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Neurodegenerative disorders are increasingly linked to a progressive decline in lysosomal function. Activating Transcription Factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy, has therefore emerged as a promising therapeutic strategy to enhance cellular clearance in these conditions. In this study, we identified KHS-101 as a novel TFEB activator through a high-throughput screen of blood–brain-barrier-permeable small molecules. We demonstrated that KHS-101 promotes TFEB nuclear translocation, enhances lysosomal biogenesis and proteolytic activity, and increases autophagic flux. Furthermore, KHS-101 significantly accelerates the degradation of pathogenic A53T mutant α-synuclein in a cellular model of Parkinson’s disease, suggesting its potential to mitigate α-synuclein-mediated proteotoxicity and hold neuroprotective potential. Our findings identify KHS-101 as a potent TFEB activator and highlight the therapeutic potential of modulating the autophagy-lysosomal pathway for treating Parkinson’s disease and related disorders.

Chimeric antigen receptor T cell (CAR-T) therapy has emerged as a highly efficacious treatment for refractory and relapsed hematological malignancies in recent years. However, the complex manufacturing procedures, stringent logistical requirements, and protracted production timelines associated with autologous ex vivo CAR-T cells render them costly and inaccessible to many patients. In contrast, in vivo CAR-T therapy directly delivers CAR-encoding transgenes to endogenous T cells, reprogramming them in situ. This approach obviates the need for apheresis, ex vivo cell manufacturing, and lymphodepleting chemotherapy inherent in conventional CAR-T therapy. Consequently, in vivo CAR-T represents a more efficient and economical paradigm, transforming CAR-T from individualized cellular products towards truly “ready-to-use” therapeutics. This review summarizes the latest research progress in in vivo CAR cell therapies, spanning from bench to bedside, to provide insights for advancing their clinical translation.

Herbaceous peony ( Paeonia lactiflora Pall.) is an ancient ornamental crop and, in recent decades, an emerging popular cut flower. Straight stems are a vital criterion for cut herbaceous peony selection, while many cultivars bend as the plant develops. Pectin helps maintain the mechanical strength of the cell wall. However, little is known about its role in the stem bending of herbaceous peony. Two herbaceous peony cultivars with contrasting stem morphologies (‘Dong Fang Shao Nv’, upright; ‘Lan Tian Piao Xiang’, bending gradually) at five developmental stages were used as materials to investigate the effects of pectin content and nanostructure on straightness using the carbazole colorimetric method and atomic force microscopy observations. The contents of water-soluble pectin (WSP), CDTA-soluble pectin (CSP), and sodium carbonate-soluble pectin (SSP) differed significantly between the two cultivars, and the contents and angle of the flower and branch showed correlations. For the pectin nanostructure, WSP showed agglomerates and long chains, with a higher proportion of broad agglomerates at the later stages of the bending cultivar than the upright cultivar. CSP showed branched chains, and the proportion of broad chains was higher in the upright cultivar at later stages, while CSP shape changed from agglomerates to chains in the bending cultivar. SSP mainly consisted of short linear main chains, and side chains in the upright stem were stacked, and the bent cultivar had more broad and short chains. It can be concluded that the contents, nanometric shape, and size of the three kinds of pectin are highly likely to affect herbaceous peony stem straightness. This study provides a theoretical basis for the role of pectin in the production and breeding of herbaceous peony cut flowers.

CAR T cell therapy has shown dramatic clinical success in relapsed or refractory B-ALL and other hematological malignancies. However, the loss of specific antigens, cell fratricide, T cell aplasia, and normal T cell separation are challenges in treating T cell leukemia/lymphoma with CAR T therapy. CD99 is a promising antigen to target T-ALL and AML as it is strongly expressed on the majority of T-ALL and AML. Here, we isolated a low-affinity CD99 (12E7) antibody, which specifically recognizes leukemia cells over normal blood cells. Moreover, T cells transduced with an anti-CD99-specific CAR that contained the 12E7 scFv expanded with minor fratricide and without normal blood cells toxicity. We observed that our anti-CD99 CAR T cells showed robust cytotoxicity specifically against CD99+ T-ALL cell lines and primary tumor cells in vitro and significantly prolonged cell line-derived xenografts (CDXs) or patient-derived xenografts (PDXs) models survival in vivo. Together, our results demonstrate that anti-CD99 CAR T cells could specifically recognize and efficiently eliminate CD99+ leukemia cells.

T-cell acute lymphoblastic leukemia (T-ALL), a form of T-cell malignancy, is a typically aggressive hematological malignancy with high rates of disease relapse and a poor prognosis. Current guidelines do not recommend any specific treatments for these patients, and only allogeneic stem cell transplant, which is associated with potential risks and toxicities, is a curative therapy. Recent clinical trials showed that immunotherapies, including monoclonal antibodies, checkpoint inhibitors, and CAR T therapies, are successful in treating hematologic malignancies. CAR T cells, which specifically target the B-cell surface antigen CD19, have demonstrated remarkable efficacy in the treatment of B-cell acute leukemia, and some progress has been made in the treatment of other hematologic malignancies. However, the development of CAR T-cell immunotherapy targeting T-cell malignancies appears more challenging due to the potential risks of fratricide, T-cell aplasia, immunosuppression, and product contamination. In this review, we discuss the current status of and challenges related to CAR T-cell immunotherapy for T-ALL and review potential strategies to overcome these limitations.

T-cell acute lymphoblastic leukemia (T-ALL) is a hematologic malignancy derived from T cells. Numerous CAR T therapies have been successfully applied to treat hematologic malignancies in the clinic. Nevertheless, there remain several challenges to the extensive application of CAR T cell therapy in T cell malignancies, especially in T-ALL. The main reason for CAR T therapy limitations is that T-ALL cells and normal T cells share antigens, which improves the difficulty of sorting pure T cells, resulting in product contamination, and would lead to CAR T cell fratricide. Thus, we considered creating a CAR on T-ALL tumor cells (CAR T-ALL) to prevent fratricide and eliminate tumor cells. We found that T-ALL cells transduced with CAR would actually commit fratricide. However, CAR T-ALL could kill only tumor cells on T-ALL cell lines, and other types of tumor cells had no killing function after being transferred with CAR. Furthermore, we created CD99 CAR with expression controlled by the Tet-On system on Jurkat cells, which could avoid the fratricide of CAR T-ALL during proliferation, ensuring the controllability of the killing time and effect. Jurkat transduced with a CAR-targeting antigen, which was expressed on other cancer cells, could kill other cancer cell lines, demonstrating that T-ALL cells could be used as tool cells for cancer therapy. Our study supplied a new feasible treatment regimen for cancer treatment in the clinic.

T-cell acute lymphoblastic leukemia (T-ALL) is a type of hematologic tumor with malignant proliferation of hematopoietic progenitor cells. However, traditional clinical treatment of T-ALL included chemotherapy and stem cell transplantation always lead to recurrence and poor prognosis, thus new therapeutic targets and drugs are urgently needed for T-ALL treatment. In this study, we showed that TET1 (ten-eleven translocation 1), a key participant of DNA epigenetic control, which catalyzes the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) to modulate gene expression, was highly upregulated in human T-ALL and negatively correlated with the prognosis of patients. Knockdown of TET1 suppressed T-ALL growth and progression, suggesting that TET1 inhibition maybe an effective way to fight T-ALL via DNA epigenetic modulation. Combining structure-guided virtual screening and cell-based high-throughput screening of FDA-approved drug library, we discovered that auranofin, a gold-containing compound, is a potent TET1 inhibitor. Auranofin inhibited the catalytic activity of TET1 through competitive binding to its substrates binding pocket and thus downregulated the genomic level of 5hmC marks and particularly epigenetically reprogramed the expression of oncogene c-Myc in T-ALL in TET1-dependent manner and resulted in suppression of T-ALL in vitro and in vivo. These results revealed that TET1 is a potential therapeutic target in human T-ALL and elucidated the mechanism that TET1 inhibitor auranofin suppressed T-ALL through the TET1/5hmC/c-Myc signaling pathway. Our work thus not only provided mechanism insights for T-ALL treatment, but also discovered potential small molecule therapeutics for T-ALL.

Promoting the mechanization of aquaculture is one of the most important supporting measures to ensure the high-quality development of the aquaculture industry in China. In order to solve the problems of predominantly manual work and to decrease the costs of aquaculture, the influencing factors of China’s aquaculture mechanization were systematically analyzed. The triple bottom theory was selected, and three aspects were identified, including environmental, economic, and social aspects. Through the literature review, the Delphi method, and the analytic hierarchy process, the comprehensive evaluation indicator system, including 18 influencing factors, was proposed. Moreover, the fuzzy comprehensive evaluation method was combined with the model to solve the evaluation results. A case study in Liaoning Province was offered and, according to the analysis results, the economic aspect at the first level was the most critical factor; the financial subsidy for the purchase of aquaculture machinery, the energy consumption of the machinery and equipment, and the promotion and use of aquaculture technology were the most important factors and had the greatest impact on the development of aquaculture mechanization in China. The effective implementation paths and countermeasures were proposed, such as the promotion of mechanized equipment and the enhancement of the machinery purchase subsidies, in order to provide an important decision-making basis for the improvement of the level of aquaculture mechanization.

Intraocular malignant tumors including primary and metastatic tumors, are mainly found in Retina and uvea, and very few cases originate from the sclera and optic nerve. Intraocular tumors can endanger the patient's vision and even life, and proper treatment is vital. There have been several traditional treatments for intraocular tumors, such as radiotherapy, chemotherapy and surgery. In recent years, new methods have been developed in clinical applications including anti-VEGF and gene therapy. This paper aims to provide a timely review about recent progress in the treatment of intraocular malignant tumor.

The straightness of Paeonia lactiflora stems is pivotal for their use in cut flowers, often influenced by cellulose and other cell wall materials. Variances in auxin (IAA) content between straight and bending cultivars have been noted, yet the underlying mechanism remains elusive. Here, we treated the bending cultivar ‘Qi Hualushuang’ with 150 mg·L −1 IAA across five developmental stages, examining morphological, anatomical, and cellulose metabolism-related changes. The results showed that exogenous IAA significantly improved stem straightness, plant height, and stem diameter. This improvement coincided with the early development of vascular tissue at the early and mid-stage of stem growth. IAA application down-regulated the expression of cellulose synthase genes, altering sucrose synthase and cellulase activities, ultimately resulting in higher cellulose content during the bud-breeding stage. Notably, an early accumulation of cellulose in vascular tissue was observed, characterized by earlier and more orderly arranged cellulose microfibrils, oriented at a smaller angle to the growth direction. This observation suggests that early cellulose development is advantageous for achieving stem straightness. Our study also found that the promotional effect of IAA on stem growth was mainly in the early stages, and other phytohormones may be jointly involved in the regulation. In summary, our study suggests that IAA enhances stem straightness by modulating the development of cell wall cellulose and vascular tissue. These findings provide a theoretical basis for the cultivation and trait improvement of P. lactiflora cut flower cultivars.