-p14), which was also identified in the subcutaneous tumor models. Subsequently, the Tet-On system was introduced to enhance the controllability and safety of therapy. Results: Cancer cells incorporated with fusogenic protein p14 FAST from reovirus fused together to form syncytia and subsequently died through apoptosis and pyroptosis. MSCs-p14 cocultured with different cancer cells and effienctly induced cancer cell fusion and caused widespread cancer cell death in vitro. In mouse tumor models, mMSCs-p14 treatment markedly suppressed tumor growth and also enhanced the activity of natural killer cells and macrophages. Controllability and safety of MSCs-p14 therapy were further improved by introducing the tetracycline-controlled transcriptional system. Conclusion: MSC-based cytotherapy carrying viral fusogenic protein in this study kills cancer cells by inducing cell–cell fusion. It has demonstrated definite efficacy in treating solid tumors and is worth considering for clinical development.

Sepsis-associated encephalopathy (SAE) is a severe and frequent septic complication, characterized by neuronal damage as key pathological features. The astrocyte–microglia crosstalk in the central nervous system (CNS) plays important roles in various neurological diseases. However, how astrocytes interact with microglia to regulate neuronal injury in SAE is poorly defined. In this study, we aim to investigate the molecular basis of the astrocyte–microglia crosstalk underlying SAE pathogenesis and also to explore the new therapeutic strategies targeting this crosstalk in this devastating disease. We established a human astrocyte/microglia coculture system on a microfluidic device, which allows real-time and high-resolution recording of glial responses to inflammatory stimuli. Based on this microfluidic system, we can test the responses of astrocytes and microglia to lipopolysaccharide (LPS) treatment, and identify the molecular cues that mediate the astrocyte–microglia crosstalk underlying the pathological condition. In addition, the SAE mouse model was utilized to determine the state of glial cells and evaluate the therapeutic effect of drugs targeting the astrocyte–microglia crosstalk in vivo. Here, we found that activated astrocytes and microglia exhibited close spatial interaction in the SAE mouse model. Upon LPS exposure for astrocytes, we detected that more microglia migrated to the central astrocyte culture compartment on the microfluidic device, accompanied by M1 polarization and increased cell motility in microglia. Cytokine array analysis revealed that less interleukin 11 (IL11) was secreted by astrocytes following LPS treatment, which further promoted reprogramming of microglia to pro-inflammatory M1 phenotype via the nuclear factor-κB (NF-κB) signaling pathway. Intriguingly, we found that IL11 addition markedly rescued LPS-induced neuronal injuries on the microfluidic system and brain injury in the SAE mouse model. This study defines an unknown crosstalk of astrocyte–microglia mediated by IL11, which contributed to the neuropathogenesis of SAE, and suggested a potential therapeutic value of IL11 in the devastating disease.

Na_v1.7 is considered a promising target for developing next-generation analgesic drugs, given its critical role in human pain pathologies. Although most reported inhibitors with strong in vitro activity and high selectivity share the aryl sulfonamide scaffold, they failed to demonstrate marked clinical efficacy. Therefore, exploring new Na_v1.7-selective antagonists is quite urgent to the development of next-generation analgesic drugs. Here, we report a highly effective 1H-indole-3-propionamide inhibitor, WN2, identified through an integrated drug discovery strategy. Notably, the structure of WN2 is quite different from previously reported aryl sulfonamide inhibitors. Molecular dynamics simulations and experimental findings reveal that the R configuration of WN2 (WN2-R) is the preferred form (IC₅₀ = 24.7 ± 9.4 nM) within the VSDIV pocket of Na_v1.7. WN2-R exhibits impressive analgesic effects in acute and chronic inflammatory pain, as well as neuropathic pain models in mice. Additionally, it displays favorable subtype selectivity and positive drug safety in acute toxicity studies. Pharmacokinetic studies indicate that WN2-R has high bioavailability (F = 20.29%), highlighting its considerable potential for drug development. Our study establishes WN2-R as a novel Na_v1.7-selective inhibitor with a unique structural scaffold, offering a promising candidate for the next generation of analgesic drugs.

Gut microbiota is crucial for protecting the homeostasis of immune locally and systemically, and its dysbiosis is essentially correlated to tumorigenesis, cancer progression, and refractoriness to cancer treatments, including the novel immunotherapy. Increasing evidence unravel the intricate role of gut microbiota in reshaping tumor microenvironment and affecting the efficacy and toxicities of immunotherapy, which shed more light on the future applications of gut microbiota in efficacious biomarker and combination treatment of immunotherapy. To better grasp the underlying crosstalk between gut microbiota and immunotherapy, more experimental and clinical trials are indispensable for the customized gut microbiota-based treatments in cancer patients undergoing immunotherapy.

Background and Aims: Metabolic syndrome (MS) is a progressive metabolic disease characterized by obesity and multiple metabolic disorders. Tryptophan (Trp) is an essential amino acid, and its metabolism is linked to numerous physiological functions and diseases. However, the mechanisms by which Trp affects MS are not fully understood. Methods and Results: In this study, experiments involving a high-fat diet (HFD) and fecal microbiota transplantation (FMT) were conducted to investigate the role of Trp in regulating metabolic disorders. In a mouse model, Trp supplementation inhibited intestinal farnesoid X receptor (FXR) signaling and promoted hepatic bile acid (BA) synthesis and excretion, accompanied by elevated levels of conjugated BAs and the ratio of non-12-OH to 12-OH BAs in hepatic and fecal BA profiles. As Trp alters the gut microbiota and the abundance of bile salt hydrolase (BSH)-enriched microbes, we collected fresh feces from Trp-supplemented mice and performed FMT and sterile fecal filtrate (SFF) inoculations in HFD-treated mice. FMT and SFF not only displayed lipid-lowering properties but also inhibited intestinal FXR signaling and increased hepatic BA synthesis. This suggests that the gut microbiota play a beneficial role in improving BA metabolism through Trp. Furthermore, fexaramine (a gut-specific FXR agonist) reversed the therapeutic effects of Trp, suggesting that Trp acts through the FXR signaling pathway. Finally, validation in a finishing pig model revealed that Trp improved lipid metabolism, enlarged the hepatic BA pool, and altered numerous glycerophospholipid molecules in the hepatic lipid profile. Conclusion: Our studies suggest that Trp inhibits intestinal FXR signaling mediated by the gut microbiota–BA crosstalk, which in turn promotes hepatic BA synthesis, thereby ameliorating MS.

Concrete is the most widely used and highest-volume basic material in the word today. Enhancing its toughness, including tensile strength and deformation resistance, can boost the structural load-bearing capacity, minimize cracking, and decrease the amount of concrete and steel required in engineering projects. These advancements are crucial for the safety, durability, energy efficiency, and emission reduction of structural engineering. This paper systematically summarized the brittle characteristics of concrete and the various structural factors influencing its performance at multiple scales, including molecular, nano-micro, and meso-macro levels. It outlines the principles and impacts of concrete toughening and crack prevention from both internal and external perspectives, and discusses recent advancements and engineering applications of toughened concrete. In situ polymerization and fiber reinforcement are currently practical and highly efficient methods for enhancing concrete toughness. These techniques can boost the matrix’s flexural strength by 30% and double its fracture energy, achieving an ultimate tensile strength of up to 20 MPa and a tensile strain exceeding 0.6%. In the future, achieving breakthroughs in concrete toughening will probably rely heavily on the seamless integration and effective synergy of multi-scale toughening methods.

The vast potential of medical big data to enhance healthcare outcomes remains underutilized due to privacy concerns, which restrict cross-center data sharing and the construction of diverse, large-scale datasets. To address this challenge, we developed a deep generative model aimed at synthesizing medical data to overcome data sharing barriers, with a focus on breast ultrasound (US) image synthesis. Specifically, we introduce CoLDiT, a conditional latent diffusion model with a transformer backbone, to generate US images of breast lesions across various Breast Imaging Reporting and Data System (BI-RADS) categories. Using a training dataset of 9,705 US images from 5,243 patients across 202 hospitals with diverse US systems, CoLDiT generated breast US images without duplicating private information, as confirmed through nearest-neighbor analysis. Blinded reader studies further validated the realism of these images, with area under the receiver operating characteristic curve (AUC) scores ranging from 0.53 to 0.77. Additionally, synthetic breast US images effectively augmented the training dataset for BI-RADS classification, achieving performance comparable to that using an equal-sized training set comprising solely real images (P = 0.81 for AUC). Our findings suggest that synthetic data, such as CoLDiT-generated images, offer a viable, privacy-preserving solution to facilitate secure medical data sharing and advance the utilization of medical big data.

Comorbid anxiety in chronic pain is clinically common, with a comorbidity rate of over 50%. The main treatments are based on pharmacological, interventional, and implantable approaches, which have limited efficacy and carry a risk of side effects. Here, we report a terahertz (THz, 10¹² Hz) wave stimulation (THS) technique, which exerts nonthermal, long-term modulatory effects on neuronal activity by reducing the binding between nano-sized glutamate molecules and GluA2, leading to the relief of pain and comorbid anxiety-like behaviors in mice. In mice with co-occurring anxiety and chronic pain induced by complete Freund’s adjuvant (CFA) injection, hyperactivity was observed in glutamatergic neurons in the anterior cingulate cortex (ACC^Glu). Using whole-cell recording in ACC slices, we demonstrated that THS (34 THz) effectively inhibited the excitability of ACC^Glu. Moreover, molecular dynamics simulations showed that THS reduced the number of hydrogen bonds bound between glutamate molecules and GluA2. Furthermore, THS target to the ACC in CFA-treatment mice suppressed ACC^Glu hyperactivity and, as a result, alleviated pain and anxiety-like behaviors. Consistently, inhibition of ACC^Glu hyperactivity by chemogenetics mimics THS-induced antinociceptive and antianxiety behavior. Together, our study provides evidence for THS as an intervention technique for modulating neuronal activity and a viable clinical treatment strategy for pain and comorbid anxiety.

Exposure to airborne fine particulate matter (PM_2.5) is strongly associated with poor fertility and ovarian damage. However, the mechanism underlying this remains largely unclear. Here, we found that PM_2.5 markedly impaired murine ovarian reserve, decreased hormone levels, and aggravated ovarian inflammation. Circulating interleukin-6 (IL-6) was elevated in PM_2.5-exposed mice and was further confirmed to mediate this damage by IL-6 recombinant protein intervention. PM_2.5 exposure led to increased alveolar macrophage infiltration in the lungs. However, alveolar macrophage clearance with clodronate liposomes could not fully reverse the elevated IL-6 levels and ovarian injury, suggesting that alveolar macrophages were probably not the only source of circulating IL-6. Further experiments indicated that IL-6 mainly targeted ovarian theca–interstitial cells and impaired testosterone synthesis via suppressing the peroxisome proliferator-activated receptor γ (PPARγ) pathway. In addition, apoptosis of granulosa cells and restriction of follicular growth were observed in co-cultures with IL-6-treated theca–interstitial cells, which could be further reversed by the PPARγ agonist. Moreover, IL-6-neutralizing antibodies ameliorated PM_2.5-induced ovarian damage. Notably, increased levels of circulating IL-6 were observed in premature ovarian aging patients and were inversely associated with their ovarian function. In summary, our findings offer a mechanistic explanation for PM_2.5-induced ovarian dysfunction and verify IL-6 as a biomarker and potential therapeutic target.

Osteoporosis presents a marked global public health challenge, characterized by deficient osteogenesis and a deteriorating immune microenvironment. Conventional clinical interventions primarily target osteoclast-mediated bone damage, yet lack a comprehensive therapeutic approach that balances bone formation and resorption. Herein, we introduce a bone-targeted nanocomposite, A-Z@Pd(H), designed to address these challenges by integrating diverse functional components. The nanocomposite incorporates internal hydrogen-carrying nanozymes, which effectively scavenge multiple reactive oxygen species (ROS) and synergistically engage the autophagy–lysosome pathway to accelerate endogenous ROS degradation in macrophages. This mechanism disrupts the vicious cycle of autophagic dysfunction–ROS accumulation–macrophage inflammation. In addition, external metal–organic frameworks release zinc ions (Zn²⁺) in response to the acidic osteoporotic environment, thereby promoting osteogenesis. In a murine model of osteoporosis, intravenous administration of A-Z@Pd(H) leads to preferential accumulation in the femur, thereby remodeling the osteoporotic microenvironment through immune regulation, osteogenesis promotion, and osteoclast inhibition. These findings suggest that this system composed of hydrogen therapy and ion therapy may be a promising candidate for bone-targeted comprehensive therapy in osteoporosis.