基于低秩表示的乳腺癌病理图像有丝分裂检测

人工检测和计算有丝分裂细胞的过程非常冗长,而且不同病理医生之间的诊断结果有较大差异性,因此,在临床中迫切希望有定量的计算机辅助自动检测方法。提出了一种基于低秩表示的计算机辅助自动检测有丝分裂方法,将有丝分裂细胞看做低秩表示中的稀疏部分,非有丝分裂部分看做低秩部分。在ICPR 2012有丝分裂竞赛提供的有丝分裂图片数据库上的实验结果表明,和已有的基于模式识别的检测方法相比,该方法能够获得较高的F-measure和recall值,分别为0.59和0.56。     

基于Aurora系统的持续型查询语言设计与实现

随着新型数据应用的不断出现,针对流形态数据的数据流管理系统已经成为数据管理领域研究的新热点。针对目前通用数据流管理系统只支持基于操作符流图的查询表达方式这一不足,设计了一种新的持续型数据流查询语言,并在通用数据流处理系统Aurora上进行了实现。为验证新语言的表达能力,该系统使用新语言定义了数据流基准测试Linear Road Benchmark的查询集,在Aurora系统上部署运行。测试结果表明针对Linear Road Benchmark的测试用例,新语言具有较完备的语义和良好的表达能力。     

基于双高斯GMM的特征参数规整及其在语音识别中的应用

对特征参数概率分布的实验分析表明,在有噪声影响的情况下,特征参数通常呈现双峰分布.据此,本文提出了一种新的,基于双高斯的高斯混合模型(Gaussian mixture model,GMM)的特征参数归一化方法,以提高语音识别系统的鲁棒性.该方法采用更为细致的双高斯模型来表达特征参数的累积分布函数(CDF),并依据估计得到的CDF进行参数变换将训练和识别时的特征参数的分布都规整为标准高斯分布,从而提高识别正确率.在Aurora 2和Aurora 3数据库上的实验结果表明,本文提出的方法的性能明显好于传统的倒谱均值规整(Cepstral mean normalization,CMN)和倒谱均值方差规整(Cepstral mean and variance normalization,CMVN)方法,而与非参数化方法-直方图均衡特征规整方法的性能基本相当.     

高中生物中有丝分裂特征及意义 和多媒体慕课教学方式创新性探讨

在高中生物中,有丝分裂是相对较为重要的内容,在生物遗传中,有着非常关键的意义.对于有丝分裂类型题的基本要求,就是学生必须将有丝分裂不同阶段的特征熟悉并掌握.本文阐述了有丝分裂的基本概念,介绍了有丝分裂不同阶段的特征及其意义,并对教学方式进行了创新性讨论.     

高中生物中有丝分裂特征及意义——通过线下教学与线上教学的有机融合创新教学方式

在高中生物中,有丝分裂是相对较为重要的内容,在生物遗传中,有着非常关键的意义.对于有丝分裂类型题的基本要求,就是学生必须将有丝分裂不同阶段的特征熟悉并掌握.本文阐述了有丝分裂的基本概念,介绍了有丝分裂不同阶段的特征及其意义,并对教学方式进行了创新性讨论.     

蛋白激酶活性及抑制性检测研究进展

蛋白激酶催化蛋白磷酸化是一种非常重要的蛋白质翻译后修饰方式,能够调节细胞内大多数蛋白的功能,在众多生理过程中发挥着至关重要的作用。磷酸化过程的异常以及激酶的过度表达往往与许多疾病密切相关,如癌症、糖尿病和老年痴呆症。因而,测定蛋白激酶的活性及筛选蛋白激酶抑制剂对基础生物医学研究和酶靶药物的开发是非常重要的。近年来,研究工作者们采用电化学法、比色法以及荧光检测法等方法研究了对蛋白激酶活性及抑制性的检测。该文回顾了蛋白激酶活性测定及抑制性检测的研究进展,主要关注了荧光检测法的应用,并对其未来的发展进行展望。     

基于支持向量机的代谢网络特征分析

把细胞内所有生化反应表示为一个网络指为代谢网络,是所有参与代谢过程的化合物之间以及所有催化酶之间的相互作用的反映,是抽象表达对细胞的代谢。在不同的物种中都含有大量的代谢翻译,却代谢网络是高度保守的。要了解包括代谢系统在内的许多自然、社会系统都起着重要的作用,所以要对于复杂网络进行研究并掌握它们的规律意义很大。利用代谢网络对微生物的耐热性进行分类研究对认识和利用细胞代谢过程有很大的帮助,从而促进发酵工程、制药工业等产业的发展。     

细胞分裂中中心体与染色体的仿真模型

在细胞有丝分裂的仿真过程中,染色体与中心体的形态和运动具有非常明显的特征,该文建立了一个基于非线性函数的染色体与中心体的仿真模型,并采用ＶｉｓｕａｌＣ＋＋进行面向对象的程序设计,结果表明该模型能较好地模拟其动态特性。     

新型内质网应激诱导蛋白 TRIM25 在乳腺癌细胞中的作用研究

内质网应激是当细胞受到缺氧或营养剥夺等外界因素刺激时而产生的一种效应,该效应与肿 瘤细胞的存活息息相关。该研究揭示了 TRIM25 作为一种新型内质网应激诱导蛋白在肿瘤细胞中所发挥 的作用,可为发现新的肿瘤靶点提供重要依据。该文以乳腺癌细胞 MCF7 为对象,先筛选构建了稳定 敲低 TRIM25 的 MCF7 细胞系;然后,检测了 TRIM25 敲低对内质网应激、未折叠蛋白反应信号通路 和内质网应激诱导的细胞凋亡的影响,以及 TRIM25 在不同乳腺细胞中的表达;最后,通过生物信息学 分析 TRIM25 表达量与乳腺癌患者预后的相关性。结果显示,内质网应激会诱导 TRIM25 表达水平的大 幅上升。通过敲低 TRIM25 可诱导内质网应激、激活未折叠蛋白反应信号通路从而显著促进乳腺癌细胞 MCF7 的凋亡。研究还发现,乳腺原发上皮细胞转化为乳腺癌细胞过程中伴随有 TRIM25 蛋白水平的上 调,生物信息学分析也显示 TRIM25 在乳腺癌组织中高表达,并提示乳腺癌患者预后不良。     

7OOV外延LDMOS模型的建立与参数提取

本文借助二维数值模拟软件MEDICI对700V外延型LDMOS特性进行分析,对其电流饱和机理做了研究,在此基础上采用宏模型的建模方法,给出LDMOS的等效电路模型.并用参数提取软件Aurora,提取了相应得参数.在Cadence下仿真取得了较好的效果.     

Molecular docking/dynamics studies of Aurora A kinase inhibitors

The binding modes of a known 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole, quinazoline, pyrimidine and indolinone series of Aurora A kinase inhibitors have been studied using molecular docking and molecular dynamics (MD) simulations. Crystallographic bound compound 8 was precisely predicted by our docking procedure as evident from 0.43 Å root mean square (rms) deviations. In addition compound 25 (AZ_68) has been successfully cross-docked within the Aurora A kinase active site, which was pre-organized for inhibitor 8. We found four key sites (A: solvent-exposed front pocket, B: hinge region, C: selectivity pocket and D: solvent-exposed phosphate binding region) of the Aurora A kinase contributing towards the binding of these compounds. We suggest that the small hydrophobic substituents at C-6 position of pyrrolopyrazole nucleus (in compounds 1–8); C-6 and C-7 positions of the quinazoline moiety (in compounds 9–23); C-2 position of the quinazoline and C-4 position of the pyrimidine (in compound 25) could be more effective and selective through increased hydrophobic contacts and selectivity pocket interactions with these modifications of Aurora A kinase inhibitors. Five representative complexes were subjected to 1000 ps of MD simulation to determine the stability of the predicted binding conformations. The low value of the root mean square deviations (ranging from 0.725 to 1.820 Å) between the starting complex structure and the energy minimized final average complex structure suggests that the Glide Extra Precision (XP) derived docked complexes are in a state of near equilibrium. The structure-based drug design strategy described in this study will be highly useful for the development of new inhibitors with high potency and selectivity.     

Identification of a high affinity selective inhibitor of Polo-like kinase 1 for cancer chemotherapy by computational approach

Polo-like kinase (Plk)1 is a key regulator of the cell cycle during mitotic phase and is an attractive anti-mitotic drug target for cancer. Plk1 is a member of Ser/Thr kinase family which also includes Plk2-4 in human. Plk1 promotes the cell division whereas Plk2 and Plk3 are reported to act as tumour suppressors. The available inhibitors of Plk1 also suppress Plk2 and Plk3 activity significantly resulting in the cell death of normal cells in addition to the cancer cells. Hence, it is imperative to explore Plk1 specific inhibitors as anti-cancer drugs. In this work, a selective potential inhibitor of Plk1 has been identified by molecular docking based high throughput virtual screening. The identified compound exploits the subtle differences between the binding sites of Plk1 and other Ser/Thr kinases including Plk2-4. The predicted binding affinity of identified inhibitor is higher than available inhibitors with a 100-fold selectivity towards Plk1 over Plk2-4 and several cell cycle kinases. It also satisfies the Lipinski's criteria of drug-like molecules and passes the other ADMET filters. This triazole compound with aryl substituent belongs to a novel class of potential inhibitor for Plk1. The suggested potential lead molecule can thus be tested and developed further as a potent and selective anti-cancer drug.     

CD317 在肿瘤发生发展及治疗方面的研究进展

CD317(Tetherin、BST-2 或 HM1.24)是由 BST-2 基因编码的一个结构独特的 II 型跨膜糖蛋白, 在多种人体组织中组成型表达,也可被干扰素等细胞因子诱导。近年来,越来越多的研究表明,CD317 在多种肿瘤中表达上调,广泛参与肿瘤细胞增殖、迁移以及凋亡抵抗等生物学过程从而促进肿瘤的发 生发展,是肿瘤治疗的潜在靶点。该文聚焦肿瘤领域,总结 CD317 的表达模式、作用机制以及靶向策 略的相关进展,为肿瘤发病理论研究、治疗策略开发提供新的思考和方向。     

Cathepsin B: Multiple roles in cancer

Proteases, including intracellular proteases, play roles at many different stages of malignant progression. Our focus here is cathepsin B, a lysosomal cysteine cathepsin. High levels of cathepsin B are found in a wide variety of human cancers, levels that often induce secretion and association of cathepsin B with the tumor cell membrane. In experimental models, such as transgenic models of murine pancreatic and mammary carcinomas, causal roles for cathepsin B have been demonstrated in initiation, growth/tumor cell proliferation, angiogenesis, invasion, and metastasis. Tumor growth in transgenic models is promoted by cathepsin B in tumor-associated cells, for example, tumor-associated macrophages, as well as in tumor cells. In transgenic models, the absence of cathepsin B has been associated with enhanced apoptosis, yet cathepsin B also has been shown to contribute to apoptosis. Cathepsin B is part of a proteolytic pathway identified in xenograft models of human glioma; targeting only cathepsin B in these tumors is less effective than targeting cathepsin B in combination with other proteases or protease receptors. Understanding the mechanisms responsible for increased expression of cathepsin B in tumors and association of cathepsin B with tumor cell membranes is needed to determine whether targeting cathepsin B could be of therapeutic benefit.     

DFG-in and DFG-out homology models of TrkB kinase receptor: induced-fit and ensemble docking

Kinases from the Trk family are important for the regulation of development and for the correct functioning of the neural system. Deregulation (over-expression) of Trks leads to survival and proliferation of different human cancers. Therefore, development of inhibitors for Trks that can disrupt the signal pathway of Trks could lead to cure against cancer as well as to nociception. Homology models built by YASARA have been used as targets for docking various libraries of known Trk inhibitors. The receptor plasticity was compensated with induced fit docking and/or ensemble docking. It was determined that DFG-in and DFG-out conformational states of TrkB kinase must be taken into account in order to get more reasonable relationships between the docking score and the activity measured by pIC?? or the corresponding ligands.     

Role of phosphoproteomics in the development of personalized cancer therapies

Cell signalling pathways driven by protein and lipid kinases contribute to the onset and progression of virtually all cancer types. Consequently, several inhibitors against these enzymes have clinical utility for the treatment of different forms of cancer. A problem that hampers further development is that not all patients respond equally well to kinase inhibitors and a significant proportion of those that initially respond eventually develop resistance. This review considers how an integrative analysis of kinase signalling may be used to address this issue. Advances in the biophysics of mass spectrometry, in biochemical procedures for phosphopeptide enrichment, and in computational approaches for label-free quantification have contributed to the development of phosphoproteomics workflows compatible with the analysis of clinical material. These developments, together with new bioinformatics tools to derive information on signalling circuitry from phosphoproteomics data, allow investigating kinase networks with unprecedented depth. Phosphoproteomics technology is starting to be used in translational research and, with further developments, such methods may also be able to measure the circuitry of cancer signalling networks in routine clinical assays. This review reflects on how this information could be used to accurately predict the best kinase inhibitor for each individual cancer patient.     

Tracing pathway activities with kinase inhibitors and reverse phase protein arrays

Controlling aberrant protein kinase activity is a promising strategy for a variety of diseases, particularly cancer. Hence, the development of kinase inhibitors is currently a focal point for pharmaceutical research. In this study we utilize a chip-based reverse phase protein array (RPA) platform for profiling of kinase inhibitors in cell-based assays. In combination with the planar wave-guide technology the assay system has an absolute LOD down to the low zeptomole range. A431 cell lysates were analyzed for the activation state of key effectors in the epidermal growth factor (EGF) and insulin signaling pathways to validate this model for compound screening. A microtiter-plate format for growing, treating, and lysing cells was shown to be suitable for this approach, establishing the value of the technology as a screening tool for characterization of large numbers of kinase inhibitors against a wide variety of cellular signaling pathways. Moreover, the reverse array format allows rapid development of site-specific phosphorylation assays, since in contrast to ELISA type systems only a single antigen-specific antibody is required.     

Roles of repetitive sequences

Repetitive sequences are ubiquitous in the DNA of eukaryotes, some as tandem arrays and others interspersed widely in the genome. Repetitive sequences have special roles in genome evolution, which increasingly detailed sequence information is helping to elucidate. Processes, including meiotic crossing over (equal and unequal), unequal mitotic sister chromatid exchange, gene conversion and transposition, with or without multiplication, can foster homogeneity of the members of a repeat family (concerted evolution) and turnover of the whole genome. Some examples are considered. Tandem repeats, satellite and minisatellite sequences are considered as well as telomeric repeats. For a minisatellite locus, in which the frequency of length mutations has been measured, comparisons are made with expectations due to unequal sister chromatid exchange, and qualitative agreement is found. Interspersed repeats, of which Alu sequences are discussed as an important example, can through unequal recombination lead to a loss or duplication of the DNA between the recombination sites and hence to genetic disease or to gene duplication. It is argued that the rate of unequal Alu recombination may be quite high in the human genome.     

Modulation of cancer cell line differentiation: A neglected proteomic analysis with potential implications in pathophysiology, diagnosis, prognosis, and therapy of cancer

The recent development of compounds that induce cell differentiation in various types of cancer cells has enabled the molecular mechanisms governing this kind of induced cancer regression to be investigated. Moreover, this approach to investigating the pathophysiology of neoplasia represents a promising experimental model for proteomic analysis of cancer cells. Modulating neoplastic cell differentiation grade may reveal cytodifferentiation-related protein expression changes, and doing so in vitro has the advantage of less biological variation. Hence, this analysis brings attention to molecular targets of the so-called differentiating factors (i.e., retinoids, hybrid polar compounds, tyrosine kinase inhibitors, etc.) as well as proteins that are frequently associated with differentiation/dedifferentiation processes. The in vitro study of these proteins and of their pathogenetic roles in cancer may ultimately result in the discovery of cancer biomarkers with diagnostic, prognostic, and therapeutic applications.     

Molecular modeling study of CP-690550 derivatives as JAK3 kinase inhibitors through combined 3D-QSAR,molecular docking,and dynamics simulation techniques

To develop more potent JAK3 kinase inhibitors, a series of CP-690550 derivatives were investigated using combined molecular modeling techniques, such as 3D-QSAR, molecular docking and molecular dynamics (MD). The leave-one-out correlation (q²) and non-cross-validated correlation coefficient (r²) of the best CoMFA model are 0.715 and 0.992, respectively. The q² and r² values of the best CoMSIA model are 0.739 and 0.995, respectively. The steric, electrostatic, and hydrophobic fields played important roles in determining the inhibitory activity of CP-690550 derivatives. Some new JAK3 kinase inhibitors were designed. Some of them have better inhibitory activity than the most potent Tofacitinib (CP-690550). Molecular docking was used to identify some key amino acid residues at the active site of JAK3 protein. 10 ns MD simulations were successfully performed to confirm the detailed binding mode and validate the rationality of docking results. The calculation of the binding free energies by MMPBSA method gives a good correlation with the predicted biological activity. To our knowledge, this is the first report on MD simulations and free energy calculations for this series of compounds. The combination results of this study will be valuable for the development of potent and novel JAK3 kinase inhibitors.