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Background Inflammation can induce cognitive dysfunction in patients who undergo surgery. Previous studies have demonstrated that both acute peripheral inflammation and anaesthetic insults, especially isoflurane (ISO), are risk factors for memory impairment. Few studies are currently investigating the role of ISO under acute peri-inflammatory conditions, and it is difficult to predict whether ISO can aggravate inflammation-induced cognitive deficits. HDACs, which are essential for learning, participate in the deacetylation of lysine residues and the regulation of gene transcription. However, the cell-specific mechanism of HDACs in inflammation-induced cognitive impairment remains unknown. Methods Three-month-old C57BL/6 mice were treated with single versus combined exposure to LPS injected intraperitoneally (i.p.) to simulate acute abdominal inflammation and isoflurane to investigate the role of anaesthesia and acute peripheral inflammation in cognitive impairment. Behavioural tests, Western blotting, ELISA, immunofluorescence, qRT-PCR, and ChIP assays were performed to detect memory, the expressions of inflammatory cytokines, HDAC2, BDNF, c-Fos, acetyl-H3, microglial activity, Bdnf mRNA, c-fos mRNA, and Bdnf and c-fos transcription in the hippocampus. Results LPS, but not isoflurane, induced neuroinflammation-induced memory impairment and reduced histone acetylation by upregulating histone deacetylase 2 (HDAC2) in dorsal hippocampal CaMKII + neurons. The hyperexpression of HDAC2 in neurons was mediated by the activation of microglia. The decreased level of histone acetylation suppressed the transcription of Bdnf and c-fos and the expressions of BDNF and c-Fos, which subsequently impaired memory. The adeno-associated virus Sh Hdac2 , which suppresses Hdac2 after injection into the dorsal hippocampus, reversed microglial activation, hippocampal glutamatergic BDNF and c-Fos expressions, and memory deficits. Conclusions Reversing HDAC2 in hippocampal CaMKII + neurons exert a neuroprotective effect against neuroinflammation-induced memory deficits.

Atropisomeric biaryls bearing carbonyl groups have attracted increasing attention due to their prevalence in diverse bioactive molecules and crucial role as efficient organo-catalysts or ligands in asymmetric transformations. However, their preparation often involves tedious multiple steps, and the direct synthesis via asymmetric carbonylation has scarcely been investigated. Herein, we report an efficient palladium-catalyzed enantioconvergent aminocarbonylation of racemic heterobiaryl triflates with amines via dynamic kinetic asymmetric transformation (DyKAT). This protocol features a broad substrate scope and excellent compatibility for rapid construction of axially chiral amides in good to high yields with excellent enantioselectivities. Detailed mechanistic investigations discover that the base can impede the intramolecular hydrogen bond-assisted axis rotation of the products, thus allowing for the success to achieve high enantioselectivity. Moreover, the achieved axially chiral heterobiaryl amides can be directly utilized as N,N,N -pincer ligands in copper-catalyzed enantioselective formation of C(sp 3 )-N and C(sp 3 )-P bonds. Axially chiral biaryls containing carbonyl groups not only exist in various drug candidates but also serve as organo-catalysts or ligands in diverse asymmetric transformations. Herein, the authors report palladium-catalyzed enantioconvergent aminocarbonylation of racemic heterobiaryl triflates via dynamic kinetic asymmetric transformation.

Identifying novel drug targets to overcome resistance to tyrosine kinase inhibitors (TKIs) and eradicating leukemia stem/progenitor cells are required for the treatment of chronic myelogenous leukemia (CML). Here, we show that ubiquitin-specific peptidase 47 (USP47) is a potential target to overcome TKI resistance. Functional analysis shows that USP47 knockdown represses proliferation of CML cells sensitive or resistant to imatinib in vitro and in vivo. The knockout of Usp47 significantly inhibits BCR-ABL and BCR-ABL T315I -induced CML in mice with the reduction of Lin − Sca1 + c-Kit + CML stem/progenitor cells. Mechanistic studies show that stabilizing Y-box binding protein 1 contributes to USP47-mediated DNA damage repair in CML cells. Inhibiting USP47 by P22077 exerts cytotoxicity to CML cells with or without TKI resistance in vitro and in vivo. Moreover, P22077 eliminates leukemia stem/progenitor cells in CML mice. Together, targeting USP47 is a promising strategy to overcome TKI resistance and eradicate leukemia stem/progenitor cells in CML. Resistance to tyrosine kinase inhibitors (TKI) is a limitation to their use in treating chronic myelogenous leukemia (CML). Here, the authors show that targeting the ubiquitin peptidase USP47 overcomes TKI resistance and eliminates leukaemia stem/progenitor cells in primary and xenograft CML murine models.

Exosomes (Exo) hold great promise as endogenous nanocarriers that can deliver biological information between cells. However, Exo are limited in terms of their abilities to target specific recipient cell types. We developed a strategy to isolate Exo exhibiting increased binding to integrin α v β 3 . Binding occurred through a modified version of a disintegrin and metalloproteinase 15 (A15) expressed on exosomal membranes (A15-Exo), which facilitated co-delivery of therapeutic quantities of doxorubicin (Dox) and cholesterol-modified miRNA 159 (Cho-miR159) to triple-negative breast cancer (TNBC) cells, both in vitro and in vivo. The targeted A15-Exo were derived from continuous protein kinase C activation in monocyte-derived macrophages. These cell-derived Exo displayed targeting properties and had a 2.97-fold higher production yield. In vitro, A15-Exo co-loaded with Dox and Cho-miR159 induced synergistic therapeutic effects in MDA-MB-231 cells. In vivo, miR159 and Dox delivery in a vesicular system effectively silenced the TCF-7 gene and exhibited improved anticancer effects, without adverse effects. Therefore, our data demonstrate the synergistic efficacy of co-delivering miR159 and Dox by targeted Exo for TNBC therapy.

Chiral spirocyclic skeletons have found widespread applications in asymmetric catalysis, drug discovery, and functional materials due to their rigid three-dimensional architecture and excellent stereochemical stability. However, the structural diversity of accessible spiro frameworks remains limited, constraining their broader utility and functional development. For instance, chiral ( N , N )-spiroketals represent a promising class of scaffolds with potential application in asymmetric catalysis and are frequently encountered in natural products and biologically active compounds, yet their efficient synthesis is still underdeveloped. Herein, we present a Pd-catalyzed cascade enantioconvergent aminocarbonylation and intramolecular dearomative nucleophilic aza-addition that enables the efficient synthesis of chiral ( N , N )-spiroketal. This formal [3 + 1 + 1] spiroannulation employs racemic quinazoline-derived heterobiaryl triflates, carbon monoxide, and amines to deliver an array of ( N , N )-spiroketal in high yields and excellent enantioselectivities. The protocol exhibits wide functional group tolerance, scalability, and downstream synthetic utility, providing access to structurally diverse spirocyclic derivatives. Mechanistic studies reveal that the stereochemical outcome of ( N , N )-spiroketal is determined by the atroposelective DyKAT aminocarbonylation step, rather than the subsequent spiroannulation. Moreover, the resulting spiroketal structure has been developed into chiral carbene ligand, as demonstrated by the successful synthesis of its corresponding Rh, Ir, Au and Pd complexes. Chiral (N, N)-spiroketals represent a promising class of scaffolds with potential application in asymmetric catalysis and are frequently encountered in natural products and biologically active compounds, yet their efficient synthesis is still underdeveloped. Herein, the authors report a Pd-catalyzed cascade enantioconvergent aminocarbonylation and intramolecular dearomative nucleophilic aza-addition that enables the efficient synthesis of chiral (N, N)-spiroketal.

Cell membrane- covered drug-delivery nanoplatforms have been garnering attention because of their enhanced bio-interfacing capabilities that originate from source cells. In this top-down technique, nanoparticles (NPs) are covered by various membrane coatings, including membranes from specialized cells or hybrid membranes that combine the capacities of different types of cell membranes. Here, hybrid membrane-coated doxorubicin (Dox)-loaded poly(lactic-co-glycolic acid) (PLGA) NPs (DPLGA@[RAW-4T1] NPs) were fabricated by fusing membrane components derived from RAW264.7(RAW) and 4T1 cells (4T1). These NPs were used to treat lung metastases originating from breast cancer. This study indicates that the coupling of NPs with a hybrid membrane derived from macrophage and cancer cells has several advantages, such as the tendency to accumulate at sites of inflammation, ability to target specific metastasis, homogenous tumor targeting abilities in vitro, and markedly enhanced multi-target capability in a lung metastasis model in vivo. The DPLGA@[RAW-4T1] NPs exhibited excellent chemotherapeutic potential with approximately 88.9% anti-metastasis efficacy following treatment of breast cancer-derived lung metastases. These NPs were robust and displayed the multi-targeting abilities of hybrid membranes. This study provides a promising biomimetic nanoplatform for effective treatment of breast cancer metastasis.

A bstract In this paper we study the recently proposed tensor networks/AdS correspondence. We found that the Coxeter group is a useful tool to describe tensor networks in a negatively curved space. Studying generic tensor network populated by perfect tensors, we find that the physical wave function generically do not admit any connected correlation functions of local operators. To remedy the problem, we assume that wavefunctions admitting such semi-classical gravitational interpretation are composed of tensors close to, but not exactly perfect tensors. Computing corrections to the connected two point correlation functions, we find that the leading contribution is given by structures related to geodesics connecting the operators inserted at the boundary physical dofs. Such considerations admit generalizations at least to three point functions. This is highly suggestive of the emergence of the analogues of Witten diagrams in the tensor network. The perturbations alone however do not give the right entanglement spectrum. Using the Coxeter construction, we also constructed the tensor network counterpart of the BTZ black hole, by orbifolding the discrete lattice on which the network resides. We found that the construction naturally reproduces some of the salient features of the BTZ black hole, such as the appearance of RT surfaces that could wrap the horizon, depending on the size of the entanglement region A .

The combination of an immuno-metabolic adjuvant and immune checkpoint inhibitors holds great promise for effective suppression of tumor growth and invasion. In this study, a pH-responsive co-delivery platform was developed for metformin (Met), a known immuno-metabolic modulator, and short interfering RNA (siRNA) targeting fibrinogen-like protein 1 mRNA (siFGL1), using a hybrid biomimetic membrane (from macrophages and cancer cells)-camouflaged poly (lactic- co -glycolic acid) nanoparticles. To improve the endo-lysosomal escape of siRNA for effective cytosolic siRNA delivery, a pH-triggered CO 2 gas-generating nanoplatform was developed using the guanidine group of Met. It can react reversibly with CO 2 to form Met-CO 2 for the pH-dependent capture/release of CO 2 . The introduction of Met, a conventional anti-diabetic drug, promotes programmed death-ligand 1 (PD-L1) degradation by activating adenosine monophosphate-activated protein kinase, subsequently blocking the inhibitory signals of PD-L1. As a result, siFGL1 delivery by the camouflaged nanoparticles of the hybrid biomimetic membrane can effectively silence the FGL1 gene, promoting T-cell-mediated immune responses and enhancing antitumor immunity. We found that a combination of PD-L1/programmed death 1 signaling blockade and FGL1 gene silencing exhibited high synergistic therapeutic efficacy against breast cancer in vitro and in vivo. Additionally, Met alleviated tumor hypoxia by reducing oxygen consumption and inducing M1-type differentiation of tumor-related macrophages, which improved the tumor immunosuppressive microenvironment. Our results indicate the potential of hybrid biomimetic membrane-camouflaged nanoparticles and combined Met-FGL1 blockade in breast cancer immunotherapy.

Human beings capable of making and using tools can accomplish tasks far beyond their innate abilities, and this paradigm of integration with tools may not be limited to humans themselves. Recently, the large language model (LLM) has demonstrated immense potential across various fields with its unique planning and reasoning abilities. However, there are still many challenges beyond its capabilities due to deficiencies in its training data and inherent illusions. Thus, integrating LLMs and tools into tool learning agents has become a new emerging research direction. To this end, we present a systematic investigation and comprehensive review of tool-learning agents in this paper. We start by introducing the definition of the tool learning task for Agents and then illustrating the typical architecture of the tool-learning models. Since these tools are all defined by users, LLM does not know what tools there are and what their functions are. Thus, LLMs should first find appropriate tools and split the tool retrieval methods into two categories: training-based and non-training-based. To accurately complete the user task, it is important to decompose the task into several sub-tasks and execute them in the correct order. Following that, we introduce the tool planning methods and organize these works by whether they rely on the model’s inherent reasoning capabilities for planning or utilize external reasoning tools. Due to the rapid development of this field, we also introduce an emerging frontier direction: using multimodal tools for LLM. In addition, we compile current open-source benchmarks and evaluation metrics, focusing on their scale, composition, calculation methods, and assessment dimensions. Next, we introduce several application scenarios for the LLM-based tool learning methods. Finally, we discuss the safety and ethical issues involved in tool learning.

Background Macrophages with tumor-tropic migratory properties can serve as a cellular carrier to enhance the efficacy of anti neoplastic agents. However, limited drug loading (DL) and insufficient drug release at the tumor site remain the main obstacles in developing macrophage-based delivery systems. In this study, we constructed a biomimetic delivery system (BDS) by loading doxorubicin (DOX)-loaded reduced graphene oxide (rGO) into a mouse macrophage-like cell line (RAW264.7), hoping that the newly constructed BDS could perfectly combine the tumor-tropic ability of macrophages and the photothermal property of rGO. Results At the same DOX concentration, the macrophages could absorb more DOX/PEG-BPEI-rGO than free DOX. The tumor-tropic capacity of RAW264.7 cells towards RM-1 mouse prostate cancer cells did not undergo significant change after drug loading in vitro and in vivo. PEG-BPEI-rGO encapsulated in the macrophages could effectively convert the absorbed near-infrared light into heat energy, causing rapid release of DOX. The BDS showed excellent anti-tumor efficacy in vivo. Conclusions The BDS that we developed in this study had the following characteristic features: active targeting of tumor cells, stimuli-release triggered by near-infrared laser (NIR), and effective combination of chemotherapy and photothermotherapy. Using the photothermal effect produced by PEG-BPEI-rGO and DOX released from the macrophages upon NIR irradiation, MAs-DOX/PEG-BPEI-rGO exhibited a significant inhibitory effect on tumor growth.