Allogeneic CD19-targeted CAR-T therapy in patients with severe myositis and systemic sclerosis.

Allogeneic chimeric antigen receptor (CAR)-T cells hold great promise for expanding the accessibility of CAR-T therapy, whereas the risks of allograft rejection have hampered its application. Here, we genetically engineered healthy-donor-derived, CD19-targeting CAR-T cells using CRISPR-Cas9 to address the issue of immune rejection and treated one patient with refractory immune-mediated necrotizing myopathy and two patients with diffuse cutaneous systemic sclerosis with these cells. This study was registered at ClinicalTrials.gov (NCT05859997). The infused cells persisted for over 3 months, achieving complete B cell depletion within 2 weeks of treatment. During the 6-month follow-up, we observed deep remission without cytokine release syndrome or other serious adverse events in all three patients, primarily shown by the significant improvement in the clinical response index scores for the two diseases, respectively, and supported by the observations of reversal of inflammation and fibrosis. Our results demonstrate the high safety and promising immune modulatory effect of the off-the-shelf CAR-T cells in treating severe refractory autoimmune diseases.

Mitochondrial outer membrane protein FUNDC2 promotes ferroptosis and contributes to doxorubicin-induced cardiomyopathy.

Ferroptosis is an iron-dependent programmed necrosis characterized by glutathione (GSH) depletion and lipid peroxidation (LPO). Armed with both the pro- and antiferroptosis machineries, mitochondria play a central role in ferroptosis. However, how mitochondria sense the stress to activate ferroptosis under (patho-)physiological settings remains incompletely understood. Here, we show that FUN14 domain-containing 2, also known as HCBP6 (FUNDC2), a highly conserved and ubiquitously expressed mitochondrial outer membrane protein, regulates ferroptosis and contributes to doxorubicin (DOX)-induced cardiomyopathy. We showed that knockout of FUNDC2 protected mice from DOX-induced cardiac injury by preventing ferroptosis. Mechanistic studies reveal that FUNDC2 interacts with SLC25A11, the mitochondrial glutathione transporter, to regulate mitoGSH levels. Specifically, knockdown of SLC25A11 in FUNDC2-knockout (KO) cells reduced mitoGSH and augmented erasin-induced ferroptosis. FUNDC2 also affected the stability of both SLC25A11 and glutathione peroxidase 4 (GPX4), key regulators for ferroptosis. Our results demonstrate that FUNDC2 modulates ferroptotic stress via regulating mitoGSH and further support a therapeutic strategy of cardioprotection by preventing mitoGSH depletion and ferroptosis.

Suppressing Metal Leaching and Sintering in Hydroformylation Reaction by Modulating the Coordination of Rh Single Atoms with Reactants.

Hydroformylation reaction is one of the largest homogeneously catalyzed industrial processes yet suffers from difficulty and high cost in catalyst separation and recovery. Heterogeneous single-atom catalysts (SACs), on the other hand, have emerged as a promising alternative due to their high initial activity and reasonable regioselectivity. Nevertheless, the stability of SACs against metal aggregation and leaching during the reaction has rarely been addressed. Herein, we elucidate the mechanism of Rh aggregation and leaching by investigating the structural evolution of Rh1@silicalite-1 SAC in response to different adsorbates (CO, H2, alkene, and aldehydes) by using diffuse reflectance infrared Fourier transform spectroscopy, X-ray adsorption fine structure, and scanning transmission electron microscopy techniques and kinetic studies. It is discovered that the aggregation and leaching of Rh are induced by the strong adsorption of CO and aldehydes on Rh, as well as the reduction of Rh3+ by CO/H2 which weakens the binding of Rh with support. In contrast, alkene effectively counteracts this effect by the competitive adsorption on Rh atoms with CO/aldehyde, and the disintegration of Rh clusters. Based on these results, we propose a strategy to conduct the reaction under conditions of high alkene concentration, which proves to be able to stabilize Rh single atom against aggregation and/or leaching for more than 100 h time-on-stream.

Efficacy and predictors of immune checkpoint inhibitors in patients with gallbladder cancer.

Immune checkpoint inhibitors (ICIs) have shown promising efficacy in multiple cancers including biliary tract cancers (BTCs). However, the data focusing on the efficacy of ICIs in patients with gallbladder cancer (GBC) is still limited. In this study, we aim to assess the efficacy of ICIs in GBC and explore the clinicopathologic and molecular markers associated with ICI benefit. We retrospective analyzed 69 GBC patients who had received ICI therapy between January 2016 and December 2020. Tumor samples were obtained for genomic sequencing and immunohistochemical analysis. The median progression-free survival (PFS) and overall survival (OS) was 4.4 months and 8.5 months, respectively. Multivariate analysis indicated that alcohol intake history, carcinoma embryonic antigen (CEA) level ≥100 U/mL, and cutaneous immune-related adverse events (irAEs) were independent prognostic factors for PFS. CEA level ≥100 U/mL and cutaneous irAEs were independent prognostic factors for OS. The objective response rate and disease control rate (DCR) were 15.9% and 37.7%, respectively. Patients with cutaneous irAEs, high CD8+ T cell infiltrated or immune inflamed GBCs had higher DCR. Patients with high CD8+ T cell infiltrated or immune inflamed GBCs also had a notably improved prognosis. These results suggest that ICIs were effective in patients with GBC. High CEA level, cutaneous irAEs, high CD8+ T cell infiltration, and immune inflamed phenotype could be useful for predicting the efficacy of ICIs in GBC.

Balancing Mass Transfer and Active Sites to Improve Electrocatalytic Oxygen Reduction by B,N Codoped C Nanoreactors.

Mass transfer is critical in catalytic processes, especially when the reactions are facilitated by nanostructured catalysts. Strong efforts have been devoted to improving the efficacy and quantity of active sites, but often, mass transfer has not been well studied. Herein, we demonstrate the importance of mass transfer in the electrocatalytic oxygen reduction reaction (ORR) by tailoring the pore sizes. Using a confined-etching strategy, we fabricate boron- and nitrogen-doped carbon (B,N@C) electrocatalysts featuring abundant active sites but different porous structures. The ORR performance of these catalysts is found to correlate with diffusion of the reactant. The optimized B,N@C with trimodal-porous structures feature enhanced O2 diffusion and better activity per heteroatomic site toward the ORR process. This work demonstrates the significance of the nanoarchitecture engineering of catalysts and sheds light on how to optimize structures featuring abundant active sites and enhanced mass transfer.

In Situ Self-Assembled Active and Stable Ir@MnOx/La0.7Sr0.3Cr0.9Ir0.1O3-δ Interfaces for CO2 Electrolysis.

Solid oxide electrolysis cells are prospective approaches for CO2 utilization but face significant challenges due to the sluggish reaction kinetics and poor stability of the fuel electrodes. Herein, we strategically addressed the long-standing trade-off phenomenon between enhanced exsolution and improved structural stability via topotactic ion exchange. The surface dynamic reconstruction of the MnOx/La0.7Sr0.3Cr0.9Ir0.1O3-δ (LSCIr) catalyst was visualized at the atomic scale. Compared with the Ir@LSCIr interface, the in situ self-assembled Ir@MnOx/LSCIr interface exhibited greater CO2 activation and easily removable carbonate intermediates, thus reached a 42 % improvement in CO2 electrolysis performance at 1.6 V. Furthermore, an improved CO2 electrolysis stability was achieved due to the uniformly wrapped MnOx shell of the Ir@MnOx/LSCIr cathode. Our approach enables a detailed understanding of the dynamic microstructure evolution at active interfaces and provides a roadmap for the rational design and evaluation of efficient metal/oxide catalysts for CO2 electrolysis.

Mitophagy receptor FUNDC1 is regulated by PGC-1α/NRF1 to fine tune mitochondrial homeostasis.

Mitophagy is an essential cellular autophagic process that selectively removes superfluous and damaged mitochondria, and it is coordinated with mitochondrial biogenesis to fine tune the quantity and quality of mitochondria. Coordination between these two opposing processes to maintain the functional mitochondrial network is of paramount importance for normal cellular and organismal metabolism. However, the underlying mechanism is not completely understood. Here we report that PGC-1α and nuclear respiratory factor 1 (NRF1), master regulators of mitochondrial biogenesis and metabolic adaptation, also transcriptionally upregulate the gene encoding FUNDC1, a previously characterized mitophagy receptor, in response to cold stress in brown fat tissue. NRF1 binds to the classic consensus site in the promoter of Fundc1 to upregulate its expression and to enhance mitophagy through its interaction with LC3. Specific knockout of Fundc1 in BAT results in reduced mitochondrial turnover and accumulation of functionally compromised mitochondria, leading to impaired adaptive thermogenesis. Our results demonstrate that FUNDC1-dependent mitophagy is directly coupled with mitochondrial biogenesis through the PGC-1α/NRF1 pathway, which dictates mitochondrial quantity, quality, and turnover and contributes to adaptive thermogenesis.

[Research progress on the effect of mitochondrial and endoplasmic reticulum stress caused by hypoxia during pregnancy on preeclampsia and intrauterine growth restriction].

Preeclampsia and intrauterine growth restriction (IUGR) of the fetus are the two most common pregnancy complications worldwide, affecting 5%-10% of pregnant women. Preeclampsia is associated with significantly increased maternal and fetal morbidity and mortality. Hypoxia-induced uteroplacental dysfunction is now recognized as a key pathological factor in preeclampsia and IUGR. Reduced oxygen supply (hypoxia) disrupts mitochondrial and endoplasmic reticulum (ER) function. Hypoxia has been shown to alter mitochondrial reactive oxygen species (ROS) homeostasis and induce ER stress. Hypoxia during pregnancy is associated with excessive production of ROS in the placenta, leading to oxidative stress. Oxidative stress occurs in a number of human diseases, including high blood pressure during pregnancy. Studies have shown that uterine placental tissue/cells in preeclampsia and IUGR show high levels of oxidative stress, which plays an important role in the pathogenesis of both the complications. This review summarizes the role of hypoxia-induced mitochondrial oxidative stress and ER stress in the pathogenesis of preeclampsia/IUGR and discusses the potential therapeutic strategies targeting oxidative stress to treat both the pregnancy complications.

Pharmacological Mechanism of Aucklandiae Radix against Gastric Ulcer Based on Network Pharmacology and In Vivo Experiment.

Background and Objectives: Aucklandiae Radix is a well-known medicinal herb that is often used to treat gastric ulcer, but its molecular mechanism of anti-ulcer action is poorly understood. This research aimed to reveal the potential active components, core targets, and mechanisms of Aucklandiae Radix in treating gastric ulcer by combining network pharmacology and animal experimentation. Materials and Methods: First, a network pharmacology strategy was used to predict the main components, candidate targets, and potential signaling pathways. Molecular docking was then used to confirm the binding affinity between the main components and primary targets. Finally, rats were treated with indomethacin 30 mg/kg to establish a gastric ulcer model. Aucklandiae Radix extract (0.15, 0.3, and 0.6 g/kg) was pre-treated in rats by oral gavage for 14 days, and the protective effect and candidate targets of network pharmacology were validated through morphological observation, pathological staining, and biochemical index detection. Results: A total of eight potential active components and 331 predicted targets were screened from Aucklandiae Radix, 37 of which were common targets with gastric ulcer. According to the component-target network and protein-protein interaction (PPI) network, stigmasterol, mairin, sitosterol, and dehydrocostus lactone were identified as the key components, and RAC-alpha serine/threonine-protein kinase (AKT1), prostaglandin-endoperoxide synthase 2 (PTGS2), interleukin 1 beta (IL1B), caspase-3 (CASP3), and CASP8 were selected as the core targets. Gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment results revealed the pharmacological mechanism of Aucklandiae Radix against gastric ulcer related to many biological processes and pathways, including antibacterial, anti-inflammatory, prostaglandin receptor response, and apoptosis. Molecular docking verification showed that the key components and core targets had good binding affinities. In the in vivo experiments, Aucklandiae Radix notably relieved the gastric ulcer by reducing the levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and myeloperoxidase (MPO) while improving the gastric histopathological features. Conclusion: The overall findings suggest that Aucklandiae Radix treats gastric ulcer with a multi-component, multi-target, and multi-mechanism model.

Design of Hollow Nanoreactors for Size- and Shape-Selective Catalytic Semihydrogenation Driven by Molecular Recognition.

Mimicking the structures and functions of cells to create artificial organelles has spurred the development of efficient strategies for production of hollow nanoreactors with biomimetic catalytic functions. However, such structure are challenging to fabricate and are thus rarely reported. We report the design of hollow nanoreactors with hollow multishelled structure (HoMS) and spatially loaded metal nanoparticles. Starting from a molecular-level design strategy, well-defined hollow multishelled structure phenolic resins (HoMS-PR) and carbon (HoMS-C) submicron particles were accurately constructed. HoMS-C serves as an excellent, versatile platform, owing to its tunable properties with tailored functional sites for achieving precise spatial location of metal nanoparticles, internally encapsulated (Pd@HoMS-C) or externally supported (Pd/HoMS-C). Impressively, the combination of the delicate nanoarchitecture and spatially loaded metal nanoparticles endow the pair of nanoreactors with size-shape-selective molecular recognition properties in catalytic semihydrogenation, including high activity and selectivity of Pd@HoMS-C for small aliphatic substrates and Pd/HoMS-C for large aromatic substrates. Theoretical calculations provide insight into the pair of nanoreactors with distinct behaviors due to the differences in energy barrier of substrate adsorption. This work provides guidance on the rational design and accurate construction of hollow nanoreactors with precisely located active sites and a finely modulated microenvironment by mimicking the functions of cells.