TRIP13通过同源重组通路提高肺腺癌细胞的放射抗性

背景与目的放疗是非小细胞肺癌(non-small cell lung cancer,NSCLC)最常用的治疗手段之一。然而,一部分肿瘤细胞对放射线的不敏感是放疗疗效差、患者预后不良的重要原因之一,探究放射抵抗背后的深层机制是解决这一临床难题的关键。本研究旨在寻找与肺腺癌(lungadenocarcinoma,LUAD)放射抵抗相关的分子,初步经数据库筛选锁定甲状腺素受体结合因子13(thyroid hormone receptor interactor 13,TRIP13)为主要研究对象,并探索TRIP13是否与LUAD的放射抵抗有关及具体机制,以期为临床接受放疗的LUAD患者的联合治疗提供理论依据和潜在靶点。方法选取基因表达综合数据库(Gene Expression Omnibus,GEO)中的GSE18842、GSE19188和GSE33532共3个数据集,借助R 4.1.3软件分别筛选3个数据集中差异表达的基因(|logFC|>1.5,P<0.05),之后使用Venn diagram找出在3个数据集中共有的差异表达基因。随后,借助STRING在线工具和Cytoscape软件,对筛选出来的差异基因进行蛋白质相互作用分析和模块分析,借助Kaplan-Meier Plotter数据库对各基因进行生存预后分析,并确定TRIP13基因作为后续主要研究分子。随后,采用亚致死性剂量照射法对人LUAD细胞系H292进行多次X射线照射,以构建具有放射抗性的细胞系H292DR。采用细胞计数试剂盒-8(cell counting kit-8,CCK-8)实验和克隆形成实验验证H292DR细胞的放射抗性能力。Western blot检测H292细胞和H292DR细胞中TRIP13蛋白的表达水平。使用小干扰RNA(small interfering RNA,siRNA)沉默H292DR细胞中TRIP 13蛋白的表达并进行Western blot检测。观察TRIP13沉默后H292DR细胞的克隆形成能力和迁移能力,随后检测共济失调-毛细血管扩张突变(ataxia telangiectasia mutated,ATM)蛋白等与同源重组密切相关的蛋白的表达水平变化。结果经多个GEO数据集筛选、外部数据集的验证以及生存分析发现,TRIP13在LUAD中高表达,并与接受过放疗的LUAD患者的不良预后有关;并且,TRIP13基因富集分析(gene set enrichment analysis,GSEA)的结果提示,TRIP13可能通过促进放疗后的同源重组修复而与LUAD放射抵抗有密切关联。经实验检测发现,TRIP13的表达在H292DR中上调,而沉默TRIP13后能够增加H292DR细胞对放射线的敏感性。结论TRIP13与接受放疗后的LUAD患者的预后不良有关,可能是通过促进同源重组修复途径来介导LUAD细胞对放射线的抵抗。

Perspectives in human brain plasticity sparked by glioma invasion:from intraoperative(re)mappings to neural reconfigurations

Exploring the aptitude of the human brain to compensate functional consequences of a lesion damaging its structural architecture is a key challenge to improve patient care in various neurological diseases,to optimize neuroscientifically-informed strategies of postlesional rehabilitation,and ultimately to develop innovative neuro-regenerative therapies.The term‘plasticity’,initially referring to the intrinsic propensity of neurons to modulate their synaptic transmission in a learning situation,was progressively transposed to brain injury research and clinical neurosciences.Indeed,in the event of brain damage,adaptive mechanisms of compensation allow a partial reshaping of the structure and activities of the central nervous system,thus permitting to some extent the maintenance of brain functions.

Mitochondrial recruitment in myelin:an anchor for myelin dynamics and plasticity?

Optimal propagation of neuronal electrical impulses depends on the insulation of axons by myelin,produced in the central nervous system by oligodendrocytes.Myelin is an extension of the oligodendrocyte plasma membrane,which wraps around an axon to form a compact multi-layered sheath.Myelin is composed of a substantially higher proportion of lipids compared to other biological membranes and enriched in a small number of specialized proteins.

Glial progenitor heterogeneity and plasticity in the adult spinal cord

Glial progenitor cells were reported to have the capacity to generate various types of cells in both the central nervous system(CNS)and peripheral nervous system.Glial progenitor cells can respond to diverse environmental signals and transform into distinct populations,each serving specific functions.Notably,the adult spinal cord hosts various populations of glial progenitors,a region integral to the central nervous system.During development,glial progenitors express glial fibrillary acidic protein(GFAP;Dimou and Gotz,2014).However,the specific identities of GFAP-expressing progenitors in the adult spinal cord were not thoroughly investigated.

From mice to humans:a need for comparable results in mammalian neuroplasticity

Brain plasticity-A universal tool with many variations:The study of brain plasticity has been gaining interest since almost a century and has now reached a huge amount of information(>80,000 results in PubMed).Overall,different types of plasticity,including stem cell-driven genesis of new neurons(adult neurogenesis),cells in arrested maturation(dormant neurons),neuro-glial and synaptic plasticity,can coexist and contribute to grant plastic changes in the brain,from a cellular to system level(Benedetti and Couillard-Despres,2022;Bonfanti et al.,2023).

Age-related differences in long-term potentiation-like plasticity and shortlatency afferent inhibition and their association with cognitive function

Background The neurophysiological differences in cortical plasticity and cholinergic system function due to ageing and their correlation with cognitive function remain poorly understood.Aims To reveal the differences in long-term potentiation(LTP)-like plasticity and short-latency afferent inhibition(SAl)between older and younger individuals,alongside their correlation with cognitive function using transcranial magnetic stimulation(TMS).Methods The cross-sectional study involved 31 younger adults aged 18-30 and 46 older adults aged 60-80.All participants underwent comprehensive cognitive assessments and a neurophysiological evaluation based on TMS.Cognitive function assessments included evaluations of global cognitive function,language,memory and executive function.The neurophysiological assessment included LTP-like plasticity and SAl.Results The findings of this study revealed a decline in LTP among the older adults compared with the younger adults(wald χ^(2)=3.98,p=0.046).Subgroup analysis further demonstrated a significant reduction in SAl level among individuals aged 70-80 years in comparison to both the younger adults(SAI(N20)):(t=-3.37,p=0.018);SAl(N20+4):(t=-3.13,p=0.038)and those aged 60-70(SAl(N20)):(t=3.26,p=0.025);SAl(N20+4):(t=-3.69,p=0.006).Conversely,there was no notable difference in SAl level between those aged 60-70 years and the younger group.Furthermore,after employing the Bonferroni correction,the correlation analysis revealed that only the positive correlation between LTP-like plasticity and language function(r=0.61,p<0.001)in the younger group remained statistically significant.Conclusions During the normal ageing process,a decline in synaptic plasticity may precede cholinergic system dysfunction.In individuals over 60 years of age,there is a reduction in LTP-like plasticity,while a decline in cholinergic system function is observed in those over 70.Thus,the cholinergic system may play a vital role in preventing cognitive decline during normal ageing.In younger individuals,LTP-like plasticity might represent a potential neurophysiological marker for language function.

Timing effect of high temperature exposure on the plasticity of internode and plant architecture in maize

The occurrence of high temperature(HT)in crop production is becoming more frequent and unpredictable with global warming,severely threatening food security.The state of an organ’s growth and development is largely determined by the temperature conditions it is exposed to over time.Maize is the main cereal crop,and its stem growth and plant architecture are closely related to lodging resistance,and especially sensitive to temperature.However,systematic research on the timing effect of HT on the sequentially developing internode and stem is currently lacking.To identify the timing effect of HT on the morphology and plasticity of the stem in maize,two hybrids(Zhengdan 958(ZD958),Xianyu 335(XY335))characterized by distinct morphological traits in the stem were exposed to a 7-day HT treatment from the V6 to V17 stages(Vn presents the vegetative stage with n leaves fully expanded)in 2019-2020.The results demonstrated that exposure to HT during V6-V12 accelerated the rapid elongation of stems.For instance,HT occurring at V7 and V12 specifically promoted the lengths and weights of the 3rd-5th and 9th-11th internodes,respectively.Meanwhile,HT slowed the growth of internodes adjacent to the promoted internodes.Interestingly,compared with control,the plant height was significantly increased soon after HT treatment,but the promotion effect became narrower at the subsequent flowering stage,demonstrating a self-adjusting mechanism in the maize plant in response to HT.Importantly,HT altered the plant architectures,including a rising of the ear position and increase in the ear position coefficient.XY335 exhibited greater sensitivity in stem development than ZD958 under HT treatment.These findings improve our systematic understanding of the plasticity of internode and plant architecture in response to the timing of HT exposure.

Superplasticity of fine-grained Mg-10Li alloy prepared by severe plastic deformation and understanding its deformation mechanisms

The superplastic behavior and associated deformation mechanisms of a fine-grained Mg-10.1 Li-0.8Al-0.6Zn alloy(LAZ1011)with a grain size of 3.2μm,primarily composed of the BCCβphase and a small amount of the HCPαphase,were examined in a temperature range of 473 K to 623 K.The microstructural refinement of this alloy was achieved by employing high-ratio differential speed rolling.The best superplasticity was achieved at 523 K and at strain rates of 10^(-4)-5×10^(-4)s^(-1),where tensile elongations of 550±600%were obtained.During the heating and holding stage of the tensile samples prior to tensile loading,a significant increase in grain size was observed at temperatures above 573 K.Therefore,it was important to consider this effect when analyzing and understanding the superplastic deformation behavior and mechanisms.In the investigated strain rate range,the superplastic flow at low strain rates was governed by lattice diffusion-controlled grain boundary sliding,while at high strain rates,lattice diffusion-controlled dislocation climb creep was the rate-controlling deformation mechanism.It was concluded that solute drag creep is unlikely to occur.During the late stages of deformation at 523 K,it was observed that grain boundary sliding led to the agglomeration of theαphase,resulting in significant strain hardening.Deformation mechanism maps were constructed forβ-Mg-Li alloys in the form of 2D and 3D formats as a function of strain rate,stress,temperature,and grain size,using the constitutive equations for various deformation mechanisms derived based on the data of the current tests.

Microstructure and mechanical properties of a cast TRIP-assisted multiphase stainless steel

Stainless steels are used in a wide range of complex environments due to their excellent corrosion resistance.Multiphase stainless steels can offer an excellent combination of strength,toughness and corrosion resistance due to the coexistence of different microstructures.The microstructure and mechanical properties of a novel cast multiphase stainless steel,composed of martensite,ferrite,and austenite,were investigated following appropriate heat treatment processes:solution treatment at 1,050℃ for 0.5 h followed by water quenching to room temperature,and aging treatment at 500℃ for 4 h followed by water quenching to room temperature.Results show reversed austenite is formed by diffusion of Ni element during aging process,and the enrichment of Ni atoms directly determines the mechanical stability of austenite.The austenite with a lower Ni content undergoes a martensitic transformation during plastic deformation.The tensile strength of the specimen exceeds 1,100 MPa and the elongation exceeds 24%after solid solution,and further increases to 1,247 MPa and 25%after aging treatment.This enhancement is due to the TRIP effect of austenite and the precipitation of the nanoscale G-phase pinning dislocations in ferrite and martensite.

Anelasticity to plasticity transition in a model two-dimensional amorphous solid

Anelasticity, as an intrinsic property of amorphous solids, plays a significant role in understanding their relaxation and deformation mechanism. However, due to the lack of long-range order in amorphous solids, the structural origin of anelasticity and its distinction from plasticity remain elusive. In this work, using frozen matrix method, we study the transition from anelasticity to plasticity in a two-dimensional model glass. Three distinct mechanical behaviors, namely,elasticity, anelasticity, and plasticity, are identified with control parameters in the amorphous solid. Through the study of finite size effects on these mechanical behaviors, it is revealed that anelasticity can be distinguished from plasticity.Anelasticity serves as an intrinsic bridge connecting the elasticity and plasticity of amorphous solids. Additionally, it is observed that anelastic events are localized, while plastic events are subextensive. The transition from anelasticity to plasticity is found to resemble the entanglement of long-range interactions between element excitations. This study sheds light on the fundamental nature of anelasticity as a key property of element excitations in amorphous solids.

TRIP13促进子宫内膜癌增殖、迁移和侵袭的影响及作用机制

目的:探讨甲状腺激素受体因子13(Thyroid hormone receptor interactor 13,TRIP13)对子宫内膜癌(Endometrial carcinoma,EC)增殖、迁移和侵袭的影响及调控机制。方法:分析TRIP13在子宫内膜癌中的表达模式;通过慢病毒敲减和质粒过表达调控子宫内膜癌细胞中TRIP13的表达量;通过CCK-8、Transwell迁移及侵袭实验观察TRIP13对子宫内膜癌细胞增殖、迁移及侵袭能力的影响;通过Western blot技术检测TRIP13表达水平的变化,并研究其对PI3K/Akt信号通路蛋白的影响。结果:癌症基因组图谱(The Cancer Genome Atlas,TCGA)分析发现,子宫内膜癌组织中TRIP13的表达水平显著高于正常子宫内膜组织(P<0.05);TRIP13的高表达与子宫内膜癌患者的低生存率呈显著正相关(P<0.05)。TRIP13过表达可促进子宫内膜癌细胞的增殖、迁移及侵袭能力(P<0.05),并上调p-PI3K、p-Akt的表达(P<0.05),而下调TRIP13后则可逆转上述结果。结论:TRIP13通过调控PI3K/Akt信号通路促进子宫内膜癌细胞的增殖、迁移和侵袭。

The interaction between KIF21A and KANK1 regulates dendritic morphology and synapse plasticity in neurons

Morphological alterations in dendritic spines have been linked to changes in functional communication between neurons that affect learning and memory.Kinesin-4 KIF21A helps organize the microtubule-actin network at the cell cortex by interacting with KANK1;however,whether KIF21A modulates dendritic structure and function in neurons remains unknown.In this study,we found that KIF21A was distributed in a subset of dendritic spines,and that these KIF21A-positive spines were larger and more structurally plastic than KIF21A-negative spines.Furthermore,the interaction between KIF21A and KANK1 was found to be critical for dendritic spine morphogenesis and synaptic plasticity.Knockdown of either KIF21A or KANK1 inhibited dendritic spine morphogenesis and dendritic branching,and these deficits were fully rescued by coexpressing full-length KIF21A or KANK1,but not by proteins with mutations disrupting direct binding between KIF21A and KANK1 or binding between KANK1 and talin1.Knocking down KIF21A in the hippocampus of rats inhibited the amplitudes of long-term potentiation induced by high-frequency stimulation and negatively impacted the animals’cognitive abilities.Taken together,our findings demonstrate the function of KIF21A in modulating spine morphology and provide insight into its role in synaptic function.

Neural stem cells promote neuroplasticity: a promising therapeutic strategy for the treatment of Alzheimer’s disease

Recent studies have demonstrated that neuroplasticity,such as synaptic plasticity and neurogenesis,exists throughout the normal lifespan but declines with age and is significantly impaired in individuals with Alzheimer’s disease.Hence,promoting neuroplasticity may represent an effective strategy with which Alzheimer’s disease can be alleviated.Due to their significant ability to self-renew,differentiate,and migrate,neural stem cells play an essential role in reversing synaptic and neuronal damage,reducing the pathology of Alzheimer’s disease,including amyloid-β,tau protein,and neuroinflammation,and secreting neurotrophic factors and growth factors that are related to plasticity.These events can promote synaptic plasticity and neurogenesis to repair the microenvironment of the mammalian brain.Consequently,neural stem cells are considered to represent a potential regenerative therapy with which to improve Alzheimer’s disease and other neurodegenerative diseases.In this review,we discuss how neural stem cells regulate neuroplasticity and optimize their effects to enhance their potential for treating Alzheimer’s disease in the clinic.

从TRIPS到CPTPP:著作权国际保护标准的提高及对中国的启示

随着后TRIPS时代的到来,TRIPS所建立的著作权国际保护体系显得难以适应快速发展的经济与科技环境。因此,各国开始以自由贸易协定的模式探索著作权国际保护新标准,比如签订CPTPP。文章通过对CPTPP与TRIPS文本的研究对比,认为CPTPP著作权国际保护标准较TRIPS有了大幅提升,扩大了复制权、向公众传播权的保护范围和权利主体范围,延长了权利保护期限,缩减了著作权的限制与例外空间,增加了损害赔偿数额,加强了执法力度和知识产权救济措施。2021年,我国正式申请加入CPTPP,为能顺利对接国际著作权保护规则,文章具体分析了国内著作权法律制度与国际规则的差异,并提出了应对之策。

3'-Deoxyadenosin alleviates methamphetamine-induced aberrant synaptic plasticity and seeking behavior by inhibiting the NLRP3 inflammasome

Methamphetamine addiction is a brain disorder characterized by persistent drug-seeking behavior, which has been linked with aberrant synaptic plasticity. An increasing body of evidence suggests that aberrant synaptic plasticity is associated with the activation of the NOD-like receptor family pyrin domain containing-3(NLRP3) inflammasome. 3′-Deoxyadenosin, an active component of the Chinese fungus Cordyceps militaris, has strong anti-inflammatory effects. However, whether 3′-deoxyadenosin attenuates methamphetamine-induced aberrant synaptic plasticity via an NLRP3-mediated inflammatory mechanism remains unclear. We first observed that 3′-deoxyadenosin attenuated conditioned place preference scores in methamphetamine-treated mice and decreased the expression of c-fos in hippocampal neurons. Furthermore, we found that 3′-deoxyadenosin reduced the aberrant potentiation of glutamatergic transmission and restored the methamphetamine-induced impairment of synaptic plasticity. We also found that 3′-deoxyadenosin decreased the expression of NLRP3 and neuronal injury. Importantly, a direct NLRP3 deficiency reduced methamphetamine-induced seeking behavior, attenuated the impaired synaptic plasticity, and prevented neuronal damage. Finally, NLRP3 activation reversed the effect of 3′-deoxyadenosin on behavior and synaptic plasticity, suggesting that the anti-neuroinflammatory mechanism of 3′-deoxyadenosin on aberrant synaptic plasticity reduces methamphetamine-induced seeking behavior. Taken together, 3′-deoxyadenosin alleviates methamphetamine-induced aberrant synaptic plasticity and seeking behavior by inhibiting the NLRP3 inflammasome.

TRIPS-Plus扩张背景下发展中国家知识产权国际保护的因应策略

TRIPS-Plus扩张消减了针对发展中国家的弹性条款和差别待遇,加重了发展中国家的知识产权实施成本,侵蚀了发展中国家争取的知识产权国际规则变革成果。包括中国在内的发展中国家应当从“随势而动”到“谋势而为”,主动成为知识产权国际规则的制定者。借鉴发达国家体制转换策略,探索自贸协定内知识产权保护的新体例。一方面,重视“南南联合”,构建新型TRIPS-Plus规则,保护发展中国家的传统资源;另一方面,正视“南北博弈”,积极设置鼓励性条款,协调南北矛盾,重构知识产权国际保护新规则,推动知识产权国际规则向更加公正合理的方向发展。

CPTPP超TRIPS边境措施的新挑战与应对——基于发展中国家的视角

CPTPP知识产权超TRIPS边境措施减损了TRIPS灵活性,增加了边境执法的不确定性,弱化了TRIPS保障性条款,破坏系统性制衡机制。在超TRIPS边境措施的条约义务与国家经济发展的现实需求之间寻求新的平衡,是发展中国家成员面临的新挑战。发展中国家成员应寻求有利于发展中国家的解释和执法空间,充分利用CPTPP关于特定公共健康谅解条款和原则性条款,对CPTPP超TRIPS边境措施进行合理解释,达到“选择性适应”。加入CPTPP符合中国的长远利益,中国在推进执法严格化的同时,应充分利用CPTPP的灵活性,推动知识产权边境执法制度向着更加公平和正义的方向发展。

一种半耦合韧性断裂准则及其在TRIP780中的应用

为研究高强钢板材在冷成形下的损伤演化与韧性断裂行为,将DF2012韧性断裂准则修正为初始损伤判据,同时参考连续损伤力学理论引入损伤变量D以衡量材料的累积损伤,并将其耦合到塑性模型中,构建了一种半耦合韧性断裂准则。以TRIP780高强钢板为研究对象,针对不同应力状态设计了6种形状的试样,借助电阻损伤测量法与DIC数字图像法进行了力学性能试验并测定初始损伤位移。采用非相关流动准则(NAFR)的Drucker各向异性屈服函数和Swift-Voce硬化模型准确描述了材料的塑性变形过程,然后分别利用试验模拟混合法和逆向工程法对初始损伤模型和损伤演化参数进行了标定。使用Fortran语言将构建的本构模型与损伤演化模型编译为VUMAT子程序并嵌入ABAQUS/Explicit模块中进行断裂模拟预测,并与未耦合损伤模型进行比较。结果表明:构建的半耦合韧性断裂准则能够准确描述TRIP780板材在不同应力状态下变形后期的损伤诱导软化行为,预测的断裂位移最大相对误差仅为1.31%。相较于常用的非耦合断裂模型,所提模型针对具有软化效应的高强钢表现出明显的优越性,适合用于高强钢板冷冲压成形的破裂预测中。

基于“TRIP”教育理念的文旅融合人才培养体系的构建与实践

本文在TRIP教学理念指导下,指出当前文旅融合人才培养面临的主要问题,通过对文旅融合人才培养目标、培养模式、课程体系、评价体系四个方面构建文旅融合人才培养体系。

组成成分对TiC/TRIP钢复合材料的力学性能影响

文章以TRIP钢为基体,TiC作为颗粒增强相,采用热压烧结工艺制备TiC/TRIP钢复合材料,研究了组成成分对TiC/TRIP钢复合材料力学性能和组织形貌的影响。结果表明,烧结温度为1150℃时,随着TiC含量的增加复合材料的致密度、抗弯强度和断裂韧性呈逐渐降低的趋势,TiC含量为10 wt.%的复合材料的致密度、抗弯强度和断裂韧性相对最高,分别为98.6wt.%、930.42MPa和26.31MPa·m1/2。而复合材料的硬度变化趋势则与以上三者不同,随TiC含量的增加呈先降低后升高的趋势,TiC含量为40 wt.%的复合材料硬度相对最大,为6.43GPa。复合材料断裂方式主要为韧性断裂,在TiC颗粒处为沿晶断裂,并伴有穿晶断裂。