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Results for “Pathway analysis”

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At least 613 records · Page 34Linked to original sources

PubMed2016

A probabilistic generative model for quantification of DNA modifications enables analysis of demethylation pathways.

We present a generative model, Lux, to quantify DNA methylation modifications from any combination of bisulfite sequencing approaches, including reduced, oxidative, TET-assisted, chemical-modification assisted, and methylase-assisted bisulfite sequencing data. Lux models all cytosine modifications (C, 5mC, 5hmC, 5fC, and 5caC) simultaneously together with experimental parameters, including bisulfite conversion and oxidation efficiencies, as well as various chemical labeling and protection steps. We show that Lux improves the quantification and comparison of cytosine modification levels and that Lux can process any oxidized methylcytosine sequencing data sets to quantify all cytosine modifications. Analysis of targeted data from Tet2-knockdown embryonic stem cells and T cells during development demonstrates DNA modification quantification at unprecedented detail, quantifies active demethylation pathways and reveals 5hmC localization in putative regulatory regions.

5-Methylcytosine↗

PubMed1999

Not resting on its laurels, Sentara taps data analysis tool to fine-tune pathways.

Artificial intelligence data analysis leads health care system to fine-tune and improve new clinical pathways. Sentara Health Care in Norfolk, VA, developed a host of new clinical protocols in recent years, but instead of sitting back and enjoying initial improved outcomes and cost savings, it went the extra mile to enhance those pathways using a sophisticated data analysis tool.

Artificial Intelligence↗

PubMed1998

Initiation of biofilm formation in Pseudomonas fluorescens WCS365 proceeds via multiple, convergent signalling pathways: a genetic analysis.

Populations of surface-attached microorganisms comprising either single or multiple species are commonly referred to as biofilms. Using a simple assay for the initiation of biofilm formation (e.g. attachment to an abiotic surface) by Pseudomonas fluorescens strain WCS365, we have shown that: (i) P. fluorescens can form biofilms on an abiotic surface when grown on a range of nutrients; (ii) protein synthesis is required for the early events of biofilm formation; (iii) one (or more) extracytoplasmic protein plays a role in interactions with an abiotic surface; (iv) the osmolarity of the medium affects the ability of the cell to form biofilms. We have isolated transposon mutants defective for the initiation of biofilm formation, which we term surface attachment defective (sad). Molecular analysis of the sad mutants revealed that the ClpP protein (a component of the cytoplasmic Clp protease) participates in biofilm formation in this organism. Our genetic analyses suggest that biofilm formation can proceed via multiple, convergent signalling pathways, which are regulated by various environmental signals. Finally, of the 24 sad mutants analysed in this study, only three had defects in genes of known function. This result suggests that our screen is uncovering novel aspects of bacterial physiology.

Adenosine Triphosphatases↗

PubMed2005

Pathway and ontology analysis: emerging approaches connecting transcriptome data and clinical endpoints.

The increasing use of gene expression profiling offers great promise in clinical research into disease biology and its treatment. Along with the ability to measure changing expression levels in thousands of genes at once, comes the challenge of analyzing and interpreting the vast sets of data generated. Analysis tools are evolving rapidly to meet such challenges. The next step is to interpret observed changes in terms of the biological properties or relationships underlying them. One powerful approach is to make associations between the genes that are under investigation and well-known biochemical or signaling pathways, and further to assess the significance of such associations. Similarly, genes can be mapped to standardized biological categories via an ontology resource. We discuss these approaches and several web-based resources and tools designed to facilitate such analyses. This information can be used to facilitate understanding and to help design more focused experiments for validating the relevance and importance of these biological pathways and processes in human disease and therapeutics.

Animals↗

PubMed2005

Pathway recognition and augmentation by computational analysis of microarray expression data.

MOTIVATION: We present a system, QPACA (Quantitative Pathway Analysis in Cancer) for analysis of biological data in the context of pathways. QPACA supports data visualization and both fine- and coarse-grained specifications, but, more importantly, addresses the problems of pathway recognition and pathway augmentation. RESULTS: Given a set of genes hypothesized to be part of a pathway or a coordinated process, QPACA is able to reliably distinguish true pathways from non-pathways using microarray expression data. Relying on the observation that only some of the experiments within a dataset are relevant to a specific biochemical pathway, QPACA automates selection of this subset using an optimization procedure. We present data on all human and yeast pathways found in the KEGG pathway database. In 117 out of 191 cases (61%), QPACA was able to correctly identify these positive cases as bona fide pathways with p-values measured using rigorous permutation analysis. Success in recognizing pathways was dependent on pathway size, with the largest quartile of pathways yielding 83% success. In cross-validation tests of pathway membership prediction, QPACA was able to yield enrichments for predicted pathway genes over random genes at rates of 2-fold or better the majority of the time, with rates of 10-fold or better 10-20% of the time. AVAILABILITY: The software is available for academic research use free of charge by email request. SUPPLEMENTARY INFORMATION: Data used in the paper may be downloaded from http://www.jainlab.org/downloads.html

Algorithms↗

PubMed2002

The evolution of developmental regulatory pathways.

Evolutionary analysis of the content of developmental regulatory pathways has been advanced by the publication of pairs of complete genome sequences from representative taxonomic groups. Annotation of the fission yeast, rice, and mouse genomes confirms that most regulatory families are shared among eukaryotes but also shows that certain gene families have restricted distributions. Theoretical advances in the past few years include development of the theory of scale-free networks, which provides a new framework in which to consider the connectivity and evolution of regulatory systems, and introduction of algorithms that use comparative data to enhance detection of transcriptional regulatory motifs.

Animals↗

PubMed2000

Least-effort pathways?: a GIS analysis of livestock trails in rugged terrain.

Livestock trails frequently evolve in pastures when plant growth or establishment cannot keep pace with vegetation disturbance. In some instances, man-made trails are established in rangeland settings to encourage uniform use of forages or facilitate livestock passage through dense vegetation or across rugged terrain. A long-term assumption has been that livestock establish pathways of least resistance between frequented areas of their pastures, but this hypothesis has never been tested. We mapped cattle trails in three 800+ ha pastures with global positioning units. A geographic information system (GIS) helped quantify characteristics of trails and the landscape and was used to plot least-effort pathways between water sources and distant points on selected trails in the pastures. Characteristics of the cattle trails and least-effort pathways were compared to test the hypothesis that cattle develop least-effort routes of travel in rugged terrain. The mean slope of the three pastures was 13.5%, and the average slope of the topography traversed by the cattle trails was 8%. The slope of the trails was reduced to 5.2% by selection of cross-slope routes. When we compared the characteristics of 10 selected cattle trails and least-effort pathways generated by our GIS, the cattle trails were 11% shorter (P=0.046) than the least-effort pathways, and the topography traversed by cattle had a gradient about 1% less than the least-effort pathways (P=0.02). The slope of the selected trails (5.5%) and pathways (5.6%) were similar (P=0.74), however. Analyses of values extracted from cost surfaces indicated that, on the average, 183 units of effort were needed to traverse the trails and 170 units of effort expended to traverse the least-effort pathways (P=0.07). These data support the hypothesis that cattle establish least-effort routes between distant points in rugged terrain and suggest that GIS software may be useful in designing systems of livestock trails in extensive settings.

Journal Article↗

PubMed2006

Structural modeling and analysis of signaling pathways based on Petri nets.

The purpose of this paper is to discuss how to model and analyze signaling pathways by using Petri net. Firstly, we propose a modeling method based on Petri net by paying attention to the molecular interactions and mechanisms. Then, we introduce a new notion "activation transduction component" in order to describe an enzymic activation process of reactions in signaling pathways and shows its correspondence to a so-called elementary T-invariant in the Petri net models. Further, we design an algorithm to effectively find basic enzymic activation processes by obtaining a series of elementary T-invariants in the Petri net models. Finally, we demonstrate how our method is practically used in modeling and analyzing signaling pathway mediated by thrombopoietin as an example.

Algorithms↗

PubMed1998

Understanding the gravitropic signal transduction pathway through the analysis of new Arabidopsis mutants.

The gravitropic response of plants can be divided into three steps: detection, transduction, and asymmetric growth. Of these the second is that on which we have the smallest knowledge. Even though we have in fact some support for a redistribution of auxin as the agent of the graviresponse (Cholodny-Went hypothesis), we still lack of a precise knowledge about the many steps which precede and follow auxin redistribution. We thereore today dispose of the powerful new techniques of molecular genetics, that can help us in dissecting the pathway. By these techniques, as is known, already a number of gravitropic mutants have been isolated in the model plant Arabidopsis, and, in addition, some of the genes involved have been cloned. These findings already permit some speculation about the gravitropic pathway, even though we still are far from an understanding of the process. With the aim thus of obtaining the information we need to elucidate the gravitropic pathway, in the last two years, we performed a screening of some significant collections of Arabidopsis mutants, isolating individuals disturbed in root gravitropism, and starting to clone the involved genes.

Arabidopsis↗

PubMed2003

Multigene analysis of Rb pathway and apoptosis control in esophageal squamous cell carcinoma identifies patients with good prognosis.

Deregulation of cell-cycle G(1)-restriction point control by disruption of Rb-pathway components is a frequent event in cancer. In concert with the inactivation of cell death pathways, such events not only contribute to tumor development but also determine the intrinsic and acquired resistance to cancer therapy and, ultimately, disease prognosis. We previously observed that the cyclin-dependent kinase inhibitor p16(INK4a) and the proapoptotic Bcl-2 homolog Bax are positive prognostic factors and identify patients with good prognosis in esophageal squamous cell carcinoma (SCC). In the present study, we therefore extend our analysis to additional genes controlling the G(1) restriction point and apoptosis, respectively. This retrospective analysis was performed in a cohort of 53 patients undergoing surgery for esophageal SCC with curative intent, i.e., R0 resection. Protein expression profiles of cyclin D1, p16(INK4a), Rb, p21(CIP/WAF-1), p53, Bax and Bcl-2 were analyzed by immunohistochemistry and compared to p53 mutational status, as determined by SSCP-PCR of exons 5-8. Loss of p16(INK4a), Rb, p21(CIP/WAF-1) or Bax and overexpression of cyclin D1 were associated individually with shorter overall survival, while Bcl-2 expression and p53 mutation were not of prognostic relevance. The longest survival was observed in a subgroup of patients whose tumors bore a combination of favorite genotypes, i.e., low cyclin D1 and high Rb, p21(CIP/WAF-1), p16(INK4a) and Bax protein expression. These results show that multigene analyses based on limited sets of functionally linked genes reliably identify patients with good vs. poor prognosis.

Adult↗

PubMed1997

Dose-volume complication analysis for visual pathway structures of patients with advanced paranasal sinus tumors.

PURPOSE: The purpose of the present work was to relate dose and volume information to complication data for visual pathway structures in patients with advanced paranasal sinus tumors. METHODS AND MATERIALS: Three-dimensional (3D) dose distributions for chiasm, optic nerve, and retina were calculated and analyzed for 20 patients with advanced paranasal sinus malignant tumors. 3D treatment planning with beam's eye view capability was used to design beam and block arrangements, striving to spare the contralateral orbit (to lessen the chance of unilateral blindness) and frequently the ipsilateral orbit (to help prevent bilateral blindness). Point doses, dose-volume histogram analysis, and normal tissue complication probability (NTCP) calculations were performed. Published tolerance doses that indicate significant risk of complications were used as guidelines for analysis of the 3D dose distributions. RESULTS: Point doses, percent volume exceeding a specified published tolerance dose, and NTCP calculations are given in detail for patients with complications versus patients without complications. Two optic nerves receiving maximum doses below the published tolerance dose sustained damage (mild vision loss). Three patients (of 13) without optic nerve sparing and/or chiasm sparing had moderate or severe vision loss. Complication data, including individual patient analysis to estimate overall risk for loss of vision, are given. CONCLUSION: 3D treatment planning techniques were used successfully to provide bilateral sparing of the globe for most patients. It was more difficult to spare the optic nerves, especially on the ipsilateral side, when prescription dose exceeded the normal tissue tolerance doses. NTCP calculations may be useful in assessing complication risk better than point dose tolerance criteria for the chiasm, optic nerve, and retina. It is important to assess the overall risk of blindness for the patient in addition to the risk for individual visual pathway structures.

Blindness↗

PubMed1990

Pathways for motion analysis: cortical connections of the medial superior temporal and fundus of the superior temporal visual areas in the macaque.

To identify the cortical connections of the medial superior temporal (MST) and fundus of the superior temporal (FST) visual areas in the extrastriate cortex of the macaque, we injected multiple tracers, both anterograde and retrograde, in each of seven macaques under physiological control. We found that, in addition to connections with each other, both MST and FST have widespread connections with visual and polysensory areas in posterior prestriate, parietal, temporal, and frontal cortex. In prestriate cortex, both areas have connections with area V3A. MST alone has connections with the far peripheral field representations of V1 and V2, the parieto-occipital (PO) visual area, and the dorsal prelunate area (DP), whereas FST alone has connections with area V4 and the dorsal portion of area V3. Within the caudal superior temporal sulcus, both areas have extensive connections with the middle temporal area (MT), MST alone has connections with area PP, and FST alone has connections with area V4t. In the rostral superior temporal sulcus, both areas have extensive connections with the superior temporal polysensory area (STP) in the upper bank of the sulcus and with area IPa in the sulcal floor. FST also has connections with the cortex in the lower bank of the sulcus, involving area TEa. In the parietal cortex, both the central field representation of MST and FST have connections with the ventral intraparietal (VIP) and lateral intraparietal (LIP) areas, whereas MST alone has connections with the inferior parietal gyrus. In the temporal cortex, the central field representation of MST as well as FST has connections with visual area TEO and cytoarchitectonic area TF. In the frontal cortex, both MST and FST have connections with the frontal eye field. On the basis of the laminar pattern of anterograde and retrograde label, it was possible to classify connections as forward, backward, or intermediate and thereby place visual areas into a cortical hierarchy. In general, MST and FST receive forward inputs from prestriate visual areas, have intermediate connections with parietal areas, and project forward to the frontal eye field and areas in the rostral superior temporal sulcus. Because of the strong inputs to MST and FST from area MT, an area known to play a role in the analysis of visual motion, and because MST and FST themselves have high proportions of directionally selective cells, they appear to be important stations in a cortical motion processing system.

Animals↗

PubMed2026

Integrative multi-omics and single-cell analysis identifies EGFR pathway activation and metabolic reprogramming as potential synthetic lethal vulnerabilities in resistance to the FGFR inhibitor AZD4547.

BACKGROUND: Although fibroblast growth factor receptor (FGFR) inhibitors (FGFRi) have demonstrated clinical promise, the inevitable emergence of acquired resistance remains a critical bottleneck, severely compromising their long-term clinical efficacy. The pan-cancer molecular landscape and heterogeneous mechanisms driving this resistance, ranging from genetic alterations to dynamic network rewiring, remain poorly understood. METHODS: We integrated large-scale pharmacogenomic profiling of the FGFR inhibitor AZD4547 from the GDSC2 and PRISM databases with single-cell RNA sequencing to dissect the multi-omics landscape of FGFRi resistance across 312 cell lines from 8 cancer types. This multi-omics framework was further extended by machine learning modeling and systematic synthetic lethality screening to uncover actionable therapeutic targets. In vitro viability assays and western blot analysis were subsequently conducted to experimentally evaluate the predicted FGFR-EGFR synthetic lethality. RESULTS: Our dual-database analysis unveiled a multi-dimensional atlas of FGFRi resistance. We identified cancer-specific genomic drivers, such as ELF4 amplification in glioblastoma, alongside key transcriptomic markers including UCP2 and FSCN1, highlighting a shift towards metabolic reprogramming and epithelial-mesenchymal transition (EMT). Single-cell analysis unveiled that resistance is linked to the heterogeneous enrichment of baseline subpopulations characterized by distinct metaprograms, including cell-cycle dysregulation. Furthermore, a random forest model built on a LASSO-derived transcriptomic signature was constructed, demonstrating promising predictive capability for AZD4547 sensitivity (mean test-set AUC = 0.73, 95% CI [0.63, 0.80]); the signature generalized well to erdafitinib but showed limited transferability to some other FGFR inhibitors (e.g. pemigatinib, BGJ398). Most notably, our synthetic lethal screening revealed a convergent reliance on compensatory RTK signaling (specifically EGFR pathway enrichment) and downstream MAPK/PI3K cascades in resistant phenotypes, providing converging computational evidence for EGFR pathway activation as an adaptive bypass mechanism. This predicted synthetic lethality was experimentally supported in two FGFR-dependent cell line models (RT112 and CCLP1), in which combined FGFR-EGFR inhibition produced marked synergistic antiproliferative effects. CONCLUSIONS: This study establishes a comprehensive multi-omics atlas of resistance to the FGFR inhibitor AZD4547, delineating convergent mechanisms of metabolic reprogramming and EGFR-mediated bypass signaling. Our findings characterize the resistance as a dynamic network rewiring and nominate rational combination strategies to overcome this therapeutic bottleneck. While FGFR-EGFR co-inhibition is experimentally supported, metabolic co-targeting remains a computationally derived, hypothesis-generating strategy.

Benzamides↗

PubMed1998

Stochastic kinetic analysis of developmental pathway bifurcation in phage lambda-infected Escherichia coli cells.

Fluctuations in rates of gene expression can produce highly erratic time patterns of protein production in individual cells and wide diversity in instantaneous protein concentrations across cell populations. When two independently produced regulatory proteins acting at low cellular concentrations competitively control a switch point in a pathway, stochastic variations in their concentrations can produce probabilistic pathway selection, so that an initially homogeneous cell population partitions into distinct phenotypic subpopulations. Many pathogenic organisms, for example, use this mechanism to randomly switch surface features to evade host responses. This coupling between molecular-level fluctuations and macroscopic phenotype selection is analyzed using the phage lambda lysis-lysogeny decision circuit as a model system. The fraction of infected cells selecting the lysogenic pathway at different phage:cell ratios, predicted using a molecular-level stochastic kinetic model of the genetic regulatory circuit, is consistent with experimental observations. The kinetic model of the decision circuit uses the stochastic formulation of chemical kinetics, stochastic mechanisms of gene expression, and a statistical-thermodynamic model of promoter regulation. Conventional deterministic kinetics cannot be used to predict statistics of regulatory systems that produce probabilistic outcomes. Rather, a stochastic kinetic analysis must be used to predict statistics of regulatory outcomes for such stochastically regulated systems.

Bacteriophage lambda↗

PubMed2003

GeneChip analysis of signaling pathways effected by nickel.

The carcinogenicity of nickel compounds has been shown in numerous epidemiological and animal studies. Carcinogenesis is generally considered as a multistep accumulation of genetic alterations. Nickel, however, being highly carcinogenic is only a weak mutagen. We hypothesize that nickel may act by modulating signaling pathways, and subsequently by reprogramming transcription factors. Insoluble nickel is considered to be more carcinogenic than soluble. In this study using GeneChip technology we compared changes in gene expression caused by soluble and insoluble nickel compounds. We found that both soluble and insoluble nickel compounds induce similar signaling pathways following 20 h of in vitro exposure. For example, both nickel compounds activated a number of transcription factors including hypoxia-inducible factor I (HIF-1) and p53. The induction of these important transcription factors exerts potent selective pressure leading to cell transformation. The obtained data are in agreement with our previous observations that acute nickel exposure activates HIF-1 and p53 transcription factors and in nickel-transformed cells, the ratio of HIF-I activity to p53 activity was shifted towards high HIF-I activity. The activation of the same signaling pathways by soluble and insoluble nickel compounds suggested that both nickel compounds have similar carcinogenic potential in vitro.

Animals↗

PubMed1990

Elucidation of the Erwinia uredovora carotenoid biosynthetic pathway by functional analysis of gene products expressed in Escherichia coli.

The most important function of carotenoid pigments, especially beta-carotene in higher plants, is to protect organisms against photooxidative damage (G. Britton, in T. W. Goodwin, ed., Plant Pigments--1988, 1988; N. I. Krinsky, in O. Isler, H. Gutmann, and U. Solms, ed., Carotenoids--1971, 1971). beta-Carotene also functions as a precursor of vitamin A in mammals (G. A. J. Pitt, in I. Osler, H. Gutmann, and U. Solms, ed., Carotenoids--1971, 1971). The enzymes and genes which mediate the biosynthesis of cyclic carotenoids such as beta-carotene are virtually unknown. We have elucidated for the first time the pathway for biosynthesis of these carotenoids at the level of enzyme-catalyzed reactions, using bacterial carotenoid biosynthesis genes. These genes were cloned from a phytopathogenic bacterium, Erwinia uredovora 20D3 (ATCC 19321), in Escherichia coli and located on a 6,918-bp fragment whose nucleotide sequence was determined. Six open reading frames were found and designated the crtE, crtX, crtY, crtI, crtB, and crtZ genes in reference to the carotenoid biosynthesis genes of a photosynthetic bacterium, Rhodobacter capsulatus; only crtZ had the opposite orientation from the others. The carotenoid biosynthetic pathway in Erwinia uredovora was clarified by analyzing carotenoids accumulated in E. coli transformants in which some of these six genes were expressed, as follows: geranylgeranyl PPiCrtB----prephytoene PPiCrtE----phytoeneCrtI---- lycopeneCrtY----beta-caroteneCrtZ----zeaxanthinCrtX--- -zeaxanthin-beta- diglucoside. The carotenoids in this pathway appear to be close to those in higher plants rather than to those in bacteria. Also significant is that only one gene product (CrtI) for the conversion of phytoene to lycopene is required, a conversion in which four sequential desaturations should occur via the intermediates phytofluene, zeta-carotene, and neurosporene.

Amino Acid Sequence↗

PubMed2006

An analysis of reaction pathways for proton tunnelling in methylamine dehydrogenase.

Computational methods have now become a valuable tool to understand the way in which enzymes catalyse chemical reactions and to aid the interpretation of a diverse set of experimental data. This study focuses on the influence of the condensed-phase environment structure on proton transfer mechanisms, with an aim to understand how C-H bond cleavage is mediated in enzymatic reactions. We shall use a combination of molecular simulation, ab initio or semi-empirical quantum chemistry and semi-classical multidimensional tunnelling methods to consider the primary kinetic isotope effects of the enzyme methylamine dehydrogenase (MADH), with reference to an analogous application to triosephosphate isomerase. Analysis of potentially reactive conformations of the system, and correlation with experimental isotope effects, have highlighted that a quantum tunnelling mechanism in MADH may be modulated by specific amino acid residues, such as Asp428, Thr474 and Asp384.

Carbon↗

PubMed1991

Comparative analysis of signaling pathways between mast cell growth factor (c-kit ligand) and granulocyte-macrophage colony-stimulating factor in a human factor-dependent myeloid cell line involves phosphorylation of Raf-1, GTPase-activating protein and mitogen-activated protein kinase.

Mast cell growth factor (MGF, the ligand for c-kit receptor) can stimulate proliferation of factor dependent myeloid cell line, M07e, and MGF synergizes with granulocyte-macrophage colony-stimulating factor (GM-CSF) or IL-3 in this effect. The effect of MGF on protein tyrosine kinase activity in M07e cells was investigated by immunoblotting with anti-phosphotyrosine mAb and this was compared with effects of GM-CSF. MGF stimulation rapidly induced or enhanced at least 12 tyrosine phosphorylated bands. Major bands had molecular weights of 145, 120, 110, 98, 62, 55 and 42 kD. P145, the most prominent phosphorylated protein, was identified as c-kit product using anti-c-kit-mAb (YB5.B8), suggesting ligand-dependent receptor autophosphorylation. Five of six tyrosine phosphorylated bands induced or enhanced by GM-CSF stimulation comigrated with those tyrosine phosphorylated by MGF (138, 120, 76, 55 and 42 kD). P42 was identified, at least in part, as mitogen-activated protein (MAP) kinase. MGF induced tyrosine phosphorylation of a complex of GTPase-activating protein (GAP, 120 kD) and GAP associated proteins (p62/p190) as detected by anti-GAP Ab immunoprecipitation followed by immunoblotting with anti-phosphotyrosine mAb. GM-CSF also stimulated slightly but consistently tyrosine phosphorylation of GAP and p190 but not p62. Both MGF and GM-CSF enhanced Raf-1 phosphorylation and increased Raf-1 associated kinase activity in vitro. Phosphoamino acid analysis revealed Raf-1 phosphorylation by these two growth factors occurred almost exclusively on serine residues. No tyrosine phosphorylation of Raf-1 protein was detected. These data suggest shared and unshared components of signaling pathways of both factors, which may be involved in cell proliferation.

Bone Marrow↗