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Spatiotemporal transformable nano-assembly for on-demand drug delivery to enhance anti-tumor immunotherapy

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Asian Journal of Pharmaceutical Sciences 2024年第1期19卷 103-118页

作者： Chenglin Liang Ge Zhang linlin Guo Xinyi Ding Heng Yang Hongling Zhang Zhenzhong Zhang lin hou School of Pharmaceutical Sciences Key Laboratory of Targeting Therapy and Diagnosis for Critical DiseasesZhengzhou UniversityZhengzhou 450001China

Induction of tumor cell senescence has become a promising strategy for anti-tumor immunotherapy,but fibrotic matrix severely blocks senescence inducers penetration and immune cells infiltration.Herein,we designed a cancer-associated fibroblasts(CAFs)triggered structure-transformable nano-assembly(HSD-P@V),which can directionally deliver valsartan(Val,CAFs regulator)and doxorubicin(DOX,senescence inducer)to the specific targets.In detail,DOX is conjugated with hyaluronic acid(HA)via diselenide bonds(Se-Se)to form HSD micelles,while CAFs-sensitive peptide is grafted onto the HSD to form a hydrophilic polymer,which is coated on Val nanocrystals(VNs)surface for improving the stability and achieving responsive release.Once arriving at tumor microenvironment and touching CAFs,HSD-P@V disintegrates into VNs and HSD micelles due to sensitive peptide detachment.VNs can degrade the extracellularmatrix,leading to the enhanced penetration of HSD.HSD targets tumor cells,releases DOX to induce senescence,and recruits effector immune cells.Furthermore,senescent cells are cleared by the recruited immune cells to finish the integrated anti-tumor therapy.In vitro and in vivo results show that the nanoassembly remarkably inhibits tumor growth as well as lungmetastasis,and extends tumorbearing mice survival.This work provides a promising paradigm of programmed delivering multi-site nanomedicine for cancer immunotherapy.

关键词： Cells senescence Tumor stroma Structure transformable Programmed delivery Anti-tumor immunotherapy

In situ autophagy regulation in synergy with phototherapy for breast cancer treatment

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Acta Pharmaceutica Sinica B 2024年第5期14卷 2317-2332页

作者： Huijuan Zhang Xiangyang Xuan Yaping Wang Zijun Qi Kexuan Cao Yingmei Tian Chaoqun Wang Junbiao Chang Zhenzhong Zhang lin hou School of Pharmaceutical Sciences Zhengzhou UniversityZhengzhou 450001China Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases Zhengzhou 450001China Collaborative Innovation Center of New Drug Research and Safety Evaluation Zhengzhou 450001China School of Chemistry and Molecular Engineering Zhengzhou UniversityZhengzhou 450001China

Autophagy is an important factor in reducing the efficacy of tumor phototherapy(including PTT and PDT).Accurate regulation of autophagy in tumor cells is a new strategy to improve the anti-tumor efficiency of PTT/PDT.This project intended to construct a tumor-activated autophagy regulator to efficiently block PTT/PDT-induced autophagy and realize synergistic sensitization to tumor phototherapy.To achieve this goal,we first synthesized TRANSFERRIN(Tf)biomimetic mineralized nano-tellurium(Tf-Te)as photosensitizer and then used disulfide bond reconstruction technology to induce Tf-Te self-assembly.The autophagy inhibitor hydroxychloroquine(HCQ)and iron ions carried by Tf were simultaneously loaded to prepare a tumor-responsive drug reservoir Tf-Te/HCQ.After entering breast cancer cells through the“self-guidance system”,Tf-Te/HCQ can generate hyperpyrexia and ROS under NIR laser irradiation,to efficiently induce PTT/PDT effect.Meanwhile,the disulfide bond broke down in response to GSH,and the nanoparticles disintegrated to release Fe2+and HCQ at fixed points.They simultaneously induce lysosomal alkalinization and increased osmotic pressure,effectively inhibit autophagy,and synergistically enhance the therapeutic effect of phototherapy.In vivo anti-tumor results have proved that the tumor inhibition rate of Tf-Te/HCQ can be as high as 88.6%on 4T1 tumor-bearing mice.This multifunctional drug delivery system might provide a new alternative for more precise and effective tumor phototherapy.

关键词： Autophagy Tumor phototherapy Synergistic sensitization HCQ TRANSFERRIN Disulfide bond reconstruction GSH Biomimetic mineralized nano-tellurium

Docking protein 6 (DOK6) selectively docks the neurotrophic signaling transduction to restrain peripheral neuropathy

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Signal Transduction and Targeted Therapy 2024年第3期9卷 1147-1164页

作者： Yan Guo Pan Xiang Xiaojiao Sun Wei Liu Jiafeng Zhou Bin Yin lin hou Boqin Qiang Huiliang Li Pengcheng Shu Xiaozhong Peng Department of Molecular Biology and Biochemistry Institute of Basic Medical SciencesMedical Primate Research CenterNeuroscience CenterChinese Academy of Medical SciencesSchool of Basic Medicine Peking Union Medical CollegeBeijingChina State Key Laboratory of Common Mechanism Research for Major Diseases Beijing 100005China Wolfson Institute for Biomedical Research University College LondonGower StreetLondon WC1E 6BTUK Chinese Institute for Brain Research Beijing 102206China State Key Laboratory of Respiratory Health and Multimorbidity Beijing 100005China Institute of Laboratory Animal Science Chinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100021China

The appropriate and specific response of nerve cells to various external cues is essential for the establishment and maintenance of neural circuits,and this process requires the proper recruitment of adaptor molecules to selectively activate downstream pathways.Here,we identified that DOK6,a member of the Dok(downstream of tyrosine kinases)family,is required for the maintenance of peripheral axons,and that loss of Dok6 can cause typical peripheral neuropathy symptoms in mice,manifested as impaired sensory,abnormal posture,paw deformities,blocked nerve conduction,and dysmyelination.Furthermore,Dok6 is highly expressed in peripheral neurons but not in Schwann cells,and genetic deletion of Dok6 in peripheral neurons led to typical peripheral myelin outfolding,axon destruction,and hindered retrograde axonal transport.Specifically,DOK6 acts as an adaptor protein for selectivitymediated neurotrophic signal transduction and retrograde transport for TrkC and Ret but not for TrkA and TrkB.DOK6 interacts with certain proteins in the trafficking machinery and controls their phosphorylation,including MAP1B,Tau and Dynein for axonal transport,and specifically activates the downstream ERK1/2 kinase pathway to maintain axonal survival and homeostasis.This finding provides new clues to potential insights into the pathogenesis and treatment of hereditary peripheral neuropathies and other degenerative diseases.

关键词： impaired restrain peripheral

An Improved Method for Approximating the Infinite-Horizon Value Function of the Discrete-Time Switched LQR Problem

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Journal of Systems Science & Complexity 2024年第1期37卷 22-39页

作者： hou Tan LI Yuanlong lin Zongli Department of Automation Shanghai Jiao Tong UniversityShanghai 200240China Key Laboratory of System Control and Information Processing Ministry of Education of ChinaShanghai 200240China Shanghai Engineering Research Center of Intelligent Control and Management Shanghai 200240China Charles L.Brown Department of Electrical and Computer Engineering University of VirginiaCharlottesvilleVA 22904-4743USA

This paper considers the problem of approximating the infinite-horizon value function of the discrete-time switched LQR problem.In particular,the authors propose a new value iteration method to generate a sequence of monotonically decreasing functions that converges exponentially to the value function.This method facilitates us to use coarse approximations resulting from faster but less accurate algorithms for further value iteration,and thus,the proposed approach is capable of achieving a better approximation for a given computation time compared with the existing methods.Three numerical examples are presented in this paper to illustrate the effectiveness of the proposed method.

关键词： Optimal control switched linear systems switched LQR problem.

Heat Transfer Characteristics of a Microchannel Heat Sink with Highly-Dense Micro-Jet Arrays

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Journal of Thermal Science 2024年第3期33卷 1148-1160页

作者： ZHANG Yu CHEN Xiaoyan MIAO lin CHEN Liang hou Yu State Key Laboratory of Multiphase Flow in Power Engineering Xi’an Jiaotong UniversityXi’an710049China Beijing Aerospace Technology Institute Beijing100083China

This paper proposed a new structure of highly-dense micro-jet arrays for hybrid jet-impingement/microchannel heat sinks(~120 jet per cm^(2) with jet width of 0.35 mm).Parametric study is performed to investigate the influence of structure and flow parameters on the convective heat transfer of water jet cooling in confined space.The simulation results show that the optimal jet width,jet spacing and impingement distance are around 0.2 mm,0.2 mm and 0.3 mm,respectively,which can achieve a low thermal resistance as well as a relatively low pressure drop.The analysis of the heat transfer pathways shows that the micro-fin jet structures can extend the impinging heat transfer area and conduct a considerable proportion of heat,which can reach up to 38.9%with the Reynolds number ranging from 797.1 to 5602.2.The heat transfer characteristics in the heat sink will shift from impingement dominated heat transfer to the channel-convection dominated heat transfer as the jet impingement distance increases.A correlation is proposed to predict the average Nusselt number on the stagnation area for the heat sink with different structure parameters,and the deviations of predictions from the numerical results are less than 10%.

关键词： hybrid heat sink impingement microchannel thermal management high heat flux

Machine Learning Analysis of Impact of Western US Fires on Central US Hailstorms

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Advances in Atmospheric Sciences 2024年第7期41卷 1450-1462页

作者： Xinming lin Jiwen FAN Yuwei ZHANG ZJason hou Pacific Northwest National Laboratory RichlandWA 99354USA Argonne National Laboratory LemontIL 60439USA

Fires,including wildfires,harm air quality and essential public services like transportation,communication,and utilities.These fires can also influence atmospheric conditions,including temperature and aerosols,potentially affecting severe convective storms.Here,we investigate the remote impacts of fires in the western United States(WUS)on the occurrence of large hail(size:≥2.54 cm)in the central US(CUS)over the 20-year period of 2001–20 using the machine learning(ML),Random Forest(RF),and Extreme Gradient Boosting(XGB)methods.The developed RF and XGB models demonstrate high accuracy(>90%)and F1 scores of up to 0.78 in predicting large hail occurrences when WUS fires and CUS hailstorms coincide,particularly in four states(Wyoming,South Dakota,Nebraska,and Kansas).The key contributing variables identified from both ML models include the meteorological variables in the fire region(temperature and moisture),the westerly wind over the plume transport path,and the fire features(i.e.,the maximum fire power and burned area).The results confirm a linkage between WUS fires and severe weather in the CUS,corroborating the findings of our previous modeling study conducted on case simulations with a detailed physics model.

关键词： wildfire severe convective storm hailstorm machine learning

Characteristics of the HIV/AIDS Epidemic among People Aged≥50 Years in China during 2018–2021

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Biomedical and Environmental Sciences 2024年第4期37卷 399-405页

作者： hou Yu Shan JIN Yi Chen CAI Chang TANG hou lin QIN Qian Qian LYU Fan National Center for AIDS/STD Control and Prevention Chinese Center for Disease Control and PreventionBeijing 102206China

Objective This study aimed to determine the current epidemiological status of PLWHA aged≥50 years in China from 2018 to 2021.It also aimed to recommend targeted interventions for the prevention and treatment of HIV/AIDS in elderly patients.Methods Data on newly reported cases of PLWHA,aged≥50 years in China from 2018 to 2021,were collected using the CRIMS.Trend tests and spatial analyses were also conducted.Results Between 2018 and 2021,237,724 HIV/AIDS cases were reported among patients aged≥50 years in China.The main transmission route was heterosexual transmission(91.24%).Commercial heterosexual transmission(CHC)was the primary mode of transmission among males,while non-marital non-CHC([NMNCHC];60.59%)was the prevalent route in women.The proportion of patients with CHC decreased over time(Z=67.716,P<0.01),while that of patients with NMNCHC increased(Z=153.05,P<0.01).The sex ratio varied among the different modes of infection,and it peaked at 17.65 for CHC.The spatial analysis indicated spatial clustering,and the high-high clustering areas were mainly distributed in the southwestern and central-southern provinces.Conclusion In China,PLWHA,aged≥50 years,were predominantly infected through heterosexual transmission.The primary modes of infection were CHC and NMNCHC.There were variations in the sex ratio among different age groups,infected through various sexual behaviors.HIV/AIDS cases exhibited spatial clustering.Based on these results,the expansion of HIV testing,treatment,and integrated behavioral interventions in high-risk populations is recommended to enhance disease detection in key regions.

关键词： HIV/AIDS Aged≥50 years China

Berberine Enhances Intestinal Mucosal Barrier Function by Promoting Vitamin D Receptor Activity

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Chinese Journal of Integrative Medicine 2024年第2期30卷 143-151页

作者： HUANG Yong-quan LIU Jia-lin CHEN Geng-xin SHEN Dan-ting ZHU Wang CHEN Xin-lin LIU Feng-bin hou Qiu-ke Graduate School Guangzhou University of Chinese MedicineGuangzhou(510405)China Department of Orthopedics the Second Affiliated Hospital of Guangzhou University of Chinese MedicineGuangzhou(510006)China Department of Preventive Medicine and Health Statistics Guangzhou University of Chinese MedicineGuangzhou(510006)China Department of Gastroenterology the First Affiliated Hospital of Guangzhou University of Chinese MedicineGuangzhou(510405)China

Objective:To evaluate if berberine can act on vitamin D receptors(VDR)and thereby regulate the expression of tight junction proteins(TJPs)in irritable bowel syndrome-diarrhea-predominant(IBS-D)rats.Methods:The newborn rats were induced into IBS-D rat model via neonatal maternal separation combined with acetic acid chemical stimulation.After modeling,the model was evaluated and rats were divided into the control group and berberine treatment groups(0.85,1.7 and 3.4 mg/kg,once a day for 2 weeks).The distal colon was obtained and colonic epithelial cells(CECs)were isolated and cultured after IBS-D model evaluation.The vitamin D receptor response element(VDRE)reporter gene was determined in the CECs of IBS-D rats to analyze the effect of berberine on the VDRE promoter.VDR overexpression or silencing technology was used to analyze whether VDR plays a role in promoting intestinal barrier repair,and to determine which region of VDR plays a role in berberine-regulated intestinal TJPs.Results:The IBS-D rat model was successfully constructed and the symptoms were improved by berberine in a dose-dependent manner(P<0.05).The activity of VDRE promoter was also effectively promoted by berberine(P<0.05).Berberine increased the expression of TJPs in IBS-D CECs(P<0.05).VDR expression was significantly increased after transfection of different domains of VDR when compared to normal control and basic plasmid groups(all P<0.05).RT-qPCR and Western blot results showed that compared with the blank group,expressions of occludin and zonula occludens-1 were significantly higher in VDR containing groups(all P<0.05).Berberine plus pCMV-Myc-VDR-N group exerted the highest expression levels of occludin and zonula occludens-1(P<0.05).Conclusion:Berberine enhances intestinal mucosal barrier function of IBS-D rats by promoting VDR activity,and the main site of action is the N-terminal region of VDR.

关键词： berberine Chinese medicine irritable bowel syndrome-diarrhea-predominant vitamin D receptors intestinal mucosal barrier tight junction proteins

S-scheme heterojunction of crystalline carbon nitride nanosheets and ultrafine WO_(3)nanoparticles for photocatalytic CO_(2)reduction

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Journal of Environmental Sciences 2024年第6期140卷 103-112页

作者： Gongjie Chen Ziruo Zhou Bifang Li Xiahui lin Can Yang Yuanxing Fang Wei lin Yidong hou Guigang Zhang Sibo Wang State Key Laboratory of Photocatalysis on Energy and Environment College of ChemistryFuzhou UniversityFujian 350116China

Highly crystalline carbon nitride polymers have shown great opportunities in overall water photosplitting;however,their mission in light-driven CO_(2)conversion remains to be explored.In this work,crystalline carbon nitride(CCN)nanosheets of poly triazine imide(PTI)embedded with melon domains are fabricated by KCl/LiCl-mediated polycondensation of dicyandiamide,the surface of which is subsequently deposited with ultrafine WO_(3)nanoparticles to construct the CCN/WO_(3)heterostructure with a S-scheme interface.Systematic characterizations have been conducted to reveal the compositions and structures of the S-scheme CCN/WO_(3)hybrid,featuring strengthened optical capture,enhanced CO_(2)adsorption and activation,attractive textural properties,as well as spatial separation and directed movement of light-triggered charge carriers.Under mild conditions,the CCN/WO_(3)catalyst with optimized composition displays a high photocatalytic activity for reducing CO_(2)to CO in a rate of 23.0μmol/hr(i.e.,2300μmol/(hr·g)),which is about 7-fold that of pristine CCN,along with a high CO selectivity of 90.6%against H2formation.Moreover,it also manifests high stability and fine reusability for the CO_(2)conversion reaction.The CO_(2)adsorption and conversion processes on the catalyst are monitored by in-situ diffuse reflectance infrared Fourier transform spectroscopy(DRIFTS),identifying the crucial intermediates of CO_(2)^(*)-,COOH^(*)and CO^(*),which integrated with the results of performance evaluation proposes the possible CO_(2)reduction mechanism.

关键词： Crystalline carbon nitride Photocatalysis CO_(2)reduction S-scheme WO_(3)