Time-resolved metabolomics reveals metabolic modulation in rice foliage

<p>Abstract</p> <p>Background</p> <p>To elucidate the interaction of dynamics among modules that constitute biological systems, comprehensive datasets obtained from "omics" technologies have been used. In recent plant metabolomics approaches, the reconstruction of metabolic correlation networks has been attempted using statistical techniques. However, the results were unsatisfactory and effective data-mining techniques that apply appropriate comprehensive datasets are needed.</p> <p>Results</p> <p>Using capillary electrophoresis mass spectrometry (CE-MS) and capillary electrophoresis diode-array detection (CE-DAD), we analyzed the dynamic changes in the level of 56 basic metabolites in plant foliage (<it>Oryza sativa </it>L. ssp. <it>japonica</it>) at hourly intervals over a 24-hr period. Unsupervised clustering of comprehensive metabolic profiles using Kohonen's self-organizing map (SOM) allowed classification of the biochemical pathways activated by the light and dark cycle. The carbon and nitrogen (C/N) metabolism in both periods was also visualized as a phenotypic linkage map that connects network modules on the basis of traditional metabolic pathways rather than pairwise correlations among metabolites. The regulatory networks of C/N assimilation/dissimilation at each time point were consistent with previous works on plant metabolism. In response to environmental stress, glutathione and spermidine fluctuated synchronously with their regulatory targets. Adenine nucleosides and nicotinamide coenzymes were regulated by phosphorylation and dephosphorylation. We also demonstrated that SOM analysis was applicable to the estimation of unidentifiable metabolites in metabolome analysis. Hierarchical clustering of a correlation coefficient matrix could help identify the bottleneck enzymes that regulate metabolic networks.</p> <p>Conclusion</p> <p>Our results showed that our SOM analysis with appropriate metabolic time-courses effectively revealed the synchronous dynamics among metabolic modules and elucidated the underlying biochemical functions. The application of discrimination of unidentified metabolites and the identification of bottleneck enzymatic steps even to non-targeted comprehensive analysis promise to facilitate an understanding of large-scale interactions among components in biological systems.</p

Investigation of transmembrane proteins using a computational approach

Background: An important subfamily of membrane proteins are the transmembrane α-helical proteins, in which the membrane-spanning regions are made up of α-helices. Given the obvious biological and medical significance of these proteins, it is of tremendous practical importance to identify the location of transmembrane segments. The difficulty of inferring the secondary or tertiary structure of transmembrane proteins using experimental techniques has led to a surge of interest in applying techniques from machine learning and bioinformatics to infer secondary structure from primary structure in these proteins. We are therefore interested in determining which physicochemical properties are most useful for discriminating transmembrane segments from non-transmembrane segments in transmembrane proteins, and for discriminating intrinsically unstructured segments from intrinsically structured segments in transmembrane proteins, and in using the results of these investigations to develop classifiers to identify transmembrane segments in transmembrane proteins. Results: We determined that the most useful properties for discriminating transmembrane segments from non-transmembrane segments and for discriminating intrinsically unstructured segments from intrinsically structured segments in transmembrane proteins were hydropathy, polarity, and flexibility, and used the results of this analysis to construct classifiers to discriminate transmembrane segments from non-transmembrane segments using four classification techniques: two variants of the Self-Organizing Global Ranking algorithm, a decision tree algorithm, and a support vector machine algorithm. All four techniques exhibited good performance, with out-of-sample accuracies of approximately 75%. Conclusions: Several interesting observations emerged from our study: intrinsically unstructured segments and transmembrane segments tend to have opposite properties; transmembrane proteins appear to be much richer in intrinsically unstructured segments than other proteins; and, in approximately 70% of transmembrane proteins that contain intrinsically unstructured segments, the intrinsically unstructured segments are close to transmembrane segments

Adaptive Double Self-Organizing Map for Clustering Gene Expression Data

This thesis presents a novel clustering technique known as adaptive double self- organizing map (ADSOM) that addresses the issue of identifying the correct number of clusters. ADSOM has a flexible topology and performs clustering and cluster visualization simultaneously, thereby requiring no a priori knowledge about the number of clusters. ADSOM combines features of the popular self-organizing map with two- dimensional position vectors, which serve as a visualization tool to decide the number of clusters. It updates its free parameters during training and it allows convergence of its position vectors to a fairly consistent number of clusters provided that its initial number of nodes is greater than the expected number of clusters. A novel index is introduced based on hierarchical clustering of the final locations of position vectors. The index allows automated detection of the number of clusters, thereby reducing human error that could be incurred from counting clusters visually. The reliance of ADSOM in identifying the number of clusters is proven by applying it to publicly available gene expression data from multiple biological systems such as yeast, human, mouse, and bacteria

Automatic discovery of cross-family sequence features associated with protein function

BACKGROUND: Methods for predicting protein function directly from amino acid sequences are useful tools in the study of uncharacterised protein families and in comparative genomics. Until now, this problem has been approached using machine learning techniques that attempt to predict membership, or otherwise, to predefined functional categories or subcellular locations. A potential drawback of this approach is that the human-designated functional classes may not accurately reflect the underlying biology, and consequently important sequence-to-function relationships may be missed. RESULTS: We show that a self-supervised data mining approach is able to find relationships between sequence features and functional annotations. No preconceived ideas about functional categories are required, and the training data is simply a set of protein sequences and their UniProt/Swiss-Prot annotations. The main technical aspect of the approach is the co-evolution of amino acid-based regular expressions and keyword-based logical expressions with genetic programming. Our experiments on a strictly non-redundant set of eukaryotic proteins reveal that the strongest and most easily detected sequence-to-function relationships are concerned with targeting to various cellular compartments, which is an area already well studied both experimentally and computationally. Of more interest are a number of broad functional roles which can also be correlated with sequence features. These include inhibition, biosynthesis, transcription and defence against bacteria. Despite substantial overlaps between these functions and their corresponding cellular compartments, we find clear differences in the sequence motifs used to predict some of these functions. For example, the presence of polyglutamine repeats appears to be linked more strongly to the "transcription" function than to the general "nuclear" function/location. CONCLUSION: We have developed a novel and useful approach for knowledge discovery in annotated sequence data. The technique is able to identify functionally important sequence features and does not require expert knowledge. By viewing protein function from a sequence perspective, the approach is also suitable for discovering unexpected links between biological processes, such as the recently discovered role of ubiquitination in transcription

Redes neuronales auto-organizativas basadas en optimización funcional. Aplicación en bioinformática y biología computacional

Tesis doctoral inédita de la Universidad Autónoma de Madrid. Escuela Politécnica Superior, Departamento de Ingeniería informática. Fecha de lectura: 25-11-200

Predicting drug-microbiome interactions with machine learning

Pivotal work in recent years has cast light on the importance of the human microbiome in maintenance of health and physiological response to drugs. It is now clear that gastrointestinal microbiota have the metabolic power to promote, inactivate, or even toxify the efficacy of a drug to a level of clinically relevant significance. At the same time, it appears that drug intake has the propensity to alter gut microbiome composition, potentially affecting health and response to other drugs. Since the precise composition of an individual's microbiome is unique, one's drug-microbiome relationship is similarly unique. Thus, in the age of evermore personalised medicine, the ability to predict individuals' drug-microbiome interactions is highly sought. Machine learning (ML) offers a powerful toolkit capable of characterising and predicting drug-microbiota interactions at the individual patient level. ML techniques have the potential to learn the mechanisms operating drug-microbiome activities and measure patients' risk of such occurrences. This review will outline current knowledge at the drug-microbiota interface, and present ML as a technique for examining and forecasting personalised drug-microbiome interactions. When harnessed effectively, ML could alter how the pharmaceutical industry and healthcare professionals consider the drug-microbiome axis in patient care

Use of neural networks to model molecular structure and function

This thesis is a study of some applications of neural networks - a recent computer algorithm - to modelling the structure and function of biologically important molecules. In Chapter 1, an introduction to neural networks is given. An overview of quantitative structure activity relationships (QSARs) is presented. The applications of neural networks to QSAR and to the prediction of structural and functional features of protein and nucleic acid sequences are reviewed. The neural network algorithms used are discussed in Chapter 2. In Chapter 3, a two-layer feed-forward neural network has been trained to recognise an ATP/GTP-binding local sequence motif. A comparably sophisticated statistical method was developed, which performed marginally better than the neural network. In a second study, described in Chapters 4 and 5, one of the largest data sets available for developing a quantitative structure activity relationship - the inhibition of dihydrofolate reductase by 2,4-diamino-6,6-dimethyl-5-phenyldihydrotriazine derivatives has been used to benchmark several computational methods. A hidden-layer neural network, a decision tree and inductive logic programming have been compared with the more established methods of linear regression and nearest neighbour. The data were represented in two ways: by the traditional Hansch parameters and by a new set of descriptors designed to allow the formulation of rules relating the activity of the inhibitors to their chemical structure. The performance of neural networks has been assessed rigourously in two distinct areas of biomolecular modelling; sequence analysis and drug design. The conclusions of these studies are presented in Chapter 6