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Induced pluripotent stem cells (iPS) are multipotent cell types generated by reprogramming adult somatic cells, with broad prospects in disease model establishment, drug screening, and regenerative medicine. This paper delves into the mechanism of iPS cell differentiation, differentiation regulation strategies, and their applications in disease model establishment. Initially, we explore the basic features of iPS cells and their differentiation potential, analyzing the key molecular and signaling pathways influencing the iPS differentiation process. Subsequently, we examine several common differentiation induction methods, supported by specific experimental data, and discuss optimization strategies to enhance differentiation efficiency and obtain specific cell types. Finally, we focus on the application of iPS cells in establishing disease models, particularly in neurodegenerative diseases, cardiovascular diseases, and genetic diseases, incorporating the latest research progress and innovative content. Through in - depth analysis, this paper aims to offer a theoretical basis and technical support for the future clinical application of iPS cells.

Costimulation of T cell responses with monoclonal antibody agonists (mAb-AG) targeting 4-1BB showed robust anti-tumor activity in preclinical models, but their clinical development was hampered by low efficacy (Utomilumab) or severe liver toxicity (Urelumab). Here we show that isotype and intrinsic agonistic strength co-determine the efficacy and toxicity of anti-4-1BB mAb-AG. While intrinsically strong agonistic anti-4-1BB can activate 4-1BB in the absence of FcγRs, weak agonistic antibodies rely on FcγRs to activate 4-1BB. All FcγRs can crosslink anti-41BB antibodies to strengthen co-stimulation, but activating FcγR-induced antibody-dependent cell-mediated cytotoxicity compromises anti-tumor immunity by deleting 4-1BB + cells. This suggests balancing agonistic activity with the strength of FcγR interaction as a strategy to engineer 4-1BB mAb-AG with optimal therapeutic performance. As a proof of this concept, we have developed LVGN6051, a humanized 4-1BB mAb-AG that shows high anti-tumor efficacy in the absence of liver toxicity in a mouse model of cancer immunotherapy. Agonistic 4-1BB antibodies developed for cancer immunotherapy have suffered from either hepatotoxicity or insufficient anti-cancer activity. Here the authors determine the contribution of FcγR binding and agonistic strength to these outcomes, and engineer a 4-1BB antibody with potent anti-tumor effect and no liver toxicity in mice.

Hepatitis B virus (HBV) remains a major cause of liver disease and premature death globally, with China bearing a significant share of the burden. However, long-term trends and future projections of HBV burden in China remain insufficiently described, despite widespread infant vaccination and expanded antiviral therapy. We analyzed hepatitis B-related mortality, age-standardized mortality rate (ASMR), disability-adjusted life years (DALYs), and age-standardized DALY rate (ASDR) in China from 1990 to 2021 using data extracted from the GBD 2021 database. Temporal trends were quantified by estimated annual percentage change (EAPC). Between 1990 and 2021, the number of deaths from hepatitis B-related liver diseases in China increased from 215 thousand to 219 thousand (+1.83%), whereas the ASMR decreased from 23.86 per 100,000 to 10.68 (EAPC: -2.78). The disability-adjusted life years (DALYs) decreased from 7.78 million in 1990 to 6.61 million in 2021 (-15.04%), with the ASDR decreasing from 774 per 100,000-329 (EAPC: -3). Despite significant reductions in HBV mortality and DALYs, the growing burden of HBV-related liver cancer, particularly among older males, remains a critical concern. Targeted early screening and treatment strategies are urgently needed. Projections for 2035 indicate a continued decline in the overall burden of hepatitis B, with the liver cancer burden showing a fluctuating decrease. Despite progress in HBV prevention and control, the increasing burden of hepatitis B-related liver cancer remains a major public health challenge.

Background Chimeric antigen receptor (CAR)-T immunotherapy fails to treat solid tumors due in part to immunosuppressive microenvironment. Excess lactate produced by tumor glycolysis increases CAR-T immunosuppression. The mechanism of lactate inducing the formation of immunosuppressive microenvironment remains to be further explored. Methods Immunocyte subpopulations and molecular characteristics were analyzed in the orthotopic xenografts of nude mice using flow cytometry assay and immunohistochemical staining after oxamate, a lactate dehydrogenase A (LDHA) inhibitor, and control T or CAR-T cells injection alone or in combination. RT-qPCR, western blot, flow cytometry, immunofluorescence, luciferase reporter assay, chromatin immunoprecipitation and ELISA were performed to measure the effect of lactate on the regulation of CD39, CD73 and CCR8 in cultured glioma stem cells, CD4 + T cells or macrophages. Results Oxamate promoted immune activation of tumor-infiltrating CAR-T cells through altering the phenotypes of immune molecules and increasing regulatory T (Treg) cells infiltration in a glioblastoma mouse model. Lactate accumulation within cells upregulated CD39, CD73 and CCR8 expressions in both lactate-treated cells and glioma stem cells-co-cultured CD4 + T cells and macrophages, and intracellular lactate directly elevated the activities of these gene promotors through histone H3K18 lactylation. Conclusions Utilizing lactate generation inhibitor not only reprogramed glucose metabolism of cancer stem cells, but also alleviated immunosuppression of tumor microenvironment and reduced tumor-infiltrating CAR-Treg cells, which may be a potential strategy to enhance CAR-T function in glioblastoma therapy.

Background Just Another Gibbs Sampling (JAGS) is a convenient tool to draw posterior samples using Markov Chain Monte Carlo for Bayesian modeling. However, the built-in function dinterval() for censored data misspecifies the default computation of deviance function, which limits likelihood-based Bayesian model comparison. Results To establish an automatic approach to specifying the correct deviance function in JAGS, we propose a simple and generic alternative modeling strategy for the analysis of censored outcomes. The two illustrative examples demonstrate that the alternative strategy not only properly draws posterior samples in JAGS, but also automatically delivers the correct deviance for model assessment. In the survival data application, our proposed method provides the correct value of mean deviance based on the exact likelihood function. In the drug safety data application, the deviance information criterion and penalized expected deviance for seven Bayesian models of censored data are simultaneously computed by our proposed approach and compared to examine the model performance. Conclusions We propose an effective strategy to model censored data in the Bayesian modeling framework in JAGS with the correct deviance specification, which can simplify the calculation of popular Kullback–Leibler based measures for model selection. The proposed approach applies to a broad spectrum of censored data types, such as survival data, and facilitates different censored Bayesian model structures.

Intrahepatic cholangiocarcinoma (iCCA) is a malignancy with difficult treatment and poor prognosis, whose pathogenesis could be associated with the expression patterns of circular RNAs (circRNAs). Here, we aim to investigate the effects and mechanism of hsa_circ_0006834 on iCCA proliferation. At first, hsa_circ_0006834 was proved to suppress iCCA cells proliferation and induce autophagy following the construction of hsa_circ_0006834 vector. And hsa_circ_0006834 is negatively linked with the proliferation, migration and invasion of iCCA cells through autophagy. Subsequently, RNA pull-down and dual-luciferase reporter assays were performed to validate the hsa_circ_0006834-has-miR-637-NGFR regulatory network. It was demonstrated by qPCR and Western blot that hsa_circ_0006834 stimulates the AMPK-mTOR pathway and triggers autophagy via NGFR after si-NGFR was synthesized and transfected into iCCA cells. Ultimately, after the successful knockdown of AMPK, the role of the AMPK-mTOR pathway in hsa_circ_0006834 regulating autophagy and proliferation was verified. Taken together, our findings revealed that hsa_circ_0006834 activates the AMPK-mTOR pathway and autophagy to suppress iCCA proliferation by has-miR-637-NGFR network, indicating the potential of hsa_circ_0006834 as a biomarker for iCCA diagnosis and therapy.

With ecological problems and energy crises intensifying today, greening is essential to sustainable development. Compared with other types of buildings, hospital buildings account for a relatively larger proportion of building energy consumption. In order to realize the rapid cycle optimization of a green hospital project in the design stage and improve the green grade of the building, a pre-evaluation Building Information Model (BIM) of green hospital building performance was established in this study. Firstly, the literature review and expert consultation established the building performance pre-evaluation index system for green hospitals. Then, BIM technology is taken to extract data needed for building a performance pre-evaluation system, and the Cloud Model and the Matter–Element Extension Theory are used to build models. The final green grade calculation is realized in MATLAB. Finally, the Maluan Bay Hospital is taken as an example to test the applicability and effectiveness of the proposed model. The results show that the green hospital building performance pre-evaluation model has advantages of simulation, cyclic optimization and fuzzy quantification, which can effectively guide the design and construction of a green hospital.

The functional trait diversity of plant communities regulates the effects of biodiversity on ecosystem functioning and stability. However, the role of functional trait diversity in explaining ecosystem productivity and stability in natural wetlands remains unclear. Using vegetation data from 1139 sites across U.S. wetlands, we examine the associations of functional diversity (trait dispersion within a community) and functional identity (community-level trait values) of plant size traits and resource economics traits with satellite-derived productivity and temporal stability at continental scales. Community-level plant size shows the strongest association with productivity and stability, which is consistent across different wetland types and levels of anthropogenic disturbance. While functional diversity is generally positively correlated with productivity and stability, these relationships vary substantially across environmental contexts. Notably, weaker correlations are observed under higher levels of anthropogenic disturbances. These findings suggest that wetland conservation and restoration efforts should focus on increasing functional diversity and prioritizing large dominant species to increase productivity and stability. Protecting healthy and stable wetlands is important for retaining biodiversity and ecosystem services. Using a nationwide wetland survey in the United States, the authors find that wetland productivity and stability are more strongly associated with community-level plant traits than with plant functional diversity.

The primary aim of this study is to delve into the potential of Acetyl-11-keto-β-boswellic acid (AKBA) in ameliorating neuronal damage induced by acute spinal cord injury, as well as to unravel the intricate underlying mechanisms. A cohort of 40 Sprague-Dawley rats was meticulously categorized into four groups. Following a seven-day oral administration of AKBA, damaged spinal cord samples were meticulously procured for Nissl staining and electron microscopy to assess neuronal demise. Employing ELISA, immunofluorescence, Western blot (WB), and quantitative polymerase chain reaction (qPCR), the modulatory effects of AKBA within the context of spinal cord injury were comprehensively evaluated. Furthermore, employing an ex vivo extraction of spinal cord neurons, an ATP + LPS-induced pyroptotic injury model was established. The model was subsequently subjected to Nrf2 inhibition, followed by a battery of assessments involving ELISA, DCFH-DA staining, flow cytometry, immunofluorescence, and WB to decipher the effects of AKBA on the spinal cord neuron pyroptosis model. By engaging the Nrf2-ROS-NLRP3 pathway, AKBA exerted a repressive influence on the expression of the pyroptotic initiator protein Caspase-1, thereby mitigating the release of GSDMD and alleviating pyroptosis. Additionally, AKBA demonstrated the ability to attenuate the release of IL-18 and IL-1β, curbing neuronal loss and expediting the restorative processes within the context of spinal cord injury. Our study elucidates that AKBA can reduce spinal cord neuronal apoptosis, providing a basis for the development of AKBA as a clinical treatment for spinal cord injury.