Comparative Analysis of Sequential Circuit Test Generation Approaches

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脑梗死前期脑局部低灌注的CT灌注成像表现及分期

脑梗死前期脑局部低灌注的CT灌注成像表现及分期
脑局部微循环的病理生理学状态 ’具有重要的临床应用价值&
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生物信息学中的基因组序列比对与表达分析

生物信息学中的基因组序列比对与表达分析

生物信息学中的基因组序列比对与表达分析近年来,随着高通量测序技术的快速发展,生物学研究的范围和深度不断拓展。

基因组序列比对和表达分析是生物信息学中两个重要的研究方向。

本文将针对这两个任务进行详细的探讨。

1. 基因组序列比对基因组序列比对是指将新测序得到的DNA序列与已知的参考序列进行比对,以确定两个序列之间的相似性和差异性。

这种比对可以帮助我们研究基因组变异、基因家族的演化以及基因组的进化等重要的生物学问题。

常用的基因组序列比对方法包括Smith-Waterman算法和BLAST算法。

Smith-Waterman算法是一种局部比对方法,可以寻找序列中的区域性匹配。

而BLAST算法则是一种更快速和高效的比对方法,可以在大规模的数据库中快速找到相似序列。

除了算法的选择,比对的质量也是非常重要的。

比对结果的准确性往往取决于参数的设置和序列的质量。

因此,在进行基因组序列比对之前,我们需要对原始数据进行预处理,包括质量控制、去除接头序列和低质量的序列等。

2. 表达分析基因的表达分析是研究基因在不同组织、时间和环境条件下的表达水平和模式的过程。

通过表达分析,我们可以了解基因在不同生物学过程中的功能和调控机制,从而揭示生物系统的运作方式。

常用的表达分析方法包括DGE(Digital Gene Expression)和RNA-seq(RNA sequencing)。

DGE是一种通过纯化和测序技术直接分析基因表达水平的方法。

而RNA-seq则是一种高通量测序技术,可以同时检测转录组中的所有序列,包括编码基因和非编码RNA。

进行表达分析的关键在于数据处理和差异表达基因的筛选。

在数据处理方面,需要对原始测序数据进行质量控制、去除接头序列、去除低质量的碱基等。

差异表达基因筛选的目的是找出在不同处理组之间具有显著差异表达的基因。

一般来说,我们会使用统计学方法,如DESeq2、edgeR等,来对表达谱数据进行差异分析。

此外,功能注释和信号通路分析也是表达分析中的重要步骤。

护理学研究习题库

护理学研究习题库

单项选择题第一章:绪论1(P2)研究结果可表现的内容不包括(C)A.描述事物的现状B.发现事物的内在联系和本质规律C.应用于实践D.引出定律或产生理论2(P3)护理研究最早选择的课题是(A)A.护理教育的研究B.护理管理的研究C.护理学历史的研究D.护理理论的研究3(P4)第一位.从事护理学研究的学者是(B)A.MorseB.南丁格尔D.Giorgi4(P5)C,南丁格尔的理论和实践为护理作为一门正式学科莫定了基础。

A.18世纪中叶B.18世纪末C.19世纪中叶D.19世纪末5(P5)20世纪20年代初期,美国的护理研究侧重于(A)A.如何加强护理教育B.结合临床探讨对护理人员合理安排、医院环境的问题、护理功能、护士的角色、在职教育、护患等方面的问题C.发现护理人员和护校学生的性格特点D.建立护理实践标准6(P5)20世纪40年代,美国护理研究的研究重点在护理教育方面,研究内容主要为(B)A.如何加强护理教育B.结合临床探讨对护理人员合理安排、医院环境的问题、护理功能、护士的角色、在职教育、护患等方面的问题C.发现护理人员和护校学生的性格特点D.建立护理实践标准7(P5)1923年,美国护理学和护理教育一项里程碑的研究为(C)A.《时间的研究》B.有关体温计的研究C.Goldmark报告D.《护理的未来》8.(P5)美国最早的护理研究课程的设立和发展始于(A)A.20世纪20年代B.20世纪30年代C.20世纪40年代D.20世纪50年代9(P7)南丁格尔理论系的核心内容是(D)A.加强护理教育B.改善护患关系C.理想的护士特征D.促进健康、预防疾病、照顾患者10(P7)美国护理科学的“成熟期”是(D)A.20世纪60年代B.20世纪70年代C.20世纪80年代D.20世纪90年代11(P)我国高等护理教育中断时间较长,研究生教育始于(C)A.1977年B.1982年C.1992年D.1997年12(P7)21l世纪护理的目标是(B)A.促进健康,预防疾病B.发展科学知识使护士能够开展以循证为基础的护理实践C.结合护理概念、模式,提高护理教育水平,从而提高护理研究水平D.使患者处于最佳状态,为患者恢复健康提供支持13.(P7)中华护理学会成立的时间和地点是(A)A.1909年8月,江西枯岭B.1922年,北京C.1909年8月,江苏南京D.1922年,上海14(P7)D年,中华护士会加人了国际护士会,为中国护理研究的发展起了重要的A.1909B.1912C.1918D.192215(P8)D,是中华护理学会建会以来,组织发展最快、学术活动最活跃的新时期。

罗伯茨绿僵菌线粒体基因组的测序及注释分析

罗伯茨绿僵菌线粒体基因组的测序及注释分析

罗伯茨绿僵菌线粒体基因组的测序及注释分析线粒体基因组因为快速进化、严格遵守母系遗传等特点已广泛应用到遗传结构与系统分类的生物学研究,是研究真菌系统进化与遗传关系的有效工具。

作为昆虫病原真菌中已有普遍应用的绿僵菌属真菌(Metarhizium),其线粒体基因组数据尚不完整。

为了进一步完善绿僵菌属线粒体基因组数据,深入昆虫病原真菌遗传与进化的研究,本论文选取罗伯茨绿僵菌(Metarhizium robertsii)ARSEF 2575,采用PDA固体培养基培养、CTAB法提取总DNA,经高通量测序、PCR扩增、Sanger测序成功组装其线粒体基因组并进行注释分析,结合在NCBI上已有的麦角菌科真菌的相关数据,开展比较线粒体基因组学比较,对17种肉座菌目真菌的14个常见的线粒体蛋白的氨基酸序列进行系统发育关系的重建。

结果如下:罗伯茨绿僵菌ARSEF 2575的完整线粒体基因组大小为24945 bp,包含14个常见蛋白编码基因、2个核糖体RNA基因和25个转运RNA基因,蛋白编码基因的种类和排列顺序与已经报道的麦角菌科真菌基本一致。

此外,同多数真菌相似,罗伯茨绿僵菌线粒体基因组的蛋白编码基因、tRNA 基因以及核糖体RNA基因均有明显的A+T偏好性。

通过分析其蛋白编码基因密码子的3位碱基的组成,发现在密码子中,位于第1位点的A、T含量相差较小,而在第2位点的T含量明显比A多出一倍之多,第3位点的A含量是三个位点中最高的,A+T总占比达到83.4%。

在14个蛋白编码基因均以ATG起始并以TAA结束,并没有发现其他起始或终止密码子。

在罗伯茨绿僵菌氨基酸组成中,亮氨酸的使用频率最高,其次为异亮氨酸、苯丙氨酸以及丝氨酸,四者共占线粒体基因氨基酸总量的42.93%。

选取数据库上已发表的肉座菌目真菌以及罗伯茨绿僵菌,基于14个蛋白质编码基因的氨基酸序列,采用最大似然法,建立系统发育树。

所得拓扑结构与目前已知的肉座菌目的分类基本一致,显示Metarhizium robertsii与Metarhizium anisopliae亲缘关系最近。

几类常见的RNA二级结构预测方法

几类常见的RNA二级结构预测方法

几类常见的RNA二级结构预测方法摘要:RNA作为生物遗传信息传递和复制的重要组成部分,其结构非常复杂。

使用计算机算法预测大分子量的RNA二级结构将是一个行之有效的途径。

本文将介绍目前常用的几种RNA二级结构预测算法,并对其特点进行初步的比较分析。

关键词:RNA二级结构;算法;自由能;茎区RNA分子是生物体内参与各种如细胞分化、代谢、记忆存储等重要生命活动的一类大分子,其常见种类有:rRNA、mRNA、tRNA。

其中除tRNA分子量较小外,其余RNA分子都具有非常大的分子量且结构复杂。

传统的物理、化学结构预测方法只适用于测量分子量较小的RNA。

而针对大分子量的RNA二级结构预测,使用计算机技术预测是一条行之有效的方法。

本文主要介绍基于系统发育比较和自由能最小两种技术的RNA二级结构预测算法,并对算法的特点做出简单的阐述。

1RNA二级结构的预测方法从1960年fresco等提出第一个RNA二级结构预测算法开始,RNA二级结构的预测算法经历了近半个世纪的发展,已日趋成熟。

1987年V on heijin对各种预测RNA二级结构的方法进行了综述[1]。

1971年Tinoco et.al首次估算了与二级结构相关的能量,包括双链区中堆叠碱基对相关的稳态能量和未配对区域的稳定影响。

1975年Pipas和McMahon开发出计算机程序可以列出tRNA序列中所有可能的螺旋区。

直到1980年Nussinov和Jacobson首次设计出一个用于预测二级结构的精确而有效的算法,该算法运用了类似动态规划的相关技术,产生了两个记分矩阵,用于记录推测出的RNA分子中碱基的相关信息。

目前,研究人员开发出多种RNA二级结构预测方法。

但总体来说,这些方法可以从研究的数据量出发将其分为两大类:基于系统发育比较技术的预测算法和基于自由能最小技术的预测算法。

1.1基于系统发育比较技术的预测算法基于系统发育比较技术的预测算法即序列比较分析方法(comparative sequence analysis),或称系统发育方法(phylogenetic methods)。

case analysis sequential propagation

case analysis sequential propagation

case analysis sequential propagationCase Analysis: Sequential PropagationIntroduction:In the field of propagation analysis, sequential propagation plays a crucial role in understanding the spread of various phenomena, such as diseases, rumors, or innovations. By examining the sequential nature of propagation, we can gain valuable insights into the factors influencing its progression. This article aims to provide a comprehensive analysis of sequential propagation, exploring its characteristics, applications, and potential implications.Characteristics of Sequential Propagation:Sequential propagation refers to the step-by-step dissemination of information, behaviors, or events from one entity to another. Unlike simultaneous propagation, which occurs simultaneously among multiple entities, sequential propagation follows a specific order or sequence. This order can be influenced by various factors, including geographical proximity, social connections, or individual preferences.Sequential propagation often exhibits a domino effect, where each step triggers the next, leading to a cascading spread. This characteristic makes it essential to understand the initial conditions and the triggering mechanisms to predict and control the propagation processeffectively.Applications of Sequential Propagation:1. Disease Spread Analysis: Sequential propagation analysis is widely used in epidemiology to study the transmission of infectious diseases. By understanding the sequential patterns of infection, researchers can identify high-risk areas or individuals, develop targetedintervention strategies, and effectively contain the spread of diseases.2. Rumor Spreading Analysis: In the era of social media, rumors can spread rapidly and have significant consequences. Sequential propagation analysis helps in understanding how rumors propagate through different online platforms and how they evolve over time. This knowledge can aid in designing effective countermeasures to debunk false information and limit its impact.3. Innovation Diffusion Analysis: Sequentialpropagation analysis is also valuable in studying the diffusion of innovations. By identifying the sequential adoption patterns of new technologies or ideas, researchers can determine influential adopters or opinion leaders who play a crucial role in driving the propagation process.This information can guide marketing strategies and accelerate the adoption of innovations.Implications of Sequential Propagation:1. Targeted Interventions: Understanding the sequential nature of propagation allows for more precise and targetedinterventions. By focusing efforts on key nodes or stagesin the propagation process, resources can be utilized more efficiently, leading to better outcomes.2. Early Warning Systems: Sequential propagation analysis can contribute to the development of early warning systems for various phenomena. By monitoring the initial stages of propagation and identifying triggering factors, authorities can detect and respond to potential threats or crises more promptly.3. Policy Making: Sequential propagation analysis provides policymakers with valuable insights into the dynamics of information or behavior spread. This information can guide the development of policies that encourage desirable propagation outcomes while mitigating negative consequences.Conclusion:Sequential propagation analysis is a powerful tool for understanding the spread of various phenomena. Its characteristics, applications, and implications make it a valuable asset in fields such as epidemiology, social sciences, and marketing. By comprehensively studying sequential propagation, we can enhance our ability to predict, control, and harness the power of propagation for positive outcomes.。

Parker P70 Series智能性能新效率模块式加载感应式阀门系列说明说明书

Parker P70 Series智能性能新效率模块式加载感应式阀门系列说明说明书

The P70 SeriesSmartperformanceNew efficiency for sequential applicationsModular Load Sensing ValvesSeries P70LSParker Hannifi n AB SE-501 78 BoråsTel.: +46 (0)33 700 52 00Fax: +46 (0)33 12 11 /euro_mcdBulletin HY17-8510-B1/UK 3 M 05/06 S&S© Copyright 2006Parker Hannifi n Corporation All rights reservedCommon features – P70 series:• Main pressure relief valve• Port relief valves with anti-cavitationfunction• Anti-cavitation valves • Application adapted spools • Pressure compensated spools • Load hold check valve• For single or multi-pump operationOptions vary for different valvesValve Pump fl ow Pressure Operation l/minbar Manual Pneumatic Hydraulic Electro-hydraulicP70CF 70 350 • • • •P70CP 90 350 • • • • P70LS90350••The ultimate cost/performance compromise!Open Centre technology taken to the limits!Lower running costs, longer service lifeThe unique P70LS solution with its built-in, intelligent load-sensing abilities will give you precise control, quick reactions and a higher overall system efficiency, resulting in lower noise and lower heat losses, and ultimately considerably lower fuel consumption and an extended service life. All this has been made possible through an ingenious adaptation of our existing mass market valve technology, reducing your time-to-market without compromising performance.Take the first step today!The new P70LS can also be a cost-reducing option to fully load sensing valves for less demanding functions in more complex systems. The P70LS technology is an ideal first step into the world of new functionality offered by Parker’s advanced load sensing technologies.TYPICAL APPLICATIONS: REFUSE VEHICLES • SKIP LOADERS • AGRICULTURAL MA CHINES • MEDIUM DUTY WHEEL LOADERS • PISTE MACHINES • FORK LIFTS • FORESTRY MACHINES • ETC.Often when designing mobile hydraulic systems, cost considerations override desired performance, functionality and ergonomics. A high-tech load sensing system would be better in many ways, but the budget just won’t stretch that far.That is when Parker’s new P70LS valve comes to the rescue. Based on a proven, economical, open centre thoroughbred technology, it enables many of the advantages of a load sensing system at a fraction of the cost.Load sensing advantages on a budgetWithout separate compensator, the P70LS achieves simultaneous function operation capabilities through our extensive spool design know-how for pilotoperated valves. The P70 in its load sensing version is a top-of-the-line complement to existing open centre based machines on the market.Copy spools– avoiding micro sinkingPressure com- pensated load signal drain for faster response• Higher productivity• Load-sensing at a fraction of the cost• Based on proven open centre technology• Reduces fuel costs significantly • Better manœuvring precision • Easy to install• M odular design – expandable and upgradeable•P erfect for sequential applications •A global product with global back-up •Simplified cirquit lay-out �������������������������������������Port relief valves with quick responseModular design – expandable and upgradableRobust mainrelief valveMachined land edges for higher precisionPressure compensatedspools for better ergonomics and smoother manœuvring。

explanatory sequential mixed method

explanatory sequential mixed method

explanatory sequential mixed method Explanatory Sequential Mixed MethodsIntroduction:Research methodology plays a crucial role in informing decision-making and understanding complex phenomena. Mixed methods research designs have gained popularity in recent years due to their ability to provide a comprehensive and holistic understanding of a research problem. One such design is the explanatory sequential mixed methods approach, which incorporates both quantitative and qualitative components in a sequential manner. This article aims to explain the explanatory sequential mixed methods design, its components, advantages, and limitations, with examples from various research studies.Components of the Explanatory Sequential Mixed Methods Design:The explanatory sequential mixed methods design consists of two distinct phases, namely the quantitative phase and the qualitative phase. In this design, the quantitative component is conducted first and is followed by the qualitative component. The purpose of the quantitative phase is to explore relationships and identify patterns in the data, while the qualitative phase aims to provide a deeper understanding of these relationships and patterns.Quantitative Phase:During the quantitative phase, researchers collect and analyze quantitative data using structured surveys, experiments, orsecondary data sources. The goal is to generate numerical data that can be analyzed using statistical techniques to test hypotheses or patterns. The findings from the quantitative analysis inform the selection of participants and the focus of the qualitative phase.Qualitative Phase:The qualitative phase involves collecting and analyzing qualitative data, such as interviews, observations, or document analysis. The purpose of this phase is to understand the underlying reasons and processes behind the quantitative findings. Qualitative data collection methods allow researchers to gather rich and detailed information that provides context and meaning to the statistical results. The qualitative analysis involves coding, categorizing, and interpreting the data to identify themes and patterns.Integration of Findings:The integration of findings is a crucial step in the explanatory sequential mixed methods design. During this stage, researchers compare and contrast the findings from both the quantitative and qualitative phases to develop a comprehensive understanding of the research problem. This integration can occur in different ways, such as comparing the results side by side, using statistical findings to interpret qualitative data, or using qualitative findings to explain statistical patterns. The aim is to provide a richer and more nuanced understanding of the research topic than could be achieved through a single method or phase.Advantages of the Explanatory Sequential Mixed Methods Design:The explanatory sequential mixed methods design offers several advantages over traditional quantitative or qualitative approaches. Firstly, it provides a more comprehensive understanding of the research problem by combining quantitative and qualitative data. The sequential nature of the design allows researchers to build on the findings from the quantitative phase and explore them in more depth during the qualitative phase. This approach strengthens the validity and reliability of the research findings.Secondly, the design allows researchers to address research questions that require both numerical data and contextual information. Some phenomena cannot be fully understood or explained by numbers alone, and qualitative data can provide valuable insights into the underlying reasons and processes.Thirdly, the design enhances triangulation, which refers to the use of multiple data sources or methods to validate findings. By combining quantitative and qualitative data, researchers can compare and contrast the different perspectives and identify converging or conflicting evidence. This strengthens the overall validity and trustworthiness of the research.Limitations of the Explanatory Sequential Mixed Methods Design:Despite its advantages, the explanatory sequential mixed methods design also has some limitations. Firstly, it requires time and resources to implement both quantitative and qualitative components. Researchers need to consider the feasibility of conducting both phases and ensure that they have the necessaryskills and expertise in both quantitative and qualitative methods.Secondly, the design may face challenges in terms of data integration and interpretation. Combining quantitative and qualitative findings can be complex and may require expertise in both types of data analysis. Researchers need to carefully consider how to integrate the findings in a meaningful and coherent manner.Example Studies:To illustrate the application of the explanatory sequential mixed methods design, three example studies are presented below:1. A study on the effectiveness of a health intervention program uses a quantitative survey to measure participants' health outcomes and satisfaction levels. The qualitative phase involves in-depth interviews with a sub-sample of participants to explore their experiences and perceptions of the program.2. A study on the impact of a teacher training program uses a quantitative pre-test and post-test design to measure changes in students' academic performance. The qualitative phase involves focus group discussions with teachers to understand their perspectives on the program's effectiveness and challenges.3. A study on the factors influencing employee satisfaction and retention uses a quantitative survey to measure employee satisfaction levels. The qualitative phase involves semi-structured interviews with a subset of employees to explore the underlying reasons for their satisfaction or dissatisfaction.Conclusion:The explanatory sequential mixed methods design offers a powerful approach to research that combines the strengths of quantitative and qualitative methods. By integrating numerical data with contextual information, this design provides a comprehensive and holistic understanding of research problems. Despite its limitations, the design has gained popularity due to its ability to address complex research questions and enhance the validity and reliability of findings. Researchers should consider the feasibility and appropriateness of this design for their specific research objectives and resources.。

Cell-free nucleic acids as biomarkers in cancer patients

Cell-free nucleic acids as biomarkers  in cancer patients

In 1948, Mandel and Métais 1 described the presence of cell-free nucleic acid (cfNA) in human blood for the first time. This attracted little attention in the scientific com-munity and it was not until 1994 that the importance of cfNA was recognized as a result of the detection of mutated RAS gene fragments in the blood of cancer patients 2,3 (TIMELINE). In 1996, microsatellite altera-tions on cell-free DNA (cfDNA) were shown in cancer patients 4, and during the past decade increasing atten-tion has been paid to cfNAs (such as DNA, mRNA and microRNAs (miRNAs)) that are present at high concentra-tions in the blood of cancer patients (FIG. 1). Indeed, their potential value as blood biomarkers was highlighted in a recent editorial in the journal Science 5.Detecting cfNA in plasma or serum could serve as a ‘liquid biopsy’, which would be useful for numer-ous diagnostic applications and would avoid the need for tumour tissue biopsies. Use of such a liquid biopsy delivers the possibility of taking repeated blood sam-ples, consequently allowing the changes in cfNA to be traced during the natural course of the disease or during cancer treatment. However, the levels of cfNA might also reflect physiological and pathological processes that are not tumour-specific 6. cfNA yields are higher in patients with malignant lesions than in patients without tumours, but increased levels have also been quantified in patients with benign lesions, inflammatory diseases and tissue trauma 7. The physi-ological events that lead to the increase of cfNA during cancer development and progression are still not well understood. However, analyses of circulating DNA allow the detection of tumour-related genetic and epi-genetic alterations that are relevant to cancer develop-ment and progression. In addition, circulating miRNAs have recently been shown to be potential cancer biomarkers in blood.This Review focuses on the clinical utility of cfNA, including genetic and epigenetic alterations that can be detected in cfDNA, as well as the quantification of nucleo s omes and miRNAs, and discusses the relationship between cfNA and micrometastatic cells.Biology of cfNAThe release of nucleic acids into the blood is thought to be related to the apoptosis and necrosis of cancer cells in the tumour microenvironment. Secretion has also been suggested as a potential source of cfDNA (FIG. 1). Necrotic and apoptotic cells are usually phagocytosed by macrophages or other scavenger cells 8. Macrophages that engulf necrotic cells can release digested DNA into the tissue environment. In vitro cell culture experiments indicated that macrophages can be either activated or dying during the process of DNA release 8. Fragments of cellular nucleic acids can also be actively released 9,10. It has been estimated that for a patient with a tumour that weighs 100 g, which corresponds to 3 × 1010 tumour cells, up to 3.3% of tumour DNA may enter the blood every day 11. On average, the size of this DNA varies between small fragments of 70 to 200 base pairs and large fragments of approximately 21 kilobases 12. Tumour cells that circulate in the blood, and micro-metastatic deposits that are present at distant sites, such as the bone marrow and liver, can also contribute to the release of cfNA 13,14.T umours usually represent a mixture of different cancer cell clones (which account for the genomic and epig-enomic heterogeneity of tumours) and other normal cell types, such as haematopoietic and stromal cells. Thus, during tumour progression and turnover both tumour-derived and wild-type (normal) cfNA can be released into the blood. As such, the proportion of cfNA that originates from tumour cells varies owing to the state*Institute of T umour Biology, Center of ExperimentalMedicine, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany.‡Department of Molecular Oncology, John Wayne Cancer Institute, Santa Monica, California 90404, USA.Correspondence to K.P . e-mail:pantel@uke.uni-hamburg.de doi:10.1038/nrc3066Published online 12 May 2011microRNAsSmall non-coding RNAmolecules that modulate the activity of specific mRNA molecules by binding and inhibiting their translation into polypeptides.Cell-free nucleic acids as biomarkers in cancer patientsHeidi Schwarzenbach*, Dave S. B. Hoon ‡ and Klaus Pantel*Abstract | DNA, mRNA and microRNA are released and circulate in the blood of cancerpatients. Changes in the levels of circulating nucleic acids have been associated with tumour burden and malignant progression. In the past decade a wealth of information indicating the potential use of circulating nucleic acids for cancer screening, prognosis and monitoring of the efficacy of anticancer therapies has emerged. In this Review, we discuss these findings with a specific focus on the clinical utility of cell-free nucleic acids as blood biomarkers.and size of the tumour. The amount of cfNA is also influ-enced by clearance, degradation and other physiological filtering events of the blood and lymphatic circulation. Nucleic acids are cleared from the blood by the liver and kidney and they have a variable half-life in the circulation ranging from 15 minutes to several hours7. Assuming an exponential decay model and plotting the natural loga-rithm of cfDNA concentration against time, serial DNA measure m ents have shown that some forms of cfNA might survive longer than others. When purified DNA was injected into the blood of mice, double-stranded DNA remained in the circulation longer than single-stranded DNA15. Moreover, viral DNA as a closed ring may survive longer than linear DNA15. However, regardless of its size or configuration, cfDNA is cleared from the circulation rapidly and efficiently16. miRNAs seem to be highly stable, but their clearance rate from the blood has not yet been well studied in cancer patients owing to the novelty of this area of research. The nuclease activ-ity in blood may be one of the important factors for the turnover of cfNA. However, this area of cfNA physiology remains unclear and needs further examination. Circulating cfDNADNA content. In patients with tumours of different histo-pathological types, increased levels of total cfDNA, which consists of epigenomic and genomic, as well as mito-chondrial and viral DNA, have been assessed by different fluorescence-based methods (such as, PicoGreen stain-ing and ultraviolet (UV) spectrometry) or quantitative PCR (such as, SYBR Green and TaqMan). Although cancer patients have higher cfDNA levels than healthy control donors, the concentrations of overall cfDNA vary considerably in plasma or serum samples in both groups17–19. A range of between 0 and >1,000 ng per ml of blood, with an average of 180 ng per ml cfDNA, has been measured20–23. By comparison, healthy subjects have concentrations between 0 and 100 ng per ml cfDNA of blood, with an average of 30 ng per ml cfDNA7. However, it is difficult to draw conclusions from these studies, as the size of the investigated patient cohort is often small and the techniques used to quantify cfDNA vary. A large prospective study assessed the value of plasma DNA levels as indicators for the development of neoplastic or pulmonary disease. The concentration of plasma DNA varied considerably between the European Prospective Investigation into Cancer and Nutrition (EPIC) centres that were involved in the study. This variation was pro-posed to be due to the type of population recruited and/or the treatment of the samples24. However, the quantifica-tion of cfDNA concentrations alone does not seem to be useful in a diagnostic setting owing to the overlapping DNA concentrations that are found in healthy individuals with those in patients with benign and malignant disease. The assessment of cfDNA concentration might prove to be useful in combination with other blood tumour bio-markers. Following surgery, the levels of cfDNA in cancer patients with localized disease can decrease to levels that are observed in healthy individuals25. However, when the cfDNA level remains high, it might indicate the presence of residual tumour cells17. Further studies are needed for the repeat assessment of quantitative cfNA in large cohorts of patients with well-defined clinical parameters. Such investigations will be crucial if we are to use cfDNA as a prognostic biomarker, as will the isolation and processingof cfNA to defined standards (discussed below).cfDNA is composed of both genomic DNA (gDNA) and mitochondrial DNA (mtDNA). Interestingly, the levels of cell-free mtDNA and gDNA do not correlate in some tumour types26,27, indicating the different nature of circulating mtDNA and gDNA. In contrast to two copies of gDNA, a single cell contains up to several hundred copies of mtDNA. Whereas gDNA usually circulates in a cell-free form, circulating mtDNA in plasma exists in both particle-associated and non-particle-associated forms28. Diverging results have been reported regarding whether cell-free mtDNA levels are increased and clinically relevant in cancer patients.The cfDNA can also include both coding and non-coding gDNA that can be used to examine microsatellite instability, loss of heterozygosity (LOH), mutations, poly-morphisms, methylation and integrity (size). In recent years, considerable attention has been paid to non-coding DNA, particularly repetitive sequences, such as ALU (which is a short interspersed nucleic element (SINE)) and as long interspersed nucleotide elements such as LINE1 (REFS 29–31) (discussed below). ALU and LINE1 are dis-tributed throughout the genome and are known to be less methylated in cancer cells compared with normal cells32. Tumour-specific LOH. Genetic alterations found in cfDNA frequently include LOH that is detected using PCR-based assays13,18,33–38(TABLE 1). Although similar plasma- and serum-based LOH detection methods have been used, a great variability in the detection of LOH in cfDNA has been reported. Despite the concordance between tumour-related LOH that is present in cfDNA in blood and LOH that is found in DNA isolated from matched primary tumours, discrepancies have also been found7. These contradictory LOH data that have been derived from blood and tumour tissue and the low incidence of LOH in cfDNA have partly been explained by technical problems and the dilution of tumour-associated cfDNA in blood by DNA released from normal cells11,39–41. Moreover, the abnormal proliferation of benign cells, owing to inflammation or tissue repair processes, for example, leads to an increase in apoptotic cell death, the accumulation of small, fragmented DNA in blood and the masking of LOH42.Alternative approaches, such as the detection of tumour-specific deletions are needed to better address the inherent problems of LOH analyses.Tumour-specific gene mutations.The analysis of cfDNA for specific gene mutations, such as those in KRAS and TP53, is desirable because these genes have a high mutation frequency in many tumour types and contribute to tumour progression43. Additionally, clini-cally relevant mutations in BRAF, epidermal growth factor receptor (EGFR) and adenomatous polyposis coli (APC) have now been studied in cfDNA. Several thera-peutic agents in clinical trials target the KRAS, BRAF, EGFR or p53 pathways44,45, and require the identifica-tion of the mutation status of the patient’s tumour to predict response to treatment. In this regard, cfDNA provides a unique opportunity to repeatedly monitor patients during treatment. In particular, in stage IV cancer patients, biopsies are not possible or repeat sam-pling of primary tumour and metastatic samples is not practical or ethical.The major problem with this approach has been assay specificity and sensitivity. Assays targeting cfDNA mutations require that the mutation in the tumour occurs frequently at a specific genomic site.A major drawback of cfDNA assays is the low frequency of some of the mutations that occur in tumours. In general, wild-type sequences often interfere with cfDNA muta-tion assays. This is due to the low level of cfDNA mutations and the dilution effect of DNA fragments and wild-type DNA in circulation. In PCR-based assays technological design can significantly limit the assay sensitivity and specificity. An example is the KRAS muta-tion tissue assay that can frequently detect mutations in tumour tissues, such as the pancreas, colon and lung;Quantitative real-time clamp PCR assayA technique that uses a peptide nucleic acid clamp and locked nucleic acid probes, which are DNA synthetic analogues that hybridize to complementary DNA and are highly sensitive and specific for recognizing single base pair mismatches.however, cfDNA mutation assays using blood sam-ples have not yet been concordantly successful46–48.New approaches are needed, such as cfDNA sequenc-ing. The BRAF mutation V600E, which is present in>70% of metastatic melanomas, can be detectedin cfDNA and has been shown to be useful in monitor-ing patients with melanoma who are receiving ther-apy49. This mutation has been detected in differentstages of melanoma (according to the American JointCommittee on Cancer (AJCC) Cancer Staging Manual)using a quantitative real-time clamp PCR assay, with thehighest levels found in the more advanced stages49. Thisis one of the first major studies to demonstrate thatcfDNA mutation assays have the sensitivity to monitorpatient responses before and after treatment. The util-ity of a cfDNA BRAF mutation assay has gained moreimportance, as new anti-BRAF drugs, such as PLX4032(Roche)50 and GSK2118436 (GlaxoSmithKline)51, haveshown substantial responses in patients in early clinicaltrials. EGFR mutations that occur in a specific subset ofpatients with lung cancers52–54 make these tumours sen-sitive to EGFR-targeted therapies; however, the detec-tion of EGFR mutations in cfDNA has not been welldeveloped owing to issues with sensitivity and specifi-city. Patients whose tumours have a specific gene muta-tion would be strong candidates for monitoring of theircfDNA in blood for the respective specific mutation.However, sensitivity, specificity and validation needto be carried out in multicentre settings to determinetrue clinical utility. Alternatively, cfDNA assays mightbe more appropriate when used with other biomarkerassays, and this might be applicable to personalizedmedicine, rather than diagnostic screens that can beused across a wide group of cancer patients.DNA integrity. Another assay that is applicable to cfDNAthat has gained interest in recent years is the integrityof non-coding gDNA, such as the repeat sequences ofALU and LINE1. The ALU and LINE1 sequences havebeen referred to as ‘junk DNA’; however, in recentyears evidence has indicated their importance invarious physiological events, such as DNA repair,transcription, epigenetics and transposon-based activ-ity55,56. Approximately 17–18% of the human genomeconsists of LINE1. In normal cells LINE1 sequencesare heavily methylated, restricting the activities ofthese retrotransposon elements and thus preventinggenomic instability. LINE1 sequences are moderatelyCpG-rich, and most methylated CpGs are locatedin the 5′ region of the sequence that can function asan internal promoter23. These forms of DNA can bedetected as cfDNA of different sizes, but also as methyl-ated and unmethylated DNA. Studies on these types ofcfDNA are still in their infancy; however, recent studieshave shown potential prognostic and diagnostic util-ity23,29–31. The assays are based on the observation thatcommon DNA repeat sequences are preferentiallyreleased by tumour cells that are undergoing non-apoptotic or necrotic cell death, and these fragmentscan be between 200 bp and 400 bp in size. The ALU andLINE1 sequences are well interspersed throughout thegenome on all chromosomes, so although specificity understood; tumour burden and tumour cell proliferation rate may have a substantial role in these events. Individual tumour types can release more than one form of cfDNA.for an individual cancer type is lost in these assays, sen-sitivity is enhanced. Using a PCR assay, the integrity of cfDNA ALU sequences in blood has been shown to be sensitive for the assessment of the early stages of breast cancer progression, including micro m etastasis30. DNA integrity cfDNA assays have also been used in testicular, prostate, nasopharyngeal and ovarian cancer31,57–59. These assays are still in their infancy and address an important challenge of whether a ‘universal’ blood biomarker for multiple cancers can be of clinical utility. Further validation of these assays will also determine their clinical utility in specific cancers.Table 1 |Detection of cfDNA and its alterations in patients with different tumour types*cancers in both males and females182. This table is not meant to be comprehensive and is based on our own view of studies that offer substantial clinical insight. cfDNA, cell-free DNA.Epigenetic alterations. Epigenetic alterations can have a substantial effect on tumorigenesis and progression (BOX 1). Several studies have revealed the presence of methylated DNA in the serum or plasma of patients with various types of malignancy (TABLE 1). The detection of methylated cfDNA represents one of the most promising approaches for risk assessment in cancer patients. Assays for the detection of promoter hypermethylation may have a higher sensitivity than microsatellite analyses, and can have advantages over mutation analyses. In gen-eral, aberrant DNA methylation, which seems to be com-mon in cancer, occurs at specific CpG dinucleotides60. The acquired hypermethylation of a specific gene can be detected by sodium bisulphite treatment of DNA, which converts unmethylated (but not methylated) cytosines to uracil. The modified DNA is analysed using either methylation-specific PCR, with primers that are specific for methylated and unmethylated DNA, or DNA sequenc-ing61. Nevertheless, to improve the assay conditions and the clinical relevance, the selection of appropriate tumour-related genes from a long list of candidate genes that are known to be methylated in neoplasia is essential. Although epigenetic alterations are not unique for a single tumour entity, there are particular tumour suppressor genes that are frequently methylated and downregulated in certain tumours62,63. For example, important epigenetic events in carcinogenesis include the hypermethylation of the promoter region of the genes pi-class glutathione S-transferase P1 (GSTP1) and APC, which are the most common somatic genome abnormalities in prostate and colorectal cancer, respectively62,63. Other important methylated genes that have shown prognostic utility using cfDNA assays in significant numbers of patients include RAS association domain family 1A (RASSF1A), retinoic acid receptor-b (RARB), septin 9 (SEPT9), oestrogen receptor-a (ESR1)and cyclin-dependent kinase inhibitor 2A (CDKN2A) (TABLE 1). The first commercial real-time PCR plasma test for the detection of early colorectal cancer (developed by Epigenomics AG and Abbott Molecular) is for the detection of SEPT9. This biomarker is still under-going validation, but it demonstrates the potential diag-nostic screening utility of methylated tumour-related cfDNA to differentiate cancer patients from healthy individuals and to identify the tumour type.It is also possible to detect tumour-related alterations in histone modifications in the blood. By monitoring changes in the circulating histones and DNA methylation pattern, the antitumour effects of histone deacetylase and histone methyltransferase inhibitors may be evalu-ated and consequently allow a better screening of cancer patients64,65.Circulating nucleosomes.Circulating gDNA that is derived from tumours seems to predominantly exist as mononucleosomes and oligonucleosomes, or it is bound to the surface of blood cells by proteins that harbour specific nucleic acid-binding properties66. A nucleosome consists of a histone octamer core wrapped twice by a 200 bp-long DNA strand. Under physiological condi-tions these complexes are packed in apoptotic particles and engulfed by macrophages67. However, an excess of apoptotic cell death, as occurs in large and rapidly pro-liferating tumours or after chemotherapy treatment, can lead to a saturation of apoptotic cell engulfment and thus increased nucleosome levels in the blood68. The detection of circulating nucleosomes that are associ-ated with cfDNA suggests that DNA in blood retains at least some features of the nuclear chromatin during the process of release.Enzyme-linked immunosorbent assays (ELISAs) have been developed to quantify circulating nucleosomes. As increased concentrations are found in both benign and malignant tumours, high nucleosome levels in blood are not indicators of malignant disease69. However, the observed changes in apoptosis-related deregulation of proteolytic activities along with the increased serum levels of nucleosomes have been linked to breast cancer progression70. As typical cell-death products, the quan-tification of circulating nucleosomes seems to be valu-able for monitoring the efficacy of cytotoxic cancer therapies71. For example, platinum-based chemotherapy induces caspase-dependent apoptosis of tumour cells and an increase in circulating nucleosomes in the blood of patients with ovarian cancer17. Moreover, the outcome of therapy can be indicated by nucleosome levels during the first week of chemotherapy and radiotherapy in patients with lung, pancreatic and colorectal cancer, as well as in patients with haematological malignancies71.Viral DNA. Viral cfDNA can also be detected in some tumour types. Viruses, such as human papillomavirus (HPV), hepatitis B virus (HBV) and Epstein–Barr virus (EBV), are aetiological factors in various malignancies, such as nasopharyngeal, cervical, head and neck, and hepatocellular cancer and lymphoma72–75. Their specific DNA may have the potential to be used as molecular biomarkers for neoplastic disease. Associations between circulating viral DNA and disease have been reported for EBV with Hodgkin’s disease, Burkitt’s lymphoma and nasopharyngeal carcinoma; for HBV with some forms of hepatic cell carcinoma; and for HPV with head and neck, cervical and hepatocellular cancers (TABLE 1). The clinical utility of EBV cfDNA in diagnosis and prognosis of nasopharyngeal carcinoma has been demonstrated in multiple studies with large cohorts of patients76–80, and the use of this cfDNA has became one of the leading cfDNA blood tests for the assessment of nasopharyngeal carci-noma progression in Hong Kong, Taiwan and China, where this cancer is highly prevalent77,78,81. The limitationof most viral cfNA assays is that benign viral infections that are caused by the same viruses can complicate the interpretation of results, particularly in diagnostic screen-ing. Establishing clinically meaningful cut-off levels is important to move these screens into the clinic. Genometastasis.The genometastasis hypothesis describes the horizontal transfer of cell-free tumour DNA to other cells that results in transformation. If true, metastases could develop in distant organs as a result of a transfection-like uptake of dominant oncogenes that are released from the primary tumour82. García-Olmo et al.83 showed that plasma isolated from patients with colon cancer is able to transform NIH-3T3 cells and that these cells can form carcinomas when injected into non-obese diabetic-severe combined immunodeficient mice83. Whether this biological function of circulating DNA has relevance in human blood is an aspect to be considered in the future.cfDNA assay issuesOne of the problems in evaluating cfNA is the standard-ization of assays, such as isolation technologies, standards, assay conditions, and specificity and sensitivity7. It remains controversial whether plasma or serum is the optimal sampling specimen. The diversity of protocols and reagents currently in use impedes the comparison of data from different laboratories.The pre-analytical phases of cfDNA analysis such as blood collection, processing (plasma and serum), storage, baseline of patients, diurnal variations and accurate clinical conditions need to be better defined before comparisons and clinical utility can be validated84.A major technical issue that hampers consistency in all the cfDNA assays is the efficacy of the extraction pro-cedures, with only small amounts of DNA obtained from plasma and serum. Another key issue is quanti-fication before assessment on specific assay platforms. Improvement is needed in these aspects for cfDNA analysis to be more robust, consistent, comparative and informative. Extraction of cfDNA can be carried out in accordance with many methods; for example, commer-cial kits, company in-house procedures or individual laboratory protocols. To date no approach has been truly developed that is consistent, robust, reproduc-ible, accurate, and validated on a large-scale patient and normal donor population. If these issues were solved a better universal standardization for the comparison of results would be provided and the clinical utility of the assays could be addressed. The development of a direct DNA assay without extraction would override many of these problems30. As new approaches in the assessment of cfDNA, such as next-generation sequencing, are being developed, the issue of extraction of DNA will continue to complicate cfDNA biomarker assay development and regulatory group approval.The other major issue for cfDNA assessment is that after DNA extraction, different platform assays are used for analysis. This can vary owing to the type of cfDNA being analysed, assay sensitivity and specificity, and ana-lytical approach. These variables are important and need to be standardized for consensus analysis and reporting. The development of PCR-based assay standardization is needed in order to report clinical and prognostic biomarker results that are similar to those outlined in the recent minimal information for the publication of quantitative real-time PCR guidelines85. However, this may take time to reach an international consensus, as has been apparent with the standardization of other cancer blood biomarkers. Unfortunately, the rate of approval of new cancer blood biomarkers over the past decade has been very slow. New regulatory guidelines, such as those listed for tumour biomarkers in clinical practice by the National Academy of Clinical Biochemistry (NACB USA)84, should help to resolve some of these issues. The NACB website provides up-to-date informative detailed guidelines with references of pre-analytical and post- analytical phases, assay validation, internal quality controls, proficiency and requirements for minimiz-ing the risk of method-related errors for biomarkers. Nevertheless, as with other types of biomarkers, new reg-ulatory guidelines mean that developing cfNA biomarkers will be more time-consuming and costly. Circulating cfRNAmRNA content. Besides the quantification of cfDNA, cir-culating gene transcripts are also detectable in the serum and plasma of cancer patients. It is known that RNA released into the circulation is surprisingly stable in spite of the fact that increased amounts of RNases circulate in the blood of cancer patients. This implies that RNA may be protected from degradation by its packaging into exosomes86, such as microparticles, microvesicles or multivesicles, which are shed from cellular surfaces into the bloodstream87. The detection and identification of RNA can be carried out using microarray technologies or reverse transcription quantitative real-time PCR88. Serum thyroglobulin levels are a specific and sensi-tive tumour marker for the detection of persistent or recurrent thyroid cancer. Levels of thyroglobulin change during thyroid hormone-suppressive therapy, as well as after stimulation with thyroid-stimulating hormone, and the levels correlate well with disease progression. The measurement of mRNA levels of thyroid-specific tran-scripts might be useful in the early detection of tumour relapse89. However, another study has shown that the detection of circulating thyroglobulin mRNA one year after thyroidectomy might be of no use in the prediction of early and midterm local and distant recurrences of this disease90.In patients with breast cancer, levels of CCND1 mRNA (encoding cyclin D1) identified patients with poor overall survival in good-prognosis groups and patients who were non-responsive to tamoxifen91. Nasopharyngeal carcinoma has been associated with disturbances in the integrity of cell-free circulating RNA, suggesting that the measurement of plasma RNA integrity may be a useful biomarker for the diagnosis and monitoring of malignant diseases92. Several groups have tried to detect human telo-merase reverse transcriptase (TERT) mRNA in plasma, and have not found any association between the pres-ence of this mRNA and clinicopathological parameters7.。

人声分离算法

人声分离算法

人声分离算法人声分离是一种音频信号处理技术,旨在从混合音频中分离或提取出特定的人声信号。

这项任务通常是在语音处理、音乐处理以及音频增强等领域中应用的重要技术。

以下是一些常见的人声分离算法:1. 基于深度学习的方法:• Deep Clustering:使用深度学习模型,如深度聚类网络(Deep Clustering Network, DCN),学习在频谱域对音频进行聚类,以实现音源分离。

该方法在训练过程中将相似的频谱点聚类在一起,从而使网络能够学到不同音源的表示。

• Deep attractor network (DAN):通过学习音源的吸引子表示,这种方法使得模型能够在频谱上分离不同的音源。

2. 基于短时傅立叶变换(STFT)的方法:• Non-negative Matrix Factorization (NMF):将音频信号表示为非负矩阵的乘积,其中一个矩阵表示基础音源,另一个矩阵表示每个时间点的激活系数。

通过调整这两个矩阵,可以分离出人声信号。

• Independent Component Analysis (ICA):基于统计模型,假设混合信号是独立的非高斯过程,通过最大似然估计方法来分离不同的源信号。

3. 基于时域处理的方法:• Ideal Binary Mask (IBM):通过分析语音和非语音的频谱差异,生成一个二进制掩码,用于选择性地过滤和分离人声信号。

• Phase-sensitive Reconstruction (PSR):基于相位信息的处理,通过在频域上对信号进行修复和重新构建来分离人声。

4. 基于卷积神经网络(CNN)的方法:• U-Net Architecture:基于 U-Net 结构的深度学习模型,通过卷积层和上采样层实现对音频信号的高级特征学习和重建。

请注意,人声分离是一个复杂的问题,其效果受到许多因素的影响,如音频质量、混合信号的复杂性以及算法的设计。

选择合适的方法取决于实际应用的要求和环境。

序列比对及进化分析的基本原理与方法

序列比对及进化分析的基本原理与方法

序列比对及进化分析的基本原理与方法随着生物技术的飞速发展,更多的生物大数据产生并被广泛应用。

其中,序列分析成为理解生物进化、发展和功能的基石。

并且,基于生物序列数据进行的进化分析也成为了研究生物多样性和演化的重要工具。

基于序列比对的分析方法使我们能够更好地了解生物序列的相似性和差异性,从而揭示生物序列的结构、功能、进化和调控机制。

本文将详细介绍序列比对和进化分析的基本原理和方法。

一、序列比对的原理及分类序列比对(Sequence Alignment)是指将两个或多个生物序列进行比较而确定它们间的相似性和差异性的算法。

序列比对是一项基础性研究,被广泛应用于蛋白质结构、功能、进化和调控等生物学领域。

常用的方法有全局比对、局部比对和多序列比对等。

1、全局比对全局比对是将整条序列进行比对,试图找到两个序列的最长公共子序列。

全局比对主要适用于两个序列相似且长度相近的情况,比对结果中缺少相对较短的片段。

2、局部比对局部比对是比对两个序列中相似片段,可以处理两个序列长度相差较大或相似度较低的情况。

3、多序列比对多序列比对是对多个序列进行比对,以确定它们之间的联系。

多序列比对可以揭示进化过程中的基因家族关系,也可以揭示功能相似的区域。

二、进化分析的基本原理及方法1、突变和进化突变是指DNA序列中的变化,包括核苷酸替换、插入和缺失等。

进化是多个突变的累积,它是生命演化的核心过程之一。

基于序列比对的进化分析可以揭示各种生物间的演化和起源,这对揭示生物多样性和演化、分型分部等生物进化相关问题有着重要的意义。

2、进化树的构建进化树是指基于序列相似性进行构建的树形结构,利用序列比对数据推断生物间的亲缘关系。

进化树建立的过程称为系统发育学,可以帮助我们理解基因适应性和表现型特征的演化历史。

3、分子钟模型分子钟模型是使用分子演化数据计算时间的模型。

分子钟模型基于假设,即进化是在恒定的速率下发生的,因此可以通过基因时钟模型估算时间。

人工智能(ai)和虚拟现实(vr)技术是应对精神疾病的有用工具

人工智能(ai)和虚拟现实(vr)技术是应对精神疾病的有用工具

Frontiers 前沿家电科技12力,曲折度和法向入射吸声率。

同时使用反向演算从实验数据中确定了大麻材料的粘性和热特征。

对比验证突出显示了数值计算方法获得的结果与实验物理参数之间的良好一致性。

本文所提出的方法具有简单和实用特性,但在最高密度下以及对于具有粗糙纤维的材料,预测结果与实验数据有一定的偏差。

实验结果和数值结果之间的差异与从同一样品的不同测量获得的实验标准偏差相当。

此外,本文所做的法向入射的吸声实验也和Johnson-Champoux-Allard 模型计算的结果进行了比较,以旁证本文所用到的简化数学模型的整体可靠性。

资料来源:Santoni et al 2019, Applied Acoustics Journal, iss. 150, pp 279–289.人工智能(AI )和虚拟现实(VR )技术是应对精神疾病的有用工具根据世界卫生组织(WHO )的报告,世界上约有四分之一的人受到了某种形式的精神障碍的困扰。

医学界越来越多地使用虚拟现实(VR ——Virtual Reality )和人工智能(AI )技术来治疗精神疾病。

目前虚拟现实技术多用于治疗创伤后的应激障碍(PTSD )、妄想症以及抑郁症。

虚拟现实技术已成功地用于治疗退伍军人,例如,带上VR 头盔设备的士兵可以重新访问他们曾经置身的危险区域。

VR 技术通过使患者体验到令人愉快和放松的环境,来缓解抑郁和焦虑。

例如,加利福尼亚的一些医院已成功实施了一项虚拟现实(VR )方案,该方案可以在虚拟环境中让人们与海豚一起在海中游泳,以帮助抑郁症患者舒缓情绪。

国际电工委员会(IEC )已与国际标准组织(ISO JTC 1-信息技术范畴)组成了联合技术委员会,负责制定信息技术标准。

其中的一个小组委员会发布了相关文件,这些文件规定了对增强现实(AR ——Augmented Reality )和虚拟现实(VR )的要求。

IEC TC 110还发布了电子显示器的标准。

sequential relationship analysis method

sequential relationship analysis method

sequential relationship analysis method全文共四篇示例,供读者参考第一篇示例:序贯关系分析方法(sequential relationship analysis method)是一种用于研究变量之间的时间序列关系的统计方法。

这种方法可以帮助研究者确定变量之间的因果关系或影响关系,从而揭示变量之间的复杂交互作用。

序贯关系分析方法在许多领域中都有广泛的应用,包括经济学、社会科学、生物学等。

在经济学中,序贯关系分析方法被用来研究不同经济变量之间的时间序列关系,从而预测未来的经济走势。

在社会科学中,这种方法可以帮助研究者理解社会现象的演变过程,揭示其中的规律和因果关系。

序贯关系分析方法的基本思想是通过统计分析来确定变量之间的时间序列关系。

研究者需要收集各个变量的时间序列数据,并对这些数据进行预处理,以确保数据的准确性和可靠性。

然后,研究者可以利用统计方法如相关分析、回归分析等来确定变量之间的关系,从而找出其中的因果关系或影响关系。

序贯关系分析方法有许多优点。

这种方法能够帮助研究者理解变量之间的动态关系,揭示变量之间的内在联系。

序贯关系分析方法能够帮助研究者预测未来的趋势和发展方向,为决策提供参考依据。

这种方法还可以帮助研究者发现变量之间的隐藏关系,为进一步研究提供新的思路和方法。

在使用序贯关系分析方法时,研究者需要注意一些问题。

要选择适当的统计方法来进行分析,以确保分析结果的可靠性和有效性。

要考虑变量之间可能存在的复杂关系,避免简单化和片面化的解释。

要注意数据的准确性和完整性,以避免分析结果的偏差和误导。

序贯关系分析方法是一种有用的工具,可以帮助研究者揭示变量之间的时间序列关系,发现其中的规律和因果关系。

通过适当的分析和解释,研究者可以更好地理解复杂系统的运行机制,为未来的研究和决策提供有益的参考。

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第二篇示例:序列关系分析方法(Sequential Relationship Analysis Method)是一种用于研究事物之间相互关系的方法。

self-report-based sequential analysis -回复

self-report-based sequential analysis -回复

self-report-based sequential analysis -回复什么是自我报告型顺序分析?自我报告型顺序分析(Self-reported sequential analysis)是一种研究方法,通过分析被试者在实验或观察过程中的自我报告来研究和理解行为和心理过程之间的关系。

通过采集被试者的自我报告数据,研究人员可以获得被试者在特定任务或情境中的内心体验、意识和观察结果,从而深入了解其心理过程的时序性。

这种方法可以帮助研究人员揭示人类行为和心理过程的细微和动态的变化。

为什么要使用自我报告型顺序分析?自我报告型顺序分析是一种非常有价值的研究方法,可以在多个领域中应用。

首先,它可以帮助研究者了解被试者在特定任务或情境中的内心体验和感受。

例如,在研究学习过程中,被试者可以记录自己在不同学习阶段的感受和心理状态,进而对学习过程中的认知和情绪变化进行分析。

其次,自我报告型顺序分析也可以用来研究心理学中的个体差异。

通过对不同个体在特定任务中的自我报告数据进行比较,研究人员可以了解不同个体在认知、情感和行为等方面的差异。

最后,自我报告型顺序分析还可以用于研究心理过程中的因果关系。

通过分析自我报告数据之间的时序关系,研究人员可以揭示心理过程中不同因素之间的相互作用和影响。

如何进行自我报告型顺序分析?自我报告型顺序分析是一种复杂的研究方法,需要进行多个步骤的数据处理和分析。

下面将一步一步地介绍自我报告型顺序分析的流程。

1. 设计实验或观察任务:首先,研究人员需要设计一个实验或观察任务,以收集被试者的自我报告数据。

任务可以是实验室内或自然环境中的情境,被试者可以根据任务要求进行自我报告。

2. 数据收集:在实验或观察任务中,被试者需要根据要求进行自我报告。

这些报告可以是定量的,如使用量表进行评估,也可以是定性的,如写下自己的感受和体验。

研究人员需要确保被试者理解任务要求,并按要求进行自我报告。

3. 数据预处理:在进行分析之前,需要对自我报告数据进行预处理。

【精编范文】各种鞋子怎么用英文来翻译-word范文 (4页)

【精编范文】各种鞋子怎么用英文来翻译-word范文 (4页)

本文部分内容来自网络整理,本司不为其真实性负责,如有异议或侵权请及时联系,本司将立即删除!== 本文为word格式,下载后可方便编辑和修改! ==各种鞋子怎么用英文来翻译大家都知道有各种各样的鞋子名称,但就不一定会知道要怎么样用英文形式来翻译这些鞋子的名字了。

一起来看看小编为大家整理收集了用英文形式来翻译各种鞋子吧,欢迎大家阅读!高筒靴的英文形式:wellingtons1. The dog ran, and Mr Taylor's trudging wellingtons made the only sound.茂密的杉树林淹没了从爱丁堡到格拉斯哥高速公路上传来的噪音,只有猎犬发出的声音和泰勒穿着高统靴走路的悉索作响。

2. Only, it seems to me that more and more people consider wearing wellingtons and raincoats `uncool` or `outdated`– maybe there are other reasons, but whenever I wear either on my way to work when it is pouring down, I get a lot of funny looks.只是,越来越多的人认为穿雨衣套鞋很傻很老土。

不知道是因为这个还是有别的原因,总之,每次下雨天我穿着雨衣套鞋走在上班路上,逃不过地会收到许许多多可笑的目光。

3. The city is flooding, so many people have to wear their wellingtons.城市水浸了,很多人穿长筒雨靴。

4. My wellingtons got stuck in a quagmire.我的威灵顿长靴陷在泥坑里。

5. Bomber Command had also been testing sights fitted in the rear turrets of Wellingtons.轰炸机司令部也在真正惠灵顿轰炸机的炮塔上测试了这种瞄准具。

生物信息学 第4章 序列特征分析

生物信息学 第4章 序列特征分析
第四章 序列特征分析
Analysis of Sequence Characterristics
第一节 引言
Section 1 Introduction
一、基因结构
基因的概念是随着遗传学、分子生物学、 生物化学等领域的发展不断完善的。从分子 生物学角度来看,基因是负载特定生物遗传 信息的DNA分子片段,在一定的条件下能 够表达这种遗传信息,产生特定的生理功能。
PromoterScan在线网页
五、密码子偏好性
密码子使用偏性是指生物体中编码同一种氨 基酸的同义密码子的非均匀使用现象。这一现象 的产生与诸多因素有关,如基因的表达水平、翻 译起始效应、基因的碱基组分、某些二核苷酸的 出现频率、G+C含量、基因的长度、tRNA的丰度、 蛋白质的结构及密码子一反密码子间结合能的大 小等。所以对密码子使用偏好性的分析具有重要 的生物学意义。
原核生物基因结构:
一个完整的原核基因结构是从基因的5'端启动子区域开 始,到3'端终止区域结束。基因的转录开始位置由转录起始 位点确定,转录过程直至遇到转录终止位点结束,转录的内 容包括5'端非翻译区、开放阅读框及3'端非翻译区。基因翻 译的准确起止位置由起始密码子和终止密码子决定,翻译的 对象即为介于这两者之间的开放阅读框ORF。
利用GENSCAN识别基因开放阅读框
GENSCAN是美国麻省理工学院的Chris Burge 于1997年开发成功的人类(或脊椎动物)基因预测 软件,它是根据基因组DNA序列来预测开放阅读框 及基因结构信息的开放式在线资源,尤其适用于脊 椎动物、拟南芥和玉米等真核生物。
GENSCAN的网址为: http:///GENSCAN.html
利用CodonW分析密码子偏好性

埃克尔斯,J.C.

埃克尔斯,J.C.

埃克尔斯,J.C.John Carew Eccles (1903~)澳大利亚神经生理学家。

1903年 1月27日生于澳大利亚墨尔本。

1925年在墨尔本大学毕业。

1927~1937年在牛津大学与生理学家C.S.谢灵顿一起工作。

1944~1951年在新西兰奥塔戈大学任教授,1951~1966年在澳大利亚国立大学任教授。

1966年移居美国,1968~1975年在纽约州立大学任教授。

自20世纪30年代起,他即对突触传递的本质──信号如何从一个神经元传到另一个神经元的机理问题进行了研究,是神经元间化学传递观点的倡导者。

他通过在灵长类动物单个神经元内部进行电记录,详细地分析了神经元连接的兴奋、抑制过程。

他还研究了神经系统的其他领域,在了解整个大脑的工作中,发现了大脑如何与小脑在功能上建立联系。

他的这些研究成果都总结在《作为神经机器的小脑》一书中。

他的主要著作有:《神经细胞生理学》、《突触生理学》、《中枢神经系统的抑制途径》、《人体的奥秘》等。

由于他对于神经元连接上兴奋与抑制本质的研究贡献,他与英国生理学家A.L.霍奇金和A.赫胥黎共同获得1963年诺贝尔生理学或医学奖。

埃克尔斯是澳大利亚科学院的创建者和领导人之一,是美国科学艺术学院的外籍院士。

基于双互信息准则的雷达自适应波形设计方法

基于双互信息准则的雷达自适应波形设计方法

基于双互信息准则的雷达自适应波形设计方法辛凤鸣; 汪晋宽; 王彬; 李梅梅【期刊名称】《《东北大学学报(自然科学版)》》【年(卷),期】2019(040)012【总页数】5页(P1690-1694)【关键词】认知雷达; 波形设计; 互信息; 信息熵; 最大边缘分配算法【作者】辛凤鸣; 汪晋宽; 王彬; 李梅梅【作者单位】东北大学秦皇岛分校计算机与通信工程学院河北秦皇岛 066004; 东北大学信息科学与工程学院辽宁沈阳 110819【正文语种】中文【中图分类】TP911.2传统雷达发射固定波形,工作模式单一.随着科技的发展,对雷达性能的要求越来越高,传统雷达难以应对,因此,加拿大学者Haykin提出认知雷达概念[1],认为是未来雷达的发展方向.在认知雷达系统研究中,自适应波形优化是一个关键技术.信息论在波形优化研究中得到广泛应用[2-9].Bell首先将互信息(mutual information, MI)理论应用到雷达自适应波形优化的研究中,利用接收信号与目标冲激响应(target impulse response, TIR)之间的互信息最大为优化准则,通过拉格朗日乘数法求解优化波形[2].文献[3]针对多目标估计任务,通过对各个目标特征互信息线性加权方法实现波形优化.Goodman团队在互信息基础上发表了一系列波形优化论文[4-7],其思想是在接收信号与TIR之间互信息最大作为优化准则的基础上,通过序贯概率比检验(sequential probability ratio test, SPRT)对目标特征进行加权优化发射波形.在文献[8]中,作者针对目标检测任务,通过最大化Kullback-Leibler divergence(KLD)作为准则优化发射波形,同时推导出KLD,MI和SNR之间的关系.文献[9]首先利用卡尔曼滤波设计优化波形使TIR估计误差最小,然后根据相邻两次接收回波信号不相关特点,通过两次回波信号之间的互信息最小作为优化准则选择最优波形.根据以上分析,基于互信息准则的波形优化方法主要通过接收信号中目标信息量最大化或者不相关参量互信息最小化作为单一的优化准则优化发射波形.本文提出基于双互信息准则优化发射波形,即:接收信号与TIR之间的互信息最大,同时接收信号与杂波冲激响应(clutter impulse response, CIR)之间互信息最小作为波形优化准则建立优化模型,通过最大边缘分配(maximum marginal allocation, MMA)算法求解最优波形,与传统雷达发射固定波形相比能够提高目标检测性能.1 信号模型及互信息1.1信号模型图1为杂波环境下雷达接收信号模型,其中x(t)为发射信号;h(t)代表目标冲激响应,其为均值为0,功率谱密度为的高斯随机过程;c(t)代表杂波冲激响应,其为均值为0,功率谱密度为的高斯随机过程;n(t)为均值为0,方差为的高斯白噪声;y(t)为接收信号.接收信号可以表示为y(t)=ys(t)+yd(t)+n(t)=x(t)*h(t)+x(t)*c(t)+n(t) .(1)其中:ys(t)=x(t)*h(t);yd(t)=x(t)*c(t).图1 杂波环境下雷达信号模型Fig.1 Signal model in the clutter environment 1.2 互信息在很小的频率间隔Fk=[fk,fk+Δf]内,当带宽Δf足够小时,对于所有的f∈Fk,有X(f)≈X(fk),Ys(f)≈Ys(fk),Yd(f)≈Yd(fk)和Y(f)≈Y(fk).X(f),Ys(f),Y d(f)和Y(f)分别为x(t),ys(t),yd(t)和y(t)的傅里叶变换.令和分别是在频域间隔Fk内与x(t),ys(t),yd(t)和y(t) 相对应的部分.在每一个频点内和的方差可以表示为[2](2)(3)式中Ty为接收信号时间长度.由式(1)可知,接收信号是3个零均值的高斯随机变量之和,所以接收信号方差为(4)在频点fk上,接收信号与目标回波信号之间的互信息在给定发射信号的情况下可以表示为(5)式中:I( · )代表互信息;H( · )代表信息熵.根据信息熵的定义,由式(2)~(4)可知(6)将式(6)和式(7)代入式(5)中,在观测时长Ty内有[2](8)考虑在整个信号频带内,通过极限思想,时域上接收信号与目标冲激响应之间的互信息可以通过频域表示为[2]IT(y(t);h(t)|x(t))=(9)2 波形优化2.1波形优化模型建立由式(1)可知,雷达接收信号包括两部分:含有目标信息的回波信号x(t)*h(t);含有杂波和噪声的干扰信息x(t)*c(t)+n(t).为了提高雷达系统性能,接收端希望接收信号含有目标信息量越多越好,同时含有的干扰信息量越少越好.因此,波形优化准则为:在给定发射信号情况下,接收信号与目标冲激响应之间的互信息最大,同时接收信号与杂波冲激响应之间的互信息最小,准则函数的数学表达式为(10)式中IC( · )为接收信号与CIR之间的互信息.准则函数(10)等效为(11)与IT(y(t);h(t)|x(t))推导类似,接收信号与CIR之间的互信息可以表示为IC(y(t);c(t)|x(t))=将式(9)与式(12)代入式(11)中,得优化准则数学表达式为(13)在发射信号能量Ex约束下,波形优化模型为(14)当杂波不存在时,即优化模型(14)与文献[2]中的优化模型相同.2.2 MMA算法求解优化波形当杂波不存在时,优化模型(14)可以通过拉格朗日乘数法求解[2],而当杂波存在时,使用拉格朗日乘数法求解困难,因此采用MMA算法求解最优波形,首先将优化模型(14)离散化:(15)令u(k)=|X(fk)|2,(16)(17)(18)将式(16)~(18)代入式(15)中,有对于波形优化问题,可以转化为在Ex/Δfk=umax约束下,寻求的最大化,其中(20)将umax=Ex/Δfk平均分为P份,有PΔ=umax,Δ称为最小能量分配单元,在算法的每一步分配Δ单位的能量,直到PΔ的能量分配完为止.在第一步中,如果L(u(j),j)>L(u(k),k),j≠k,则令u(j)=Δ,然后重复该步骤,直到选择分配下一个Δ到产生式(21)最大的k值,或者产生最大边缘增长的k值.{L(Δ,0),L(Δ,1),…,L(Δ,j-1),L(2Δ,j)-L(Δ,j),L(Δ,j+1),…,L(Δ,N)}.(21)由于在第1步中已经将Δ分配到k=j处,此时边缘增长为L(2Δ,j)-L(Δ,j),即能量分配从Δ增加到2Δ,对于其他k值,边缘增长也是相同情况,整个过程直到即能量全部分配完毕[10].为了更好理解MMA算法,举例说明,令N=3,u(1)+u(2)+u(3)=umax=4,Δ=1.希望(22)达到最大,在总能量为4的情况下,可以将0Δ,1Δ,2Δ,3Δ或者4Δ能量单位分配给u(1),u(2)或者u(3).表1为初始分配能量时L(u(k),k)可能的值.初始分配能量Δ=1时,对于k=1,2,3,L(u(k),k)的值分别为0.287 7,0.223 1和0.182 3,最大值为0.287 7,所以第一步时,Δ单位能量分配给k=1处.第一次能量分配后,产生新的边缘能量,见表2,新的边缘能量分别为0.048 8,0.223 1和0.182 3.最大值为0.223 1,因此Δ单位能量分配给k=2处.按照相同的原理,第二次分配后见表3,最后一次能量分配后见表4.表5总结了最终的能量分配情况,即u(1)=Δ,u(2)=2Δ,u(3)=Δ.表1 不同u(k)对应的L(u(k),k)值Table 1 Values of L(u(k),k) for various values ofu(k)u(k)k=1k=2k=3u(k)=40.36770.33650.2513u(k)=30.35670.31850.2412u( k)=20.33650.28770.2231u(k)=10.28770.22310.1823u(k)=0000表2 第一次分配后不同的u(k)对应的L(u(k),k)的边缘值Table 2 Values ofL(u(k),k) for various values ofu(k) after 1stallocationu(k)k=1k=2k=3u(k)=40.33650.2513u(k)=30.080.31850.2412u(k)= 20.0690.28770.2231u(k)=10.04880.22310.1823u(k)=0000表3 第二次分配后不同的u(k)对应的L(u(k),k)的边缘值Table 3 Values ofL(u(k),k) for various values ofu(k) after 2ndallocationu(k)k=1k=2k=3u(k)=40.2513u(k)=30.080.11340.2412u(k)=20.069 0.09540.2231u(k)=10.04880.06460.1823u(k)=0000表4 第三次分配后不同的u(k)对应的L(u(k),k)的边缘值Table 4 Values ofL(u(k),k) for various values ofu(k) after 3rdallocationu(k)k=1k=2k=3u(k)=4u(k)=30.080.11340.069u(k)=20.0690.09540. 0589u(k)=10.04880.06460.0408u(k)=0000表5 最终能量分配Table 5 Final allocation ofenergiesStepk=1k=2k=3D1Δ0.28772Δ0.51083Δ0.69314Δ0.7577最终分配Δ2ΔΔ3 仿真实验及分析假设发射信号能量Ex=10(能量单位),噪声功率谱密度杂波噪声功率比(clutter-to-noise ratio, CNR)CNR=12.9 dB,目标噪声功率比(target-to-noise ratio, TNR)TNR=-5.39 dB.目标谱与杂波谱如图2所示.基于双互信息准则的优化波形能量谱如图3所示,优化波形的主要特点:图2 目标谱与杂波谱Fig. 2 The target PSD and clutter PSD图3 基于双互信息准则的优化波形能量谱Fig. 3 Optimal waveform based on dual MI criterion1) 优化波形将主要能量集中分配给目标特征谱强度大的频带内,虽然目标频谱关于0频率点左右对称,然而由于杂波在频带(-0.5,0)范围内的强度小于(0,0.5)频带内的强度,因此优化波形将能量更多地分配给(-0.5,0)频带内目标频谱强度大的两个频段.2) 由于算法考虑了接收信号与杂波之间互信息最小因素,因此优化波形将能量仅仅分配给目标频谱强度大于杂波频谱的频带,当杂波强度大于目标强度时,即使在某频带内目标特征很强,优化波形也不会分配能量.以线性调频信号(LFM)波形作为对比波形,优化波形的检测性能曲线如图4所示.从图中可以看到优化波形的检测性能在不同的恒虚警概率下始终好于固定LFM波形的检测性能,这是由于优化波形能够将能量分配给目标频谱特征强的频带内,使目标特征获得更多的能量,增加了接收信号的SINR从而提高目标检测性能.图4 目标检测性能Fig.4 Probability of target detection4 结语本文提出了一种基于双互信息准则的波形优化方法,该方法考虑接收信号与目标之间互信息最大同时,还考虑接收信号与杂波之间互信息最小,以此作为优化准则,在能量约束下建立优化模型.所提方法的优化波形可将发射能量分配给目标特征强,且目标特征强于杂波特征的频带内,与固定发射波形相比,提高了目标检测性能. 参考文献:【相关文献】[1] Haykin S.Cognitive radar:a way of the future[J].IEEE Signal ProcessingMagazine,2006,23 (1):30-40.[2] Bell M rmation theory and radar waveform design[J].IEEE Transactions on Information Theory,1993,39(5):1578-1597.[3] Leshem A,Naparstek O,Nehorai rmation theoretic adaptive radarwaveform[J].IEEE Journal of Selected Topics in Signal Processing,2007,1(1):42-55.[4] Goodman N A,Venkata P R,Neifeld M A.Adaptive waveform design and sequential hypothesis testing for target recognition with active sensors[J].IEEE Journal of Selected Topics in Signal Processing,2007,1(1):105-113.[5] Romero R A,Goodman N A.Waveform design in signal-dependent interference and application to target recognition with multiple transmissions[J].IET Radar Sonar and Navigation,2009 3(4):328-340.[6] Romero R A,Bae J,Goodman N A.Theory and application of SNR and mutual information matched illumination waveform[J].IEEE Transactions on Aerospace and Electronic Systems,2011,47(2):912-927.[7] Kim H S,Goodman N A,Lee G K,et al.Improved waveform design for radar target classification[J].IET Electronics Letters,2017,53(13):879-881.[8] Zhu Z,Kay S,Raghavan R rmation-theoretic optimal radar waveform design[J].IEEE Signal Processing Letters,2017,24(3):274-278.[9] Yao Y,Zhao J,Wu L.Cognitive radar waveform optimization based on mutual information and Kalman filtering[J].Entropy,2018,20(9):653-666.[10]Kay S.Waveform design for multistatic radar detection[J].IEEE Transactions on Aerospace and Electronic Systems,2009,45(3):1153-1165.。

比较基因组学分析uas基序

比较基因组学分析uas基序

比较基因组学分析uas基序
比较基因组学简介人类基因组计划的实施(The Human Genome Project)开启了基因组时代。

随着测序技术的不断进步和测序成本的下降,越来越多的物种基因组被测序,随着原核生物以及真核生物等各种不同物种基因组数据的产生以及研究的深入,开阔了人类对物种进化及生命之树认识的眼界,推动了物种间的比较基因组学的研究。

比较基因组学(Comparative genomics)是基于基因组图谱和测序技术,对一个物种的多个个体(群体)基因组或多个物种基因组的结构和功能基因区域进行比较分析。

基因组的结构和功能基因区域主要包括DNA序列,基因,基因家族,基因排序,调控序列,和其它的基因组结构标志。

比较基因组学分析,具体来讲就是借助生物信息学的方法通过对多个物种的基因组结构特征进行比较,找出其中的的异同。

进而研究物种间基因家族收缩与扩张,分化时间和演化关系,以及新基因的产生与进化等。

比较基因组学分析usa内容:比较基因组学分析usa通过比较多物种蛋白序列或者基因位置与相对顺序,包括基因的丢失、复制、水平转移等。

鉴定物种之间保守的基因(找物种相似之处),或者某个生物自身特有的基因(找物种不同之处),旨在阐释物种多样性的分子遗传基础。

1、基因家族聚类分析
2、查找直系同源基因
3、系统进化分析
4、物种分歧时间的估算分析
5、鉴定基因融合与基因簇
6、信号通路基因簇重构
7、基因家族收缩与扩张
8、全基因组复制事件分析
9、全基因组共线性比较。

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Comparative Analysis of Sequential Circuit Test Generation ApproachesJ. Raik, A. Krivenko, R. UbarDepartment of Computer Engineering, TTU, Raja 15, 12618 Tallinn, Estonia, E-mail: jaan@pld.ttu.eeABSTRACT: Current paper presents a comparative study of popular test pattern generation approaches based on three tools: a genetic algorithm test generator GATEST, a deterministic logic-level tool HITEC and a hierarchical tool DECIDER. The main reason for this study was to find out, which fault types are likely to be covered by different approaches. Additional motivation for the work was to find guidelines for improving the fault models implemented in the hierarchical test pattern generator DECIDER, which is being developed at TTU.1 IntroductionSeveral approaches to generating tests for structural faults in sequential circuits have been proposed over the years. However, the problem still lacks a commonly accepted solution. At the gate-level, a number of deterministic test generation tools, both academic [1, 2] and commercial, have been implemented. However, the bottom-line is that none of these methods can efficiently handle sequential designs of even a couple of thousands of gates. With the further growth of the circuit size fault coverages tend to drop while run times increase exponentially.Better performance has been generally obtained with simulation-based approaches. Here, genetic algorithm based methods have been widely used [3, 4]. Recently, efficient results have been obtained by spectral methods [5]. The approaches belonging to this class are fast for smaller circuits only but become ineffective when number of primary inputs and the sequential depth of the circuit increase.Several works on functional test generation have been published in the past [6, 7]. In this field, an efficient technique based on BDD manipulation of data domain partitions has been proposed [8]. However, the main principal shortcoming of the approaches that rely on functional fault models only is that they cannot guarantee satisfactory structural level fault coverages.Hierarchical automatic test pattern generation (ATPG) has been a promising alternative to tackle complex sequential circuits for already more than a decade. In hierarchical testing, top-down and bottom-up strategies are known. In the bottom-up approach [9], tests generated at the lower level will be later assembled at the higher abstraction level. Such algorithms ignore the incompleteness problem: constraints imposed by other modules and/or the network structure may prevent test vectors from being assembled. Thus, while being fast, this type of approach is not really applicable for sequential circuits with difficult to test feedback loops. The method considered in current paper relies on the top-down approach [10], where constraints are extracted at the higher level with the goal to be considered when deriving tests for modules at the lower level.In this paper we have compared three test pattern generation tools: a genetic algorithm test generator GATEST [3], a deterministic logic-level tool HITEC [1] and a hierarchical tool DECIDER [10]. The first two are popular public domain programs from University of Illinois. The latter is a software developed at Tallinn TU. Table 1. shows the comparison of fault coverages and run times achieved by each of the tools. As we can see from the Table, DECIDER (the hierarchical ATPG) is the most efficient tool with 88.9 % average fault cover and short run times, followed by GATEST (genetic algorithms) with 87.9 % and HITEC (deterministic) with 76.9 % coverage.Table 1. Comparison of sequential circuit test generation toolscircuit faults HITEC GATEST DECIDER TotalF.C., % time, s F.C., % time, s F.C., % time, s F.C., %gcd 454 81.1 169.5 91.0 75 89.9 129.8 91.7sosq 1938 77.3 728.4 79.9 739 80.1 129.6 80.3mult8x8 2036 65.9 1243 69.2 821.6 74.7 93.7 74.8ellipf 5388 87.9 2090 94.7 6229 95.04 1258.9 95.06risc 6434 52.8 49,020 96.0 2459 96.5 150.5 96.7diffeq 10,008 96.2 13,320 96.40 3000 97.09 453.7 97.20 average F.C.: 76.9 87.9 88.989.3However, the goal of the paper is not to compare the absolute results of the tools, which has been done in earlier works [10], but to find out, what regions of the circuit space are covered by the tools implementing completely different approaches. Our study reveals a number of facts previously not known about the capabilities of test tools. For example, what we noticed isthat although genetic algorithm based tool performed well on the absolute scale, it contributed little if any new faults to the two remaining tools. Also, the hierarchical test pattern generator achieves highest results for five out of six benchmark circuits but it is still far from the combined fault coverage of the three tools summed. The combined results are presented in the last column of Table 1.The paper is organized as follows. Section 2 explains the register-transfer level view to synchronous sequential circuits. Section 3 presents the comparative experiments showing the circuit regions covered by each of the tools. Finally, Conclusions are given. Fig. 1. RT-level view of a digital circuit 2 Register-transfer level view to circuitsAt the RT-level, the design is assumed to be partitionedinto a datapath and a control part. Figure 1 shows this type of architecture. Here, the control part is a Finite State Machine (FSM) with a state register (represented by variable x S in the corresponding DD model), next state logic and output logic. As input signals to the FSM are the primary inputs of the design (variables x I ), status bits originating from the datapath (variables x N ) and the previous value of the state variable x S . Outputs of the FSM are the primary outputs of the design (variables x O ), control signals (variables x C ) and currentt value of x S . not be a criterion in selection of the papers for the program. The deterministic ATPG HITEC and genetic algorithm based tool GATEST rely on logic gate-level descriptions of the circuit. However, DECIDER takes advantage of the RT-level structure as well. A combination of three fault models is implemented in thehierarchical tool. These include a hierarchical fault model for Functional Units (FU), a functional model for multiplexers and a combined hierarchical-functional model for conditional operations. Circuit areas targeted by each of the above models are marked in Fig. 1 by grey circles.As we can see from the Figure, the set of fault models implemented in the hierarchical ATPG cover a large part of the design. However, a portion of the control part FSM is not targeted by the hierarchical fault models. The study presented in the following Section confirms that the fault covering probabilities of the hierarchical ATPG DECIDER in FSMs are low. 3 Comparative study of the ATPGs In current study we compared three test generators on six different sequential circuit benchmarks. We examined the fault space covered by different generators in order to determine the sets of overlappings between the tools. We in type of the circuit modules (functional units,For the experiments the following benchmark circuits gcd is a greatest common divisor circuit, is a 8-bit multiplier, diffeq is a circuit equation calculation sosq implements sum of squares, risc is an ALU-microprocessor, ellipf is a DSP circuit Gcd , ellipf and diffeq[12]. Table 1 benchmarks byThe fault list sizes for the circuits are second column of the Table. Theexperiments were run on a 366 MHz SUN UltraSPARC60 server with 512 MB RAM under SOLARIS 2.8 operating system.Figures 2 and 3 give a more detailed look to the test results of Table 1. Figure 2 shows overlappings of the faults covered by the three generators for the six example circuits. Here, “hierarchical” denotes the ATPG DECIDER [10], “genetic” stands for GATEST [3] and “deterministic” is for HITEC [1]. The most important observations we can make basing on Figure 2 are the following:1. While experiments in Table 1 indicate that DECIDERgives in most cases the highest fault coverage, we can see that there are some unique portions of faults covered by GATEST and HITEC.In fact, the union of the sets of faults covered by the three test generators gives a fault coverage that is in average 0.4 (!) per cent higher than the average fault cover of DECIDER.hierarchical genetic deterministic 79.3 % 0 % 0 %0.7 %1.8% 0 %9.9 % GCD:hierarchical genetic deterministic95.9 %0.08 % 0 %0.5 %0.03 % 0.2 %0.46 %DIFFEQ: hierarchicalgeneticdeterministic87.7 %0.02 % 0 %0.19 % 0 % 0.13%7.0 %ELLIPF: hierarchical genetic deterministic 75.5 %0.2 % 0 %0.2 %0 % 0 %4.4 %SOSQ:hierarchicalgenetic deterministic52.7 %0 % 0.06% 0.73%0.15 %0 %43 %RISC:hierarchical genetic deterministic 62.2 %0.05 % 0.1 %2.7 %0 % 3.6 %6.2 %MULT8x8:Fig. 2. Portions of faults detected by hierarchical, genetic and deterministic ATPGshierarchical geneticdeterministic 756 ‰0.6 ‰ 0.4 ‰8.3 ‰3.2‰ 6.5 ‰119 ‰ Total:hierarchical genetic deterministic48 ‰0.42 ‰ 0.16‰0.16‰3.0‰ 0.4 ‰1.8 ‰FSM:hierarchicalgeneticdeterministic178 ‰0.08 ‰ 0 ‰0.48‰ 0.13‰1.4 ‰8.1 ‰Register: hierarchical genetic deterministic 450 ‰0 ‰ 0 ‰5.4‰0‰ 2.0 ‰82 ‰Functional unit: hierarchical genetic deterministic120 ‰0 ‰ 0.1‰1.5‰0.07‰2.1 ‰19.1‰MUX:hierarchical genetic deterministic 21 ‰0.07 ‰ 0 ‰0.6‰0 ‰0.07‰ 6.7 ‰Comparison:Fig. 3. Coverage of circuit regions for the three test generators2. Table 1 also shows that GATEST performs well interms of the absolute fault coverage numbers.However, it fails to detect nearly any unique faults.If we look at Figure 2, it can be seen that the genetic tool GATEST does not provide any new unique faults at all for four out of six benchmarks: gcd, sosq, ellipf, diffeq. HITEC, whose fault coverage numbers are roughly 11 per cent lower than GATEST’s, detects much higher number of unique faults.This leads to a conclusion that there are many ‘hard-to-test’ random pattern resistant faults that GATEST as a simulation-based method is not capable of detecting. While deterministic methods are known to have difficulties with larger sequential designs they could still provide useful addition in terms of detecting hard-to-test faults.Figure 3 presents the distribution of achieved fault coverages by module types. Five different types are distinguished: functional unit, comparison operation, MUX, register and control part FSM. ‘Total’ denotes the summed result for the whole circuit. In the Figure, average values for the set of six circuits are shown.One of the conclusions that can be made based on Figure 3 is that DECIDER covers well the faults in functional units, comparison operators and MUXs. These are the modules it explicitly tests (See the grey circles Figure 1!). However, control part FSM is poorly covered by the hierarchical tool. This means that fault models for testing control part could be useful improvement to the tool in the future.4 Conclusions and future workA comparative study of popular test pattern generation approaches based on three tools: a genetic algorithm test generator GATEST, a deterministic logic-level tool HITEC and a hierarchical tool DECIDER is presented. Experiments on a set of six sequential benchmark circuits lead to the following conclusions:− While genetic algorithm based tool performs well in terms of the absolute fault coverage numbers, it fails to detect nearly any unique faults.− Deterministic tool has difficulties with larger sequential designs but it is capable of detecting a portion of hard-to-test faults.− The union of the sets of faults covered by the three test generators has a fault coverage that is in average0.4 per cent higher than the fault cover of the besttool in the comparison: DECIDER.− DECIDER loses fault coverage mainly in the control part FSM.The analysis carried out will be helpful for further development of the hierarchical ATPG DECIDER. Moreover, the authors hope that the results presented here could give valuable guidelines for the developers of future test pattern generators in general. 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