N G van Kampen 1981 Amsterdam: North-Holland xiv + 419 pp price Dfl 180 This is a book which, at a lower price, could be expected to become an essential part of the library of every physical scientist concerned with problems involving fluctuations and stochastic processes, as well as those who just enjoy a beautifully written book. It provides an extensive graduate-level introduction which is clear, cautious, interesting and readable.

https://iopscience.iop.org/article/10.1088/0031-9112/34/4/040/pdf

Stochastic Processes in Physics and Chemistry

https://www.linkgroup.hu/docs/13PharmTher.pdf

Structure and dynamics of molecular networks: A novel paradigm of drug discovery: A comprehensive review

A reflection of our ultimate understanding of a complex system is our ability to control its behavior. Typically, control has multiple prerequisites: It requires an accurate map of the network that governs the interactions between the system's components, a quantitative description of the dynamical laws that govern the temporal behavior of each component, and an ability to influence the state and temporal behavior of a selected subset of the components. With deep roots in nonlinear dynamics and control theory, notions of control and controllability have taken a new life recently in the study of complex networks, inspiring several fundamental questions: What are the control principles of complex systems? How do networks organize themselves to balance control with functionality? To address these here we review recent advances on the controllability and the control of complex networks, exploring the intricate interplay between a system's structure, captured by its network topology, and the dynamical laws that govern the interactions between the components. We match the pertinent mathematical results with empirical findings and applications. We show that uncovering the control principles of complex systems can help us explore and ultimately understand the fundamental laws that govern their behavior.

Control Principles of Complex Networks

Conventional evolutionary game theory predicts that natural selection favours the selfish and strong even though cooperative interactions thrive at all levels of organization in living systems. Recent investigations demonstrated that a limiting factor for the evolution of cooperative interactions is the way in which they are organized, cooperators becoming evolutionarily competitive whenever individuals are constrained to interact with few others along the edges of networks with low average connectivity. Despite this insight, the conundrum of cooperation remains since recent empirical data shows that real networks exhibit typically high average connectivity and associated single-to-broad–scale heterogeneity. Here, a computational model is constructed in which individuals are able to self-organize both their strategy and their social ties throughout evolution, based exclusively on their self-interest. We show that the entangled evolution of individual strategy and network structure constitutes a key mechanism for the sustainability of cooperation in social networks. For a given average connectivity of the population, there is a critical value for the ratio W between the time scales associated with the evolution of strategy and of structure above which cooperators wipe out defectors. Moreover, the emerging social networks exhibit an overall heterogeneity that accounts very well for the diversity of patterns recently found in acquired data on social networks. Finally, heterogeneity is found to become maximal when W reaches its critical value. These results show that simple topological dynamics reflecting the individual capacity for self-organization of social ties can produce realistic networks of high average connectivity with associated single-to-broad–scale heterogeneity. On the other hand, they show that cooperation cannot evolve as a result of “social viscosity” alone in heterogeneous networks with high average connectivity, requiring the additional mechanism of topological co-evolution to ensure the survival of cooperative behaviour.

Cooperation prevails when individuals adjust their social ties

RNA-protein interactions (RPIs) play important roles in a wide variety of cellular processes, ranging from transcriptional and post-transcriptional regulation of gene expression to host defense against pathogens. High throughput experiments to identify RNA-protein interactions are beginning to provide valuable information about the complexity of RNA-protein interaction networks, but are expensive and time consuming. Hence, there is a need for reliable computational methods for predicting RNA-protein interactions. We propose RPISeq, a family of classifiers for predicting R NA-p rotein i nteractions using only seq uence information. Given the sequences of an RNA and a protein as input, RPIseq predicts whether or not the RNA-protein pair interact. The RNA sequence is encoded as a normalized vector of its ribonucleotide 4-mer composition, and the protein sequence is encoded as a normalized vector of its 3-mer composition, based on a 7-letter reduced alphabet representation. Two variants of RPISeq are presented: RPISeq-SVM, which uses a Support Vector Machine (SVM) classifier and RPISeq-RF, which uses a Random Forest classifier. On two non-redundant benchmark datasets extracted from the Protein-RNA Interface Database (PRIDB), RPISeq achieved an AUC (Area Under the Receiver Operating Characteristic (ROC) curve) of 0.96 and 0.92. On a third dataset containing only mRNA-protein interactions, the performance of RPISeq was competitive with that of a published method that requires information regarding many different features (e.g., mRNA half-life, GO annotations) of the putative RNA and protein partners. In addition, RPISeq classifiers trained using the PRIDB data correctly predicted the majority (57-99%) of non-coding RNA-protein interactions in NPInter-derived networks from E. coli, S. cerevisiae, D. melanogaster, M. musculus, and H. sapiens. Our experiments with RPISeq demonstrate that RNA-protein interactions can be reliably predicted using only sequence-derived information. RPISeq offers an inexpensive method for computational construction of RNA-protein interaction networks, and should provide useful insights into the function of non-coding RNAs. RPISeq is freely available as a web-based server at http://pridb.gdcb.iastate.edu/RPISeq/
 .

/pdf/predicting-rna-protein-interactions-using-only-sequence-wdia0rrn9s.pdf

Predicting RNA-Protein Interactions Using Only Sequence Information

The possibility of controlling and directing a complex system's behavior at will is rooted in its interconnectivity and can lead to significant advances in disparate fields, ranging from nationwide energy saving to therapies that involve multiple targets. In this work, we address complex network controllability from the perspective of the minimum dominating set (MDS). Our theoretical calculations, simulations using artificially generated networks as well as real-world network analyses show that the more heterogeneous a network degree distribution is, the easier it is to control the entire system. We demonstrate that relatively few nodes are needed to control the entire network if the power-law degree exponent is smaller than 2, whereas many nodes are required if it is larger than 2.

/pdf/dominating-scale-free-networks-with-variable-scaling-5d0io0v5k7.pdf

Dominating scale-free networks with variable scaling exponent: heterogeneous networks are not difficult to control

The interactions between fundamental life molecules, people and social organisations build complex architectures that often result in undesired behaviours. Despite all of the advances made in our understanding of network structures over the past decade, similar progress has not been achieved in the controllability of real-world networks. In particular, an analytical framework to address the controllability of bipartite networks is still absent. Here, we present a dominating set (DS)-based approach to bipartite network controllability that identifies the topologies that are relatively easy to control with the minimum number of driver nodes. Our theoretical calculations, assisted by computer simulations and an evaluation of real-world networks offer a promising framework to control unidirectional bipartite networks. Our analysis should open a new approach to reverting the undesired behaviours in unidirectional bipartite networks at will.

/pdf/structural-controllability-of-unidirectional-bipartite-3qknidj4rq.pdf

Structural controllability of unidirectional bipartite networks

Recent studies have highlighted the importance of interconnectivity in a large range of molecular and human disease-related systems. Network medicine has emerged as a new paradigm to deal with complex diseases. Connections between protein complexes and key diseases have been suggested for decades. However, it was not until recently that protein complexes were identified and classified in sufficient amounts to carry out a large-scale analysis of the human protein complex system. We here present the first systematic and comprehensive set of relationships between protein complexes and associated drugs and analyzed their topological features. The network structure is characterized by a high modularity, both in the bipartite graph and in its projections, indicating that its topology is highly distinct from a random network and that it contains a rich and heterogeneous internal modular structure. To unravel the relationships between modules of protein complexes, drugs and diseases, we investigated in depth the origins of this modular structure in examples of particular diseases. This analysis unveils new associations between diseases and protein complexes and highlights the potential role of polypharmacological drugs, which target multiple cellular functions to combat complex diseases driven by gain-of-function mutations.

/pdf/modularity-in-protein-complex-and-drug-interactions-reveals-2qx2kyw6yd.pdf

Modularity in protein complex and drug interactions reveals new polypharmacological properties

The identification of interactions between drugs and proteins plays key roles in understanding mechanisms underlying drug actions and can lead to new drug design strategies. Here, we present a novel statistical approach, namely PDTD (Predicting Drug Targets with Domains), to predict potential target proteins of new drugs based on derived interactions between drugs and protein domains. The known target proteins of those drugs that have similar therapeutic effects allow us to infer interactions between drugs and protein domains which in turn leads to identification of potential drug-protein interactions. Benchmarking with known drug-protein interactions shows that our proposed methodology outperforms previous methods that exploit either protein sequences or compound structures to predict drug targets, which demonstrates the predictive power of our proposed PDTD method.

Predicting drug targets based on protein domains.

Background 
After IR stress, DNA double-strand breaks (DSBs) occur and repair proteins (RPs) bind to them, generating DSB-RP complexes (DSBCs), which results in repaired DSBs (RDSBs). In recent experimental studies, it is suggested that the ATM proteins detect these DNA lesions depending on the autophosphorylation of ATM which exists as a dimer before phosphorylation. Interestingly, the ATM proteins can work as a sensor for a small number of DSBs (approximately 18 DSBs in a cell after exposure to IR). Thus the ATM proteins amplify the small input signals based on the phosphorylation of the ATM dimer proteins. The true DSB-detection mechanism depending on ATM autophosphorylation has yet to be clarified.
Methodology/Principal Findings 
We propose a mathematical model for the detection mechanism of DSBs by ATM. Our model includes both a DSB-repair mechanism and an ATM-phosphorylation mechanism. We model the former mechanism as a stochastic process, and obtain theoretical mean values of DSBs and DSBCs. In the latter mechanism, it is known that ATM autophosphorylates itself, and we find that the autophosphorylation induces bifurcation of the phosphorylated ATM (ATM*). The bifurcation diagram depends on the total concentration of ATM, which makes three types of steady state diagrams of ATM*: monostable, reversible bistable, and irreversible bistable. Bistability exists depending on the Hill coefficient in the equation of ATM autophosphorylation, and it emerges as the total concentration of ATM increases. Combining these two mechanisms, we find that ATM* exhibits switch-like behaviour in the presence of bistability, and the detection time after DNA damage decreases when the total concentration of ATM increases.
Conclusions/Significance 
This work provides a mathematical model that explains the DSB-detection mechanism depending on ATM autophosphorylation. These results indicate that positive auto-regulation works both as a sensor and amplifier of small input signals.

/pdf/a-mathematical-model-for-the-detection-mechanism-of-dna-3hsf9zaubj.pdf

Jose C. Nacher

Papers

Dominating scale-free networks with variable scaling exponent: heterogeneous networks are not difficult to control

Structural controllability of unidirectional bipartite networks

Modularity in protein complex and drug interactions reveals new polypharmacological properties

Predicting drug targets based on protein domains.

A mathematical model for the detection mechanism of DNA double-strand breaks depending on autophosphorylation of ATM.