A Ternary Protein State Network Study And Its Application In Regulatory Strategies For Non-small Cell Lung Cancer

The current focus of biomedical research is mainly on the level of biological entities such as genes,proteins and small biological molecules.Since the implementation of the Genome Project,the structure and function of a large number of biological entities(genes,proteins,etc.)have been widely studied,but no breakthrough treatment plan has been brought to the treatment of complex diseases.As the research on biological entities has become more and more in-depth and related data has become more and more abundant,in 2004,Network Biology,which uses the tools and methods of graph theory to represent and analyze biological systems,was proposed.Biological networks based on biological entities provide unforeseen possibilities for understanding the relationships between entities within cells and the biological functions of cells,making people realize that although a single molecule is important,but the cell functions are determined by the system in which countless biological entities interact.However,the research based on biological entity network has not revolutionized the treatment of complex diseases.This study believes that the previous biological research focused on the biological entity level,while the treatment of disease focused on the state level,which is one of the reasons for this phenomenon.For example,in the textbook of physiology and pathology,the definition of disease is the deviation from homeostasis,and the state of disease is also a kind of steady state between normal state and death state,and the deviation value from homeostasis is used as the index of disease diagnosis.The goal of disease treatment is to adjust the patient back to the normal state or prevent the patient from transforming into the death state.It can be seen that the basic experimental research is mainly focused on biological entities,such as genes,proteins,transcription factors,messenger RNA,etc.While clinical treatment takes the regulation of patients' biological system state as the standard,and the lack of direct transformation between biological entities and systematic states is an important reason why many experimental studies can not be directly applied to clinical treatment.In this study,aiming at the logical fracture between biological entity research and disease state,a physical state network is proposed to analyze biological entity state directly.This study mainly includes the following four aspects.1.Definition of Entity State NetworkAn entity states network(ESN)is a quintuple,ESN=(VN,VT,F,P,S):(1)VN=VN1?VN2?VN3,VN is a finite set of nonterminal symbols.VN1 is the variable "entity name(ID)",that is,VN1={"entity name"},VN2 is a finite set of other entity variables except the variable "entity name",and VN3 is a finite set of units of entity variables;(2)VT=VT1?VT2?VT3,VT is a finite set of terminal symbols,VT1 is a finite set of values of"entity name",VT2 is a finite set of values of entity variables except "entity name",VT3 is a finite set of units of entity variables,and VN ?VT=?;(3)F is a finite set of options,F={fi|fi:(E(V,F)n?E(V,F),1?i?m,m?N,n?N},where V=VN?VT;(4)P is a finite set of productions ??? with ??E+(V,F)and ??E(V,F),the productions are used in the parallel manner;(5)S is the start entities.The entity state network expresses the entity state through the relevant data of the entity,and takes the state of the entity that constitutes the system as the node of the network,transforming the research object of the biological network from the entity level to the state level.The entity state network has the following three characteristics:(1)The entity state network is a directed network,the nodes in the state network are entity states,and the edges in the network represent the transformation direction of the states;(2)The state network can dynamically display the state change direction of the system,and it is convenient to analyze the state and state change of the system;(3)the entity state network is composed of all the entities and all the states of the entities that make up the system,so the state network can represent all the states of the system.2.Construction of Entity State NetworkIn this study,on the basis of the binary state "0" for "down-regulation(low)" and "1" for"up-regulation(high)",the third-value state "1/2" is introduced to represent the "normal" state.According to the state rules of binary multi-node regulation of Boolean networks,the ternary state transformation rules of multi-node regulation are derived.According to the number of nodes upstream,the corresponding state network structure is different.When there is only one node upstream in the entity relation network,the corresponding state network structure of the node is a single layer structure,and there are only state nodes in the network;When there are multiple nodes regulating upstream of the node in the entity relation network,the corresponding state network structure of the node is double structure,one layer is the state node,the other layer is the state transition node,and the two work together to complete the entity state transformation under the specific system state condition.Generally,there are four steps to build a system's entity state network:The first step is to determine the entities of the system and the relationships among them,and build a network of entity relations;The second step is to construct the entity state system and determine the specific contents of V,F,P and S in the entity state system.The third step,through the reasoning of the constructed entity state system to get the transformation relationship between states,to form the entity state network;The fourth step,network visualization.3.Steady-state analysis method of ESNIn this study,two methods for analyzing the steady state of the state network are proposed,one is to reason the given system state through the state reasoning system,and the other is to find out the steady state of the system by analyzing the ring structure in the state network.(1)By constructing the state reasoning system,the state change of the system can be obtained without going through the state network diagram,which is suitable for the situation when the structure of the state network diagram is complex,and the steady state of the system can be analyzed.(2)In the steady-state analysis of the ring structure of the state network,the state of the system can be reasonably distributed on the ring structure,and then the state reasoning can be carried out according to the direction of state transformation.As long as there is a ring structure in the state network,the ring structure must contain the steady state of the system.Because the ring structure in the state network always returns to that point from a certain point through the edge of the network,that is to say,the state of the system must undergo periodic changes,so the system generally has multistability at the ring structure;in particular,when the values of the states in the ring structure are consistent,that is,all "1",all "1/2" or all "0",the system is in monostable state.The ring structure in the state network represents two cases of the system state,one is the normal steady state,the other is the completely abnormal steady state,and the steady state between the two ring structures is the transition steady state,that is,the normal steady state can transition to the completely abnormal steady state through the transition steady state,and vice versa,which provides the basis for the state regulation of the system based on the state network.4.Three-value ESN analysis of non-small cell lung cancerThis chapter constructs the ERN(entity relationship network)and the three-value ESN(entity state network)of NCLC(non-small cell lung cancer).A graph search method based on graph theory was used to search the positive feedback and negative feedback loops in the ERN of non-small cell lung cancer,and the state inference system was used to calculate the system state transition map(attractor landscape)for NCLC.Then the steady states were analyzed.The ESN is a directed network that characterizes the system state and state changes based on experimental data.This study provides the construction of a biological network from a state perspective,and a direct analysis of non-small cell lung cancer from the state level,which provides certain guidance for the evolution of non-small cell lung cancer.In summary,in order to promote the transformation of experimental research to clinical disease treatment,this research puts forward the concept of entity state network,which can use experimental data to describe the state of the system and the path of state changes.This study introduces the third value "1/2" on the basis of the binary state values "0" and "1" to describe the normal state of the entity,and gives the transition rules for the three-valued state in the state network.Finally,this research discusses the construction method and analysis method of the state network.This research provides the construction of a biological network from the perspective of the state,and the direct analysis of the biological system from the state level,which provides certain guidance for the evolution of the state of systemic diseases.