Degradation of FAK-targeting by proteolytic targeting chimera technology to inhibit the metastasis of hepatocellular carcinoma

Liver cancer is a prevalent malignant cancer,ranking third in terms of mortality rate.Metastasis and recurrence primarily contribute to the high mortality rate of liver cancer.Hepatocellular carcinoma(HCC)has low expression of focal adhesion kinase(FAK),which increases the risk of metastasis and recurrence.Nevertheless,the efficacy of FAK phosphorylation inhibitors is currently limited.Thus,investigating the mechanisms by which FAK affects HCC metastasis to develop targeted therapies for FAK may present a novel strategy to inhibit HCC metastasis.This study examined the correlation between FAK expression and the prognosis of HCC.Additionally,we explored the impact of FAK degradation on HCC metastasis through wound healing experiments,transwell invasion experiments,and a xenograft tumor model.The expression of proteins related to epithelial-mesenchymal transition(EMT)was measured to elucidate the underlying mechanisms.The results showed that FAK PROTAC can degrade FAK,inhibit the migration and invasion of HCC cells in vitro,and notably decrease the lung metastasis of HCC in vivo.Increased expression of E-cadherin and decreased expression of vimentin indicated that EMT was inhibited.Consequently,degradation of FAK through FAK PROTAC effectively suppressed liver cancer metastasis,holding significant clinical implications for treating liver cancer and developing innovative anti-neoplastic drugs.

“Rigid-elastic chimera” pore skeleton model and overpressure porosity measurement method for shale: A case study of the deep overpressure siliceous shale of Silurian Longmaxi Formation in southern Sichuan Basin, SW China

Based on analysis of pore features and pore skeleton composition of shale,a“rigid elastic chimeric”pore skeleton model of shale gas reservoir was built.Pore deformation mechanisms leading to increase of shale porosity due to the pore skeleton deformation under overpressure were sorted out through analysis of stress on the shale pore and skeleton.After reviewing the difficulties and defects of existent porosity measurement methods,a dynamic deformed porosity measurement method was worked out and used to measure the porosity of overpressure Silurian Longmaxi Formation shale under real formation conditions in southern Sichuan Basin.The results show:(1)The shale reservoir is a mixture of inorganic rock particles and organic matter,which contains inorganic pores supported by rigid skeleton particles and organic pores supported by elastic-plastic particles,and thus has a special“rigid elastic chimeric”pore structure.(2)Under the action of formation overpressure,the inorganic pores have tiny changes that can be assumed that they don’t change in porosity,while the organic pores may have large deformation due to skeleton compression,leading to the increase of radius,connectivity and ultimately porosity of these pores.(3)The“dynamic”deformation porosity measurement method combining high injection pressure helium porosity measurement and kerosene porosity measurement method under ultra-high variable pressure can accurately measure porosity of unconnected micro-pores under normal pressure conditions,and also the porosity increment caused by plastic skeleton compression deformation.(4)The pore deformation mechanism of shale may result in the"abnormal"phenomenon that the shale under formation conditions has higher porosity than that under normal pressure,so the overpressure shale reservoir is not necessarily“ultra-low in porosity”,and can have porosity over 10%.Application of this method in Well L210 in southern Sichuan has confirmed its practicality and reliability.

45,X/47,XYY性发育异常一例并文献复习

45,X/47,XYY性发育异常是一种由于罕见的染色体异常导致的性发育异常疾病。报告1例收治的45,X/47,XYY嵌合型性发育异常患者,该患者主因原发性闭经并出现男性化表现就诊,具有特纳综合征(Turner syndrome,Turner综合征)的表现,腹腔镜探查显示一侧性腺为条索状,另一侧外观睾丸样,病理为卵睾型性腺,手术切除双侧附件并予人工周期治疗,有月经来潮。结合本例及检索到的文献报道的女性表型中因原发性闭经就诊的病例共11例,对该病的临床表现、诊断及治疗方式进行总结。女性表型45,X/47,XYY性发育异常患者临床表现多样,以Turner综合征表现合并男性化表现多见,应尽早发现并切除发育不良的性腺,防止性腺肿瘤的发生和男性化表现出现。术后进行长期激素替代治疗,同时注重患者精神心理的疏导。

1例错误否定父权的嵌合体STR分析

随着科学技术的不断发展,亲子鉴定中的嵌合体案例逐渐被发现。亲子鉴定目前通常是在现场采取血样,也有少数机构采取口腔拭子进行STR分型检测。在排除医源性人造异源嵌合体和检材被污染风险因素后,当不同基因座出现多个等位基因异常情况时,往往会考虑被检者为先天嵌合体。但是,如果嵌合体的血液中只存在一种细胞群的时候,血样常染色体STR分型不会出现异常,很容易得出错误的鉴定结论,直接排除亲缘关系。本文所分析案例,就属此类非常罕见的情况。

基于Chimera网格的固定床反应器内局部流动模拟

采用基于三维Chimera网格的有限体积方法对球形颗粒随机填充的固定床内部小Reynolds数(9～50)下的局部流动进行了数值模拟。为了考察固定床内局部流动特点,本文模拟的固定床反应器的填充颗粒的数目较大,分别为120和500,直径比(固定床内径与填充颗粒直径之比)分别为7和10。由于计算量巨大,采用了基于PVM的分布式并行计算。模拟结果提供了固定床内局部流动的详细流场信息,显示了流动的不均匀性、壁面效应和沟流的存在。为固定床内进一步的流动与传热及反应耦合研究奠定了基础。

介绍一款优秀的分子图形软件Chimera

为提高信息技术在化学科研教育中的应用,介绍了一款名为UCSF chimera的优秀的分子图形软件,其自由的可视化功能及其他附属工具使用方便,在生物、医药、化学的科研、教育等方面都有着广泛的用途。

45,X/46,XY染色体嵌合型不育症一例

45,X/46,XY染色体嵌合是临床上比较少见的疾病,具有这种嵌合核型的患者可表现为男性或者女性外观,临床特征相似于特纳综合征(Turner syndrome,Turner综合征),但症状轻于Turner综合征。报告1例因不育就诊的男性表型患者,经G显带染色体核型分析和全基因组拷贝数变异(copy number variation,CNV)技术分析患者外周血提取的DNA,染色体核型诊断为45,X/46,XY嵌合型,外周血淋巴细胞染色体核型共分析50个染色体核型,核型诊断结果为45,X[27]/46,XY[23],全基因组CNV检测结果为-(mosaic)(Y)(64%),Y染色体微缺失检测结果为未见明显异常。45,X/46,XY染色体嵌合型男性表型案例较少,本例患者身材矮小,生殖器畸形,是临床表型较轻的男性表型患者。

新型布鲁顿氏酪氨酸激酶蛋白水解靶向嵌合体(BTK PROTAC)的设计合成及活性评价

目的 设计合成新型布鲁顿氏酪氨酸激酶蛋白水解靶向嵌合体(BTK PROTAC),并在体外评估这些分子对BTK蛋白的降解活性。方法 以Nurix Therapeutics公司临床化合物NX-5948为先导化合物,分析其与靶蛋白的相互作用,通过引入并环代替吡嗪胺的骨架跃迁思路对其进行结构改造,成功合成了一系列新型BTK PROTACs,通过时间分辨荧光共振能量转移技术(TR-FRET)、MTS法和蛋白质免疫印迹法分别测定目标化合物的激酶活性、细胞增殖抑制活性和BTK蛋白降解活性。结果 共合成6个目标化合物(化合物B~G),活性测试结果显示,大部分化合物都具有优异的细胞增殖抑制活性和BTK降解活性,其中化合物B表现出较优的BTK蛋白降解能力,其半数最大降解浓度(DC_(50))值约为0.1 nmol·L^(-1)。结论 基于NX-5948,通过骨架跃迁的方法设计合成了一类新颖的BTK PROTAC化合物,进行了构效关系的初步探索,可为BTK PROTAC降解剂的进一步研究提供参考。

An intelligent control method based on artificial neural network for numerical flight simulation of the basic finner projectile with pitching maneuver

In this paper,an intelligent control method applying on numerical virtual flight is proposed.The proposed algorithm is verified and evaluated by combining with the case of the basic finner projectile model and shows a good application prospect.Firstly,a numerical virtual flight simulation model based on overlapping dynamic mesh technology is constructed.In order to verify the accuracy of the dynamic grid technology and the calculation of unsteady flow,a numerical simulation of the basic finner projectile without control is carried out.The simulation results are in good agreement with the experiment data which shows that the algorithm used in this paper can also be used in the design and evaluation of the intelligent controller in the numerical virtual flight simulation.Secondly,combined with the real-time control requirements of aerodynamic,attitude and displacement parameters of the projectile during the flight process,the numerical simulations of the basic finner projectile’s pitch channel are carried out under the traditional PID(Proportional-Integral-Derivative)control strategy and the intelligent PID control strategy respectively.The intelligent PID controller based on BP(Back Propagation)neural network can realize online learning and self-optimization of control parameters according to the acquired real-time flight parameters.Compared with the traditional PID controller,the concerned control variable overshoot,rise time,transition time and steady state error and other performance indicators have been greatly improved,and the higher the learning efficiency or the inertia coefficient,the faster the system,the larger the overshoot,and the smaller the stability error.The intelligent control method applying on numerical virtual flight is capable of solving the complicated unsteady motion and flow with the intelligent PID control strategy and has a strong promotion to engineering application.

小分子药物筛选技术研究现状及其应用进展

小分子药物筛选技术伴随着药物的发现正在不断更新和拓展,药物筛选技术的创新可以提高研发效率和成功率、缩短研发周期、降低成本。从基于已知活性化合物和高通量筛选等传统筛选技术,到基于结构的药物发现、基于片段的药物发现、DNA编码化合物库、蛋白降解靶向联合体等新技术,小分子药物筛选技术在不断拓宽小分子药物的市场潜力。该文将介绍目前小分子药物筛选技术整体现状,系统综述各技术及其优劣势,为小分子药物筛选新技术的发展提供重要参考。

填充床流动求解与基于Chimera网格的分布式并行计算

填充床是一种常见的化学和生化反应器。由于内部结构的复杂性,填充床的局部流动求解一直是个颇有挑战性的问题。传统的填充床数值模拟是在CFD软件Fluent的平台上,采用非结构化网格求解。采用非结构网格求解存在网格生成困难,网格数目过多以及计算时间长等问题。Chimera网格的应用大大减少了填充床网格的数目及网格生成的难度。PVM分布式并行计算与Chimera网格的结合,使填充床的求解效率得到很大的提高。通过对两种方法在计算使用时间、内存使用量及计算结果的具体比较,阐述了Chimera网格结合PVM分布式并行计算在填充床流动求解中的优势。

碳离子束辐射诱变水稻基因突变嵌合体的分子特征

嵌合体是辐射诱变M1代普遍存在的现象,然而,有关水稻的嵌合体突变效应及变异遗传机制尚不清楚。本研究采用靶向捕获测序技术获得碳离子束辐照后的OsNramp5突变嵌合体,并利用10kb液相芯片检测该嵌合体的M1代及突变M2代基因组的SNP/InDel发生及变异遗传分离特征。结果表明:水稻M1代嵌合体中检测到的OsNramp5基因突变位点未遗传至M2代,即在M1代体细胞检测到的突变位点未进入生殖细胞遗传;另外,在M1基因组突变类型中,转换是颠换的2倍,虽然超过一半变异位点遗传至M2代,但很少位点来自基因功能编码区。本研究揭示了碳离子束辐照诱变的体细胞M1代嵌合体的基因组变异特征及其在M2代的遗传特征,为研究碳离子束辐照后的嵌合体突变效应机制和选择诱变育种程序提供参考。

多能干细胞异种嵌合体研究进展

异种嵌合是指两个及两个以上具有不同遗传性状的早期胚胎或细胞聚合发育的现象。将具有多能性和分化潜能的干细胞通过囊胚互补技术注射到另一器官发育缺陷的物种囊胚中,可嵌合发育出具有功能性的新组织器官,有望为解决世界移植器官短缺问题提供新手段。本文综述了异种嵌合领域的最新进展以及其目前面临的技术问题和伦理问题,以期为生物学教学中相关知识的拓展及器官异种嵌合领域研究提供参考。

基于PROTACs技术的表观遗传抗肿瘤药物研究进展

蛋白水解靶向嵌合体(Proteolysis Targeting Chimeras,PROTACs)是异型双功能分子,可通过天然泛素蛋白酶体系统选择性地降解目标蛋白质。这种化学诱导蛋白质降解的新策略为药物发现提供了新的可能性,因此已被应用于各种靶标,包括(核)受体、激酶和转录因子等。表观遗传蛋白在肿瘤的发生、发展、转移和侵袭中发挥着重要作用,被认为是抗肿瘤药物研发的重要靶点。由于其小分子抑制剂易产生脱靶效应和耐药性,而PROTACs技术为解决这些问题提供了一种全新的策略,在表观遗传抗肿瘤药物研发中具有重要意义。介绍了PROTACs的原理及优势,系统综述了采用该技术靶向降解表观遗传蛋白的最新研究进展,并展望了基于PROTACs技术的表观遗传靶向抗肿瘤药物的发展前景。

基于蛋白降解靶向嵌合体的IRAK4降解剂的设计、合成及生物活性评价

目的 设计并合成具有抗肿瘤活性的白细胞介素-1受体相关激酶4(IRAK4)降解剂。方法 将IRAK4蛋白配体与E3连接酶配体经不同类型和长度的连接链进行连接,合成目标化合物,其结构经MS谱和~1H NMR谱确证。以大B细胞淋巴瘤细胞OCI-LY10为测试细胞株,对所合成的目标化合物进行体外抗肿瘤活性评价以及对IRAK4的降解测试。结果 合成了9个靶向IRAK4的降解剂,活性测试结果显示目标化合物均可抑制大B细胞淋巴瘤细胞OCI-LY10细胞增殖,其中化合物Ⅲ、Ⅶ、Ⅷ、Ⅸ对IRAK4有较强的降解活性,半数最大降解浓度(DC_(50))值在1~10 nmol·L^(-1)。结论 利用蛋白降解靶向嵌合体技术,通过对IRAK4的降解,实现对肿瘤细胞的增殖抑制,值得进一步研究。

Germline competence of mouse ES and iPS cell lines: Chimera technologies and genetic background

In mice,gene targeting by homologous recombination continues to play an essential role in the understanding of functional genomics.This strategy allows precise location of the site of transgene integration and is most commonly used to ablate gene expression("knock-out"),or to introduce mutant or modified alleles at the locus of interest("knock-in").The efficacy of producing live,transgenic mice challenges our understanding of this complex process,and of the factors which influence germline competence of embryonic stem cell lines.Increasingly,evidence indicates that culture conditions and in vitro manipulation can affect the germline-competence of Embryonic Stem cell(ES cell) lines by accumulation of chromosome abnormalities and/or epigenetic alterations of the ES cell genome. The effectiveness of ES cell derivation is greatly strain-dependent and it may also influence the germline transmission capability.Recent technical improvements in the production of germline chimeras have been focused on means of generating ES cells lines with a higher germline potential.There are a number of options for generating chimeras from ES cells (ES chimera mice);however,each method has its advantages and disadvantages.Recent developments in induced pluripotent stem(iPS)cell technology have opened new avenues for generation of animals from genetically modified somatic cells by means of chimera technologies.The aim of this review is to give a brief account of how the factors mentioned above are influencing the germline transmission capacity and the developmental potential of mouse pluripotent stem cell lines.The most recent methods for generating specifically ES and iPS chimera mice,including the advantages and disadvantages of each method are also discussed.

Four-cluster chimera state in non-locally coupled phase oscillator systems with an external potential

Dynamics of a one-dimensional array of non-locally coupled Kuramoto phase oscillators with an external potential is studied. A four-cluster chimera state is observed for the moderate strength of the external potential. Different from the clustered chimera states studied before, the instantaneous frequencies of the oscillators in a synchronized cluster are different in the presence of the external potential. As the strength of the external potential increases, a bifurcation from the two-cluster chimera state to the four-cluster chimera states can be found. These phenomena are well predicted analytically with the help of the Ott-Antonsen ansatz.

Proteolysis targeting chimera technology:a novel strategy for treating diseases of the central nervous system

Neurological diseases such as stroke,Alzheimer’s disease,Parkinson’s disease,and Huntington’s disease are among the intractable diseases for which appropriate drugs and treatments are lacking.Proteolysis targeting chimera(PROTAC)technology is a novel strategy to solve this problem.PROTAC technology uses the ubiquitin-protease system to eliminate mutated,denatured,and harmful proteins in cells.It can be reused,and utilizes the protein destruction mechanism of the cells,thus making up for the deficiencies of traditional protein degradation methods.It can effectively target and degrade proteins,including proteins that are difficult to identify and bind.Therefore,it has extremely important implications for drug development and the treatment of neurological diseases.At present,the targeted degradation of mutant BTK,mHTT,Tau,EGFR,and other proteins using PROTAC technology is gaining attention.It is expected that corresponding treatment of nervous system diseases can be achieved.This review first focuses on the recent developments in PROTAC technology in terms of protein degradation,drug production,and treatment of central nervous system diseases,and then discusses its limitations.This review will provide a brief overview of the recent application of PROTAC technology in the treatment of central nervous system diseases.

Production of chicken chimeras by fusing blastodermal cells with electroporation

Aim: To establish techniques for producing somatic and germline chimeric chicken by transferring blastodermal cellsfused with electroporation. Methods: Stage-X blastodermal cells isolated from freshly laid fertile unincubated whiteLeghorn and Rhode Island red chicken eggs were fused with electroporation. The treated cell suspension was transferredto the recovery medium (DMEM containing 10% FBS) and was injected into the subgenninal cavity of recipient unin-cubated embryos (stage X). Results: Of 177 recipient embryos injected with the fusing blastodermal cells, 6(3.4 %) survived to hatching. Somatic chimerism was examined in the melanocyte of the feather. The presence offeathers originating from the donor cell was observed in 1 bird (16.7%) out of the 6 hatched birds. After 21 days ofincubation two birds out of five embryos were subjected to polymerase chain reaction (PCR) analysis for W-chromo-some-specific DNA for each tissue. One bird possessed W-chromosome-specific DNA in the stomach, and the other ex-hibited the same DNA in the left and right gonads and other tissues, but not the stomach. Conclusion: Recipientembryo having electrofused blastodennal cells yields somatic and germline chimeric chickens more successfully.(Asian J Androl 2000 Dec; 2: 271-275)

Rotor wake capture improvement based on high-order spatially accurate schemes and chimera grids

A high-order upwind scheme has been developed to capture the vortex wake of a helicopter rotor in the hover based on chimera grids. In this paper, an improved fifth-order weighted essentially non-oscillatory （WENO） scheme is adopted to interpolate the higher-order left and right states across a cell interface with the Roe Riemann solver updating inviscid flux, and is compared with the monotone upwind scheme for scalar conservation laws （MUSCL）. For profitably capturing the wake and enforcing the period boundary condition, the computation regions of flows are discretized by using the struc- tured chimera grids composed of a fine rotor grid and a cylindrical background grid. In the background grid, the mesh cells located in the wake regions are refined after the so- lution reaches the approximate convergence. Considering the interpolation characteristic of the WENO scheme, three layers of the hole boundary and the interpolation boundary are searched. The performance of the schemes is investigated in a transonic flow and a subsonic flow around the hovering rotor. The results reveal that the present approach has great capabilities in capturing the vortex wake with high resolution, and the WENO scheme has much lower numerical dissipation in comparison with the MUSCL scheme.