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Endoplasmic reticulum-targeted delivery of celastrol and PD-L1 siRNA for reinforcing immunogenic cell death and potentiating cancer immunotherapy

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Acta Pharmaceutica Sinica B 2024年第8期14卷 3643-3660页

作者： Jie wang Zilong Zhang Yan Zhuo Zhuan Zhang Rongrong Chen Li Liang Xiaohe Jiang Di Nie Chang Liu Zhiwen Zou Xiang Li Jiaxin Li Bingqi wang Rui wang Yong Gan Miaorong Yu School of Pharmacy Shanghai University of Traditional Chinese MedicineShanghai 201203China State Key Laboratory of Drug Research Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China Jiangxi Medical College Nanchang UniversityNanchang 330006China School of Pharmacy Nanjing University of Chinese MedicineNanjing 210023China University of Chinese Academy of Sciences Beijing 100049China NMPA Key Laboratory for Quality Research and Evaluation of Pharmaceutical Excipients National Institutes for Food and Drug ControlBeijing 100050China

The prospect of employing chemoimmunotherapy targeted towards the endoplasmic reticulum(ER)presents an opportunity to amplify the synergistic effects of chemotherapy and *** this study,we initially validated celastrol(CEL)as an inducer of immunogenic cell death(ICD)by promoting ER stress and autophagy in colorectal cancer(CRC)***,an ER-targeted strategy was posited,involving the codelivery of CEL with PD-L1 small interfering RNAs(siRNA)using KDEL peptide-modified exosomes derived from milk(KME),to enhance chemoimmunotherapy *** findings demonstrate the efficient transportation of KME to the ER via the Golgi-to-ER *** to their non-targeting counterparts,KME exhibited a significant augmentation of the CEL-induced ICD ***,it facilitated the release of danger signaling molecules(DAMPs),thereby stimulating the antigen-presenting function of dendritic cells and promoting the infiltration of T cells into the ***,the ER-targeted delivery of PD-L1 siRNA resulted in the downregulation of both intracellular and membrane PD-L1 protein expression,consequently fostering the proliferation and activity of CD8^(+)T ***,the ER-targeted formulation exhibited enhanced anti-tumor efficacy and provoked anti-tumor immune responses against orthotopic colorectal tumors in ***,a robust ER-targeted delivery strategy provides an encouraging approach for achieving potent cancer chemoimmunotherapy.

关键词： Chemoimmunotherapy Targeted drug delivery Endoplasmic reticulum Endoplasmic reticulum stress Immunogenic cell death siRNA Chemoimmunotherapy Targeted drug delivery Endoplasmic reticulum Endoplasmic reticulum stress Immunogenic cell death siRNA

Simulating the evolution of focused waves by a two-layer Boussinesq-type model

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Acta Oceanologica Sinica 2024年第5期43卷 91-99页

作者： Ping wang Zhongbo Liu Kezhao Fang Wenfeng Zou Xiangke Dong Jiawen Sun State Environmental Protection Key Laboratory of Marine Ecosystem Restoration National Marine Environmental Monitoring CenterDalian 116023China College of Transportation Engineering Dalian Maritime UniversityDalian 116026China State Key Laboratory of Coastal and Offshore Engineering Dalian University of TechnologyDalian 116024China

Accurate simulation of the evolution of freak waves by the wave phase focusing method requires accurate linear and nonlinear properties,especially in deep-water *** this paper,we analyze the ability to simulate deep-water focused waves of a two-layer Boussinesq-type(BT)model,which has been shown to have excellent linear and nonlinear *** further improve the numerical accuracy and stability,the internal wavegenerated method is introduced into the two-layer Boussinesq-type ***,the sensitivity of the numerical results to the grid resolution is analyzed to verify the convergence of the model;secondly,the focused wave propagating in two opposite directions is simulated to prove the symmetry of the numerical results and the feasibility of the internal wave-generated method;thirdly,the limiting focused wave condition is simulated to compare and analyze the wave surface and the horizontal velocity of the profile at the focusing position,which is in good agreement with the measured *** the simulation of focused waves in very deep waters agrees well with the measured values,which further demonstrates the capability of the two-layer BT model in simulating focused waves in deep waters.

关键词： focused waves numerical simulation Boussinesq-type model velocity profile

MiR-142-3p Regulates ILC1s by Targeting HMGB1 via the NF-κB Pathway in a Mouse Model of Early Pregnancy Loss

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Current Medical Science 2024年第1期44卷 195-211页

作者： Xiang-li PANG Jie LI Jing wang Si-si YAN Jing YANG Department of Obstetrics and Gynecology Renmin Hospital of Wuhan UniversityWuhan 430060China Reproductive Medical Center Renmin Hospital of Wuhan UniversityWuhan 430060China Clinic Research Center for Assisted Reproductive Technology and Embryonic Development in Hubei Province Wuhan 430060China

Objective Innate lymphoid cells(ILCs)are a class of newly discovered *** 1 ILCs(ILC1s)are identified in the decidua of humans and *** mobility group box 1(HMGB1)is predicted to be one of the target genes of miR-142-3p,which is closely related to pregnancy-related ***,miR-142-3p and HMGB1 are involved in regulating the NF-κB signaling *** study aimed to examine the regulatory effect of miR-142-3p on ILC1s and the underlying mechanism involving HMGB1 and the NF-κB signaling *** Mouse models of normal pregnancy and abortion were constructed,and the alterations of ILC1s,miR-142-3p,ILC1 transcription factor(T-bet),and pro-inflammatory cytokines of ILC1s(TNF-α,IFN-γand IL-2)were detected in mice from different *** targeting regulation of HMGB1 by miR-142-3p in ILC1s,and the expression of HMGB1 in normal pregnant mice and abortive mice were *** addition,the regulatory effects of miR-142-3p and HMGB1 on ILC1s were detected in vitro by CCK-8,Annexin-V/PI,ELISA,and RT-PCR,***,changes of the NF-κB signaling pathway in ILC1s were examined in the different *** the in vivo studies,miR-142-3p-Agomir was injected in the uterus of abortive mice to evaluate the abortion rate and alterations of ILC1s at the maternal-fetal interface,and further detect the expression of HMGB1,pro-inflammatory cytokines,and the NF-κB signaling *** The number of ILC1s was significantly increased,the level of HMGB1 was significantly upregulated,and that of miR-142-3p was considerably downregulated in the abortive mice as compared with the normal pregnant mice(all P<0.05).In addition,miR-142-3p was found to drastically inhibit the activation of the NF-κB signaling pathway(P<0.05).The number of ILC1s and the levels of pro-inflammatory cytokines were significantly downregulated and the activation of the NF-κB signaling pathway was inhibited in the miR-142-3p Agomir group(all P<0.05).Conclusion

关键词： maternal-fetal interface group 1 innate lymphoid cells(ILCis) high mobility group box 1(HMGB1) miR-142-3p abortion

Train-induced aerodynamic characteristics of vertical sound barriers influenced by several factors

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Railway Engineering Science 2024年第2期32卷 177-193页

作者： Xiaowei Qiu Xiaozhen Li Jing Zheng Ming wang State Key Laboratory of Bridge Intelligent and Green Construction Southwest Jiaotong UniversityChengdu 611756SichuanChina Wind Engineering Key Laboratory of Sichuan Province Southwest Jiaotong UniversityChengdu 611756SichuanChina School of Architecture and Civil Engineering West Anhui UniversityLu’anAnhuiChina

Investigations into the aerodynamic properties of vertical sound barriers exposed to high-speed operations employ computational fluid *** primary focus of this research is to evaluate the influence of train speed and the distance(D)from the track centerline under various operating *** findings elucidate a marked elevation in the aerodynamic effect amplitude on sound barriers as train speeds *** single-train passages,the aerodynamic effect amplitude manifests a direct relationship with the square of the train *** two trains pass each other,the aerodynamic amplitude intensifies due to an additional aerodynamic increment on the sound *** increment exhibits an approximate quadratic correlation with the retrograde train ***,the impact of high-speed trains on sound barrier aerodynamics surpasses that of low-speed trains,and this discrepancy amplifies with larger speed differentials between ***,the train-induced aerodynamic effect diminishes significantly with greater distance(D),with occurrences of pressure coefficient(CP)exceeding the standard thresholds during dual-train *** study culminates in the formulation of universal equations for quantifying the influence of train speed and distance(D)on sound barrier aerodynamic characteristics across various operational scenarios.

关键词： Aerodynamic characteristic Sound barrier Two trains passing each other Distance from track centerline CFD simulation

Asymptotic Behavior of Singular Solution to the k-Hessian Equation with a Matukuma-Type Source

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Wuhan University Journal of Natural Sciences 2024年第3期29卷 242-256页

作者： LIU Jinyu wang Biao CHANG Caihong College of Science Xi'an University of Science and TechnologyXi'an 710054ShaanxiChina

This paper is concerned with radially positive solutions of the k-Hessian equation involving a Matukuma-type source S_(k)(D^(2)(-φ))=|x|^(λ-2)/(1+|x|^(2))^(λ2)φ^(q),x∈Ω,where S_(k)(D^(2)(-φ))is the k-Hessian operator,q>k>1,λ>0,n>2k,k∈N,andΩis a suitable bounded do-main in R~*** turns out that there are two different types of radially positive solutions for k>1,i.e.,M-solution(singular at r=0)and Esolution(regular at r=0),which is distinct from the case when k=*** 1

关键词： k-Hessian equation singular solutions asymptotic expansion

In-situ U-Pb Dating of Quartz:A Preliminary Study

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Journal of Earth Science 2024年第2期35卷 726-728页

作者： Entao Liu Jian-Xin Zhao Songqi Pan Detian Yan Hua wang Hubei Key Laboratory of Marine Geological Resources China University of GeosciencesWuhan 430074China Radiogenic Isotope Facility School of Earth and Environmental SciencesThe University of QueenslandBrisbane Qld 4072Australia PetroChina Research Institute of Petroleum Exploration&Development Beijing 100083China Key Laboratory of Tectonics and Petroleum Resources Ministry of EducationChina University of GeosciencesWuhan 430074China

CHALLENGES AND RESEARCH PROGRESS Recent advancements in analytical capabilities and the precision of measuring instruments in in-situ laser ablation mass spectrometry(LA-MC-ICPMS)have markedly broad ened the utility of the U-Pb isotopic *** progress has paved the way for accurately determining the ab solute ages of minerals with low uranium *** re cent years,in-situ U-Pb dating has witnessed rapid advance ments across diverse mineral types,encompassing calcite,dolo mite,fluorite,nacrite,anatase,and wolframite(Roberts et al.,2020).

关键词： dating minerals isotopic

Strengthening-softening transition and maximum strength in Schwarz nanocrystals

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Nano Materials Science 2024年第3期6卷 320-328页

作者： Hanzheng Xing Jiaxi Jiang Yujia wang Yongpan Zeng Xiaoyan Li Center for Advanced Mechanics and Materials Applied Mechanics LaboratoryDepartment of Engineering MechanicsTsinghua UniversityBeijing100084China Institute of High Performance Computing(IHPC) Agency for ScienceTechnology and Research(A*STAR)Singapore138632Singapore

Recently,a Schwarz crystal structure with curved grain boundaries(GBs)constrained by twin-boundary(TB)networks was discovered in nanocrystalline Cu through experiments and atomistic *** Cu with nanosized Schwarz crystals exhibited high strength and excellent thermal ***,the grainsize effect and associated deformation mechanisms of Schwarz nanocrystals remain ***,we performed large-scale atomistic simulations to investigate the deformation behaviors and grain-size effect of nanocrystalline Cu with Schwarz *** simulations showed that similar to regular nanocrystals,Schwarz nanocrystals exhibit a strengthening-softening transition with decreasing grain *** critical grain size in Schwarz nanocrystals is smaller than that in regular nanocrystals,leading to a maximum strength higher than that of regular *** simulations revealed that the softening in Schwarz nanocrystals mainly originates from TB migration(or detwinning)and annihilation of GBs,rather than GB-mediated processes(including GB migration,sliding and diffusion)dominating the softening in regular *** analyses of simulation data further showed that compared with those in regular nanocrystals,the GB-mediated processes in Schwarz nanocrystals are suppressed,which is related to the low volume fraction of amorphous-like GBs and constraints of TB *** smaller critical grain size arises from the suppression of GB-mediated processes.

关键词： Schwarz nanocrystal Curved grain boundary Atomistic simulation Grain size effect Maximum strength

Secoemestrin C Ameliorates Psoriasis-like Skin Inflammation in Mice by Suppressing the TNF-α/NF-κB Signaling Pathway

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Current Medical Science 2024年第1期44卷 232-240页

作者： Zhi-bin ZHU Meng-jie LIU Jing wang Zhou SHU Jie CAO Department of Stomatology Chengdu Seventh People's HospitalChengdu 610044China Department of Pharmacy Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430022China

Objective Secoemestrin C(SC),an epitetrathiodioxopiperazine isolated from Aspergillus nidulans,has been previously reported to have immunomodulatory and hepatoprotective effects against acute autoimmune ***,the effect of SC on regulating the inflammation and its underlying mechanisms in the pathogenesis of psoriasis remain *** study aimed to evaluate the effects of SC on inflammatory dermatosis both in vitro and in *** In vitro,HaCaT cells were induced with tumor necrosis factor-alpha(TNF-α,10 ng/mL)to establish an inflammatory injury model,and the expression of nuclear transcription factor-κB(NF-κB)pathway components was measured using qRT-PCR and Western *** in vivo mouse model of imiquimod(IMQ)-induced psoriasis-like skin inflammation was used to evaluate the effectiveness of SC in alleviating *** SC significantly blocked the activation of NF-κB signaling in TNF-α-stimulated HaCaT *** addition,systemic and local administration of SC improved psoriatic dermatitis in the IMQ-induced mouse *** reduced skin scale and significantly inhibited the secretion of inflammatory factors in skin *** The protective effect of SC against psoriatic-associated inflammation reveals its potential therapeutic value for treating psoriasis.

关键词： secoemestrin C(SC) psoriasis tumor necrosis factor-alpha(TNF-α) nuclear transcription factor-kB(NF-kB) inflammation

Underwater self-interference suppression method based on multistage delay estimation and transfer function fitting

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Chinese Journal of Acoustics 2024年第2期43卷 199-217页

作者： wang Boheng ZHANG Qunfei SHI Wentao School of Marine Science and Technology Northwestern Polytechnical UniversityXi'an 710072

In order to suppress strong self-interference signals in received signals, a selfinterference suppression method based on transfer function fitting and multistage delay estimation is proposed. Firstly, the transfer function of transmitting leakage is estimated by frequency domain deconvolution to construct the basic cancellation signal. Then, the multistage delay estimation based on the cross correlation method and the cross spectrum method is used to accurately compensate the cancelling signals to obtain a good selfinterference suppression effect. The processing results of the actual sea trial data indicate that the suppression ratio of the proposed method can reach 36 d B, and the signal-tointerference ratio of the detectable echo can be reduced from-30 d B to-55 d B when the unmanned undersea vehicle(UUV) integrated system is used to transmit multi-frame linear frequency modulated(LFM) signals in the working sector of the side array for active detection of the target ship. The same suppression effect is found for the subsequent selfinterference signals. The above results indicate that the method can suppress the strong self-interference signal, and presents stability, so that the echo signal submerged in the strong self-interference signal can be detected.

关键词： estimation delay function