The hidden impact of inter-individual genomic variations on cellular function

An analysis of the degree of genomic variation between two individual genomes suggests that there may be considerable biochemical differences among individuals. Examination of DNA sequence variations in 14 canonical signaling pathways and Monte-Carlo simulation modeling suggest that the kinetic and quantitative behavior of signaling pathways in many individuals may be significantly perturbed from the 'healthy' norm. Signal transduction pathways in some individuals may suffer context-specific failures, or they may function normally but fail easily in the face of additional environmental perturbations or somatic mutations. These findings argue for new systems biology approaches that can predict pathway status in individuals using personal genome sequences and biomarker data

Computational Challenges of Personal Genomics

It is widely predicted that cost and efficiency gains in sequencing will usher in an era of personal genomics and personalized, predictive, preventive, and participatory medicine within a decade. I review the computational challenges ahead and propose general and specific directions for research and development. There is an urgent need to develop semantic ontologies that span genomics, molecular systems biology, and medical data. Although the development of such ontologies would be costly and difficult, the benefits will far outweigh the costs. I argue that availability of such ontologies would allow a revolution in web-services for personal genomics and medicine

Cis-regulatory logic in the endo16 gene: switching from a specification to a differentiation mode of control

The endo16 gene of Strongylocentrotus purpuratus encodes a secreted protein of the embryonic and larval midgut. The overall functional organization of the spatial and temporal control system of this gene are relatively well known from a series of earlier cis-regulatory studies. Our recent computational model for the logic operations of the proximal region of the endo16 control system (Module A) specifies the function of interactions at each transcription factor target site of Module A. Here, we extend sequence level functional analysis to the adjacent cis-regulatory region, Module B. The computational logic model is broadened to include B/A interactions as well as other Module B functions. Module B drives expression later in development and its major activator is responsible for a sharp, gut-specific increase in transcription after gastrulation. As shown earlier, Module B output undergoes a synergistic amplification that requires interactions within Module A. The interactions within Module B that are required to generate and transmit its output to Module A are identified. Logic considerations predicted an internal cis-regulatory switch by which spatial control of endo16 expression is shifted from Module A (early) to Module B (later). This prediction was confirmed experimentally and a distinct set of interactions in Module B that mediate the switch function was demonstrated. The endo16 computational model now provides a detailed explanation of the information processing functions executed by the cis-regulatory system of this gene throughout embryogenesis. Early in development the gene participates in the specification events that define the endomesoderm; later it functions as a gut-specific differentiation gene. The cis-regulatory switch mediates this functional change

The gene regulatory network basis of the “community effect,” and analysis of a sea urchin embryo example

The “Community Effect” denotes intra-territorial signaling amongst cells which constitute a particular tissue or embryonic progenitor field. The cells of the territory express the same transcriptional regulatory state, and the intra-territorial signaling is essential to maintenance of this specific regulatory state. The structure of the underlying gene regulatory network (GRN) subcircuitry explains the genomically wired mechanism by which community effect signaling is linked to the continuing transcriptional generation of the territorial regulatory state. A clear example is afforded by the oral ectoderm GRN of the sea urchin embryo where cis-regulatory evidence, experimental embryology, and network analysis combine to provide a complete picture. We review this example and consider less well known but similar cases in other developing systems where the same subcircuit GRN topology is present. To resolve mechanistic issues that arise in considering how community effect signaling could operate to produce its observed effects, we construct and analyze the behavior of a quantitative model of community effect signaling in the sea urchin embryo oral ectoderm. Community effect network topology could constitute part of the genomic regulatory code that defines transcriptional function in multicellular tissues composed of cells in contact, and hence may have arisen as a metazoan developmental strategy

The evaluation of psychiatric drug therapy on oral lichen planus patients with psychiatric disorders

Objectives: Current treatments of oral lichen planus are palliative, not curative. Because psychiatric disorders significantly influence the development and severity of oral lichen planus, the use of psychiatric drug therapy may be an adjunct in treatment. The purpose of this study was to determine the efficacy of drug therapy of psychiatric disorders in oral lichen planus. Study design: Our controlled clinical study consisted of forty-six patients with oral lichen planus and psychiatric disorders who were randomly divided into two groups. Both groups were given topical corticosteroids and the study group received additional psychiatric drug therapy. Patients were monitored for a period of 6 months. Response to treatment was evaluated in each group and was compared with the other group using Mann-Whitney tests. We evaluated the correlation between psychiatric disorders and the recovery of oral lesions using Spearman?s correlation coefficient analysis. Results: Decrease in the size of the lesions was significantly greater in the study group after six months, but this difference was not significant in relationship to the pain experienced and the kind of lesion. Spearman?s correlation coefficient analysis demonstrated that, in the sixth month, there was a significant and direct relationship between recovery from the psychiatric disorders and response to treatment of OLP lesions, particularly as it pertained to the kind of lesion. Conclusion: The present study indicates that the combination of psychiatric drug therapy and routine treatment methods were effective in reducing the size of the lesions, but did not have any significant effect on the symptoms

Menu-driven cloud computing and resource sharing for R and Bioconductor

Summary: We report CRdata.org, a cloud-based, free, open-source web server for running analyses and sharing data and R scripts with others. In addition to using the free, public service, CRdata users can launch their own private Amazon Elastic Computing Cloud (EC2) nodes and store private data and scripts on Amazon's Simple Storage Service (S3) with user-controlled access rights. All CRdata services are provided via point-and-click menus. Availability and Implementation: CRdata is open-source and free under the permissive MIT License (opensource.org/licenses/mit-license.php). The source code is in Ruby (ruby-lang.org/en/) and available at: github.com/seerdata/crdata

The ERATO Systems Biology Workbench: Architectural Evolution

Systems biology researchers make use of a large number of different software packages for computational modeling and analysis as well as data manipulation and visualization. To help developers easily provide the ability for their applications to communicate with other tools, we have developed a simple, open-source, application integration framework, the ERATO Systems Biology Workbench (SBW). In this paper, we discuss the architecture of SBW, focusing on our motivations for various design decisions including the choice of the message-oriented communications infrastructure

The ERATO Systems Biology Workbench: An Integrated Environment for Multiscale and Multitheoretic Simulations in Systems Biology

Over the years, a variety of biochemical network modeling packages have been developed and used by researchers in biology. No single package currently answers all the needs of the biology community; nor is one likely to do so in the near future, because the range of tools needed is vast and new techniques are emerging too rapidly. It seems unavoidable that, for the foreseeable future, systems biology researchers are likely to continue using multiple packages to carry out their work. In this chapter, we describe the ERATO Systems Biology Workbench (SBW) and the Systems Biology Markup Language (SBML), two related efforts directed at the problems of software package interoperability. The goal of the SBW project is to create an integrated, easy-to-use software environment that enables sharing of models and resources between simulation and analysis tools for systems biology. SBW uses a modular, plug-in architecture that permits easy introduction of new components. SBML is a proposed standard XML-based language for representing models communicated between software packages; it is used as the format of models communicated between components in SBW

The ERATO Systems Biology Workbench: Enabling Interaction and Exchange Between Software Tools for Computational Biology

Researchers in computational biology today make use of a large number of different software packages for modeling, analysis, and data manipulation and visualization. In this paper, we describe the ERATO Systems Biology Workbench (SBW), a software framework that allows these heterogeneous application components--written in diverse programming languages and running on different platforms--to communicate and use each others' data and algorithmic capabilities. Our goal is to create a simple, open-source software infrastructure which is effective, easy to implement and easy to understand. SBW uses a broker-based architecture and enables applications (potentially running on separate, distributed computers) to communicate via a simple network protocol. The interfaces to the system are encapsulated in client-side libraries that we provide for different programming languages. We describe the SBW architecture and the current set of modules, as well as alternative implementation technologies