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.

Protein phosphatase 2A (PP2A) is one of the most abundant serine/threonine phosphatases and plays critical roles in regulating cell fate and function. We previously showed that PP2A regulates the differentiation of CD4⁺ T cells and the development of thymocytes. Nevertheless, its role in CD8⁺ T cells remains elusive. By ablating the catalytic subunit α (Cα) of PP2A in CD8⁺ T cells, we revealed the essential role of PP2A in promoting the effector functions of CD8⁺ T cells. Notably, PP2A Cα-deficient CD8⁺ T cells exhibit reduced proliferation and decreased cytokine production upon stimulation in vitro. In vivo, mice lacking PP2A Cα in T cells displayed defective immune responses against lymphocytic choriomeningitis virus infection, associated with reduced CD8⁺ T cell expansion and decreased cytokine production. Consistently, the ablation of the PP2A Cα subunit in CD8⁺ T cells results in attenuated antitumor activity in mice. There is a notable decrease in the infiltration of PP2A Cα-deficient CD8⁺ T cells within the tumor microenvironment, and the cells that do infiltrate exhibit diminished effector functions. Mechanistically, PP2A Cα deficiency impedes CD28-induced AKT Ser⁴⁷³ phosphorylation, thus impairing CD8⁺ T cell costimulation signal. Collectively, our findings underscore the critical role of phosphatase PP2A as a propeller for CD28-mediated costimulation signaling in CD8⁺ T cell effector function by fine-tuning T cell activation.

As global populations become increasingly aged, existing elderly care models are proving insufficient. The development and application of nursing robots have shown potential in addressing the challenges of elder care in aging societies. This perspective outlines current state and potential applications of nursing robots in promoting healthy aging. Given this background, a networked intelligent elderly care model for nursing robots, which integrates technologies such as big data, artificial intelligence, the Internet of Things, and nursing robotics, is proposed. This model would synergistically combine elderly health monitoring, capability assessment, and intelligent allocation functions to revolutionize global elderly care practices and promote healthy aging.

Drug resistance to a single agent is common in cancer-targeted therapies, and rational drug combinations are a promising approach to overcome this challenge. Many Food and Drug Administration-approved drugs can induce cellular senescence, which possesses unique vulnerabilities and molecular signatures. However, there is limited analysis on the effect of the combination of cellular-senescence-inducing drugs and targeted therapy drugs. Here, we conducted a comprehensive evaluation of cellular senescence using 7 senescence-associated gene sets. We quantified the cellular senescence states of ~10,000 tumor samples from The Cancer Genome Atlas and examined their associations with targeted drug responses. Our analysis revealed that tumors with higher cellular senescence scores exhibited increased sensitivity to targeted drugs. As a proof of concept, we experimentally confirmed that etoposide-induced senescence sensitized lung cancer cells to 2 widely used targeted drugs, erlotinib and dasatinib. Furthermore, we identified multiple genes whose dependencies were associated with senescence status across ~1,000 cancer cell lines, suggesting that cellular senescence generates unique vulnerabilities for therapeutic exploitation. Our study provides a comprehensive overview of drug response related to cellular senescence and highlights the potential of combining senescence-inducing agents with targeted therapies to improve treatment outcomes in lung cancer, revealing novel applications of cellular senescence in targeted cancer therapies.

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.

The electrocatalytic carbon dioxide reduction reaction (CO₂RR) at industrial-level current densities provides a sustainable approach to converting CO₂ into value-added fuels and feedstocks using renewable electricity. However, the CO₂RR conducted typically in alkaline and neutral electrolytes encounters some challenges due to the inevitable reaction between CO₂ and OH⁻ ions, which undermines CO₂ utilization and leads to poor operational stability. Acidic media present a viable alternative by reducing (bi)carbonate production, thereby enhancing the carbon efficiency and stability in CO₂RR. The objective of this paper is to provide a concise account of the recent advancements and challenges in the field of acidic CO₂RR, with an emphasis on future developments and opportunities.

Numerous diseases have been connected to protein arginine methylations mediated by protein arginine methyltransferase 5 (PRMT5). Clinical investigations of the PRMT5-specific inhibitor GSK3326595 are currently being conducted, and the results are promising for preventing cancers. However, the detailed mechanism of PRMT5 promoting colorectal cancer (CRC) malignant progression remains unclear. Here, we found that PRMT5 directly catalyzes AlkB homologue 5 (ALKBH5) symmetric dimethylation at the R316 residue (meR316-ALKBH5), which enhances TRIM28-mediated ALKBH5 ubiquitination degradation. Then, an ALKBH5 decrease attenuates ALKBH5-mediated m6A demethylation on the CD276 transcript 3′ untranslated region, which increases CD276 messenger RNA stability and its expression in CRC cells. Furthermore, a CD276 expression increase facilitates CRC immune evasion by inhibiting cytotoxic T-cell functions. Moreover, we revealed that PRMT5-mediated meR316-ALKBH5 activates CD276 transcription by increasing its messenger RNA m6A modification to increase CRC immune evasion in vitro and in vivo. Furthermore, we consistently showed a strong association between meR316-ALKBH5 and poor outcomes in patients with CRC. Finally, we demonstrated that combining an anti-PD1 antibody with the PRMT5 inhibitor GSK3326595 markedly halts the progression of CRC. Our findings could serve as a basis for the development of a PRMT5–meR316-ALKBH5–CD276 axis-targeting treatment approach for CRC.

Metals have traditionally served as the primary functional phase in the development of metamaterials exhibiting epsilon-near-zero (ENZ) and epsilon-negative (EN) responses, albeit with persisting ambiguities regarding their response mechanisms. This paper presents the tunable ENZ (ε′ ~ 0) and EN (ε′ < 0) parameters at the 20-MHz to 1-GHz region based on Cu/CaCu₃Ti₄O₁₂ (Cu/CCTO) metacomposites. By means of first-principles calculations and multi-physics simulations, the underlying mechanisms governing ENZ and EN responses are unveiled. The intricate pathways through which metacomposites achieve 2 dielectric response mechanisms are delineated: At low Cu content, a weak EN response (|ε′| < 200) was excited by electric dipole resonance, accompanied by ENZ effect; conversely, at high Cu content, due to the increase in effective electron concentration, plasmonic oscillation behavior occurs in the constructed 3-dimensional Cu network, resulting in strong EN response (|ε′| ~ 1,000) in the radio frequency band. These phenomena are explicated through 2 distinct Cu/CCTO models: Cu in an isolated state and a connected network state. This study not only comprehensively elucidates the 2 EN response mechanisms achieved by typical metacomposites with metals as functional phases but also delves into their associated electromagnetic shielding and thermal properties, providing a theoretical basis for their practical applications.