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Results for “Pathway informed transformer”

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At least 127 records · Page 7Linked to original sources

PubMed2004

Smad3 deficiency attenuates renal fibrosis, inflammation,and apoptosis after unilateral ureteral obstruction.

BACKGROUND: Transforming growth factor-beta (TGF-beta) has been implicated in the development of renal fibrosis induced by unilateral ureteral obstruction (UUO). However, there is little information on signaling pathways mediating TGF-beta activity involved in molecular and cellular events leading to renal fibrosis induced by UUO. In this study, we sought to determine whether Smad3, a major signaling component of TGF-beta, mediated renal fibrosis induced by UUO. METHODS: Renal fibrosis, inflammation, and apoptosis induced by UUO were macroscopically and histologically compared between wild-type mice and Smad3 null mice. RESULTS: Gross appearance of the kidney after UUO showed relatively intact kidney in Smad3 null mice [Smad3(-/-) mice] when compared with that of wild-type mice [Smad3(+/+) mice]. Renal interstitial fibrosis based on the interstitial area stained with Aniline-blue or Sirius red solution was significantly attenuated in the obstructed kidney of Smad3(-/-) mice when compared with that of Smad3(+/+) mice. Deposition of type I and type III collagens were also significantly reduced in the obstructed kidney of Smad3(-/-) mice. In addition, the numbers of myofibroblasts, macrophages, and CD4/CD8 T cells infiltrated into the kidney after UUO were significantly attenuated in the obstructed kidney of Smad3(-/-) mice when compared with that of Smad3(+/+) mice. Furthermore, terminal deoxynucleotidyltransferase-mediated deoxyuridine triphosphate (dUTP) nick-end labeling (TUNEL) staining after UUO showed significantly reduced number of tubular apoptotic cells in the obstructed kidney of Smad3(-/-) mice when compared with that of Smad3(+/+) mice. Endogenous Smad pathway was activated in the obstructed kidney after UUO in wild-type mice as judged by the increase of phosphorylated Smad2 or phosphorylated Smad2/3-positive cells in renal interstitial area. CONCLUSION: Smad3 deficiency attenuated renal fibrosis, inflammation, and apoptosis after UUO, suggesting that Smad3 was a key molecule mediating TGF-beta activity leading to real fibrosis after UUO.

Animals↗

PubMed1983

Temporal selectivity in the central auditory system of the leopard frog.

Amplitude modulation is a predominant temporal feature in many vocal signals. The leopard frog, Rana pipiens, has a class of neurons in the central auditory system that respond selectively to particular rates of amplitude modulation; these neurons can be characterized by a temporal tuning curve. Such selectivity is absent in the peripheral auditory system. This type of transformation may be fundamental in processing temporal information in the vertebrate sensory nervous system.

Animal Communication↗

PubMed1993

Antigens targeted to the Leishmania phagolysosome are processed for CD4+ T cell recognition.

Processing of antigen for recognition by class II-restricted CD4+ T cells occurs within acidic compartments of the antigen-presenting cell. The exact nature of this compartment has yet to be precisely defined, however, but may vary depending upon the cell type studied and the antigen used. The acidic compartments of macrophages are also responsible for the degradation of ingested micro-organisms and play host to others which are adapted to an intracellular existence. To determine whether the phagolysosome (PL) formed in activated macrophages after ingestion of Leishmania parasites is also a site for entry of antigen into the class II presentation pathway, we have used the approach of genetic transformation. Hence, Leishmania were transfected with the genes for the protein antigens ovalbumin (OVA) and beta-galactosidase (beta-gal) and after infection were able to deliver these antigens specifically into the PL. Delivery of antigen to this site resulted in the ability of infected macrophages to present these antigens to antigen-specific CD4+ T cells. After taking into account the absolute levels of antigen uptake by macrophages, a 4-h processing period for OVA delivered by this or a soluble route led to equivalent levels of T cell activation. Unlike macrophages pulsed with soluble OVA, those with PL-targeted OVA still retained the ability to stimulate T cells after a 24-h processing period. This enhanced lifespan of antigen in macrophages corresponded to the kinetics of degradation of the parasite, suggesting slow release of antigen into the processing pathway. beta-gal presentation from the PL was tenfold less efficient under the same conditions. In addition to providing the first information on antigen processing in a protozoan PL, these studies highlight the usefulness of genetically transformed parasites for these types of studies.

Animals↗

PubMed2026

Proteomics as a theranostic compass in BCR::ABL1-negative myeloproliferative neoplasms: Integrating biomarker discovery with therapeutic stratification.

Classic BCR::ABL1-negative myeloproliferative neoplasms (MPNs)-polycythaemia vera, essential thrombocythaemia, and primary myelofibrosis-are clonal haematopoietic stem cell disorders with marked heterogeneity in clinical phenotype, disease trajectory, and therapeutic response. Genomic stratification by driver and cooperating mutations only partially accounts for this variability, leaving gaps in predicting thrombotic risk, fibrotic progression, leukaemic transformation, and treatment benefit. Proteomics bridges this gap by providing function-proximal readouts of protein abundance, post-translational modifications, pathway activity, and intercellular signalling that genomics and transcriptomics cannot capture, positioning it as a theranostic platform in which the same molecular readouts simultaneously inform diagnostic stratification and therapeutic decision-making. We propose a five-stage translational framework spanning from discovery-scale mass spectrometry and affinity-based plasma profiling to targeted validation, multicentre standardisation, and machine learning-integrated clinical panels. Proteomic evidence is synthesised across the following four disease axes: clonal fitness in haematopoietic stem and progenitor cells; bone marrow microenvironmental remodelling and fibrosis; chronic inflammation and thrombosis; and leukaemic transformation. We further describe how phosphoproteomics reveals resistance mechanisms to JAK inhibitors, including AXL-MAPK bypass and PP2A-autophagy-mediated tolerance, and how protein-level biomarkers (BCL2-BCL-XL, RAS-ERK, CAMK2G, and ROCK1/2) can guide individualised therapeutic selection. Affinity-based platforms (Olink PEA and SomaScan) and spatially resolved technologies (CODEX and single-cell proteomics) complement discovery proteomics. At present, however, this evidence base is constrained by small and heterogeneous cohorts, limited cross-platform reproducibility, and a scarcity of independent external validation for candidate protein panels. Realising this vision will require multicentre standardisation, analytically validated panel assays, and prospective clinical studies that translate molecular findings into decision-grade tools for patients with MPNs.

Humans↗

PubMed1990

The MRC-5 human embryonal lung fibroblast two-dimensional gel cellular protein database: quantitative identification of polypeptides whose relative abundance differs between quiescent, proliferating and SV40 transformed cells.

A new version of the MRC-5 two-dimensional gel cellular protein database (Celis et al., Electrophoresis 1989, 10, 76-115) is presented. Gels were scanned with a Molecular Dynamics laser scanner and processed by the PDQUEST II software. A total of 1895 [35S]methionine-labeled cellular polypeptides (1323 with isoelectric focusing and 572 with nonequilibrium pH gradient electrophoresis) are recorded in this database, containing quantitative and qualitative data on the relative abundance of cellular proteins synthesized by quiescent, proliferating and SV40 transformed MRC-5 fibroblasts. Of the 592 proteins quantitated so far, the levels of 138 were up- or down-regulated (51 and 87, respectively) by two times or more in the transformed cells as compared to their normal proliferating counterparts, while only 14 behaved similarly in quiescent cells. Seven MRC-5 SV40 proteins, including plastin and two interferon-induced proteins, were not detected in the master MRC-5 images. The identity of 36 of the transformation-sensitive proteins whose levels are up or down regulated by two times or more was determined and additional information can be transferred from the master transformed human epithelial amnion cells (AMA) database (Celis et al., Electrophoresis 1990, 11, 989-1071) for those polypeptides of known and unknown identity that have been matched to AMA polypeptides. As more information is gathered in this and other laboratories, including data on oncogene proteins and transcription factors, this comprehensive database will outline an integrated picture of the expression levels and properties of the thousands of protein components of organelles, pathways and cytoskeletal systems that may be directly or indirectly involved in properties associated with the transformed state.

Cell Transformation, Viral↗

PubMed2004

Novel biocatalysis by database mining.

Broad-based adoption of biocatalytic methods will require widely available database tools, analogous to previous efforts compiling information for the facilitation of chemical synthesis. The analog to chemical reagents are enzymes. The analog to chemical synthetic routes are metabolic pathways. The free on-line database BRENDA exemplifies efforts to compile relevant information on enzymes for biocatalytic purposes. Likewise, the University of Minnesota Biocatalysis/Biodegradation Database focuses on novel enzymes and metabolic pathways useful in environmental and industrial biotechnology. The development of biocatalytic protocols will be facilitated by the increasing availability of well-curated database information on enzymatic enantioselectivity and capabilities for transforming disparate chemical functional groups.

Catalysis↗

PubMed2004

Signalling pathways in the molecular pathogenesis of ovarian granulosa cell tumours.

Granulosa cell tumours represent approximately 5% of all malignant ovarian tumours. They exhibit many morphological, biochemical and hormonal features of proliferating normal preovulatory granulosa cells, including both estrogen and inhibin biosynthesis. The aetiology of these tumours remains unclear, although many recent studies and several animal models have focused on signalling pathways that are known to be important in the regulation of granulosa cell proliferation. Here, we discuss the information currently available about the possible molecular changes that might lead to neoplastic transformation in human granulosa cells. The identification of these changes might lead not only to improved diagnosis, management and treatment of granulosa cell tumours, but could also offer new insights into normal granulosa cell biology.

Animals↗

PubMed2000

Insight into the tumor suppressor function of CBP through the viral oncoprotein tax.

CREB binding protein (CBP) is a cellular coactivator protein that regulates essentially all known pathways of gene expression. The transcriptional coactivator properties of CBP are utilized by at least 25 different transcription factors representing nearly all known classes of DNA binding proteins. Once bound to their target genes, these transcription factors are believed to tether CBP to the promoter, leading to activated transcription. CBP functions to stimulate transcription through direct recruitment of the general transcription machinery as well as acetylation of both histone and transcription factor substrates. Recent observations indicate that a critical dosage of CBP is required for normal development and tumor suppression, and that perturbations in CBP concentrations may disrupt cellular homeostasis. Furthermore, there is accumulating evidence that CBP deregulation plays a direct role in hematopoietic malignancies. However, the molecular events linking CBP deregulation and malignant transformation are unclear. Further insight into the function of CBP, and its role as a tumor suppressor, can be gained through recent studies of the human T-cell leukemia virus, type I (HTLV-I) Tax oncoprotein. Tax is known to utilize CBP to stimulate transcription from the viral promoter. However, recent data suggest that as a consequence of the Tax-CBP interaction, many cellular transcription factor pathways may be deregulated. Tax disruption of CBP function may play a key role in transformation of the HTLV-I-infected cell. Thus, Tax derailment of CBP may lend important information about the tumor suppressor properties of CBP and serve as a model for the role of CBP in hematopoietic malignancies.

Animals↗

PubMed1998

Experimental tumour induction by SV40 transformed cells.

Although SV40 transforms cells from many species, transformed cells from species other than the Syrian hamster are rarely tumorigenic in immunocompetent animals. However, secondary manipulations of SV40-transformed cells can result in increased tumorigenicity. Some early observations on tumour induction by SV40 and transformed cells will be followed by a selected review of evidence suggesting that tumorigenicity of SV40-transformed cells involves serial mutations. An SV40-transformed rat cell model will be described to illustrate the changes in tumorigenic phenotype that can occur during tumour progression. This information will be used to propose that SV40 immortalization of cells (other than hamster cells) is only the first in a series of steps in the pathway toward tumorigenicity and that a complete understanding of the oncogenicity of SV40 will require definition of the secondary genetic events which complement SV40 immortalization to create the fully tumorigenic phenotype.

Animals↗

PubMed1984

State of research: environmental pathways and food chain transfer.

Data on the chemistry of biologically active components of petroleum, synthetic fuel oils, certain metal elements and pesticides provide valuable generic information needed for predicting the long-term fate of buried waste constituents and their likelihood of entering food chains. Components of such complex mixtures partition between solid and solution phases, influencing their mobility, volatility and susceptibility to microbial transformation. Estimating health hazards from indirect exposures to organic chemicals involves an ecosystem's approach to understanding the unique behavior of complex mixtures. Metabolism by microbial organisms fundamentally alters these complex mixtures as they move through food chains. Pathway modeling of organic chemicals must consider the nature and magnitude of food chain transfers to predict biological risk where metabolites may become more toxic than the parent compound. To obtain predictions, major areas are identified where data acquisition is essential to extend our radiological modeling experience to the field of organic chemical contamination.

Air Pollutants↗

PubMed2002

Rationale for a tissue-based selenium criterion for aquatic life.

This paper proposes a national tissue-based criterion for the protection of aquatic life in the United States based on the growing body of selenium literature, but may be of international importance due to the raising global awareness of selenium contamination. A recent peer consultation workshop was undertaken by the US Environmental Protection Agency to address the technical issues underlying the freshwater aquatic life chronic criterion for selenium. The workshop participants discussed concerns associated with three possibilities for a new criterion: a water-based criterion, a tissue-based criterion, and a sediment-based criterion. Since the current national water quality criterion was established in 1987, several publications have reported adverse effects in fish from dietary selenium exposure with waterborne concentrations below the current criterion of 5 microg/l. Based on this literature, a water-based criterion seems unsuitable because of the propensity for selenium to bioaccumulate through the food chain to toxic dietary concentrations. There is little information to support a sediment-based criterion. A tissue-based criterion accounts for selenium's biogeochemical pathways because it integrates the route, duration, and magnitude of exposure, chemical form, metabolic transformations, and modifying biotic and abiotic factors. The convergence of laboratory and field data shows 4 microg/g to be a conservative value for a national tissue-based criterion for selenium.

Animals↗

PubMedDate not supplied

Deconstructing clinical pathways: mapping the landscape of health care.

Grounded in a critical feminist methodology, this article undertakes a deconstructive discourse analysis of a newly emergent discourse within nursing care management, "clinical pathways." Using a Foucaultian approach to deconstructive discourse analysis, the power relations inherent in the "clinical pathways" discourse are identified and the underlying philosophical assumptions informing the discourse are explored. The metaphors of "map" and "landscape" are employed to examine the power relations within the discourse of "clinical pathways." Finally, an alternative, praxis-based approach to transforming the discourse of "clinical pathways" from a focus of social control to one of situated engagement and community is proposed.

Critical Pathways↗

PubMed2000

Use of oligonucleotide arrays to analyze drug toxicity.

The advent of oligonucleotide arrays allows the simultaneous analysis of the expression of thousands of genes. This powerful technology, highly dependent on advanced analysis tools, can transform the level of information currently available on the mechanisms underlying drug-related toxicity. It is now possible to analyze the global transcriptional response to a drug and determine the global pathways associated with the effects of this agent. This analysis can be performed on samples from patients that developed a toxic effect, on cells exposed to the toxic agent, and in animal models of toxicity. Especially useful is the comparison of transcriptional responses in animals susceptible to drug-induced disease with those of genetically modified animals that are resistant to this effect. This analytic strategy allows the delineation of specific mechanisms relevant and specific to drug-induced toxicity and thus might lead to novel therapeutic interventions in these toxic reactions.

Animals↗

PubMed2006

Cytokines in atherosclerosis: pathogenic and regulatory pathways.

Atherosclerosis is a chronic disease of the arterial wall where both innate and adaptive immunoinflammatory mechanisms are involved. Inflammation is central at all stages of atherosclerosis. It is implicated in the formation of early fatty streaks, when the endothelium is activated and expresses chemokines and adhesion molecules leading to monocyte/lymphocyte recruitment and infiltration into the subendothelium. It also acts at the onset of adverse clinical vascular events, when activated cells within the plaque secrete matrix proteases that degrade extracellular matrix proteins and weaken the fibrous cap, leading to rupture and thrombus formation. Cells involved in the atherosclerotic process secrete and are activated by soluble factors, known as cytokines. Important recent advances in the comprehension of the mechanisms of atherosclerosis provided evidence that the immunoinflammatory response in atherosclerosis is modulated by regulatory pathways, in which the two anti-inflammatory cytokines interleukin-10 and transforming growth factor-beta play a critical role. The purpose of this review is to bring together the current information concerning the role of cytokines in the development, progression, and complications of atherosclerosis. Specific emphasis is placed on the contribution of pro- and anti-inflammatory cytokines to pathogenic (innate and adaptive) and regulatory immunity in the context of atherosclerosis. Based on our current knowledge of the role of cytokines in atherosclerosis, we propose some novel therapeutic strategies to combat this disease. In addition, we discuss the potential of circulating cytokine levels as biomarkers of coronary artery disease.

Animals↗

PubMed2005

Coding of color and form in the geniculostriate visual pathway (invited review).

We review how neurons in the principal pathway connecting the retina to the visual cortex represent information about the chromatic and spatial characteristics of the retinal image. Our examination focuses particularly on individual neurons: what are their visual properties, how might these properties arise, what do these properties tell us about visual signal transformations, and how might these properties be expressed in perception? Our discussion is inclined toward studies on old-world monkeys and where possible emphasizes quantitative work that has led to or illuminates models of visual signal processing.

Action Potentials↗

PubMed2004

HIP1: trafficking roles and regulation of tumorigenesis.

During recent years, alterations in proteins of the endocytic pathway have been associated with tumors. Disrupted regulation of the endocytic pathway is a relatively unstudied mechanism of tumorigenesis, which can concomitantly disrupt several different signaling pathways to affect growth, differentiation and survival. Several endocytic proteins have been identified, either as part of tumor-associated translocations or to have the ability to transform cells. Here, we summarize the information known about huntingtin interacting protein 1 (HIP1), an endocytic protein with transforming properties that is involved in a cancer-causing translocation and which is overexpressed in a variety of human cancers. We describe the known normal functions of HIP1 in endocytosis and receptor trafficking, the evidence for its role as an oncoprotein and how HIP1 might be altered to promote tumorigenesis.

Alleles↗

PubMed1996

Ras effectors.

The search for proteins which interact with the active GTP-bound form of Ras in order to transmit signals for proliferation, differentiation and oncogenesis has been a long one. Now there are several strong candidates for Ras effectors that include protein kinases, lipid kinases and guanine nucleotide exchange factors. Structural information on how one Ras-binding domain in an effector interacts with Ras.GTP has recently been obtained. Recent data show that transformation by Ras oncoproteins requires the activation of several signal transduction pathways, including those which transmit signals via members of the Rho family of GTPases.

Animals↗

PubMed1992

Metabolism of the Catharanthus alkaloids: from Streptomyces griseus to monoamine oxidase B.

More than three decades after their discovery and implementation in medicine, essentially nothing is known about the metabolism or the implications of metabolism in mechanism of action or toxicity of the Catharanthus alkaloids. The frustrating paucity of information about pathways of metabolism has limited a major source of structure-activity relationship information and has blocked a critical avenue necessary for the logical development of new and more useful Catharanthus alkaloids. Microbial transformations, peroxidases, copper oxidases, mouse and rat cytochrome P-450 systems, and mouse brain and bovine liver monoamine oxidase (MAO) preparations have been explored in the study of Catharanthus alkaloid metabolism. In this report, we present results which have clarified the involvement of enzymatic and chemically catalyzed one-electron oxidations that yield nitrogen-centered cation radicals, iminium, and carbinolamine intermediates, all of which explain how new carbon-carbon and carbon-oxygen bonds form, or break and rearrange. The dimeric Catharanthus alkaloids are recalcitrant to oxidations catalyzed by monoamine oxidases and to both normal and induced P-450 rat microsomal preparations. However, the Catharanthus alkaloids appear to be selective reversible inhibitors of MAO-B. Chemical and biochemical aspects of the metabolic transformations of dimeric Catharanthus alkaloids are reviewed together with the implications of our findings.

Animals↗