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PubMed2000

A multiple alignment algorithm for metabolic pathway analysis using enzyme hierarchy.

In many of the chemical reactions in living cells, enzymes act as catalysts in the conversion of certain compounds (substrates) into other compounds (products). Comparative analyses of the metabolic pathways formed by such reactions give important information on their evolution and on pharmacological targets (Dandekar et al. 1999). Each of the enzymes that constitute a pathway is classified according to the EC (Enzyme Commission) numbering system, which consists of four sets of numbers that categorize the type of the chemical reaction catalyzed. In this study, we consider that reaction similarities can be expressed by the similarities between EC numbers of the respective enzymes. Therefore, in order to find a common pattern among pathways, it is desirable to be able to use the functional hierarchy of EC numbers to express the reaction similarities. In this paper, we propose a multiple alignment algorithm utilizing information content that is extended to symbols having a hierarchical structure. The effectiveness of our method is demonstrated by applying the method to pathway analyses of sugar, DNA and amino acid metabolisms.

Algorithms↗
PubMed2006

Novel signal transduction pathways: analysis of STAT-3 and Rac-1 signaling in inflammatory bowel disease.

Although the precise etiology of inflammatory bowel disease still remains unclear, considerable progress has been made in the identification of novel signal transduction pathways that elucidate the immunopathogenesis involved in the perpetuation of the inflammatory process. Augmented T cell resistance against apoptosis is regarded as a pivotal factor in the pathogenesis, as it impairs mucosal homeostasis and leads to unrestrained accumulation of activated T cells, which subsequently lead to the amplification of the inflammatory response. Therefore novel therapeutic strategies aim at restoring mucosal T cell susceptibility to apoptosis through targeting of signal transduction pathways that are elemental for augmented resistance of T lymphocytes against apoptosis. For example, a newly developed humanized anti-IL-6R monoclonal antibody that induces intestinal T cell apoptosis showed clinical efficacy in patients with active Crohn;s disease. Moreover, recent data that relate the immunosuppressive effects of azathioprine in inflammatory bowel disease to its apoptosis-inducing potential, have important implications for the design of a more specific therapeutic approach. The examination of these novel signal transduction pathways has elucidated the pathogenetic mechanisms involved in inflammatory bowel disease and gives hope for the development of new strategies that may result in a more effective and less toxic therapeutic procedure.

Apoptosis↗
PubMedDate not supplied

Information content in organic molecules: reaction pathway analysis via Brownian processing.

Carbon chemistry offers infinite possibilities for molecules as information carriers. Moreover, there is no boundary on the number of ways in which a carrier's information can change via a chemical reaction. Organic reaction pathways thus pose new types of informatic variables which compel characterization using Brownian methods. We apply the tools of the preceding paper to these variable types for select reactions and classes. Along the way, geometric descriptors are formulated which complement the structure graph sequences of chemistry texts and journals. In addition, the statistical structure underpinning carbon transformations is explored more deeply. Overall, this work brings to light several informatic principles of organic reactions. Knowledge of these can assist in synthetic designs on both large- and small-scales. Brownian methods are able to address the pathway structures of all organic reactions: those reported in the literature, explored in the lab, or in the developmental stage.

Journal Article↗
PubMed2002

Genome-wide pathway analysis and visualization using gene expression data.

Visualization of results for high performance computing pose special problems due to the complexity and the volume of data these systems manipulate. We present an approach for visualization of c-DNA microarray gene expression data in metabolic and regulatory pathways using multi-resolution animation at different levels of detail. We describe three scoring functions to characterize pathways at the transcriptional level based on gene expression, coregulation and cascade effect. We also assess the significance of each pathway score on the basis of their biological connotation.

Animals↗
PubMed2004

Pathway analysis of informative genes from microarray data reveals that metabolism and signal transduction genes distinguish different subtypes of lymphomas.

Recent clinicopathological studies identified a unique subgroup of diffuse large B-cell lymphoma (DLBCL) that expresses CD5 on the cell surface. This 'de novo CD5+ DLBCL' comprises 10% of all DLBCL and has a poorer prognosis than CD5- DLBCL. Comparison of gene expression profiles between de novo CD5+ DLBCLs and CD5- DLBCLs shows that de novo CD5+ DLBCL expresses high levels of integrin beta1 in tumor cells and CD36 in the vascular cells. On the other hand, comparison between mantle cell lymphomas (MCLs) and DLBCLs expectedly identified cyclin D1 as a top feature gene. To gain insight into the molecular pathway differences among the three types of lymphoma, we evaluated the functional categories of groups of genes important for the discrimination among the three groups. We first selected 280 (from 2,142) genes, according to their individual discriminatory power. We then used the gene-shaving clustering algorithm and identified 22 clusters of genes. Of the 22 clusters, six were highly correlated with the class labels of the patients and the top three clusters accounted for the major difference among the three lymphoma subtypes. A multidimensional scaling (MDS) analysis using the average genes from the top three clusters separated the three lymphoma subtypes quite well. The functions of the genes in the top three gene clusters showed a significant enrichment of metabolism and signal transduction. To further examine whether genes of particular functions reflect more faithfully the difference between the subtypes of lymphomas, we separated the 280 informative genes into six different functional groups and performed MDS analysis using each of the gene groups. Four of the gene-function groups (metabolism, signal transduction pathway, transcriptional factors, cell adhesion and migration), separated the three lymphoma subtypes well, whereas apoptosis genes and cell cycle genes did not result in good separation.

Algorithms↗
PubMed1989

[Immediate complications of fulguration of ventricular tachycardia and accessory pathways. Analysis of 318 endocavitary shocks].

Abnormal events occurring immediately following electric stimulation were studied in 85 patients--mean age 38.5 years (14-78)--during the performance of 318 intracardiac shocks applied in 110 sessions. This electric stimulation was done for treatment of tachycardias related to an accessory pathway (series AP: 64 patients), or ventricular tachycardias (series VT: 21 patients). The number of shocks per session was 2.4 +/- 1.4 and 4.6 +/- 3, for the series AP and VT respectively, and the cumulative energy per session, was 405 +/- 221 J and 1,007 +/- 735 J. Only events occurring within the first 30 minutes following the shocks, were evaluated. In the series AP, the 64 patients received a total of 208 shocks in 86 sessions, and 68 abnormal events were observed (33%): 35 complete atrio-ventricular blocks, of more than 10 seconds (17%), 29 sinus pauses exceeding 3 seconds (14%) and able to stretch to 30 seconds, 3 ventricular fibrillations (1.4%) and 1 atrial fibrillation. In the series TV, 21 patients received 110 shocks in 24 sessions, and only 10 abnormal events occurred (9%): 2 transient episodes of electromechanical dissociation (1.8%), 3 uniform VT (2.7%), 1 complete atrio-ventricular block (10 min.), 1 cardiac pause (4 sec), 1 ventricular fibrillation, 1 isolated haemodynamic depression and 1 Prinzmetal syndrome. All these events were temporary, 5 ventricular arrhythmias in 6 were treated with a new intracardiac shock, and there were no deaths related to electric stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed2005

Pathway analysis of coronary atherosclerosis.

Large-scale gene expression studies provide significant insight into genes differentially regulated in disease processes such as cancer. However, these investigations offer limited understanding of multisystem, multicellular diseases such as atherosclerosis. A systems biology approach that accounts for gene interactions, incorporates nontranscriptionally regulated genes, and integrates prior knowledge offers many advantages. We performed a comprehensive gene level assessment of coronary atherosclerosis using 51 coronary artery segments isolated from the explanted hearts of 22 cardiac transplant patients. After histological grading of vascular segments according to American Heart Association guidelines, isolated RNA was hybridized onto a customized 22-K oligonucleotide microarray, and significance analysis of microarrays and gene ontology analyses were performed to identify significant gene expression profiles. Our studies revealed that loss of differentiated smooth muscle cell gene expression is the primary expression signature of disease progression in atherosclerosis. Furthermore, we provide insight into the severe form of coronary artery disease associated with diabetes, reporting an overabundance of immune and inflammatory signals in diabetics. We present a novel approach to pathway development based on connectivity, determined by language parsing of the published literature, and ranking, determined by the significance of differentially regulated genes in the network. In doing this, we identify highly connected "nexus" genes that are attractive candidates for therapeutic targeting and followup studies. Our use of pathway techniques to study atherosclerosis as an integrated network of gene interactions expands on traditional microarray analysis methods and emphasizes the significant advantages of a systems-based approach to analyzing complex disease.

Adult↗
PubMed1982

Differentiation restriction in the neutrophil-granulocyte, macrophage, eosinophil-granulocyte pathway: analysis by equilibrium density centrifugation.

Bone marrow culture techniques and equilibrium density centrifugation of human bone marrow cells were used to analyse the neutrophil-granulocyte, macrophage and eosinophil-granulocyte progenitor hierarchy. The buoyant density of progenitor cells changes as cells differentiate down the granulocyte-macrophage pathway and this allows the construction of a density 'map' of the points at which differentiation decisions are made. Unipotent progenitors, neutrophil-granulocyte (G), monocyte-macrophage (M), eosinophil-granulocyte (Eo), are more dense than bi- and tripotent progenitors (GM and EoGM) and have a lower 7-day proliferative capacity (assessed as the clone size achieved in maximally stimulated agar cultures). Experiments in which marrow cells were separated on a basis of their density and either cultured in agar immediately or after an interval of 6 days in suspension culture, were performed to establish the density of the cells which give rise to each type of progenitor, i.e. to investigate parent-progeny relationships. In each case the parent cells were of lower density than the unipotent or bipotent progenitor in question. The ability to separate, at least partially, unipotent, bipotent and multipotent cells of closely related lineages is important since it facilitates studies of the intracellular events taking place as restriction of the cell's differentiation options takes place.

Bone Marrow Cells↗
PubMed1988

A pathway analysis approach for determining acceptable levels of contamination of radionuclides in soil.

A methodology for determining acceptable levels for decontamination of soil containing radionuclides at waste sites is described. This methodology calculates the annual radiation dose that an individual receives while living on property that has been decommissioned and decontaminated. Pathways of exposure include direct radiation from ground surfaces, ingestion of contaminated food, inhalation of resuspended radionuclides and drinking contaminated water. Results calculated using this methodology were compared with U.S. Department of Energy (DOE) guidelines for a southeastern U.S. site. There is good agreement between the two methods provided similar assumptions are used.

Animals↗
PubMed2004

An algorithm for an automatic NOE pathways analysis of 2D NMR spectra of RNA duplexes.

An algorithm is proposed to provide the tool for an automatic resonance assignment of 2D-NOESY spectra of RNA duplexes. The algorithm, based on a certain subproblem of the Hamiltonian path, reduces a number of possible connections between resonances within aromatic and anomeric region of 2D-NOESY spectra. Appropriate pathways between H6/H8 and H1' resonances were obtained by subsequent implementation of experimental data as limiting factors. Predictive power of the algorithm was tested on both experimental and simulated data for RNA and DNA duplexes.

Algorithms↗
PubMed2004

Reproduction pathway analysis of several Hypericum perforatum L. somaclonal families.

Flow cytometry seed screen of mature seeds originating from several in vitro regenerated Hypericum perforatum L. somaclones and their seed progenies were used to screen the ways of reproduction of 4 subsequent generations of several somaclonal families and to search for the relation between the ploidy and prevalent mode of reproduction. The prevalent reproduction pathway of diploid plants was sexual reproduction. Seed samples of plants with higher ploidy levels showed an extensive variation in the mode of reproduction: BII and BIII hybrid formation and/or aposporous pseudogamy including parthenogenetic development of a reduced embryo sac.

Cells, Cultured↗
PubMed2007

Genetic network and pathway analysis of differentially expressed proteins during critical cellular events in fracture repair.

Bone repair consists of inflammation, intramembranous ossification, chondrogenesis, endochondral ossification, and remodeling. To better understand the translational regulation of these distinct but interrelated cellular events, we used the second generation of BD Clontechtrade mark Antibody Microarray to dissect and functionally characterize proteins differentially expressed between intact and fractured rat femur at each of these cellular events. Genetic network analysis showed that proteins differentially expressed within a given cellular event tend to be physically or functionally correlated. Seventeen such interacting networks were established over five cellular events that were most frequently associated with cell cycle, cell death, cell-to-cell signaling and interaction, and cell growth and proliferation. Eighteen molecular pathways were significantly enriched during the bone repair process, of which ERK/MAPK, NF-kB, PDGF, and T-cell receptor signaling pathways were significant during three or more cellular events. The analyses revealed dynamic temporal expression patterns and cellular-event-specific functions. The inflammation event on Day 1 was characteristic of the cell cycle-related molecular changes. The relative quiet stage of intramembranous ossification on Day 4 and the molecularly most active stage of chondrogenesis on Day 7 were featured by coordinated cell death and cell-proliferation signals. Endochondral ossification on Day 14 experienced a clear transition from the molecular/cellular function to the physiological system development/function. The osteoclast-mediated remodeling on Day 28 was highlighted by the integrin signaling pathway. The distinct changes in protein expression during these cellular events provide a molecular basis for developing cellular event-targeted therapeutic strategy to accelerate bone healing.

Animals↗
PubMed2006

Pathway analysis identifies perturbation of genetic networks induced by butyrate in a bovine kidney epithelial cell line.

Ruminant species have evolved to metabolize the short-chain volatile fatty acids (VFA), acetate, propionate, and butyrate, to fulfill up to 70% of their nutrient energy requirements. The inherent VFA dependence of ruminant cells was exploited to add a level of increased sensitivity to the study of the role of butyrate gene-response elements in regulatory biochemical pathways. Global gene expression profiles of the bovine kidney epithelial cells regulated by sodium butyrate were investigated with high-density oligonucleotide microarrays. The detailed mechanisms by which butyrate induces cell growth arrest and apoptosis were analyzed using the Ingenuity Pathways Knowledge Base. The functional category and pathway analyses of the microarray data revealed that four canonical pathways (Cell cycles: G2/M DNA damage checkpoint, and pyrimidine metabolism; G1/S checkpoint regulation and purine metabolism) were significantly perturbed. The biologically relevant networks and pathways of these genes were also identified. IGF2, TGFB1, TP53, E2F4, and CDC2 were established as being centered in these genomic networks. The present findings provide a basis for understanding the full range of the biological roles and the molecular mechanisms that butyrate may play in animal cell growth, proliferation, and energy metabolisms.

Animals↗
PubMed1986

Comparative pathway analysis of radiocesium in the Hudson River Estuary: environmental measurements and regulatory dose assessment models.

This work summarizes the measurements and associated environmental dosimetry of reactor-released 137Cs and 134Cs and weapons-produced 137Cs in samples of water, shoreline sediment and fish collected from 1971 to 1980 in the Hudson River Estuary. Trends observed in annual mean concentrations and the resultant dose implications for man from each source are discussed. The human exposure pathways examined are: fish consumption, water consumption, swimming and recreational use of the shoreline. Based on environmental measurements, a maximum, adult, whole-body, 50-y committed effective dose equivalent (CEDE) of 0.79 mu Sv (79 mu rem) is estimated from fish consumption in 1971, the year of maximum reactor discharge of the radiocesiums. For comparison, during the period 1974-79, mean estimates (+/- 1 SD) of the CEDE based on environmental measurements and attributed to other pathways are as follows: consumption of indigenous fish species caught downstream of the reactor outfall, 0.05 +/- 0.02 mu Sv (5 +/- 2 mu rem); consumption of fresh water sampled upstream of the reactors, 0.02 +/- 0.03 mu Sv (2 +/- 3 mu rem); and swimming, 10(-4) +/- 10(-4) mu Sv (0.01 +/- 0.01 mu rem). In addition, external, whole-body exposure resulting from recreational use of the shoreline 1.6 km downstream of the reactors is estimated to be 1.2 X 10(-8) C kg-1 (46 +/- 11 mu R yr-1). The above dose estimates are based on consumption factors of 3.9 and 803 kg y-1 (fish and water, respectively) and on usage factors of 50 and 140 h y-1 (swimming and shoreline recreation, respectively). Differences in dose estimates obtained from these long-term environmental measurements and from assessment models currently recommended for use by the U.S. Nuclear Regulatory Commission (NRC) are discussed.

Adult↗
PubMed2000

Assessment of the metabolic capabilities of Haemophilus influenzae Rd through a genome-scale pathway analysis.

The annotated full DNA sequence is becoming available for a growing number of organisms. This information along with additional biochemical and strain-specific data can be used to define metabolic genotypes and reconstruct cellular metabolic networks. The first free-living organism for which the entire genomic sequence was established was Haemophilus influenzae. Its metabolic network is reconstructed herein and contains 461 reactions operating on 367 intracellular and 84 extracellular metabolites. With the metabolic reaction network established, it becomes necessary to determine its underlying pathway structure as defined by the set of extreme pathways. The H. influenzae metabolic network was subdivided into six subsystems and the extreme pathways determined for each subsystem based on stoichiometric, thermodynamic, and systems-specific constraints. Positive linear combinations of these pathways can be taken to determine the extreme pathways for the complete system. Since these pathways span the capabilities of the full system, they could be used to address a number of important physiological questions. First, they were used to reconcile and curate the sequence annotation by identifying reactions whose function was not supported in any of the extreme pathways. Second, they were used to predict gene products that should be co-regulated and perhaps co-expressed. Third, they were used to determine the composition of the minimal substrate requirements needed to support the production of 51 required metabolic products such as amino acids, nucleotides, phospholipids, etc. Fourth, sets of critical gene deletions from core metabolism were determined in the presence of the minimal substrate conditions and in more complete conditions reflecting the environmental niche of H. influenzae in the human host. In the former case, 11 genes were determined to be critical while six remained critical under the latter conditions. This study represents an important milestone in theoretical biology, namely the establishment of the first extreme pathway structure of a whole genome.

Genome, Bacterial↗
PubMed1996

In vivo effects of insulin-like growth factor-I on the development of sensory pathways: analysis of the primary somatic sensory cortex (S1) of transgenic mice.

In the rodent brain, insulin-like growth factor I (IGF-I) messenger RNA is transiently expressed in sensory projection neurons during periods of synaptogenesis and neuronal growth. Transgenic (Tg) mice with brain IGF-I overexpression and ectopic brain expression of IGF-binding protein-1 (IGFBP-1), an inhibitor of IGF-I actions, show changes in brain size and myelination. We used these mouse models to evaluate in vivo IGF-I effects on sensory pathway development by conducting anatomical studies in the S1 barrel field. Brain size, cortical area, and barrel field dimensions were increased in IGF-I and reduced in IGFBP-1 Tg mice compared with those in wild-type (wt) mice. The brain and cerebral cortex of Tg mice with the highest transgene expression were the most altered in size. Cortex and barrel field size changes were not precisely proportional, because in some Tg mice barrels were relatively more affected than the cortex, whereas in others the opposite was observed. Brain IGF-I overexpression increased the average number of neurons per barrel, neuronal cell body cross-sectional area, and barrel neuropil volume, whereas brain expression of IGFBP-1 reduced each. Neuronal density was greatly reduced in IGF-I Tg mice and increased in IGFBP-1 Tg mice. No differences in body weight, whisker pad and follicle areas, and whisker pad innervation density were found among Tg and wt mice. These observations indicate that IGF-I enhances neuronal growth in developing sensory pathways and support the concept that modified availability of local trophic factors, such as IGF-I, changes brain, neocortical, and S1 relative dimensions by altering neuronal survival and neuropil elaboration. Study of the S1 cortex provides an excellent model to probe the in vivo mechanisms of IGF actions.

Animals↗
PubMed2004

Pathway analysis for population-total health impacts of toxic metal emissions.

This article describes a simple model for quantifying the health impacts of toxic metal emissions. In contrast to most traditional models it calculates the expectation value of the total damage (summed over the total population and over all time) for typical emission sites, rather than "worst-case" estimates for specific sites or episodes. Such a model is needed for the evaluation of many environmental policy measures, e.g., the optimal level of pollution taxes or emission limits. Based on the methodology that has been developed by USEPA for the assessment of multimedia pathways, the equations and parameters are assembled for the assessment of As, Cd, Cr, Hg, Ni, and Pb, and some typical results are presented (the dose from seafood is not included and for Hg the results are extremely uncertain); the model is freely available on the web. The structure of the model is very simple because, as we show, if the parameters can be approximated by time-independent constants (the case for the USEPA methodology), the total impacts can be calculated with steady-state models even though the environment is never in steady state. The collective ingestion dose is found to be roughly 2 orders of magnitude larger than the collective dose via inhalation. The uncertainties are large, easily an order of magnitude, the main uncertainties arising from the parameter values of the model, in particular the transfer factors. Using linearized dose-response functions, estimates are provided for cancers due to As, Cd, Cr, and Ni as well as IQ loss due to Pb emissions in Europe.

Air Pollutants↗
PubMed2026

Adolescent depression as a systemic multimorbidity catalyst: integrated genetic and metabolic pathway analysis.

BACKGROUND: Although adolescent depression has been linked to individual chronic conditions, its broader role in shaping multimorbidity risk remains understudied. METHODS: A total of 87,562 UK Biobank participants were included, of whom 18,851 had documented adolescent depression. Cox proportional hazards models were applied to evaluate associations between adolescent depression and 24 chronic diseases, followed by stratified analyses by sex and age. Two-sample Mendelian randomization (MR) was then conducted to infer causality for diseases showing significant associations. Genomic colocalization analyses were performed using relevant GWAS data to identify shared causal variants. Mediation analyses were performed to detect possible mediating factors, including the frailty index, KDM biological age acceleration, allostatic load and 30 circulating biomarkers. RESULTS: Adolescent depression was associated with elevated risk for 12 chronic diseases, with strongest associations for hypothyroidism (HR = 1.29 [1.18-1.42]), diabetes (HR = 1.25 [1.13-1.38]) and chronic obstructive pulmonary disease (COPD) (HR = 1.74 [1.50-2.01]). Risks were notably higher among females and younger adults. MR confirmed likely causal relationships for hypothyroidism (OR = 1.45 [1.03-2.05]), diabetes (OR = 1.01 [1.01-1.02]) and COPD (OR = 1.04 [1.02-1.06]). Genomic colocalization revealed a shared genetic signal at the CDSN/PSORS1C1 locus between adolescent depression and hypothyroidism. Mediation analyses revealed disease-specific pathways: creatinine for hypothyroidism, testosterone for diabetes, KDM biological ageing for COPD and frailty index across all three conditions. CONCLUSIONS: Adolescent depression confers systemic vulnerability through genetic and metabolic mechanisms, with amplified risks in females and individuals aged ≤55 years. These findings support early, integrated interventions to mitigate long-term multimorbidity.

Humans↗