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Results for “knowledge accumulation”

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PubMed1997

The gene coding for the DOPA dioxygenase involved in betalain biosynthesis in Amanita muscaria and its regulation.

Genomic and cDNA clones derived from the gene (dodA) coding for DOPA dioxygenase, a key enzyme in the betalain pathway, were obtained from the basidiomycete Amanita muscaria. A cDNA library was established in the phage lambda ZapII and dodA clones were isolated using polyclonal antibodies raised against the purified enzyme. Their identity was confirmed by comparison of the deduced amino acid sequence with the sequence of several tryptic peptide fragments of DOPA dioxygenase. The gene coded for a 228-amino acid protein that showed no homology to published sequences. The coding region was interrupted by five short introns. Regulation was shown to occur at the transcriptional level; the mRNA accumulated to high levels only in the coloured cap tissue. dodA was found to be a single-copy gene in A. muscaria. To our knowledge, this is the first gene from the betalain pathway to be cloned. It encodes a type of aromatic ring-cleaving dioxygenase that has not been previously described.

Amanita↗

PubMed2005

Human gross cyst breast disease and cystic fluid: bio-molecular, morphological, and clinical studies.

For more than one and a half century the cystic disease of the breast has been recognized as the most frequent female benign breast lesion. Although some conundrums and controversies exist about the relation between gross cysts and breast cancer, recent evidence suggests that the multidisciplinary study of gross cystic breast disease (GCBD) may be a powerful tool for predicting the natural history of the multifaceted gross cyst pathology. A lot of papers have been published on breast cyst fluids (BCF) concerning biochemical, hormonal and morphological aspects, demonstrating that the intracystic fluid contains a wide variety of components (such as ions, lipids, proteins, enzymes, growth factors and antigens) and suggesting that their profile provides additional knowledge on both physiopathology and etiologic pathways of human gross cystic breast disease. The aim of this overview is the critical evaluation of all data accumulated in the last thirty years, in order to highlight the utility of biochemical and epidemiological studies to identify gross cysts, if any, at higher breast cancer risk.

Biomarkers, Tumor↗

PubMed1993

Cellular automata simulations of fungal growth on solid substrates.

Growth of filamentous fungi on the surface of cereal grains is a critical aspect of solid substrate fermentation (SSF). Numerous mathematical models have been developed to describe various aspects of fungal growth in SSF. These models consider hyphal geometry and nutrient availability as determinants of colony morphology and fungal physiological state. This work describes the use of cellular automata (CA) as an alternative method of modeling fungal growth. CA models reliant on a very limited set of rules or "knowledge base" display a rich array of behaviors that mimic fungal growth. By incorporating probablistic growth rules into CA models, colony characteristics such as biomass accumulation rate, colony radial growth rate, mycelial density and fungal differentiation are readily generated.

Journal Article↗

PubMed2005

Schisandrin B--a novel inhibitor of P-glycoprotein.

P-glycoprotein-mediated drug efflux is one of the major causes of the cancer multidrug resistance (MDR). Inhibition of P-glycoprotein could reverse cancer MDR. Here, we show that schisandrin B, a naturally occurring compound from Schisandra chinensis (Turcz.) Baill, bears strong potency to inhibit P-glycoprotein. Schisandrin B reversed the drug resistance of four MDR cell lines characterized with overexpression of P-glycoprotein and fully restored the intracellular drug accumulation by interacting with P-glycoprotein. Schisandrin B has a core structure of dibenzocyclooctadiene, representing a novel P-glycoprotein inhibitor. To our best knowledge, the role of schisandrin B to inhibit P-glycoprotein has not been reported.

ATP Binding Cassette Transporter, Subfamily B↗

PubMed2001

Cellular pathology and pathogenic aspects of neuronal ceroid lipofuscinoses.

Lysosomal accumulation of autofluorescent, ceroid lipopigment material in various tissues and organs is a common feature of the neuronal ceroid lipofuscinoses (NCLs). However, recent clinicopathologic and genetic studies have evidenced that NCLs encompass a group of highly heterogeneous disorders. In five of the eight NCL variants distinguished at present, genes associated with the disease process have been isolated and characterized (CLN1, CLN2, CLN3, CLN5, CLN8). Only products of two of these genes, CLN 1 and CLN2, have structural and functional properties of lysosomal enzymes. Nevertheless, according to the nature of the material accumulated in the lysosomes, NCLs in humans as well as natural animal models of these disorders can be divided into two major groups: those characterized by the prominent storage of saposins A and D, and those showing the predominance of subunit c of mitochondrial ATP synthase accumulation. Thus, taking into account the chemical character of the major component of the storage material, NCLs can be classified currently as proteinoses. Of importance, although lysosomal storage material accumulates in NCL subjects in various organs, only brain tissue shows severe dysfunction and cell death, another common feature of the NCL disease process. However, the relation between the genetic defects associated with the NCL forms, the accumulation of storage material, and tissue damage is still unknown. This chapter introduces the reader to the complex pathogenesis of NCLs and summarizes our current knowledge of the potential consequences of the genetic defects of NCL-associated proteins on the biology of the cell.

Adolescent↗

PubMed2001

Studies of the microvascular effects of adrenomedullin and related peptides.

Adrenomedullin (ADM) exerts potent vasoactive effects in the microvasculature. These activities have been most extensively studied in the cutaneous microcirculation. In this review we examine the knowledge gained to date of the ability of ADM to influence microvascular effects that include increased blood flow, microvascular permeability (leading to edema formation), neutrophil accumulation and cutaneous thermal hyperalgesia. ADM is structurally related to the vasodilator neuropeptide calcitonin gene-related peptide (CGRP). The peptides are considered to act via a family of receptor activity modifying proteins (RAMPs) that interact with a G-protein linked receptor, calcitonin receptor-like receptor (CRLR). A correlation of microvascular activity with effects mediated via CRLR and RAMP is discussed.

Adrenomedullin↗

PubMed1997

Artemia mitochondrial genome: molecular biology and evolutive considerations.

During the last two decades an increasing amount of information has been accumulated regarding the gene structure and organization of the mitochondrial genome from various organisms. Many studies carried out mainly in mammals, have contributed to the knowledge of the basic elements involved in the replication and transcription of mitochondrial DNA. However, very little is known about these processes in invertebrates. In this review we discuss our current knowledge of the animal mitochondrial genetic system and briefly summarize the structure of the Artemia mitochondrial genome, the characteristics of its transcriptional machinery and how its expression is controlled during early development, in relation with what is known in other organisms. Artemia is the only crustacean where the mtDNA has been studied at this level of detail up to date.

Animals↗

PubMed2002

Understanding the etiology of Stargardt's disease.

Stargardt's disease is a form of juvenille macular degeneration. Patients with Stargardt's disease typically present in the first or second decade of life, complaining of decreased visual acuity. Recent research allows for a three-step explanation of the pathophysiology of Stargardt's disease: 1) Defective Rim Protein, a protein encoded by the ABCA4 gene, causes an accumulation of protonated N-retinylidene-PE in the rod outer segments; 2) A2-E, a byproduct of N-retinylidene-PE, then accumulates in the RPE cells and is toxic to them; 3) Photoreceptors eventually die secondary to loss of the RPE support function. With our new knowledge of the etiology of Stargardt's disease, we can devise future studies directed at treating affected patients.

Humans↗

PubMedDate not supplied

Advances towards understanding heart valve response to injury.

BACKGROUND: Composed of endocardial endothelial, valvular interstitial, cardiac muscle, and smooth muscle cells (SMC), heart valves are prone to various pathologic conditions the morphology of which has been well described. The morphology of diseased valves suggest that the "response to injury" process occurs in these valves, and is associated with an accumulation of interstitial cells and matrix, valvular inflammation and calcification, conditions that lead to dysfunction. The purpose of this study is to describe the current knowledge of the regulation of the valvular "response to injury" process, since we feel that this paradigm is essential to understanding valve disease. METHODS: The pertinent literature relating to the cell and molecular biology of valvular repair, and specifically interstitial cell function in valve repair, is reviewed. RESULTS: The cell and molecular biology of valve interstitial cells are poorly understood. Molecules regulating some of the aspects of the "response to injury" process have been studied, however, the signal transduction pathways, gene activation, and interactions of bioactive molecules with each other, with cells, and with the matrix have not been characterized. Initial studies identify the cell and molecular biology of interstitial cells to be an important area of research. Agents that have been studied include nitric oxide (NO) and FGF-2 and several matrix-related proteins including osteopontin. The present review suggests several directions for future study and a working model of valvular repair is presented. DISCUSSION: The regulation of the "response to injury" process in the human heart valve is still largely unknown. The cell and molecular events and processes that occur in heart valve function and repair remain poorly understood. These events and processes are vital to our understanding of the pathobiology of heart valve disease, and to the successful design of tissue engineered replacement valves.

Endocardium↗

PubMed2002

Drug transport to the brain: key roles for the efflux pump P-glycoprotein in the blood-brain barrier.

1. The blood-brain barrier (BBB) contributes to brain homeostastis and fulfills a protective function by controlling the access of solutes and toxic substances to the central nervous system (CNS). The efflux transporter P-glycoprotein (P-gp) is a key element of the molecular machinery that confers special permeability properties to the BBB. 2. P-gp, which was initially recognized for its ability to expel anticancer drugs from multidrug-resistant cancer cells, is strongly expressed in brain capillaries. Its expression in the BBB limits the accumulation of many hydrophobic molecules and potentially toxic substances in the brain. 3. The purpose of this review is to summarize the current state of knowledge about the expression of P-gp, its cellular localization as well as its possible functions in the BBB.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2003

[Multixenobiotic defense mechanism (MDMX) in bivalves].

Multixenobiotic defence mechanism (MXDM) consists in a cellular system that functions as membrane extrusion pumps effluxing organic compounds out of the cells. In bivalves, it represents a primordial protection against toxic effects of organic xenobiotics in preventing their cellular accumulation. It has raised attention during the last decade for its potential to be used as a biomarker of pollution. This article reviews the fundamental knowledge on the MXDM system in bivalves and the methods proposed to assess its activity. Finally, it reviews the major results of laboratory and field studies that enabled to hypothesise that MXDM could be used as a biomarker of environmental stress rather than of pollutant exposure.

Animals↗

PubMed2001

Ultrasonic tissue characterization: review of an approach to assess hypertrophic myocardium.

It is well known that left ventricular hypertrophy is associated with increased cardiovascular morbidity and mortality. Recently, there has been considerable interest in the application and refinement of noninvasive diagnostic techniques for identification of myocardial tissue composition to permit differentiation between left ventricular hypertrophy that may be associated with irreversible, and therefore, possibly adverse, collagen accumulation ("pathological hypertrophy") as opposed to the type of possibly "benign" hypertrophy devoid of such characteristics (i.e., "physiological hypertrophy"). We review the current state of knowledge in the application of ultrasonic tissue characterization that addresses this question with respect to left ventricular myocardium.

Cardiomyopathies↗

PubMed2005

iGNM: a database of protein functional motions based on Gaussian Network Model.

MOTIVATION: The knowledge of protein structure is not sufficient for understanding and controlling its function. Function is a dynamic property. Although protein structural information has been rapidly accumulating in databases, little effort has been invested to date toward systematically characterizing protein dynamics. The recent success of analytical methods based on elastic network models, and in particular the Gaussian Network Model (GNM), permits us to perform a high-throughput analysis of the collective dynamics of proteins. RESULTS: We computed the GNM dynamics for 20 058 structures from the Protein Data Bank, and generated information on the equilibrium dynamics at the level of individual residues. The results are stored on a web-based system called iGNM and configured so as to permit the users to visualize or download the results through a standard web browser using a simple search engine. Static and animated images for describing the conformational mobility of proteins over a broad range of normal modes are accessible, along with an online calculation engine available for newly deposited structures. A case study of the dynamics of 20 non-homologous hydrolases is presented to illustrate the utility of the iGNM database for identifying key residues that control the cooperative motions and revealing the connection between collective dynamics and catalytic activity.

Algorithms↗

PubMed1995

Predicting the efficacy of antimicrobial agents in respiratory infections--is tissue concentration a valid measure?

Despite methodological and interpretive problems associated with studies of antibiotic concentrations in tissues, it is important to confirm the presence of a drug in significant concentrations in tissues and fluids at a particular site. For antibiotics used in the treatment of community-acquired respiratory infections, tissue distribution at sites of potential infection in the respiratory tree has been related to clinical outcome. Measurement of antibiotic concentrations achieved in lung parenchyma epithelial lining fluid, bronchial mucosa or bronchial secretions has indicated significant levels for beta-lactams and macrolides. Many respiratory infections are caused by obligate or facultative intracellular pathogens, which may be eradicated as a result of intracellular penetration and accumulation of macrolides, as shown in several models of phagocytic cells, and of intracellular antibacterial activities. For bacterial infections located in extracellular pulmonary sites, a knowledge of achievable concentrations of beta-lactam and of macrolides should be of value. For bacteria multiplying in alveolar macrophages the high concentrations of the new macrolides that can be achieved in extravascular and intracellular fluids should have clinical relevance, as shown in this review. Moreover with newer macrolides one may expect a better patient compliance due to prolonged persistence of drug in tissues and cells which results in shorter duration of treatment and once-daily dose administration. Finally, for some sites of infection and particularly in the human respiratory tree, there is a clear relationship between local concentrations and clinical efficacy.

Animals↗

PubMed2004

Inferring pathways and networks with a Bayesian framework.

Numerous mathematical methods have been adapted and developed to quantitatively reverse engineer biological networks, for example, signal transduction pathways, from experimental micro-array data. Compared with stochastic methods, such as Boolean networks, and deterministic methods, such as thermodynamic or differential equation-based models, Bayesian network analysis has the ability to assess, with scoring metrics, causal relations based on conditional probabilities and thus permit hypothesis testing. The goal of this paper is to illustrate the integration of several Bayesian based techniques into a unified Bayesian framework that can infer hepatocellular networks from metabolic data. Reverse engineering of pathways and networks provides a framework for predictive modeling and hypotheses testing to gain deeper insight into living organisms, disease mechanisms, and targeted therapeutics. Evaluating this methodology initially against the known biochemical network provides confidence in the networks that are uncovered from the experimental data using this framework. From the metabolic data we inferred the known sub-networks, such as the tricarboxylic acid (TCA) and urea cycles. In addition, we combined the relationships learned from the data and our current knowledge of the biological system to postulate several alternative metabolic sub-network models that can predict a particular cellular function, such as intracellular triglyceride accumulation.

Algorithms↗

PubMed2006

Exploiting protein structure data to explore the evolution of protein function and biological complexity.

New directions in biology are being driven by the complete sequencing of genomes, which has given us the protein repertoires of diverse organisms from all kingdoms of life. In tandem with this accumulation of sequence data, worldwide structural genomics initiatives, advanced by the development of improved technologies in X-ray crystallography and NMR, are expanding our knowledge of structural families and increasing our fold libraries. Methods for detecting remote sequence similarities have also been made more sensitive and this means that we can map domains from these structural families onto genome sequences to understand how these families are distributed throughout the genomes and reveal how they might influence the functional repertoires and biological complexities of the organisms. We have used robust protocols to assign sequences from completed genomes to domain structures in the CATH database, allowing up to 60% of domain sequences in these genomes, depending on the organism, to be assigned to a domain family of known structure. Analysis of the distribution of these families throughout bacterial genomes identified more than 300 universal families, some of which had expanded significantly in proportion to genome size. These highly expanded families are primarily involved in metabolism and regulation and appear to make major contributions to the functional repertoire and complexity of bacterial organisms. When comparisons are made across all kingdoms of life, we find a smaller set of universal domain families (approx. 140), of which families involved in protein biosynthesis are the largest conserved component. Analysis of the behaviour of other families reveals that some (e.g. those involved in metabolism, regulation) have remained highly innovative during evolution, making it harder to trace their evolutionary ancestry. Structural analyses of metabolic families provide some insights into the mechanisms of functional innovation, which include changes in domain partnerships and significant structural embellishments leading to modulation of active sites and protein interactions.

Algorithms↗

PubMed2006

Mechanisms linking diabetes mellitus to the development of atherosclerosis: a role for endoplasmic reticulum stress and glycogen synthase kinase-3.

Recent decades have seen a significant increase in the incidence of diabetes mellitus. The number of individuals with diabetes is projected to reach 300 million by the year 2025. Diabetes is a leading cause of blindness, renal failure, lower limb amputation, and an independent risk factor for atherosclerotic cardiovascular disease (CVD)--a leading cause of death in Western society. Understanding the molecular and cellular mechanisms by which diabetes mellitus promotes atherosclerosis is essential to developing methods to treat and prevent diabetes-associated CVD. This review summarizes our current knowledge of the mechanisms by which diabetes may promote atherogenesis and specifically focuses on a novel pathway linking these 2 conditions. We hypothesize that the accumulation of intracellular glucosamine observed in conditions of chronic hyperglycaemia may promote atherogenesis via a mechanism involving dysregulated protein folding, activation of endoplasmic reticulum (ER) stress, and increased glycogen synthase kinase (GSK)-3 activity. The identification of this novel mechanism provides a promising hypothesis and multiple new targets for potential therapeutic intervention in the treatment of diabetes mellitus and accelerated atherosclerosis.

Animals↗

PubMed1990

Mucosal inflammation in asthma.

Over the past decade, it has become increasingly recognized that airways inflammation is one of the major components of asthma. Until recently, measurements of bronchial responsiveness and mediators of allergic reactions were the only methods of studying pathogenetic mechanisms in asthma. With improved diagnostic procedures such as fiberoptic bronchoscopy, it has become possible to investigate these mechanisms and the resulting inflammatory changes in situ. BAL has highlighted the presence of mast cells and eosinophils and has given proof of their mediator participation in airways inflammation and hyperresponsiveness. Endobronchial biopsies have so far yielded results that are similar to those obtained from postmortem studies, although it appears that there are varying degrees of inflammation in living asthmatics. Even in mild disease, the histopathologic features of bronchial asthma are consistent with chronic inflammation. Indirect evidence obtained from allergen challenge leading to increased bronchial hyperresponsiveness during LAR, and direct evidence of inflammatory cells and their mediators in the airway mucosa and lumen after allergen challenge argue for an active role of cells in bringing about inflammatory changes. At present, however, it is not possible to relate precisely the findings obtained by bronchoscopy to the clinical presentation and progression of asthma. Cell activation with production of potent mediators of inflammation may be more relevant to inflammation than the simple presence of these cells in the airways. Almost all the inflammatory cells present in the bronchial wall and lumen have been implicated in the pathogenesis of mucosal inflammation in asthma, but with our current state of knowledge, none can be singled out as the most important contributor. The mast cell was the first to be investigated in depth, and despite the accumulation of large amounts of data concerning its ultrastructure and function, it remains uncertain to what extent this cell is involved in inflammatory responses. Thus, while its main role appears to be that of initiator of allergen-induced responses, the eosinophil has attracted more attention as a proinflammatory cell rather than as an antiinflammatory cell with a capacity to be selectively recruited from the circulation in response to IgE-dependent signals. The eosinophil secretes potent mediators that cause damage to the bronchial epithelium and lead to bronchoconstriction. The role of other cells is at present not as well defined.(ABSTRACT TRUNCATED AT 400 WORDS)

Asthma↗