13,424 research outputs found
From data towards knowledge: Revealing the architecture of signaling systems by unifying knowledge mining and data mining of systematic perturbation data
Genetic and pharmacological perturbation experiments, such as deleting a gene
and monitoring gene expression responses, are powerful tools for studying
cellular signal transduction pathways. However, it remains a challenge to
automatically derive knowledge of a cellular signaling system at a conceptual
level from systematic perturbation-response data. In this study, we explored a
framework that unifies knowledge mining and data mining approaches towards the
goal. The framework consists of the following automated processes: 1) applying
an ontology-driven knowledge mining approach to identify functional modules
among the genes responding to a perturbation in order to reveal potential
signals affected by the perturbation; 2) applying a graph-based data mining
approach to search for perturbations that affect a common signal with respect
to a functional module, and 3) revealing the architecture of a signaling system
organize signaling units into a hierarchy based on their relationships.
Applying this framework to a compendium of yeast perturbation-response data, we
have successfully recovered many well-known signal transduction pathways; in
addition, our analysis have led to many hypotheses regarding the yeast signal
transduction system; finally, our analysis automatically organized perturbed
genes as a graph reflecting the architect of the yeast signaling system.
Importantly, this framework transformed molecular findings from a gene level to
a conceptual level, which readily can be translated into computable knowledge
in the form of rules regarding the yeast signaling system, such as "if genes
involved in MAPK signaling are perturbed, genes involved in pheromone responses
will be differentially expressed"
The Regularizing Capacity of Metabolic Networks
Despite their topological complexity almost all functional properties of
metabolic networks can be derived from steady-state dynamics. Indeed, many
theoretical investigations (like flux-balance analysis) rely on extracting
function from steady states. This leads to the interesting question, how
metabolic networks avoid complex dynamics and maintain a steady-state behavior.
Here, we expose metabolic network topologies to binary dynamics generated by
simple local rules. We find that the networks' response is highly specific:
Complex dynamics are systematically reduced on metabolic networks compared to
randomized networks with identical degree sequences. Already small topological
modifications substantially enhance the capacity of a network to host complex
dynamic behavior and thus reduce its regularizing potential. This exceptionally
pronounced regularization of dynamics encoded in the topology may explain, why
steady-state behavior is ubiquitous in metabolism.Comment: 6 pages, 4 figure
High-resolution temporal profiling of transcripts during Arabidopsis leaf senescence reveals a distinct chronology of processes and regulation
Leaf senescence is an essential developmental process that impacts dramatically on crop yields and involves altered
regulation of thousands of genes and many metabolic and signaling pathways, resulting in major changes in the leaf. The
regulation of senescence is complex, and although senescence regulatory genes have been characterized, there is little
information on how these function in the global control of the process. We used microarray analysis to obtain a highresolution
time-course profile of gene expression during development of a single leaf over a 3-week period to senescence.
A complex experimental design approach and a combination of methods were used to extract high-quality replicated data
and to identify differentially expressed genes. The multiple time points enable the use of highly informative clustering to
reveal distinct time points at which signaling and metabolic pathways change. Analysis of motif enrichment, as well
as comparison of transcription factor (TF) families showing altered expression over the time course, identify clear groups
of TFs active at different stages of leaf development and senescence. These data enable connection of metabolic
processes, signaling pathways, and specific TF activity, which will underpin the development of network models to
elucidate the process of senescence
Gill transcriptome response to changes in environmental calcium in the green spotted puffer fish
Abstract Background Calcium ion is tightly regulated in body fluids and for euryhaline fish, which are exposed to rapid changes in environmental [Ca2+], homeostasis is especially challenging. The gill is the main organ of active calcium uptake and therefore plays a crucial role in the maintenance of calcium ion homeostasis. To study the molecular basis of the short-term responses to changing calcium availability, the whole gill transcriptome obtained by Super Serial Analysis of Gene Expression (SuperSAGE) of the euryhaline teleost green spotted puffer fish, Tetraodon nigroviridis, exposed to water with altered [Ca2+] was analysed. Results Transfer of T. nigroviridis from 10 ppt water salinity containing 2.9 mM Ca2+ to high (10 mM Ca2+ ) and low (0.01 mM Ca2+) calcium water of similar salinity for 2-12 h resulted in 1,339 differentially expressed SuperSAGE tags (26-bp transcript identifiers) in gills. Of these 869 tags (65%) were mapped to T. nigroviridis cDNAs or genomic DNA and 497 (57%) were assigned to known proteins. Thirteen percent of the genes matched multiple tags indicating alternative RNA transcripts. The main enriched gene ontology groups belong to Ca2+ signaling/homeostasis but also muscle contraction, cytoskeleton, energy production/homeostasis and tissue remodeling. K-means clustering identified co-expressed transcripts with distinct patterns in response to water [Ca2+] and exposure time. Conclusions The generated transcript expression patterns provide a framework of novel water calcium-responsive genes in the gill during the initial response after transfer to different [Ca2+]. This molecular response entails initial perception of alterations, activation of signaling networks and effectors and suggests active remodeling of cytoskeletal proteins during the initial acclimation process. Genes related to energy production and energy homeostasis are also up-regulated, probably reflecting the increased energetic needs of the acclimation response. This study is the first genome-wide transcriptome analysis of fish gills and is an important resource for future research on the short-term mechanisms involved in the gill acclimation responses to environmental Ca2+ changes and osmoregulation.Peer Reviewe
Systems analysis of host-parasite interactions.
Parasitic diseases caused by protozoan pathogens lead to hundreds of thousands of deaths per year in addition to substantial suffering and socioeconomic decline for millions of people worldwide. The lack of effective vaccines coupled with the widespread emergence of drug-resistant parasites necessitates that the research community take an active role in understanding host-parasite infection biology in order to develop improved therapeutics. Recent advances in next-generation sequencing and the rapid development of publicly accessible genomic databases for many human pathogens have facilitated the application of systems biology to the study of host-parasite interactions. Over the past decade, these technologies have led to the discovery of many important biological processes governing parasitic disease. The integration and interpretation of high-throughput -omic data will undoubtedly generate extraordinary insight into host-parasite interaction networks essential to navigate the intricacies of these complex systems. As systems analysis continues to build the foundation for our understanding of host-parasite biology, this will provide the framework necessary to drive drug discovery research forward and accelerate the development of new antiparasitic therapies
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Experimental Acute Exposure to Thirdhand Smoke and Changes in the Human Nasal Epithelial Transcriptome: A Randomized Clinical Trial.
Importance:No previous studies have shown that acute inhalation of thirdhand smoke (THS) activates stress and survival pathways in the human nasal epithelium. Objective:To evaluate gene expression in the nasal epithelium of nonsmoking women following acute inhalation of clean air and THS. Design, Setting, and Participants:Nasal epithelium samples were obtained from participants in a randomized clinical trial (2011-2015) on the health effects of inhaled THS. In a crossover design, participants were exposed, head only, to THS and to conditioned, filtered air in a laboratory setting. The order of exposures was randomized and exposures were separated by at least 21 days. Ribonucleic acid was obtained from a subset of 4 healthy, nonsmoking women. Exposures:By chance, women in the subset were randomized to receive clean air exposure first and THS exposure second. Exposures lasted 3 hours. Main Outcomes and Measures:Differentially expressed genes were identified using RNA sequencing with a false-discovery rate less than 0.1. Results:Participants were 4 healthy, nonsmoking women aged 27 to 49 years (mean [SD] age, 42 [10.2] years) with no chronic diseases. A total of 389 differentially expressed genes were identified in nasal epithelium exposed to THS, while only 2 genes, which were not studied further, were affected by clean air. Enriched gene ontology terms associated with stress-induced mitochondrial hyperfusion were identified, such as respiratory electron transport chain (q = 2.84 × 10-3) and mitochondrial inner membrane (q = 7.21 × 10-6). Reactome pathway analysis identified terms associated with upregulation of DNA repair mechanisms, such as nucleotide excision repair (q = 1.05 × 10-2). Enrichment analyses using ingenuity pathway analysis identified canonical pathways related to stress-induced mitochondrial hyperfusion (eg, increased oxidative phosphorylation) (P = .001), oxidative stress (eg, glutathione depletion phase II reactions) (P = .04), and cell survival (z score = 5.026). Conclusions and Relevance:This study found that acute inhalation of THS caused cell stress that led to the activation of survival pathways. Some responses were consistent with stress-induced mitochondrial hyperfusion and similar to those demonstrated previously in vitro. These data may be valuable to physicians treating patients exposed to THS and may aid in formulating regulations for the remediation of THS-contaminated environments
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