AMCB: A software toolkit for construction and analysis of Aggregate Maps in Cell Biology

细胞核是哺乳动物细胞的主要组成部分，携带着大量的遗传物质，并调节着细胞的许多方面。细胞核是一个非常复杂的实体，在细胞的整个生命周期中经历着动态的变化。细胞生物学的研究对于充分理解这个生命基本单位的基本运作至关重要。反过来，这种理解转化为对许多疾病的洞察力，以及诊断标志物甚至治愈方法的遥远前景。除了遗传物质，细胞核还包含大量其他对正常运作至关重要的分子机制。检查适当准备的细胞核显微镜图像揭示了一个复杂的安排功能的对象，实例化这一机制。这些物体，通常是点状的，似乎随机散布在细胞核内。然而，对多个原子核的仔细检查和定量分析表明，这些物体的散射虽然是随机的，但似乎遵循微妙的规则。这些观察结果提供了一个诱人的建议，即核的组成部分的空间布局，部分地，以反映其功能作用的方式定位。然而，现有的分析工具通常是基于空间偏好的相对评估。例如，观察到一种类型的功能对象非常接近不同类型的功能对象。这种分析足以说明特定功能对象之间的关系，但不能提供有关核内对象的绝对空间偏好的信息。这项研究将提供新的数据分析方法，明确解决这一缺陷。基本的假设是，有一些绝对的空间组织，可以通过一种新颖的方式检查多个核图像来捕获。这种新的方法包括从统计形状分析领域的数学变换的集合。这些变换首先从多个图像中找到细胞核的平均形状，然后使用特殊的数学变形来迫使每个细胞核及其内部成为平均形状。通过这种方式，所有的原子核都被放置在一个共同的坐标系中，这意味着可以分析绝对的空间偏好。公共坐标系中的数据集合称为聚合地图（AM）。AM的分析和可视化提供了关于空间结构的全新见解，并为分析扰动细胞提供了很好的机会。需要一些研究步骤来开发这种方法，用于分析三维共焦显微镜图像，包括一个非常彻底的评估阶段。在完成这项研究后，我们将发布AMCB，一个用于构建和分析聚合地图的软件工具。这将使世界各地的细胞生物学研究人员能够朝着虚拟细胞核的全功能模型的最终终点迈进，并揭示其功能组织的基本原理。

Nuclear biology is concerned with understanding the construction and operation of the cell nucleus, a major component of mammalian cells, which carries the bulk of the genetic material and regulates many aspects of cellular operation.The cell nucleus is an incredibly complex entity which undergo dynamic changes throughout the cell's lifecycle. Research in cell biology is crucial to fully understand the basic operation of this fundamental unit of life. In turn, this understanding translates into insight about a host of diseases, and the distant promise of diagnostic markers and even cures. In addition to genetic material, the nucleus contains a great deal of other molecular machinery that is crucial for normal operation. Examining suitably prepared microscopy images of the nucleus reveals a complex arrangement of functional objects that instantiate this machinery. These objects, often punctate, appear to scatter randomly inside nucleus. However, close inspection of multiple nuclei and quantitative analysis suggest that the scattering of these objects, while stochastic, appears to follow subtle rules. These observations provide that tantalising suggestion that the spatial layout of the components of the nucleus are, in part, positioned in a manner that reflects their functional roles. However, existing analysis tools are typically based on a relative assessment of spatial preference. For example, functional objects of one type are observed in close proximity to functional objects of a different type. Such analysis is adequate for making statements about the relationship between the specific functional objects, but provides no information about the absolute spatial preference of the objects within the nucleus. This research will provide new data analysis methodology that will explicitly address this shortcoming. The fundamental hypothesis is that there is some absolute spatial organisation that can be captured by examining multiple nuclear images in a novel way. This novel approach consists of a collection of mathematical transformations from the area of statistical shape analysis. These transformations first find the average shape of the nucleus from multiple images, and then use a special mathematical deformation to force each nucleus and it interior into the average shape. In this way, all nuclei are placed in a common coordinate system, which means analysis of absolute spatial preference is possible. The collection of data in the common coordinate system is called an aggregate map (AM). Analysis and visualisation of the AM provides completely new insights about spatial architecture, and offers great opportunities for analysis of perturbed cells. A number of research steps are required to develop this methodology for analysis of 3-dimensional confocal microscopy images, including a very thorough evaluation phase. On completion of this research, we will release AMCB, a software tool for constructing and analysing aggregate maps. This will allow cell biology researchers worldwide to move towards the ultimate end point of a fully functioning model of a virtual cell nucleus and to uncover the basic principles underlying its functional organisation.