A prognosis model for predicting immunotherapy response of esophageal cancer based on oxidative stress-related signatures

Oxidative stress(OS)is intimately associated with tumorigenesis and has been considered a potential therapeutic strategy.However,the OS-associated therapeutic target for esophageal squamous cell carcinoma(ESCC)remains unconfirmed.In our study,gene expression data of ESCC and clinical information from public databases were downloaded.Through LASSO-Cox regression analysis,a risk score(RS)signature map of prognosis was constructed and performed external verification with the GSE53625 cohort.The ESTIMATE,xCell,CIBERSORT,TIMER,and ImmuCellAI algorithms were employed to analyze infiltrating immune cells and generate an immune microenvironment(IM).Afterward,functional enrichment analysis clarified the underlying mechanism of the model.Nomogram was utilized for forecasting the survival rate of individual ESCC cases.As a result,we successfully constructed an OS-related genes(OSRGs)model and found that the survival rate of high-risk groups was lower than that of low-risk groups.The AUC of the ROC verified the strong prediction performance of the signal in these two cohorts further.According to independent prognostic analysis,the RS was identified as an independent risk factor for ESCC.The nomogram and follow-up data revealed that the RS possesses favorable predictive value for the prognosis of ESCC patients.qRT-PCR detection demonstrated increased expression of MPC1,COX6C,CYB5R3,CASP7,and CYCS in esophageal cancer patients.In conclusion,we have constructed an OSRGs model for ESCC to predict patients’prognosis,offering a novel insight into the potential application of the OSRGs model in ESCC.

早期胚胎极性建立及对谱系分化的影响

极性建立是影响早期胚胎发育的关键因素之一。极性建立起始于8细胞胚胎的肌球蛋白磷酸化,磷酸化激活肌动蛋白导致其启动收缩力。随后,肌动蛋白发生重组在每个卵裂球的非接触表面形成富含微绒毛的顶端结构域,并在极性蛋白复合物等的共同作用下形成标志着顶端结构域成熟的肌动球蛋白环。从极性建立的过程可知,顶端结构域的形成受到肌动蛋白相关蛋白以及极性蛋白复合物的影响,并且部分合子基因组激活(zygote genome activation,ZGA)和谱系分化特异性基因也会调控极性建立。在早期胚胎发育过程中,极性建立是第一次细胞谱系分化的基础。它通过影响不对称细胞分裂、谱系分化因子的不对称定位以及Hippo信号通路的活性来调控谱系分离和形态发生。本文对哺乳动物早期胚胎极性建立及对谱系分化影响的相关研究进行了梳理和总结,并讨论了目前已有研究在调控机制和物种方面的不足,以期为阐明早期胚胎极性建立提供线索与系统性视角。

基于工程教育专业认证构建一致化的教学大纲——以高分子物理课程为例

作为课程运行的指挥棒,传统课程大纲难以满足工程教育专业认证的要求,重建课程大纲迫在眉睫。基于工程认证标准,笔者以高分子物理课程为例,制定了标准的教学大纲,实现教学环节、学习活动和评价方式构建一致化。1)根据课程可支撑的毕业指标点,设立了定位准确、支撑强度合理的课程目标;2)细化了与课程目标对接的课程内容和教学环节;3)设置了课程考核方式和评分标准,科学量化学生学习效果。该标准化课程大纲不仅为达成课程目标提供了保障,而且为建立其他课程大纲树立了典范。

CT影像组学在肺癌诊治中应用的研究进展和问题探索

影像组学是一种基于多模态医学影像处理分析的技术,该技术能够基于高性能计算机及算法从目前普遍使用的计算机断层扫描(computed tomography, CT)、磁共振图像(magnetic resonance imaging, MRI)和正电子发射/断层图像(positron emission tomography/computed tomography, PET/CT)中自动提取海量数据进行分析,对疾病的早期诊断、良恶性肿瘤鉴别、疾病治疗全程管理,个体化精准治疗等需求提供更多有价值信息。近年来,许多研究表明基于CT的影像组学技术在肺癌的早期诊断、基因表型预测、疗效预测及预后评估均有良好的应用价值,且影像学检查具有无创、经济、可重复等优势。其对临床的指导价值已有所展露,在肺癌的个体化、精准化治疗和研究方面具有较大价值,但是,影像组学特征的重复性和一致性问题以及在肺部肿瘤图像提取中的特征筛选还需进一步研究。

第一代酪氨酸激酶抑制剂治疗中发生进展的非小细胞肺癌血浆表皮生长因子受体(EGFR)T790M突变提示了失败部位并预测了临床预后:一项前瞻性观察研究

背景与目的血浆循环肿瘤DNA(circulating tumor DNA,ctDNA)是检测表皮生长因子受体(epidermal growth factor receptor,EGFR)T790M突变的理想方法。T790M突变是第一代EGFR酪氨酸激酶抑制剂(tyrosine kinase inhibitor,TKI)耐药的主要机制。本研究旨在探讨ctDNA来源的T790M突变与非小细胞肺癌(non-small cell lung cancer,NSCLC)患者疾病失败部位及临床预后的关系。方法第一代TKI治疗发生进展的患者被分为局限胸内进展(chest limited,CF)、局限颅内进展(brain limited,BF)和其他部位进展(other,OF)组。采用扩增阻滞突变系统(amplification refractory mutation system,ARMS)和微滴式数字PCR(droplet digital PCR,ddPCR)对ctDNA中T790M突变进行了检测。采用Kaplan-Meier法分析了预后。结果 2种方法的总体一致性为78.3%。根据ARMS和ddPCR,OF组患者的T790M突变率明显高于BF组和CF组(P <0.001),OF组的T790M突变丰度也明显高于CF组和BF组(P <0.001)。AZD9291是T790M+患者最佳治疗选择,为EGFR-TKI治疗后进展的所有组中T790M+患者提供了最长的生存期;接受其他治疗的T790M-患者亚组的预后各不相同。结论本研究表明ctDNA中T790M突变与NSCLC患者EGFR-TKI治疗失败部位相关,失败部位和T790M突变状态对治疗选择和预后都有很大影响。

Research on improved integrated FDD/FTC with effectiveness factors

This paper investigates the integrated fault detection and diagnosis（FDD） with fault tolerant control（FTC） method of the control system with recoverable faults.Firstly,a quasi-linear parameter-varying（QLPV） model is set up,in which effectiveness factors are modeled as time-varying parameters to quantify actuators and sensors faults.Based on the certainty equivalency principle,replacing the real time states in the nonlinear term of the QLPV model with the estimated states,the parameters and states can be estimated by a two-stage Kalman filtering algorithm.Then,a polynomial eigenstructure assignment（PEA） controller with time-varying parameters and states is designed to guarantee the performance of the system with recoverable faults.Finally,mathematical simulation is performed to validate the solution in a satellite closed-loop attitude control system,and simulation results show that the solution is fast and effective for on-orbit real-time computation.

免疫检查点抑制剂相关不良反应预测的研究进展

免疫检查点抑制剂开启了肿瘤治疗的新纪元,然而免疫治疗在使患者获益的同时也可能引起免疫相关不良反应,这些不良反应会累及全身各器官和系统,并可能发生在治疗的任何阶段,甚至会危及生命。由于临床表现和发病时间的多样化导致对此类不良反应的预测和诊断进一步复杂化。本文旨在对免疫检查点抑制剂相关不良反应的临床特征以及预测的生物标志物进行综述,以帮助临床医生评估药物风险并提前预警不良反应。

Fault reconstruction observer design for continuous-time systems with measurement disturbances via descriptor system approach

This paper addresses a problem of observer-based sensor fault reconstruction for continuous-time systems subject to sensor faults and measurement disturbances via a descriptor system approach. An augmented descriptor plant is first formulated, by assembling measurement disturbances and sensor faults into an auxiliary state vector. Then a novel descriptor state observer for the augmented plant is constructed such that simultaneous reconstruction of original system states, sensor faults and measurement disturbances are obtained readily. Sufficient conditions for the existence of the proposed observer are explicitly provided, and the application scope of the observer is further discussed. In addition, an extension of the proposed linear approach to a class of nonlinear systems with Lipschitz constraints is investigated. Finally, two numerical examples are simulated to illustrate the effectiveness of the proposed fault-reconstructing approaches.

Review on the mesoscale characterization of cement-stabilized macadam materials

The base layer constructed by cement-stabilized macadam(CSM)has been widely used in highway construction due to its low elasticity deformation and high carrying capacity.As a bearing layer,the CSM base is not exempt from fatigue cracking under cyclic loading in the service process.Cracks in the base will create irreversible structural and functional deficiencies,such as the potential for reflective cracking of subsequently placed asphalt concrete overlays.The fracture of the base will shorten the service life of the pavement.The quality of the CSM base is directly related to the bearing capacity and integrity of the whole pavement structure.It is of practical significance to further study the fatigue failure behavior of CSM material for the long-term performance of the pavement.The CSM material is a typical heterogeneous multiphase composite.On the mesoscale,CSM consists of aggregate,cement mortar,pores,and the interface transitional zone(ITZ).On the microscale,the hardened mortar contains a large number of capillary pores,unhydrated particles,hydrated crystals,etc.,which makes the spatial distribution of its material properties stochastic.In addition,cement hydration,dry shrinkage,and temperature shrinkage can also produce micro-crack defects in cement mortar.These microcracks will have crossscale evolution under load,resulting in structural fracture.Macroscopic complex deformation and mechanical response are the reflections of its microscopic and even mesoscale composition and structure.This study summarized the existing studies on the mesoscopic properties of CSM materials,respectively from the three aspects of mesostructure,structural characterization,and mesoscale fatigue damage analysis,to help the development of long-life pavement.The future research direction is to explore the mesoscale characteristics of CSM using multiscale representation and analysis methods,to establish the connection between mesoscale characteristics and macroscopic mechanical properties.

Analysis of Factors Influencing Farmers' Participation in Forest Farmers Cooperatives Based on Empirical Research of Zhejiang Province

Based on field research data of farmers in Zhejiang Province, the authors analyzed factors influencing farmers' participation in forest farmers cooperatives (hereafter referred to as FFCs) by the binary logistic regression model. Results show that understanding of farmers about cooperatives has a great influence on their behavior of participation in FFCs. Besides, educational level of householders and existing member scale of cooperatives also have significant influence on farmers' behavior of participation in cooperatives. Therefore, it is required to strengthen propaganda of cooperatives, deepen their understanding of cooperatives; cultivate new high quality farmers to provide talents for development of cooperatives; establish incentive mechanism to encourage farmers to participate in cooperatives.

Josephin domain containing 2(JOSD2)promotes lung cancer by inhibiting LKB1(Liver kinase B1)activity

Non-small cell lung cancer(NSCLC)ranks as one of the leading causes of cancer-related deaths worldwide.Despite the prominence and effectiveness of kinase-target therapies in NSCLC treatment,these drugs are suitable for and beneficial to a mere~30%of NSCLC patients.Consequently,the need for novel strategies addressing NSCLC remains pressing.Deubiquitinases(DUBs),a group of diverse enzymes with well-defined catalytic sites that are frequently overactivated in cancers and associated with tumorigenesis and regarded as promising therapeutic targets.Nevertheless,the mechanisms by which DUBs promote NSCLC remain poorly understood.Through a global analysis of the 97 DUBs’contribution to NSCLC survival possibilities using The Cancer Genome Atlas(TCGA)database,we found that high expression of Josephin Domain-containing protein 2(JOSD2)predicted the poor prognosis of patients.Depletion of JOSD2 significantly impeded NSCLC growth in both cell/patient-derived xenografts in vivo.Mechanically,we found that JOSD2 restricts the kinase activity of LKB1,an important tumor suppressor generally inactivated in NSCLC,by removing K6-linked polyubiquitination,an action vital for maintaining the integrity of the LKB1-STRAD-MO25 complex.Notably,we identified the first small-molecule inhibitor of JOSD2,and observed that its pharmacological inhibition significantly arrested NSCLC proliferation in vitro/in vivo.Our findings highlight the vital role of JOSD2 in hindering LKB1 activity,underscoring the therapeutic potential of targeting JOSD2 in NSCLC,especially in those with inactivated LKB1,and presenting its inhibitors as a promising strategy for NSCLC treatment.

In Vivo Voltammetric Imaging of Metal Nanoparticle-Catalyzed Single-Cell Electron Transfer by Fermi Level-Responsive Graphene

Metal nanomaterials can facilitate microbial extracellular electron transfer(EET)in the electrochemically active biofilm.However,the role of nanomaterials/bacteria interaction in this process is still unclear.Here,we reported the single-cell voltammetric imaging of Shewanella oneidensis MR-1 at the single-cell level to elucidate the metal-enhanced EET mechanism in vivo by the Fermi level-responsive graphene electrode.Quantified oxidation currents of~20 fA were observed from single native cells and gold nanoparticle(AuNP)-coated cells in linear sweep voltammetry analysis.On the contrary,the oxidation potential was reduced by up to 100 mV after AuNP modification.It revealed the mechanism of AuNP-catalyzed direct EET decreasing the oxidation barrier between the outer membrane cytochromes and the electrode.Our method offered a promising strategy to understand the nanomaterials/bacteria interaction and guide the rational construction of EET-related microbial fuel cells.

High-resolution multimodal flexible coherent Raman endoscope

Coherent Raman scattering microscopy is a fast,label-free,and chemically specific imaging technique that shows high potential for future in vivo optical histology.However,the imaging depth in tissues is limited to the sub-millimeter range because of absorption and scattering.Realization of coherent Raman imaging using a fiber endoscope system is a crucial step towards imaging deep inside living tissues and providing information that is inaccessible with current microscopy tools.Until now,the development of coherent Raman endoscopy has been hampered by several issues,mainly related to the fiber delivery of the excitation pulses and signal collection.Here,we present a flexible,compact,coherent Raman,and multimodal nonlinear endoscope(4.2mm outer diameter,71mm rigid length)based on a resonantly scanned hollow-core Kagomé-lattice double-clad fiber.The fiber design enables distortion-less,background-free delivery of femtosecond excitation pulses and back-collection of nonlinear signals through the same fiber.Sub-micrometer spatial resolution over a large field of view is obtained by combination of a miniature objective lens with a silica microsphere lens inserted into the fiber core.We demonstrate high-resolution,high-contrast coherent anti-Stokes Raman scattering,and second harmonic generation endoscopic imaging of biological tissues over a field of view of 320μm at a rate of 0.8 frames per second.These results pave the way for intraoperative label-free imaging applied to real-time histopathology diagnosis and surgery guidance.

Numerical simulation of mesoscopic cracking of cement-treated base material based on random polygon aggregate model

Cracking failure of cement-treated base(CTB)has always been the concern of highway constructors.Mesoscale cracking analysis is an important means to study the damage degradation mechanism,which is difficult to be characterized by experimental techniques alone.The objective of this paper is to develop a random aggregate modelling method to simulate the mesoscopic cracking of CTB material.A minimum rectangle area method was proposed to calculate the polygon aggregate size,which is closer to the sieving analysis than the average radius method.A buffer zone method was proposed to determine the distance between randomly generated polygon aggregates.Based on the proposed random algorithm,finite element method(FEM)was adopted to build the mesoscopic model of CTB including aggregate,mortar,interfacial transition zone(ITZ)and air voids.Laboratory tests were conducted to validate the numerical model.Then the sensitivity analyses were conducted to study the influencing factors on cracking behavior.The simulation results indicate that the higher aggregate content and the finer gradation lead to the increase of ITZ,thus reducing the cracking resistance of the CTB material.Low porosity content is able to significantly reduce the stress concentration and thus improves the cracking resistance.The research results of this paper could be used to guide the crack resistant design of CTB material.

Inhibiting cancer cell hallmark features through nuclear export inhibition

Treating cancer through inhibition of nuclear export is one of the best examples of basic research translation into clinical application.Nuclear export factor chromosomal region maintenance 1(CRM1;Xpo1 and exportin-1)controls cellular localization and function of numerous proteins that are critical for the development of many cancer hallmarks.The diverse actions of CRM1 are likely to explain the broad ranging anti-cancer potency of CRM1 inhibitors observed in pre-clinical studies and/or clinical trials(phase I–III)on both advanced-stage solid and hematological tumors.In this review,we compare and contrast the mechanisms of action of different CRM1 inhibitors,and discuss the potential benefit of unexplored non-covalent CRM1 inhibitors.This emerging field has uncovered that nuclear export inhibition is well poised as an attractive target towards low-toxicity broad-spectrum potent anti-cancer therapy.

Visible Light-Driven Catalyst-Free Amination of Indoles Initiated by Electron Donor-Acceptor Complexes

The visible light-driven C2 or C3 amination of indoles without any additives was initiated via electron donor-acceptor (EDA) complex formed by indole and N-aminopyridinium salt.This method was compatible with a wide range of substrates and could proceed smoothly without the addition of any photocatalysts,transition-metal catalysts,or bases.A variety of studies were carried out to examine the presence of EDA complex.

A grasp planning algorithm under uneven contact point distribution scenario for space non-cooperative target capture

The contact point configuration should be carefully chosen to ensure a stable capture,especially for the non-cooperative target capture mission using multi-armed spacecraft.In this work scenario,the contact points on the base and on the arms are distributed on the opposite side of the target.Otherwise,large forces will be needed.To cope with this problem,an uneven-oriented distribution union criterion is proposed.The union criterion contains a virtual symmetrical criterion and a geometry criterion.The virtual symmetrical contact point criterion is derived from the proof of the force closure principle using computational geometry to ensure a stable grasp,and the geometry criterion is calculated by the volume of the minimum polyhedron formed by the contact points to get a wide-range distribution.To further accelerate the optimization rate and enhance the global search ability,a line array modeling method and a continuous-discrete global search algorithm are proposed.The line array modeling method reduces the workload of calculating the descent direction and the gradient available,while the continuous-discrete global search algorithm reducing the optimization dimension.Then a highly efficient grasping is achieved and the corresponding contact point is calculated.Finally,an exhaustive verification is conducted to numerically analyze the disturbance resistance ability,and simulation results demonstrate the effectiveness of the proposed algorithms.

Epidermal growth factor receptor (EGFR) T790M mutation identified in plasma indicates failure sites and predicts clinical prognosis in non-small cell lung cancer progression during first-generation tyrosine kinase inhibitor therapy: a prospective observational study

Introduction:Plasma circulating tumor DNA(ctDNA)is an ideal approach to detecting the epidermal growth factor receptor(EGFR)T790M mutation,which is a major mechanism of resistance to first-generation EGFR-tyrosine kinase inhibitor(TKI)therapy.The present study aimed to explore the association of ctDNA-identified T790M mutation with disease failure sites and clinical prognosis in non-small cell lung cancer(NSCLC)patients.Methods:Patients who progressed on first-generation TKIs were categorized into failure site groups of chest limited(CF),brain limited(BF)and other(OF).Amplification refractory mutation system(ARMS)and droplet digital PCR(ddPCR)were used to identify the T790M mutation in ctDNA.Prognosis was analyzed with Kaplan-Meier methods.Results:Overall concordance between the two methods was 78.3%.According to both ARMS and ddPCR,patients in the OF group had a significantly higher rate of T790M mutation than did patients in the BF and CF groups(P<0.001),and a significantly higher T790M mutation rate was also observed in OF-group patients than in those in the CF and BF groups(P<0.001).AZD9291 was found to be an excellent treatment option and yielded the longest survival for T790M+patients in all groups who had progressed on EGFR-TKIs;for other treatments,the prognosis of T790M−patient subgroups varied.Conclusions:The present study demonstrates that T790M mutation in ctDNA is associated with failure sites for NSCLC patients after EGFR-TKI therapy and indicates that both failure site and T790M mutational status greatly influ-ence treatment selection and prognosis.

DNA functionalized plasmonic nanoassemblies as SERS sensors for environmental analysis

Surface-enhanced Raman scattering(SERS)is among the most widely applied analytical techniques due to its easy execution and extreme sensitivity.Target molecules can be detected and distinguished based upon the fingerprint spectra that arise when absorbed on the SERS substrates surface,particularly on the SERS-active hotspots.Thus,rational fabricating the enhancing substrates plays a key role in broadening SERS application.Programmable DNA functionalized plasmonic nanoassemblies,where DNA acts as both structure basis and functional unit,combine the specificity of DNA recognition,and modulate the assembly of plasmonic nanoparticles(NPs).Specifically designed DNA not only improves the selectivity to target molecules but also promotes the sensitivity of the optical signals through precisely regulating the distance between the molecule and the substrate.A variety of DNA-functionalized SERS sensors have been reported and obtained well performance in the analysis of heavy metal ions in water,toxins,pesticide residues,antibiotics,hormones,illicit drugs,or other small molecules.This review places an emphasis on the design and sensing strategies of the DNA-functionalized plasmonic nanoassemblies,as well as basic principles of Raman enhancement,and recent advances for environmental analysis.The current challenges and potential trends in the development of DNAfunctionalized SERS sensors for environmental pollutant monitoring in complicated scenarios are subsequently discussed.