论文标题
逐步的目标可控性确定多发性硬化症中巨噬细胞网络的失调途径
Step-wise target controllability identifies dysregulated pathways of macrophage networks in multiple sclerosis
论文作者
论文摘要
确定有可能影响网络状态的节点对于许多复杂系统来说是一个相关问题。在许多应用中,通常必须测试单个节点控制网络特定目标子集的能力。在生物网络中,这可能提供有关单个基因如何调节细胞中特定分子的表达的宝贵信息。考虑到这些约束,我们提出了一种基于卡尔曼等级条件的优化启发式,以量化节点的中心性作为它可以控制的目标节点的数量。通过在目标集合中的节点之间引入层次结构,并进行逐步研究,我们确保稀疏和有向网络可以在显着降低的空间和时间复杂性中识别可控制的驱动程序目标配置。我们展示了该方法如何用于简单的网络配置,然后使用它来表征与多发性硬化症患者中与巨噬细胞功能障碍相关的分子基因网络中的炎症途径。结果表明,靶向的分子通常可以由参与不同细胞功能的大量驱动节点(51%)控制,即感应,信号和转录。但是,在炎症反应期间,只有从人类血液样本获得的基因表达数据测量的所有可能的驱动因子对中的中等部分是显着共激活的。值得注意的是,它们在多发性硬化症患者和健康对照组之间有所不同,我们发现这与可控制的步道沿着失调的基因存在有关。我们的方法(我们命名逐步目标可控性)代表了一种实用解决方案,可以在有导的复杂网络中识别可控制的驱动程序目标配置,并从功能上的角度测试其相关性。
Identifying the nodes that have the potential to influence the state of a network is a relevant question for many complex systems. In many applications it is often essential to test the ability of an individual node to control a specific target subset of the network. In biological networks, this might provide precious information on how single genes regulate the expression of specific groups of molecules in the cell. Taking into account these constraints, we propose an optimized heuristic based on the Kalman rank condition to quantify the centrality of a node as the number of target nodes it can control. By introducing a hierarchy among the nodes in the target set, and performing a step-wise research, we ensure for sparse and directed networks the identification of a controllable driver-target configuration in a significantly reduced space and time complexity. We show how the method works for simple network configurations, then we use it to characterize the inflammatory pathways in molecular gene networks associated with macrophage dysfunction in patients with multiple sclerosis. Results indicate that the targeted secreted molecules can in general be controlled by a large number of driver nodes (51%) involved in different cell functions, i.e. sensing, signaling and transcription. However, during the inflammatory response only a moderate fraction of all the possible driver-target pairs are significantly coactivated, as measured by gene expression data obtained from human blood samples. Notably, they differ between multiple sclerosis patients and healthy controls, and we find that this is related to the presence of dysregulated genes along the controllable walks. Our method, that we name step-wise target controllability, represents a practical solution to identify controllable driver-target configurations in directed complex networks and test their relevance from a functional perspective.