Identification of functional modules in human protein interaction networks.

The novel method proposed in this thesis is able to identify functional modules making use of large-scale interaction and expression data. While theveri tion of these subnetworks remains di ult, they identify sets of proteins, which may play a key role in the development of malignancies. The modules provide an attractive basis for further research and may provide new targets for drug development

Multivariate gene expression analysis reveals functional connectivity changes between normal/tumoral prostates

<p>Abstract</p> <p>Background</p> <p>Prostate cancer is a leading cause of death in the male population, therefore, a comprehensive study about the genes and the molecular networks involved in the tumoral prostate process becomes necessary. In order to understand the biological process behind potential biomarkers, we have analyzed a set of 57 cDNA microarrays containing ~25,000 genes.</p> <p>Results</p> <p>Principal Component Analysis (PCA) combined with the Maximum-entropy Linear Discriminant Analysis (MLDA) were applied in order to identify genes with the most discriminative information between normal and tumoral prostatic tissues. Data analysis was carried out using three different approaches, namely: (i) differences in gene expression levels between normal and tumoral conditions from an univariate point of view; (ii) in a multivariate fashion using MLDA; and (iii) with a dependence network approach. Our results show that malignant transformation in the prostatic tissue is more related to functional connectivity changes in their dependence networks than to differential gene expression. The MYLK, KLK2, KLK3, HAN11, LTF, CSRP1 and TGM4 genes presented significant changes in their functional connectivity between normal and tumoral conditions and were also classified as the top seven most informative genes for the prostate cancer genesis process by our discriminant analysis. Moreover, among the identified genes we found classically known biomarkers and genes which are closely related to tumoral prostate, such as KLK3 and KLK2 and several other potential ones.</p> <p>Conclusion</p> <p>We have demonstrated that changes in functional connectivity may be implicit in the biological process which renders some genes more informative to discriminate between normal and tumoral conditions. Using the proposed method, namely, MLDA, in order to analyze the multivariate characteristic of genes, it was possible to capture the changes in dependence networks which are related to cell transformation.</p

Physical modelling of epithelia: reverse engineering cell competition in silico

Cell competition is a phenomenon in which less fit cells are removed from a tissue for optimal survival of the host. Competition has been observed in many physiological and pathophysiological conditions, especially in the prevention of tumor development. While there have been extensive population-scale experimental studies of competition, the competitive strategies and their underlying mechanisms in single cells are poorly understood. To date, two main mechanisms of cell competition have been described. Mechanical competition arises when the two competing cell types have different sensitivities to crowding. In contrast, during biochemical competition, signaling occurs at the interface between cell types leading to apoptosis of the loser cells. However, rigorously testing these hypotheses remains challenging due to the difficulty of obtaining sufficient single cell level information to bridge scales to the whole tissue. In this thesis, I present metrics aimed at characterising competition at the single cell level. Then, I demonstrate the development of a multi-layered, cell-scale computational model that I use to gain understanding on the single cell mechanisms that govern mechanical competition and decipher the "rules of the cellular game". After benchmarking cell growth and homeostasis in pure populations, I show that competition emerges when both cell types are included in simulations. I then investigate the impact of each computational parameter on the outcome of cell competition. Intriguingly, the outcome of biochemical competition is controlled by topological entropy between cell types, whereas the outcome of mechanical cell competition is exclusively controlled by differences in energetic potential between cell types. As 90% of cancers arise from epithelia and a number of genetic diseases present symptoms of epithelial fragility, I anticipate that my model of realistic implementation of epithelia will be of use to the biophysics and computational modelling community

Allo-network drugs: Extension of the allosteric drug concept to protein-protein interaction and signaling networks

Allosteric drugs are usually more specific and have fewer side effects than orthosteric drugs targeting the same protein. Here, we overview the current knowledge on allosteric signal transmission from the network point of view, and show that most intra-protein conformational changes may be dynamically transmitted across protein-protein interaction and signaling networks of the cell. Allo-network drugs influence the pharmacological target protein indirectly using specific inter-protein network pathways. We show that allo-network drugs may have a higher efficiency to change the networks of human cells than those of other organisms, and can be designed to have specific effects on cells in a diseased state. Finally, we summarize possible methods to identify allo-network drug targets and sites, which may develop to a promising new area of systems-based drug design

Section Abstracts: Structural Biology, Biochemistry and Biophysics

Abstracts of the Structural Biology, Biochemistry and Biophysics Section for the 91st Annual Virginia Journal of Science Meeting, May 201

Network link prediction by global silencing of indirect correlations

Predicting physical and functional links between cellular components is a fundamental challenge of biology and network science. Yet, correlations, a ubiquitous input for biological link prediction, are affected by both direct and indirect effects, confounding our ability to identify true pairwise interactions. Here we exploit the fundamental properties of dynamical correlations in networks to develop a method to silence indirect effects. The method receives as input the observed correlations between node pairs and uses a matrix transformation to turn the correlation matrix into a highly discriminative silenced matrix, which enhances only the terms associated with direct causal links. Achieving perfect accuracy in model systems, we test the method against empirical data collected for the Escherichia coli regulatory interaction network, showing that it improves on the best preforming link prediction methods. Overall the silencing methodology helps translate the abundant correlation data into valuable local information, with applications ranging from link prediction to inferring the dynamical mechanisms governing biological networks

Predicting Proteome-Early Drug Induced Cardiac Toxicity Relationships (Pro-EDICToRs) with Node Overlapping Parameters (NOPs) of a new class of Blood Mass-Spectra graphs

The 11th International Electronic Conference on Synthetic Organic Chemistry session Computational ChemistryBlood Serum Proteome-Mass Spectra (SP-MS) may allow detecting Proteome-Early Drug Induced Cardiac Toxicity Relationships (called here Pro-EDICToRs). However, due to the thousands of proteins in the SP identifying general Pro-EDICToRs patterns instead of a single protein marker may represents a more realistic alternative. In this sense, first we introduced a novel Cartesian 2D spectrum graph for SP-MS. Next, we introduced the graph node-overlapping parameters (nopk) to numerically characterize SP-MS using them as inputs to seek a Quantitative Proteome-Toxicity Relationship (QPTR) classifier for Pro-EDICToRs with accuracy higher than 80%. Principal Component Analysis (PCA) on the nopk values present in the QPTR model explains with one factor (F1) the 82.7% of variance. Next, these nopk values were used to construct by the first time a Pro-EDICToRs Complex Network having nodes (samples) linked by edges (similarity between two samples). We compared the topology of two sub-networks (cardiac toxicity and control samples); finding extreme relative differences for the re-linking (P) and Zagreb (M2) indices (9.5 and 54.2 % respectively) out of 11 parameters. We also compared subnetworks with well known ideal random networks including Barabasi-Albert, Kleinberg Small World, Erdos-Renyi, and Epsstein Power Law models. Finally, we proposed Partial Order (PO) schemes of the 115 samples based on LDA-probabilities, F1-scores and/or network node degrees. PCA-CN and LDA-PCA based POs with Tanimoto’s coefficients equal or higher than 0.75 are promising for the study of Pro-EDICToRs. These results shows that simple QPTRs models based on MS graph numerical parameters are an interesting tool for proteome researchThe authors thank projects funded by the Xunta de Galicia (PXIB20304PR and BTF20302PR) and the Ministerio de Sanidad y Consumo (PI061457). González-Díaz H. acknowledges tenure track research position funded by the Program Isidro Parga Pondal, Xunta de Galici

Applied Computational Techniques on Schizophrenia Using Genetic Mutations

[Abstract] Schizophrenia is a complex disease, with both genetic and environmental influence. Machine learning techniques can be used to associate different genetic variations at different genes with a (schizophrenic or non-schizophrenic) phenotype. Several machine learning techniques were applied to schizophrenia data to obtain the results presented in this study. Considering these data, Quantitative Genotype – Disease Relationships (QDGRs) can be used for disease prediction. One of the best machine learning-based models obtained after this exhaustive comparative study was implemented online; this model is an artificial neural network (ANN). Thus, the tool offers the possibility to introduce Single Nucleotide Polymorphism (SNP) sequences in order to classify a patient with schizophrenia. Besides this comparative study, a method for variable selection, based on ANNs and evolutionary computation (EC), is also presented. This method uses half the number of variables as the original ANN and the variables obtained are among those found in other publications. In the future, QDGR models based on nucleic acid information could be expanded to other diseases.Programa Iberoamericano de Ciencia y Tecnología para el Desarrollo; 209RT-0366Xunta de Galicia; 10SIN105004PRInstituto de Salud Carlos III; RD07/0067/0005Xunta de Galicia; Ref. 2009/5

Information processing in the transcriptional regulatory network of yeast: Functional robustness

<p>Abstract</p> <p>Background</p> <p>Gene networks are considered to represent various aspects of molecular biological systems meaningfully because they naturally provide a systems perspective of molecular interactions. In this respect, the functional understanding of the transcriptional regulatory network is considered as key to elucidate the functional organization of an organism.</p> <p>Results</p> <p>In this paper we study the functional robustness of the transcriptional regulatory network of <it>S. cerevisiae</it>. We model the information processing in the network as a first order Markov chain and study the influence of single gene perturbations on the global, asymptotic communication among genes. Modification in the communication is measured by an information theoretic measure allowing to predict genes that are 'fragile' with respect to single gene knockouts. Our results demonstrate that the predicted set of fragile genes contains a statistically significant enrichment of so called essential genes that are experimentally found to be necessary to ensure vital yeast. Further, a structural analysis of the transcriptional regulatory network reveals that there are significant differences between fragile genes, hub genes and genes with a high betweenness centrality value.</p> <p>Conclusion</p> <p>Our study does not only demonstrate that a combination of graph theoretical, information theoretical and statistical methods leads to meaningful biological results but also that such methods allow to study information processing in gene networks instead of just their structural properties.</p

Efficiency of the immunome protein interaction network increases during evolution

Details of the mechanisms and selection pressures that shape the emergence and development of complex biological systems, such as the human immune system, are poorly understood. A recent definition of a reference set of proteins essential for the human immunome, combined with information about protein interaction networks for these proteins, facilitates evolutionary study of this biological machinery