Single-cell CAR T atlas reveals type 2 function in 8-year leukaemia remission.

Despite a high response rate in chimeric antigen receptor (CAR) T cell therapy for acute lymphocytic leukaemia (ALL)1-3, approximately 50% of patients relapse within the first year4-6, representing an urgent question to address in the next stage of cellular immunotherapy. Here, to investigate the molecular determinants of ultralong CAR T cell persistence, we obtained a single-cell multi-omics atlas from 695,819 pre-infusion CAR T cells at the basal level or after CAR-specific stimulation from 82 paediatric patients with ALL enrolled in the first two CAR T ALL clinical trials and 6 healthy donors. We identified that elevated type 2 functionality in CAR T infusion products is significantly associated with patients maintaining a median B cell aplasia duration of 8.4 years. Analysis of ligand-receptor interactions revealed that type 2 cells regulate a dysfunctional subset to maintain whole-population homeostasis, and the addition of IL-4 during antigen-specific activation alleviates CAR T cell dysfunction while enhancing fitness at both transcriptomic and epigenomic levels. Serial proteomic profiling of sera after treatment revealed a higher level of circulating type 2 cytokines in 5-year or 8-year relapse-free responders. In a leukaemic mouse model, type 2high CAR T cell products demonstrated superior expansion and antitumour activity, particularly after leukaemia rechallenge. Restoring antitumour efficacy in type 2low CAR T cells was attainable by enhancing their type 2 functionality, either through incorporating IL-4 into the manufacturing process or by priming manufactured CAR T products with IL-4 before infusion. Our findings provide insights into the mediators of durable CAR T therapy response and suggest potential therapeutic strategies to sustain long-term remission by boosting type 2 functionality in CAR T cells.

Influence of surface water and groundwater gradient on spatial distribution of typical vegetation in the hinterland of Taklamakan desert.

Water resources are essential for desert oases and are key drivers of local ecological processes critical to the growth of desert vegetation. In this study, the oasis in the hinterland of the Taklamakan Desert, China, was selected as the research subject. Using high-precision classification of oasis vegetation through machine learning, surface water within the oasis was identified and extracted from multi-year Landsat remote sensing data. The spatial distribution patterns of the main community-building species, Populus euphratica and Tamarix ramosissima, were studied under different moisture gradients using environmental covariates and measured groundwater depth to invert its spatial distribution and K-mean clustering to construct surface water and groundwater moisture gradients. The results indicated that the classification accuracy for the two species reached 0.917. Gradients 1-5 were used to categorize the water resources, dividing surface water and groundwater into five gradients. Gradient 3 exhibited the optimal moisture conditions, with a high surface water distribution frequency (0.017) and shallow groundwater depth (3.158 m), while Gradient 4 showed the least optimal moisture conditions, characterized by a low surface water distribution frequency (0.008) and deep groundwater depth (4.820 m). The water gradient decreased in the following order: Gradient 3 > Gradient 5 > Gradient 1 > Gradient 2 > Gradient 4. The optimum gradients for growth of P. euphratica and T. ramosissima were gradients 5, 1, and 2. The normalized vegetation index spatial distribution patterns of the two species were consistent with that of the moisture gradient. Tamarix ramosissima was found to be more tolerant to salinity and drought than P. euphratica. Overall, this study provides valuable information on the effect of the spatial distribution of water resource gradients on oasis vegetation and can guide future water delivery policies in oases.

Efficacy study of neuronavigation-assisted stereotactic drilling of urokinase drainage versus craniotomy in the treatment of massive intracerebral haemorrhage in elderly patientsa.

To evaluate the efficacy of neuronavigation-assisted stereotactic drilling drainage compared with that of craniotomy in the treatment of massive intracerebral haemorrhage (ICH) in elderly patients. This was a randomized, controlled, blind endpoint clinical study. Elderly patients with massive ICH treated at our neurosurgery department, without the formation of brain herniation preoperatively, all underwent neurosurgical intervention. Patients were randomly assigned to two groups: the minimally invasive surgery (MIS) group, which received neuronavigation-assisted stereotactic drilling drainage, and the craniotomy haematoma removal surgery (CHRS) group. Patient characteristics, surgical anaesthesia methods, surgery duration, intraoperative bleeding volume, duration of ICU stay duration of hospital stay, complications, and modified Rankin scale (mRS) scores at 90 days posttreatment were compared between the two groups. Statistical analysis was performed on the collected data. A total of 67 patients were randomly assigned, with 33 (49.25%) in the MIS group and 34 (50.75%) in the CHRS group. Compared with the CHRS group, the MIS group had advantages, including the use of local anaesthesia, shorter surgery duration, less intraoperative bleeding, shorter ICU stay, and fewer complications (P < 0.05). The MIS group had a significantly improved patient prognosis at 90 days (mRS 0-3). However, there were no significant differences in hospital stay or 90-day survival rate between the two groups (P > 0.05). For elderly patients with massive ICH without brain herniation, stereotactic drilling drainage is a simple surgical procedure that can be performed under local anaesthesia. Patients treated with this approach seem to have better outcomes than those treated with craniotomy. In clinical practice, neuronavigation-assisted stereotactic drilling drainage is recommended for surgical treatment in elderly patients with massive ICH without brain herniation.Clinical trial registration number: NCT04686877.

Microvesicles derived from mesenchymal stem cells inhibit acute respiratory distress syndrome-related pulmonary fibrosis in mouse partly through hepatocyte growth factor.

BACKGROUND: Pulmonary fibrosis is one of the main reasons for the high mortality rate among acute respiratory distress syndrome (ARDS) patients. Mesenchymal stromal cell-derived microvesicles (MSC-MVs) have been shown to exert antifibrotic effects in lung diseases. AIM: To investigate the effects and mechanisms of MSC-MVs on pulmonary fibrosis in ARDS mouse models. METHODS: MSC-MVs with low hepatocyte growth factor (HGF) expression (siHGF-MSC-MVs) were obtained via lentivirus transfection and used to establish the ARDS pulmonary fibrosis mouse model. Following intubation, respiratory mechanics-related indicators were measured via an experimental small animal lung function tester. Homing of MSC-MVs in lung tissues was investigated by near-infrared live imaging. Immunohistochemical, western blotting, ELISA and other methods were used to detect expression of pulmonary fibrosis-related proteins and to compare effects on pulmonary fibrosis and fibrosis-related indicators. RESULTS: The MSC-MVs gradually migrated and homed to damaged lung tissues in the ARDS model mice. Treatment with MSC-MVs significantly reduced lung injury and pulmonary fibrosis scores. However, low expression of HGF (siHGF-MSC-MVs) significantly inhibited the effects of MSC-MVs (P < 0.05). Compared with the ARDS pulmonary fibrosis group, the MSC-MVs group exhibited suppressed expression of type I collagen antigen, type III collagen antigen, and the proteins transforming growth factor-ß and α-smooth muscle actin, whereas the siHGF-MVs group exhibited significantly increased expression of these proteins. In addition, pulmonary compliance and the pressure of oxygen/oxygen inhalation ratio were significantly lower in the MSC-MVs group, and the effects of the MSC-MVs were significantly inhibited by low HGF expression (all P < 0.05). CONCLUSION: MSC-MVs improved lung ventilation functions and inhibited pulmonary fibrosis in ARDS mice partly via HGF mRNA transfer.

Birthweight influences liver structure, function and disease risk: Evidence of a causal association.

AIM: Low birthweight is an issue during pregnancy associated with an increased risk of developing liver disease later in life. Previous Mendelian randomisation (MR) studies which explored this issue have not isolated the direct impact of the foetus on birthweight. In the present study, MR was used to assess whether direct foetal effects on birthweight were causally associated with liver structure, function and disease risk independent of intrauterine effects. MATERIALS AND METHODS: We extracted single nucleotide polymorphisms (SNPs) from genome-wide association studies (GWAS) about direct foetal-affected birthweight (321 223 cases) to conduct univariable and multivariable MR analyses to explore the relationships between birthweight and 4 liver structure measures, 9 liver function measures and 18 liver diseases. A two-step MR analysis was used to further assess and quantify the mediating effects of the mediators. RESULTS: When isolating direct foetal effects, genetically predicted lower birthweight was associated with a higher risk of non-alcoholic fatty liver disease (NAFLD) (odds ratios [OR], 95% confidence interval [CI]: 1.61, 1.29-2.02, p < 0.001), higher magnetic resonance imaging [MRI] proton density fat fraction (PDFF) and higher serum gamma glutamyltransferase (GGT). Two-step MR identified two candidate mediators that partially mediate the direct foetal effect of lower birthweight on NAFLD, including fasting insulin (proportion mediated: 22.29%) and triglycerides (6.50%). CONCLUSIONS: Our MR analysis reveals a direct causal association between lower birthweight and liver MRI PDFF, as well as the development of NAFLD, which persisted even after accounting for the potential influence of maternal factors. In addition, we identified fasting insulin and triglycerides as mediators linking birthweight and hepatic outcomes, providing insights for early clinical interventions.

Histamine synthesis and transport are coupled in axon terminals via a dual quality control system.

Monoamine neurotransmitters generated by de novo synthesis are rapidly transported and stored into synaptic vesicles at axon terminals. This transport is essential both for sustaining synaptic transmission and for limiting the toxic effects of monoamines. Here, synthesis of the monoamine histamine by histidine decarboxylase (HDC) and subsequent loading of histamine into synaptic vesicles are shown to be physically and functionally coupled within Drosophila photoreceptor terminals. This process requires HDC anchoring to synaptic vesicles via interactions with N-ethylmaleimide-sensitive fusion protein 1 (NSF1). Disassociating HDC from synaptic vesicles disrupts visual synaptic transmission and causes somatic accumulation of histamine, which leads to retinal degeneration. We further identified a proteasome degradation system mediated by the E3 ubiquitin ligase, purity of essence (POE), which clears mislocalized HDC from the soma, thus eliminating the cytotoxic effects of histamine. Taken together, our results reveal a dual mechanism for translocation and degradation of HDC that ensures restriction of histamine synthesis to axonal terminals and at the same time rapid loading into synaptic vesicles. This is crucial for sustaining neurotransmission and protecting against cytotoxic monoamines.

CAR-T and CAR-NK as cellular cancer immunotherapy for solid tumors.

In the past decade, chimeric antigen receptor (CAR)-T cell therapy has emerged as a promising immunotherapeutic approach for combating cancers, demonstrating remarkable efficacy in relapsed/refractory hematological malignancies in both pediatric and adult patients. CAR-natural killer (CAR-NK) cell complements CAR-T cell therapy by offering several distinct advantages. CAR-NK cells do not require HLA compatibility and exhibit low safety concerns. Moreover, CAR-NK cells are conducive to "off-the-shelf" therapeutics, providing significant logistic advantages over CAR-T cells. Both CAR-T and CAR-NK cells have shown consistent and promising results in hematological malignancies. However, their efficacy against solid tumors remains limited due to various obstacles including limited tumor trafficking and infiltration, as well as an immuno-suppressive tumor microenvironment. In this review, we discuss the recent advances and current challenges of CAR-T and CAR-NK cell immunotherapies, with a specific focus on the obstacles to their application in solid tumors. We also analyze in depth the advantages and drawbacks of CAR-NK cells compared to CAR-T cells and highlight CAR-NK CAR optimization. Finally, we explore future perspectives of these adoptive immunotherapies, highlighting the increasing contribution of cutting-edge biotechnological tools in shaping the next generation of cellular immunotherapy.

The expression and clinical significance of ARHGAP25 in osteosarcoma based on bioinformatics analysis.

ARHGAP25, a member of the ARHGAP family, encodes a negative regulator of Rho-GTPase that is important for actin remodeling, cell polarity, and cell migration. ARHGAP25 is down-regulated in a variety of solid tumors and promotes cancer cell growth, migration, and invasion. However, nothing is understood about ARHGAP25's biological function in osteosarcoma. This work used qPCR and WB to confirm the expression of ARHGAP25 in osteosarcoma following the initial analysis of its expression in pan-cancer. For GO and KEGG analysis, we have chosen 300 genes from the TARGET osteosarcoma data that had the strongest positive correlation with ARHGAP25, and we created nomogram and calibration charts. We simultaneously overexpressed ARHGAP25 in osteosarcoma cells to examine its impact on apoptosis and proliferation. By using MSP, we determined their methylation status in osteosarcoma cells and normal bone cells. We observed that ARHGAP25 was significantly downregulated in a range of malignancies, including osteosarcoma, and was associated with poor patient outcomes. The decrease of ARHGAP25 expression in osteosarcoma is related to DNA methylation. Overexpression of ARHGAP25 induced apoptosis and inhibited the proliferation of osteosarcoma cells in vitro. In addition, ARHGAP25 is also associated with immune-related pathways in osteosarcoma. These findings suggest that ARHGAP25 is a valuable prognostic biomarker in osteosarcoma patients.

Catalytic asymmetric functionalization and dearomatization of thiophenes.

The asymmetric synthesis of thiophene-derived compounds, including catalytic asymmetric dearomatization of thiophene and atroposelective synthesis of benzothiophene derivatives, has rarely been reported. In this work, the asymmetric transformation of the thiophene motif is investigated. Through the rational design of substrates with a thiophene structure, by using the vinylidene ortho-quinone methide (VQM) intermediate as a versatile tool, axially chiral naphthyl-benzothiophene derivatives and thiophene-dearomatized chiral spiranes were obtained in high yields with excellent enantioselectivities.

Integrated network pharmacology and metabolomics to reveal the mechanism of Pinellia ternata inhibiting non-small cell lung cancer cells.

Lung cancer is a malignant tumor with highly heterogeneous characteristics. A classic Chinese medicine, Pinellia ternata (PT), was shown to exert therapeutic effects on lung cancer cells. However, its chemical and pharmacological profiles are not yet understood. In the present study, we aimed to reveal the mechanism of PT in treating lung cancer cells through metabolomics and network pharmacology. Metabolomic analysis of two strains of lung cancer cells treated with Pinellia ternata extracts (PTE) was used to identify differentially abundant metabolites, and the metabolic pathways associated with the DEGs were identified by MetaboAnalyst. Then, network pharmacology was applied to identify potential targets against PTE-induced lung cancer cells. The integrated network of metabolomics and network pharmacology was constructed based on Cytoscape. PTE obviously inhibited the proliferation, migration and invasion of A549 and NCI-H460 cells. The results of the cellular metabolomics analysis showed that 30 metabolites were differentially expressed in the lung cancer cells of the experimental and control groups. Through pathway enrichment analysis, 5 metabolites were found to be involved in purine metabolism, riboflavin metabolism and the pentose phosphate pathway, including D-ribose 5-phosphate, xanthosine, 5-amino-4-imidazolecarboxyamide, flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD). Combined with network pharmacology, 11 bioactive compounds were found in PT, and networks of bioactive compound-target gene-metabolic enzyme-metabolite interactions were constructed. In conclusion, this study revealed the complicated mechanisms of PT against lung cancer. Our work provides a novel paradigm for identifying the potential mechanisms underlying the pharmacological effects of natural compounds.

Amplifying Chinese physicians' emphasis on patients' psychological states beyond urologic diagnoses with ChatGPT-A multi-center cross-sectional study.

BACKGROUND: Artificial intelligence (AI) technologies, particularly large language models (LLMs), have been widely employed by the medical community. In addressing the intricacies of urology, ChatGPT offers a novel possibility to aid in clinical decision-making. This study aimed to investigate the decision-making ability of LLMs in solving complex urology-related problems and assess its effectiveness in providing psychological support to patients with urological disorders. MATERIALS AND METHODS: This study evaluated the clinical and psychological support capabilities of ChatGPT 3.5 and 4.0 in the field of urology. A total of 69 clinical and 30 psychological questions were posed to the AI models, and their responses were evaluated by both urologists and psychologists. As a control, clinicians from Chinese medical institutions provided responses under closed-book conditions. Statistical analyses were conducted separately for each subgroup. RESULTS: In multiple-choice tests covering diverse urological topics, ChatGPT 4.0, performed comparably to the physician group, with no significant overall score difference. Subgroup analyses revealed variable performance, based on disease type and physician experience, with ChatGPT 4.0 generally outperforming ChatGPT 3.5 and exhibiting competitive results against physicians. When assessing the psychological support capabilities of AI, it is evident that ChatGPT4.0 outperforms ChatGPT3.5 across all urology-related psychological problems. CONCLUSIONS: The performance of LLMs in dealing with standardized clinical problems and providing psychological support has certain advantages over clinicians. AI stands out as a promising tool for potential clinical aid.

Variation Law of Hybrid Explosion Characteristic Parameters of Gas and Coal Dust Coupled with Multiple Factors.

This study aims at extensively investigating the explosion characteristics of a hybrid mixture of gas and coal dust. Accordingly, the standard 20 L spherical explosion system was applied to measure parameters such as the lower explosion limit, maximum explosion pressure, and index of the hybrid mixture of different concentrations of gas and coal dust. Moreover, different coal dust particle sizes and components were measured. With regard to coal dust with different particle sizes and components, the obtained results revealed that, while the addition of gas significantly reduced the lower explosion limit, the maximum explosion pressure and index were increased; that is to say, the presence of gas will increase the explosion risk of coal dust. However, under conditions in which the particle size of the coal dust was large or the volatile content was low, the addition of gas was found to lead to a higher decrease of the lower explosion limit; this is, while the maximum explosion pressure and explosion index were increased. Consequently, gas can be argued to have a greater influence on the explosion risk of coal dust with a large particle size or low volatile content. Furthermore, regardless of the particle size or the volatile content of coal dust, the maximum explosion pressure and explosion index of the hybrid mixture were observed to be higher than that of the pure coal dust but lower than that of the pure gas. That is to say, the explosion intensity of the gas/coal dust composite system is higher than that of pure coal dust but less than that of pure gas. The research results can provide theoretical basis for coal mine explosion disaster prevention and control and have important significance.

Fusing Science with Industry: Perovskite Photovoltaics Moving Rapidly into Industrialization.

The organic-inorganic lead halide per materials have emerged as highly promising contenders in the field of photovoltaic technology, offering exceptional efficiency and cost-effectiveness. The commercialization of perovskite photovoltaics hinges on successfully transitioning from lab-scale perovskite solar cells to large-scale perovskite solar modules (PSMs). However, the efficiency of PSMs significantly diminishes with increasing device area, impeding commercial viability. Central to achieving high-efficiency PSMs is fabricating uniform functional films and optimizing interfaces to minimize energy loss. This review sheds light on the path toward large-scale PSMs, emphasizing the pivotal role of integrating cutting-edge scientific research with industrial technology. By exploring scalable deposition techniques and optimization strategies, the advancements and challenges in fabricating large-area perovskite films are revealed. Subsequently, the architecture and contact materials of PSMs are delved while addressing pertinent interface issues. Crucially, efficiency loss during scale-up and stability risks encountered by PSMs is analyzed. Furthermore, the advancements in industrial efforts toward perovskite commercialization are highlighted, emphasizing the perspective of PSMs in revolutionizing renewable energy. By highlighting the scientific and technical challenges in developing PSMs, the importance of combining science and industry to drive their industrialization and pave the way for future advancements is stressed.

Broadband chaos of an interband cascade laser with a 6-GHz bandwidth.

Near-infrared semiconductor lasers subject to optical feedback usually produce chaos with a broad bandwidth of a few GHz. However, the reported mid-infrared interband cascade lasers (ICLs) only show chaos with a limited bandwidth below 1 GHz. Here we show that an ICL with optical feedback is able to generate broadband chaos as well. The mid-infrared chaos exhibits a remarkable bandwidth of about 6 GHz, which is comparable to that of the near-infrared counterpart. In addition, the spectral coverage in the electrical domain reaches as high as 17.7 GHz. It is found that the chaos bandwidth generally broadens with increasing feedback ratio and/or increasing pump current of the laser, while it is insensitive to the feedback length.

Tmem30a protects against podocyte injury through suppression of pyroptosis.

Podocytopathies, such as focal segmental glomerulosclerosis (FSGS), are characterized by podocyte injury and can easily progress to end-stage kidney disease. However, the mechanisms underlying podocyte injury remain unclear. We observed podocyte injury along with pyroptosis in patients with FSGS. Bioinformatic analysis of public datasets revealed that transmembrane protein 30a (Tmem30a) might be associated with FSGS. The expression of Temem30a and the podocyte-related protein, nephrin, were significantly downregulated in patients with FSGS, adriamycin (ADR)-induced mice, and podocyte-specific Tmem30a lox P /loxP ; NPHS2-Cre mice, whereas the expression of NLR family pyrin domain containing 3 (NLRP3) and ASC, two pyroptosis-related proteins, were significantly upregulated. Meanwhile, the pyroptosis inhibitor MCC950 and disulfiram (DSF) increased Tmem30a and podocyte-related proteins expression, and inhibited pyroptosis-related proteins expression in ADR-induced mouse podocytes and Tmem30a knockdown (KD) mouse podocytes. Therefore, Tmem30a might protect against podocyte injury by inhibiting pyroptosis, suggesting a potential therapeutic target for podocytopathies.

Nonlinear dynamics of an interband cascade laser with optical injection.

This work reports the nonlinear dynamics of a mid-infrared interband cascade laser (ICL) subject to optical injection. It is shown that the stable locking regime is asymmetric and broadens with increasing injection strength. Outside the locking regime, the ICL mostly produces period-one oscillations. However, three categories of periodic pulse oscillations are observed in the vicinity of the Hopf bifurcation and the saddle-node bifurcation. In particular, it is found that the ICL generates broadband chaos at a near-threshold pump current, and the chaos bandwidth is over 300 MHz.

Analysis of physical and mechanical behaviors and microscopic mineral characteristics of thermally damaged granite.

Temperature's influence on the physical and mechanical properties of rocks is a crucial concern for the rational design of deep rock engineering structures and the assurance of their long-term stability. To systematically comprehend the impact of the evolution of mineral composition and micro characteristics on the physical and mechanical behavior of thermally damaged granite, we observed the microscopic structural defects inside the rocks with a polarizing microscope and revealed the thermal damage mechanism of granite from a microscopic perspective by combining ultrasound detection and XRD phase characteristic analysis. The results show that the physical properties of the specimens changed significantly at three characteristic temperature points: 400 °C, 800 °C, and 1000 °C. Under high temperature conditions, the diffraction intensity of all minerals in granite, except for quartz, generally decreased, and stable minerals decomposed. Albite and potash feldspar decomposed to form anorthoclase, thereby reducing the structural stability of the rock material. In addition, the peak width of various minerals decreased to varying degrees with increasing temperature. The increase in mineral volume further damaged the internal structure of the rock material while promoting the transformation from grain boundary to intergranular cracks and from intragranular cracks to transgranular cracks, ultimately forming a interconnected crack network. Thermal damage significantly reduced the longitudinal wave velocity, uniaxial compressive strength, and elastic modulus of the specimens, while the stress-strain curve relationship indicated that the specimens underwent two opposite processes of transformation from brittleness to ductility and then from ductility to brittleness. The thermal damage threshold of granite in this study was 600 °C.

Advancing arrhythmia education through the CDIO approach: a new paradigm in nursing student training.

BACKGROUND: The accurate diagnosis and effective management of arrhythmias are crucial, with nurses playing a key role in the early detection and treatment, significantly impacting patient outcomes. Improving education on arrhythmias among nurses, especially in critical care and perioperative settings, can enhance patient safety and the quality of care. METHODS: A total of 116 trainee nurses were randomly divided into two groups: one utilizing the conceive-design-implement-operate (CDIO) model and the other employing a traditional lecture-based learning (LBL) method, to undergo arrhythmia training. The studyassessed the effects of the two teaching methods and investigated the students' attitudes toward these educational practices, with all participants completing pre- and post-course tests. RESULTS: The CDIO model significantly enhances nursing students' arrhythmia proficiency, yielding higher test scores and sustained improvement after 24-week compared to the traditional LBL method, alongside markedly better self-learning enthusiasm, understanding, satisfaction with the teaching approach and effectiveness, and interest in learning arrhythmia. The CDIO model in nursing arrhythmia courses boosts theoretical knowledge and application, showing potential in clinical skill enhancement. CONCLUSIONS: Our study introduces the CDIO model in nursing arrhythmia courses, with improvement in knowledge and skills, and promise for broader application.