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Progress,implications,and challenges in using humanized immune system mice in CAR-T therapy-Application evaluation and improvement

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Animal Models and Experimental Medicine 2024年第1期7卷 3-11页

作者： Hanwei Yue Lin Bai NHC Key Laboratory of Human Disease comparative Medicine Institute of Laboratory Animal SciencesCAMS and PUMCChao-yang DistrictBeijingChina

In recent years,humanized immune system(HIS)mice have been gradually used as models for preclinical research in pharmacotherapies and cell therapies with major breakthroughs in tumor and other fields,better mimicking the human immune system and the tumor immune microenvironment,compared to traditional immunodeficient mice.To better promote the application of HIS mice in preclinical research,we se-lectively summarize the current prevalent and breakthrough research and evaluation of chimeric antigen receptor(CAR)-T cells in various antiviral and antitumor treat-ments.By exploring its application in preclinical research,we find that it can better reflect the actual clinical patient condition,with the advantages of providing high-efficiency detection indicators,even for progressive research and development.We believe that it has better clinical patient simulation and promotion for the updated design of CAR-T cell therapy than directly transplanted immunodeficient mice.The characteristics of the main models are proposed to improve the use defects of the existing models by reducing the limitation of antihost reaction,combining multiple models,and unifying sources and organoid substitution.Strategy study of relapse and toxicity after CAR-T treatment also provides more possibilities for application and development.

关键词： antitumor antiviral CAR-T humanized immune system model humanized mice preclinical research

Apolipoprotein E4 interferes with lipid metabolism to exacerbate depression-like behaviors in 5xFAD mice

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Animal Models and Experimental Medicine 2024年第3期7卷 347-361页

作者： Yanju Gong Mingfeng Li Min Liu Xinghan Wu Yanhong Li Chuan Qin Ling Zhang iNHC Key Laboratory of Human Disease comparative Medicine Beijing Engineering Research Center for Experimental Animal Models of Human Critical DiseasesInternational Center for Technology and lnnovation of Animal ModelComparative Medicine CenterInstitute of Laboratory Animal SciencesChinese Academy of Medical Sciences(CAMS)and Peking Union Medical College(PuMC)BeijingChina Changping National Laboratory(CPNL) BeijingChina

Background:Apolipoprotein E4(ApoE4)allele is the strongest genetic risk factor for late-onset Alzheimer's disease,and it can aggravate depressive symptoms in non-AD patients.However,the impact of ApoE4 on AD-associated depression-l ike behaviors and its underlying pathogenic mechanisms remain unclear.Methods:This study developed a 5xFAD mouse model overexpressing human ApoE4(E4FAD).Behavioral assessments and synaptic function tests were conducted to explore the effects of ApoE4 on cognition and depression in 5xFAD mice.Changes in peripheral and central lipid metabolism,as well as the levels of serotonin(5-HT)andγ-aminobutyric acid(GABA)neurotransmitters in the prefrontal cortex,were examined.In addition,the protein levels of 24-dehydrocholesterol reductase/glycogen synthase kinase-3 beta/mammalian target of rapamycin(DHCR24/GSK3β/m TOR)and postsynaptic density protein 95/calmodulin-dependent protein kinase II/brain-derived neurotrophic factor(PSD95/CaMK-II/BDNF)were measured to investigate the molecular mechanism underlying the effects of ApoE4 on AD mice.Results:Compared with 5xFAD mice,E4FAD mice exhibited more severe depressionlike behaviors and cognitive impairments.These mice also exhibited increased amyloid-beta deposition in the hippocampus,increased astrocyte numbers,and decreased expression of depression-related neurotransmitters 5-HT and GABA in the prefrontal cortex.Furthermore,lipid metabolism disorders were observed in E4FAD,manifesting as elevated low-density lipoprotein cholesterol and reduced high-density lipoprotein cholesterol in peripheral blood,decreased cholesterol level in the prefrontal cortex,and reduced expression of key enzymes and proteins related to cholesterol synthesis and homeostasis.Abnormal expression of proteins related to the DHCR24/GSK3β/m TOR and PSD95/CaMK-II/BDNF pathways was also observed.Conclusion:This study found that ApoE4 overexpression exacerbates depressionlike behaviors in 5xFAD mice and confirmed that ApoE4 reduces cognitive function in these mice.The mechanism may

关键词： 5xFAD mice Alzheimer's disease ApoE4 allele depression like

The relationship between compartment models and their stochastic counterparts:A comparative study with examples of the COVID-19 epidemic modeling

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Journal of Biomedical Research 2024年第2期38卷 175-188,I0016-I0018页

作者： Ziyu Zhao Yi Zhou Jinxing Guan Yan Yan Jing Zhao Zhihang Peng Feng Chen Yang Zhao Fang Shao Department of Biostatistics School of Public HealthNanjing Medical UniversityNanjingJiangsu 211166China Nanjing Hanwei Public health Research Institute Co. LtdNanjingJiangsu 210005China China International Cooperation Center for Environment and Human health Center for Global HealthNanjing Medical UniversityNanjingJiangsu 211166China The Center of Biomedical Big Data and the Laboratory of Biomedical Big Data Nanjing Medical UniversityNanjingJiangsu 211166China Jiangsu Key Lab of Cancer Biomarkers Prevention and TreatmentCollaborative Innovation Center for Cancer Personalized MedicineNanjing Medical UniversityNanjingJiangsu 211166China

Deterministic compartment models(CMs)and stochastic models,including stochastic CMs and agent-based models,are widely utilized in epidemic modeling.However,the relationship between CMs and their corresponding stochastic models is not well understood.The present study aimed to address this gap by conducting a comparative study using the susceptible,exposed,infectious,and recovered(SEIR)model and its extended CMs from the coronavirus disease 2019 modeling literature.We demonstrated the equivalence of the numerical solution of CMs using the Euler scheme and their stochastic counterparts through theoretical analysis and simulations.Based on this equivalence,we proposed an efficient model calibration method that could replicate the exact solution of CMs in the corresponding stochastic models through parameter adjustment.The advancement in calibration techniques enhanced the accuracy of stochastic modeling in capturing the dynamics of epidemics.However,it should be noted that discrete-time stochastic models cannot perfectly reproduce the exact solution of continuous-time CMs.Additionally,we proposed a new stochastic compartment and agent mixed model as an alternative to agent-based models for large-scale population simulations with a limited number of agents.This model offered a balance between computational efficiency and accuracy.The results of this research contributed to the comparison and unification of deterministic CMs and stochastic models in epidemic modeling.Furthermore,the results had implications for the development of hybrid models that integrated the strengths of both frameworks.Overall,the present study has provided valuable epidemic modeling techniques and their practical applications for understanding and controlling the spread of infectious diseases.

关键词： compartment models agent-based models compartment-agent mixed models comparative study COVID-19

Essential oils improve nursery pigs' performance and appetite via modulation of intestinal health and microbiota

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Animal Nutrition 2024年第1期16卷 174-188页

作者： Bi-Chen Zhao Tian-Hao Wang Jian Chen Bai-Hao Qiu Ya-Ru Xu Jin-Long Li College of Veterinary Medicine Northeast Agricultural University Heilongjiang Key Laboratory for Laboratory Animals and comparative Medicine Northeast Agricultural University Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment Northeast Agricultural University

Optimal intestinal health and functionality are essential for animal health and performance,and simultaneously intestinal nutrient transporters and intestinal peptides are also involved in appetite and feed intake control mechanisms.Given the potential of essential oil (EO) in improving animal performance and improving feed palatability,we hypothesized that dietary supplementation of cinnamaldehyde and carvacrol could improve performance and appetite of nursery pigs by modulating intestinal health and microbiota.Cinnamaldehyde (100 mg/kg),carvacrol (100 mg/kg),and their mixtures(including 50 mg/kg cinnamaldehyde and 50 mg/kg carvacrol) were supplemented into the diets of 240 nursery pigs for 42 d,and data related to performance were measured.Thereafter,the influence of EO on intestinal health,appetite and gut microbiota and their correlations were explored.EO supplementation increased (Phealth and bacterial structure.

关键词： Nursery pig Essential oil Intestinal health Appetite Microbiota

comparative analysis of goat and bovine milk proteins in the improvement of sarcopenia based on host-microbial interactions

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Food Science and Human Wellness 2024年

作者： Ruoyu Wang Yuxin Ma Meng Sun Lutong Li Zhaofeng Zhang Department of Nutrition and Food Hygiene School of Public health Peking University Department of Social Medicine and health Education School of Public health Peking University Beijing's Key Laboratory of Food Safety Toxicology Research and Evaluation

Introduction: Diet intervention， especially supplementation with high-quality protein， is considered to be a critical strategy in sarcopenia. However， different sources and types of protein have different health impacts. Objectives: The aim of this study is to explore the differences in the ameliorative effects and mechanisms of different sources and types of proteins on sarcopenia， providing an optimal path for the prevention and treatment of sarcopenia. Methods: A sarcopenia model was established by intraperitoneal injection of dexamethasone (5 mg/kg). Sixty male C57BL/6 mice (8 months old) were randomly divided into the normal control， sarcopenia， goat whey protein， goat milk casein， bovine whey protein， and bovine milk casein groups. Animals were treated for eight consecutive weeks. Organism-level and molecular phenotypes， 16S rRNA gene sequencing， and untargeted metabolomics profiling based on GC-TOF/MS were employed to investigate the correlation between host metabolism， microbial metabolism， autophagy and inflammation and their influence on sarcopenia in C57BL/6 male mice. Results: All four proteins increased muscle mass， and goat whey protein improved muscle strength in sarcopenic mice. Goat and bovine milk proteins promoted muscle regeneration by increasing MyoD1 and MyoG expression， and the former had a more distinct effect in inducing autophagy and decreasing inflammation than the latter. In addition， goat whey protein and casein could modulate host-microbial arginine co-metabolism. Notably， goat milk proteins responded well to sarcopenia comorbidities， including sarcopenic obesity， osteosarcopenia， and osteoarthritis. Conclusions: The study confirmed that goat milk proteins were more effective than bovine milk proteins for the control of sarcopenia. Moreover， we found that whey protein and casein could modulate host-microbial arginine co-metabolism， which shows their potential as precision nutritional supplements for the management of sarcopenia. Our study provides theoretical support for the prev

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Ultrasound-driven self-decomposition porphyrins as metal-free CO precursors for gas and sonodynamic synergistic therapy

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Science China Chemistry 2024年第5期67卷 1624-1635页

作者： Shuxin Liu Jinjuan Ma Xiang Xu Aiguo Wang Nan Zheng School of Chemical Engineering Dalian University of TechnologyDalian 116024China Department of comparative Medicine Laboratory Animal Center Dalian Medical UniversityDalian 116000China Cancer Hospital of Dalian University of Technology Shenyang 116000China

Carbon monoxide(CO) is an endogenous therapeutic gas with an anti-tumor effect. The precise delivery and controlled release of CO in tumor tissues play crucial roles in anti-cancer treatment. However, efficient in situ generation of CO from metal-free COreleasing molecules(CORMs) remains a formidable challenge. Herein, we develop ultrasound(US)-driven self-decomposition porphyrin as organic and metal-free US-CORMs, which can spatiotemporally control the CO release(347 mmol CO/mol porphyrin) efficiently under physiologically harmless US conditions(1.0 MHz, 1.5 W/cm^(2), 50% duty cycle, 50 min). Moreover,porphyrin as a sonosensitizer can also generate reactive oxygen species(ROS) under US treatment to achieve sonodynamic therapy(SDT). Advanced functions of such porphyrin-based CORMs in CO gas-sonodynamic synergistic treatment have been demonstrated by evaluating the in vitro and in vivo anti-tumor effects.

关键词： porphyrin sonodynamic therapy metal-free CO precursors ultrasound-driven gas therapy

Seasonal Characteristics of Forecasting Uncertainties in Surface PM_(2.5)Concentration Associated with Forecast Lead Time over the Beijing-Tianjin-Hebei Region

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Advances in Atmospheric Sciences 2024年第5期41卷 801-816页

作者： Qiuyan DU Chun ZHAO Jiawang FENG Zining YANG Jiamin XU Jun GU Mingshuai ZHANG Mingyue XU Shengfu LIN Deep Space Exploration Laboratory/School of Earth and Space Sciences University of Science and Technology of ChinaHefei 230026China CAS Center for Excellence in comparative Planetology University of Science and Technology of ChinaHefei 230026China

Forecasting uncertainties among meteorological fields have long been recognized as the main limitation on the accuracy and predictability of air quality forecasts.However,the particular impact of meteorological forecasting uncertainties on air quality forecasts specific to different seasons is still not well known.In this study,a series of forecasts with different forecast lead times for January,April,July,and October of 2018 are conducted over the Beijing-Tianjin-Hebei(BTH)region and the impacts of meteorological forecasting uncertainties on surface PM_(2.5)concentration forecasts with each lead time are investigated.With increased lead time,the forecasted PM_(2.5)concentrations significantly change and demonstrate obvious seasonal variations.In general,the forecasting uncertainties in monthly mean surface PM_(2.5)concentrations in the BTH region due to lead time are the largest(80%)in spring,followed by autumn(~50%),summer(~40%),and winter(20%).In winter,the forecasting uncertainties in total surface PM_(2.5)mass due to lead time are mainly due to the uncertainties in PBL heights and hence the PBL mixing of anthropogenic primary particles.In spring,the forecasting uncertainties are mainly from the impacts of lead time on lower-tropospheric northwesterly winds,thereby further enhancing the condensation production of anthropogenic secondary particles by the long-range transport of natural dust.In summer,the forecasting uncertainties result mainly from the decrease in dry and wet deposition rates,which are associated with the reduction of near-surface wind speed and precipitation rate.In autumn,the forecasting uncertainties arise mainly from the change in the transport of remote natural dust and anthropogenic particles,which is associated with changes in the large-scale circulation.

关键词： PM_(2.5) forecasting uncertainties forecast lead time meteorological fields Beijing-Tianjin-Hebei region

Prenatal cadmium exposure impairs neural tube closure via inducing excessive apoptosis in neuroepithelium

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Journal of Environmental Sciences 2024年第4期138卷 572-584页

作者： Shiyong Zhu Xuenan Li Xueyan Dai Jinlong Li College of Veterinary Medicine Northeast Agricultural UniversityHarbin 150030China Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment Northeast Agricultural UniversityHarbin 150030China Heilongjiang Key Laboratory for Laboratory Animals and comparative Medicine Northeast Agricultural UniversityHarbin 150030China

Birth defects have become a public health concern.The hazardous environmental factors exposure to embryos could increase the risk of birth defects.Cadmium,a toxic environmental factor,can cross the placental barrier during pregnancy.Pregnant woman may be subjected to cadmium before taking precautionary protective actions.However,the link between birth defects and cadmium remains obscure.Cadmium exposure can induce excessive apoptosis in neuroepithelium during embryonic development progresses.Cadmium exposure activated the p53 via enhancing the adenosine 5‘-monophosphate(AMP)-activated protein kinase(AMPK)and reactive oxygen species'(ROS)level.And cadmium decreases the level of Paired box 3(Pax3)and murine double minute 2(Mdm2),disrupting the process of p53 ubiquitylation.And p53 accumulation induced excessive apoptosis in neuroepithelium during embryonic development progresses.Excessive apoptosis led to the failure of neural tube closure.The study emphasizes that environmental materials may increase the health risk for embryos.Cadmium caused the failure of neural tube closure during early embryotic day.Pregnant women may be exposed by cadmium before taking precautionary protective actions,because of cadmium concentration-containing foods and environmental tobacco smoking.This suggests that prenatal cadmium exposure is a threatening risk factor for birth defects.

关键词： Cadmium Neural tube closure Excessive apoptosis p53 Embryogenesis

Infection with SARS-CoV-2 can cause pancreatic impairment

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Signal Transduction and Targeted Therapy 2024年第5期9卷 2143-2160页

作者： Wei Deng Linlin Bao Zhiqi Song Ling Zhang Pin Yu Yanfeng Xu Jue Wang Wenjie Zhao Xiuqin Zhang Yunlin Han Yanhong Li Jiangning Liu Qi Lv Xujian Liang Fengdi Li Feifei Qi Ran Deng Siyuan Wang Yibai Xiong Ruiping Xiao Hongyang Wang Chuan Qin NHC Key Laboratory of comparative Medicine Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious DiseasesInstitute of Laboratory Animal ScienceChinese Academy of Medical Sciences and Comparative Medicine CenterPeking Union Medical CollegeBeijing 100021China Institute of Molecular Medicine College of Future TechnologyPeking UniversityBeijing 100871China Beijing Key Laboratory of Cardiometabolic Molecular Medicine Peking UniversityBeijing 100871China State Key Laboratory of Biomembrane and Membrane Biotechnology Peking-Tsinghua Center for Life SciencesBeijing 100871China Chinese Academy of Engineering Eastern Hepatobiliary Surgery Hospital225 Changhai RoadYangpu DistrictShanghai 200438China International Co-operation Laboratory on Signal Transduction Eastern Hepatobiliary Surgery InstituteSecond Military Medical UniversityShanghai 200438PR China National Laboratory for Oncogenes and Related Genes Cancer Institute of Shanghai Jiao Tong UniversityShanghai 200441PR China Changping National laboratory(CPNL) Beijing 102206China State Key Laboratory of Respiratory health and Multimorbidity National Health Commission of the People’s Republic of ChinaBeijingPR China

Evidence suggests associations between COVID-19 patients or vaccines and glycometabolic dysfunction and an even higher risk of the occurrence of diabetes.Herein,we retrospectively analyzed pancreatic lesions in autopsy tissues from 67 SARS-CoV-2 infected non-human primates(NHPs)models and 121 vaccinated and infected NHPs from 2020 to 2023 and COVID-19 patients.Multi-label immunofluorescence revealed direct infection of both exocrine and endocrine pancreatic cells by the virus in NHPs and humans.Minor and limited phenotypic and histopathological changes were observed in adult models.Systemic proteomics and metabolomics results indicated metabolic disorders,mainly enriched in insulin resistance pathways,in infected adult NHPs,along with elevated fasting C-peptide and C-peptide/glucose ratio levels.Furthermore,in elder COVID-19 NHPs,SARS-CoV-2 infection causes loss of beta(β)cells and lower expressed-insulin in situ characterized by islet amyloidosis and necrosis,activation ofα-SMA and aggravated fibrosis consisting of lower collagen in serum,an increase of pancreatic inflammation and stress markers,ICAM-1 and G3BP1,along with more severe glycometabolic dysfunction.In contrast,vaccination maintained glucose homeostasis by activating insulin receptorαand insulin receptorβ.Overall,the cumulative risk of diabetes post-COVID-19 is closely tied to age,suggesting more attention should be paid to blood sugar management in elderly COVID-19 patients.

关键词： infected elevated homeostasis