Fine-tuning the activation behaviors of ternary modular cabazitaxel prodrugs for efficient and on-target oral anti-cancer therapy

The disulfide bond plays a crucial role in the design of anti-tumor prodrugs due to its exceptional tumor-specific redox responsiveness. However, premature breaking of disulfide bonds is triggered by small amounts of reducing substances (e.g., ascorbic acid, glutathione, uric acid and tea polyphenols) in the systemic circulation. This may lead to toxicity, particularly in oral prodrugs that require more frequent and high-dose treatments. Fine-tuning the activation kinetics of these prodrugs is a promising prospect for more efficient on-target cancer therapies. In this study, disulfide, steric disulfide, and ester bonds were used to bridge cabazitaxel (CTX) to an intestinal lymph vessel-directed triglyceride (TG) module. Then, synthetic prodrugs were efficiently incorporated into self-nanoemulsifying drug delivery system (corn oil and Maisine CC were used as the oil phase and Cremophor EL as the surfactant). All three prodrugs had excellent gastric stability and intestinal permeability. The oral bioavailability of the disulfide bond-based prodrugs (CTX-(C)S-(C)S-TG and CTX-S-S-TG) was 11.5- and 19.1-fold higher than that of the CTX solution, respectively, demonstrating good oral delivery efficiency. However, the excessive reduction sensitivity of the disulfide bond resulted in lower plasma stability and safety of CTX-S-S-TG than that of CTX-(C)S-(C)S-TG. Moreover, introducing steric hindrance into disulfide bonds could also modulate drug release and cytotoxicity, significantly improving the anti-tumor activity even compared to that of intravenous CTX solution at half dosage while minimizing off-target adverse effects. Our findings provide insights into the design and fine-tuning of different disulfide bond-based linkers, which may help identify oral prodrugs with more potent therapeutic efficacy and safety for cancer therapy.

Beware of the serious harm of veterinary drug poisoning:a case report

Veterinary drugs are substances(including pharmaceutical feed additives)used to prevent,treat,and diagnose diseases or regulate the physiological functions of animals.Veterinary drug poisoning in humans is relatively rare both in China and the rest of the world.Here,we report a case of death from veterinary drug poisoning from avermectin-closantel.Avermectin-closantel is a broad-spectrum antiparasitic drug,which has high efficacy against a variety of trematodes and nematodes.

政府间规范秩序:一个扩展的政策过程理论

论文通过分析碳排放权交易计划政策过程中的国际、国内和地方政府互动,提出了政府间规范秩序(Trans-governmental Normative Orders,TNO)理论和共识治理模型。TNO理论揭示了全球治理背景下中国政策过程的新特征,即将政策目标背后的价值理念和规范作为共识目标,将复合治理机制作为共识机制,将多重规范性秩序作为共识体系。基于对地方和全国两级碳市场试点计划的详细考察,论文总结了共识治理模型三个层面的演进与发展:(1)共识目标从国内改革攻坚演进为统筹全球治理和本国治理秩序;(2)在共识机制层面发展出动员-赋权、试验-反馈、推广-扩散等多类型的政策创新机制;(3)在共识体系层面,以制度建设规范来兼容政策方案多样性、以国家治理规范来调适政策目标多元性、以社会治理规范来消纳政策风险不确定性,最终推动形成国际国内间、央地政府间以及政府与市场间的规范性秩序体系。

拟人化机器人完美代替人工?——一个有调节的中介效应模型

在人工智能技术飞速发展的今天,拟人化机器人的使用进入许多服务消费领域。在这些领域内,鲜有研究关注消费者心理因素对拟人化机器人使用意愿的影响。基于社会排斥与归属需求理论,本研究构建了由社会排斥通过归属感的中介作用影响拟人化机器人使用意愿的有调节中介模型,以自我建构来调节归属感的中介效应。三个实验的结果证明,相比社会接纳,社会排斥降低归属感进而降低消费者对拟人化机器人的使用意愿,通过自我建构调节归属感的中介作用。在独立型自我建构下,归属感不起中介作用;在互依型自我建构下,归属感起完全中介作用。从消费者心理因素的角度出发,本文一方面拓展了关于拟人化机器人使用意愿影响因素的研究视角,另一方面进一步揭示了社会排斥对拟人化机器人使用意愿产生影响的适用背景,以期帮助企业更好地引导消费者使用拟人化机器人。

基于MOPSO的斜齿轮传动几何参数多目标优化设计

斜齿轮作为机械设备传动装置中的主要零/部件,应用较为广泛。为了避免在使用过程中斜齿轮部分轮齿因强度低而发生提前失效的情况,综合考虑变位系数、齿数和模数等对齿轮强度的影响,建立以斜齿轮几何参数为设计变量,以斜齿轮副满足强度、重合度和齿顶厚度要求等为约束条件,以斜齿轮副齿根最大弯曲应力的差值最小、齿面接触应力最小为优化目标的数学模型,利用多目标粒子群优化(Multi-Objective Particle Swarm Optimization,MOPSO)算法编写相应的Matlab程序,对所建立的数学模型进行优化求解,并通过MASTA软件对优化前、后齿轮副进行仿真分析。结果表明,在满足设计条件的情况下,斜齿轮副弯曲强度差值与齿面承载能力均有所改善。该研究为斜齿轮宏观几何参数的优化设计提供了参考。

ABI5 promotes heat stress-induced chlorophyll degradation by modulating the stability of MYB44 in cucumber

The yellowing of leaves caused by the decomposition of chlorophyll(Chl)is a characteristic event during senescence,which can be induced by various environmental stresses.However,the molecular mechanisms of high temperature-induced Chl degradation in horticultural plants remain poorly understood.Here,we found that heat stress induced Chl degradation and the expression of ABI5 and MYB44 in cucumber.Silencing of ABI5 compromised heat stress-induced Chl degradation,and the transcription of pheophytinase(PPH)and pheophorbide a oxygenase(PAO),two key genes in Chl catabolic pathway,but silencing of MYB44 exhibited the opposite results.Furthermore,ABI5 interacted with MYB44 in vitro and in vivo.ABI5 positively regulated heat stress-induced Chl degradation through two pathways.ABI5 directly bound to PPH and PAO promoters to promote their expression,leading to accelerating Chl degradation.On the other hand,the interaction between ABI5 and MYB44 reduced the binding of MYB44 to PPH and PAO promoters and led to the ubiquitination-depended protein degradation of MYB44,thereby alleviating the transcription inhibitory effect of MYB44 on PPH and PAO.Taken together,our findings propose a new regulatory network for ABI5 in regulating heat stress-induced Chl degradation.

Well logging evaluation of fine-grained hydrate-bearing sediment reservoirs: Considering the effect of clay content

Hydrate reservoirs are different from the host reservoirs of all other fossil energy sources because the characteristics of hydrate reservoirs are generally controlled by deep-sea fine-grained sedimentation. In such reservoirs, the reliability of the classical logging evaluation models established for diagenetic reservoirs is questionable. This study used well W8 in the Qiongdongnan Basin to explore the clay content, porosity, saturation, and hydrate-enriched layer identification of a logging-based hydrate reservoir, and it was found that considering the effect of the clay content on the log response is necessary in the logging evaluation of hydrate reservoirs. In the evaluation of clay content, a method based on the optimization inversion method can obtain a more reliable clay content than other methods. Fine-grained sediment reservoirs have a high clay content, and the effect of clay on log responses must be considered when calculating porosity. In addition, combining density logging and neutron porosity logging data can obtain the best porosity calculation results, and the porosity calculation method based on sonic logging predicted that the porosity of the studied reservoir was low. It was very effective to identify hydrate layers based on resistivity, but the clay distribution and pore structure will also affect the relationship between resistivity, porosity and saturation, and it was suggested that the factors effecting the resistivity of different layers should be considered in the saturation evaluation and that a suitable model should be selected. This study also considered the lack of clarity of the relationships among the lithology, physical properties, hydrate-bearing occurrence properties, and log response properties of hydrate reservoirs and the lack of specialized petrophysical models. This research can directly help to improve hydrate logging evaluation.

装载机动臂孔组同轴度视觉检测系统设计

针对装载机动臂孔组尺寸大、距离远、现有的测量仪器和检测方案难以满足长距离异面通孔同轴度在线检测等问题,设计了基于机器视觉的装载机动臂孔组同轴度视觉检测系统。首先,根据装载机动臂孔组的结构特点建立动臂孔组同轴度误差模型,确定检测方案;然后,对工业相机进行标定,通过机器视觉联合伺服运动获取装载机动臂孔组图像,对获得的图像进行处理,得到装载机动臂孔组的边缘轮廓及圆心空间坐标,并计算装载机动臂孔组的同轴度;最后,通过企业实机验证,证明装载机动臂孔组同轴度视觉检测系统的检测精度和稳定性均达到检测要求,且在检测效率和自动化程度等方面均优于传统检测方案,满足流水线在线检测需求。

Strong spin frustration and magnetism in kagoméantiferromagnets LnCu_(3)(OH)_(6)Br_(3)(Ln=Nd,Sm,and Eu)

To study the effects of lanthanide ions on the geometrically frustrated antiferromagnets and their magnetic properties,we grew high-quality single crystals of LnCu_(3)(OH)_(6)Br_(3)(Ln=Nd,Sm,and Eu)by hydrothermal method and studied their crystal structures and magnetic properties.The refinements of the crystal structure referred to the powder x-ray diffraction data show that LnCu_(3)(OH)_(6)Br_(3)adopt a Kapellasite-type layer structure,which is isostructural to their chlorine analogue.Magnetic susceptibilities demonstrate that LnCu_(3)(OH)_(6)Br_(3)have strong antiferromagnetic coupling and a pronounced magnetic frustration effect.Magnetization measurements indicate canted antiferromagnetic ordering of Cu^(2+)ions around 16 K within the kagoméplane and weak ferromagnetic coupling.Moreover,shoulder-like anomalies in specific heat around 16 K could be a signature of emergent of magnetic ordering.The low-temperature negative magnetization and specific heat of LnCu_(3)(OH)_(6)Br_(3)(Ln=Nd,Sm,and Eu)indicate that Ln^(3+)ions induce more exotic magnetic ground state properties.

Clinical application of SARS-CoV-2 antibody detection and monoclonal antibody therapies against COVID-19

The purpose of this study was to investigate the clinical application of severe acute respiratory distress syndrome coronavirus-2(SARS-CoV-2)specific antibody detection and anti-SARS-CoV-2 specific monoclonal antibodies(mAbs)in the treatment of coronavirus infectious disease 2019(COVID-19).The dynamic changes of SARS-CoV-2 specific antibodies during COVID-19 were studied.Immunoglobulin M(IgM)appeared earlier and lasted for a short time,while immunoglobulin G(IgG)appeared later and lasted longer.IgM tests can be used for early diagnosis of COVID-19,and IgG tests can be used for late diagnosis of COVID-19 and identification of asymptomatic infected persons.The combination of antibody testing and nucleic acid testing,which complement each other,can improve the diagnosis rate of COVID-19.Monoclonal anti-SARS-CoV-2 specific antibodies can be used to treat hospitalized severe and critically ill patients and non-hospitalized mild to moderate COVID-19 patients.COVID-19 convalescent plasma,highly concentrated immunoglobulin,and anti-SARS-CoV-2 specific mAbs are examples of anti-SARS-CoV-2 antibody products.Due to the continuous emergence of mutated strains of the novel coronavirus,especially omicron,its immune escape ability and infectivity are enhanced,making the effects of authorized products reduced or invalid.Therefore,the optimal application of anti-SARS-CoV-2 antibody products(especially anti-SARS-CoV-2 specific mAbs)is more effective in the treatment of COVID-19 and more conducive to patient recovery.

Chromosome-scale genome sequence of Suaeda glauca sheds light on salt stress tolerance in halophytes

Soil salinity is a growing concern for global crop production and the sustainable development of humanity.Therefore,it is crucial to comprehend salt tolerance mechanisms and identify salt-tolerance genes to enhance crop tolerance to salt stress.Suaeda glauca,a halophyte species well adapted to the seawater environment,possesses a unique ability to absorb and retain high salt concentrations within its cells,particularly in its leaves,suggesting the presence of a distinct mechanism for salt tolerance.In this study,we performed de novo sequencing of the S.glauca genome.The genome has a size of 1.02 Gb(consisting of two sets of haplotypes)and contains 54761 annotated genes,including alleles and repeats.Comparative genomic analysis revealed a strong synteny between the genomes of S.glauca and Beta vulgaris.Of the S.glauca genome,70.56%comprises repeat sequences,with retroelements being the most abundant.Leveraging the allele-aware assembly of the S.glauca genome,we investigated genome-wide allele-specific expression in the analyzed samples.The results indicated that the diversity in promoter sequences might contribute to consistent allele-specific expression.Moreover,a systematic analysis of the ABCE gene families shed light on the formation of S.glauca’s flower morphology,suggesting that dysfunction of A-class genes is responsible for the absence of petals in S.glauca.Gene family expansion analysis demonstrated significant enrichment of Gene Ontology(GO)terms associated with DNA repair,chromosome stability,DNA demethylation,cation binding,and red/far-red light signaling pathways in the co-expanded gene families of S.glauca and S.aralocaspica,in comparison with glycophytic species within the chenopodium family.Time-course transcriptome analysis under salt treatments revealed detailed responses of S.glauca to salt tolerance,and the enrichment of the transition-upregulated genes in the leaves associated with DNA repair and chromosome stability,lipid biosynthetic process,and isoprenoid metabolic process.Additionally,genome-wide analysis of transcription factors indicated a significant expansion of FAR1 gene family.However,further investigation is needed to determine the exact role of the FAR1 gene family in salt tolerance in S.glauca.

大学与区域创新体系建设的协同路径探析

大学作为人类知识创新和传播的主要载体,为经济社会发展和文明进步提供了催化剂和动力源。我国明确推动若干区域率先建设国际科技创新中心,为新时期一流大学建设赋予了重要使命和机遇。本文梳理了国内外大学与区域创新互动的理论发展和案例,总结了相关模式和经验,关注了大学与区域创新体系如何实现系统性协同的具体路径。通过剖析上海交通大学服务上海建设具有全球影响力的科技创新中心城市的实践案例,从战略路径匹配、组织机构重构、基础原创策源、产学研开放融合、创新创业生态等方面,阐述了大学在对接提升全球科技创新中心城市过程中协同路径的选择与思考、设计与实施、特色与成效。研究结论可以为我国新时期区域创新和一流大学建设融合发展提供参考,并对政府和大学提出了相关政策性建议。

德国职业教育数字化发展政策与实践

为满足“工业4.0”等数字化发展的需求,德国政府通过出台一系列政策,完成了职业教育数字化转型的顶层设计。在这些政策的扶持下,职业学校、企业等利益相关者积极参与数字化转型,合作探索出一些富有创新性的数字化实践模式。文章对德国整体推进职业教育数字化发展的代表性政策和实践案例进行详细分析,重点介绍了四个有代表性的实践案例:未来教室和无纸化教室、数字烘焙项目、掌控VR、数字教学系统。最后从德国职业教育数字化发展实践中得出三点启示:需要政府科学而周密的顶层设计,大力推动职业教育数字化转型;需要所有利益相关者通力协作,充分整合优势资源发挥协同效应;需要明确界定学生和教师数字化能力标准,为课程和教学提供明确导向。

基于拓扑栅格建模的AGV路径规划算法优化

为解决不规则布局的智能制造车间中自动导引车(automated guided vehicle,AGV)的路径规划问题,提出一种实现AGV路径规划的双层环境建模方法,在此基础上对其路径规划算法进行有效改进,改进算法附加考虑路径的平滑度,提出模拟退火的种群选择方法。通过仿真实验验证,改进后的算法规划出的路径更加平滑,有效避免了传统遗传算法易陷入局部最优的缺陷。仿真实验还验证了改进算法的有效性区间,当障碍物栅格占全环境比小于等于40%时,改进算法比传统遗传算法有效,在此范围内,障碍物占比越高,算法有效性越好。

甘蔗刮板输送装置的动态仿真及尺寸优化

对切断式联合甘蔗收获机的刮板输送装置进行动态仿真,得出在运输状态中甘蔗段对刮板输送装置的动态力谱,为刮板输送装置的分析提供了更为准确地约束工况。为减少机器能耗,提高工作效率,基于产品轻量化思想对刮板输送装置的构件厚度进行尺寸优化。以输送装置构件加权特征值最小为优化目标,刮板输送装置质量和甘蔗段质量为约束,采用规划法进行优化设计,得到结构厚度的最优尺寸。通过尺寸优化设计,输送装置质量在原来的基础上减少了312 kg,达到轻量化的目的,可为甘蔗收获机输送装置的同类优化设计提供参考。

Prognostic value of programmed death.1, programmed death-ligand 1, programmed death-ligand 2 expression, and CD8(+) T cell density in primary tumors and metastatic lymph nodes from patients with stage T1.4N+M0 gastric adenocarcinoma

Background: Anti-programmed death-1/programmed death-ligand 1(PD-1/PD-L1) immunotherapy has been proved to be effective on gastric cancer in ongoing clinical trials. However, the value of PD-L1 in predicting responses of patients with gastric cancer to anti-PD-1/PD-L1 immunotherapy is controversial. Some studies suggested that intra-and inter-tumoral heterogeneity of PD-L1 expression might explain the controversy.This study aimed to analyze the expression of PD-L1, PD-L2, and PD-1 as well as CD8(+) T-cell density in primary tumors and lymph nodes from patients with stage T1-4 N+M0 gastric adenocarcinoma to explore the heterogeneity of PD-1 signaling pathway molecules.Methods: In primary tumors and metastatic as well as non-metastatic lymph nodes from patients with stage T1-4 N+M0 gastric adenocarcinoma, we detected PD-L1 and PD-L2 expression with immunohistochemistry. CD8(+)T-cell density in primary tumors and PD-1 expression on CD8(+)T cells were detected with immunofluorescence. Univariate analysis was used to determine the prognostic values of them. Cox proportional hazard regression model was used to identify independent risk factors that affect patients' overall survival and disease-free survival.Results: Among 119 eligible patients who had undergone surgical resection, the positive rate of PD-L1 was higher in metastatic lymph nodes than in primary tumors(45.4% vs. 38.7%, P = 0.005); the positive rate of PD-1 on CD8(+)T cells was significantly higher in primary tumors and metastatic lymph nodes than in tumor-free lymph nodes(both P < 0.001). The intensity of PD-1 expression on CD8(+) T cells in primary tumors and in metastatic lymph nodes were stronger than that in tumor-free lymph nodes from the same patient. Beside, the positive rate of PD-L2 did not show any differences between primary tumors and metastatic lymph nodes. In multivariate analysis, PD-L1 expression,PD-L2 expression, a low density of CD8(+) T cells in primary tumors, and PD-1 expression on CD8(+) T cells in primary tumors were associated with poor prognosis.Conclusion: The expression of PD-L1 is heterogeneous in primary tumors and in metastatic lymph nodes from patients with stageT1-4 N+M0 gastric adenocarcinoma, which might explain the inconsistent results in assessing the prognostic value of PD-L1 expression in previous studies.

The endocytosis and intracellular fate of nanomedicines: Implication for rational design

Nanomedicines employ multiple endocytic pathways to enter cells.Their following fate is interesting,but it is not sufficient understood currently.This review introduces the endocytic pathways,presents new technologies to confirm the specific endocytic pathways and discusses factors for pathway selection.In addition,some intriguing implication about nanomedicine design based on endocytosis will also be discussed at the end.This review may provide new thoughts for the design of novel multifunctional nanomedicines.

pH-sensitive polymeric micelles triggered drug release for extracellular and intracellular drug targeting delivery

Most of the conventional chemotherapeutic agents used for cancer chemotherapy suffer from multidrug resistance of tumor cells and poor antitumor efficacy.Based on physiological differences between the normal tissue and the tumor tissue,one effective approach to improve the efficacy of cancer chemotherapy is to develop pH-sensitive polymeric micellar delivery systems.The copolymers with reversible protonationedeprotonation core units or acid-liable bonds between the therapeutic agents and the micelle-forming copolymers can be used to form pH-sensitive polymeric micelles for extracellular and intracellular drug smart release.These systems can be triggered to release drug in response to the slightly acidic extracellular fluids of tumor tissue after accumulation in tumor tissues via the enhanced permeability and retention effect,or they can be triggered to release drug in endosomes or lysosomes by pH-controlled micelle hydrolysis or dissociation after uptake by cells via the endocytic pathway.The pH-sensitive micelles have been proved the specific tumor cell targeting,enhanced cellular internalization,rapid drug release,and multidrug resistance reversal.The multifunctional polymeric micelles combining extracellular pH-sensitivity with receptor-mediated active targeting strategies are of great interest for enhanced tumor targeting.The micelles with receptor-mediated and intracellular pH targeting functions are internalized via receptor-mediated endocytosis followed by endosomal-pH triggered drug release inside the cells,which reverses multidrug resistance.The pH sensitivity strategy of the polymeric micelles facilitates the specific drug delivery with reduced systemic side effects and improved chemotherapeutical efficacy,and is a novel promising platform for tumor-targeting drug delivery.

Distinct immune response induced by peptidoglycan derived from Lactobacillus sp

AIM： To analyze the distinct immune responses induced by Lactobacillus peptidoglycan （PG）. METHODS： BALB/c mice were intraperitoneally injected with PG once a day for three consecutive days, Peritoneal macrophage and splenocyte mRNA was extracted and the gene expression profile was studied using high-density oligonudeotide microarrays. Inhibitory effects of Lactobacillus PG on colon tumor tissue were studied in vitro and in vivo, RESULTS： The gene expression profiles revealed that the TLR-NF-kB and Jak-STAT signaling pathways were highly activated. An inflammatory phenotype was induced when peritoneal macrophages were initially exposed to Lactobacillus PG and switched to a more complex phenotype when BALB/c mice were treated with three doses of Lactobacillus PG. A protective physiological inflammatory response was induced after three consecutive days of PG treatment. It was tending toward Thl dominant immune response. Lactobacillus PG also appeared to induce a significant in vivo anti-colon tumor effect. CONCLUSION： Lactobacillus PG is responsible for certain immune responses induced by Lactobacilli. Anti-tumor effects of Lactobacilliare likely to attribute to the activation of macrophages by PG expressed on the bacterial cell surface.

Small changes in the length of diselenide bond-containing linkages exert great influences on the antitumor activity of docetaxel homodimeric prodrug nanoassemblies

Homodimeric prodrug-based self-assembled nanoparticles,with carrier-free structure and ultrahigh drug loading,is drawing more and more attentions.Homodimeric prodrugs are composed of two drug molecules and a pivotal linkage.The influence of the linkages on the self-assembly,in vivo fate and antitumor activity of homodimeric prodrugs is the focus of research.Herein,three docetaxel(DTX)homodimeric prodrugs are developed using different lengths of diselenide bond-containing linkages.Interestingly,compared with the other two linkages,the longest diselenide bond-containing linkage could facilitate the self-delivery of DTX prodrugs,thus improving the stability,circulation time and tumor targeting of prodrug nanoassemblies.Besides,the extension of linkages reduces the redox-triggered drug release and cytotoxicity of prodrug nanoassemblies in tumor cells.Although the longest diselenide bond-containing prodrug nanoassemblies possessed the lowest cytotoxicity to 4T1 cells,their stable nanostructure maintained intact during circulation and achieve the maximum accumulation of DTX in tumor cells,which finally“turned the table”.Our study illustrates the crucial role of linkages in homodimeric prodrugs,and gives valuable proposal for the development of advanced nano-DDS for cancer treatment.