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Results for “Pathway informed transformer”

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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↗

PubMedDate not supplied

Biocatalysis, biodegradation and bioinformatics.

Biocatalysis, biodegradation and bioinformatics are prominent scientific fields in industrial microbiology and biotechnology. This paper describes developments in these fields with a focus on the role of David T Gibson as a researcher and mentor. He has pioneered studies on the mechanisms by which aerobic microorganisms transform aromatic hydrocarbons. In addition, his research has served as a model for further investigations into bacterial atrazine and dichloromethane catabolism described here. Microbial catabolism research requires information on organic chemistry, microorganisms, metabolic pathways, catabolic genes, and enzymes. These information needs are now being met more comprehensively by development of the University of Minnesota Biocatalysis/Biodegradation Database.

Bacteria↗

PubMed1990

Neuroblastoma--clinical applications of molecular parameters.

At least two genetic events have been identified which are characteristic of certain neuroblastomas. These are loss of a critical region on the short arm of chromosome 1, and amplification of the MYCN proto-oncogene. Our studies suggest that the two genetic events may be related, and that loss of heterozygosity (LOH) for chromosome 1p may precede the development of amplification. RAS gene mutations appear to be rare, and no other oncogene has been shown to be consistently activated by amplification or other mechanism. LOH for chromosome 14q has been identified recently, but its frequency and significance is not clear. Based on flow cytometric analysis of DNA content, tumour cytogenetics and molecular studies, three distinct genetic subsets of neuroblastomas are emerging. The first is characterized by a hyperdiploid or near-triploid modal karyotype, with few if any cytogenetic rearrangements. These patients are generally less than one year of age with localized disease and a good prognosis. The second group is characterized by a near-diploid or near-tetraploid karyotype, with no consistent rearrangement identified to date. They are generally older patients with more advanced stages of disease that progress slowly and are ultimately fatal. The third group is characterized by a near-diploid or tetraploid karyotype, with deletions or LOH for chromosome 1p, amplification of MYCN, or both. These patients are generally older with advanced stages of disease which is rapidly progressive. Thus, genetic analysis of neuroblastoma cells by karyotype, flow cytometry and determination of MYCN copy number provides information that has prognostic significance and can more appropriately direct the choice of treatment. A better understanding of these genetic abnormalities and the biochemical pathways that they effect may provide insights into malignant transformation and progression, as well as provide targets for future therapeutic approaches.

Aneuploidy↗

PubMed2001

Alterations of cell-mediated immunity following cardiac operations: clinical implications and open questions.

Cardiac surgery with cardiopulmonary bypass (CPB) is known to induce an immune response whose nature has been increasingly elucidated during the recent decade. Clinically, patients usually show two to three of the four symptoms, which define the so-called systemic inflammatory response syndrome (SIRS). In addition, all parameters of the innate, nonspecific immune system, e.g., polymorphonuclear cells, elastase, and complement, are activated. This also applies to the proinflammatory mediators interleukin (IL)-1beta, -6, and -8, and tumor necrosis factor (TNF)-alpha. Within the adaptive, specific immune system, a decrease of T lymphocytes and T helper (TH) cells is observed, whereas suppressor/ cytotoxic T cells and B cells appear to be nearly unaffected. Cytokine measurements provide more detailed information: IL-2 and IL-12, which are important for the activation of the type-1 TH-cell (TH1)-mediated immune response, are depressed following cardiac operation. In contrast, IL-10 and transforming growth factor-beta essential to TH2-mediated humoral or anti-inflammatory immune response, are upregulated. In vivo tests, e.g., delayed type hypersensitivity skin reaction and tetanus antibody production, confirm the polarization of the adaptive immune response towards the TH2 pathway. However, all these alterations usually do not result in clinical adverse events. Therefore, more information is needed about the immune response of patients at high preoperative risk or with serious perioperative complications to find out whether clinically relevant events are correlated to alterations of immune response. For this purpose, more readily available, standardized methods for immunologic monitoring appear highly desirable.

Cardiac Surgical Procedures↗

PubMed2003

Somatosensory imprinting in spinal reflex modules.

Understanding how sensory information is used by motor systems for motor commands requires detailed knowledge about how the body shape and biomechanics are represented in the motor circuits. We have used the withdrawal reflex system as a model for studies of sensorimotor transformation. This system has a modular organisation in the adult. Each module performs a detailed and functionally adapted sensorimotor transformation related to the withdrawal efficacy of its output muscle(s). The weight distribution of the cutaneous input to a module is determined by the pattern of withdrawal efficacy of the muscle. Recently, we found that the somatotopic organisation and weight of the cutaneous input to the dorsal horn of the lower lumbar cord is related to this modular organisation. The dorsal horn in the lower lumbar cord thus appears to be organised in a column-like fashion, where each column performs a basic sensorimotor transformation related to the movement caused by a single muscle and the body shape. Since the withdrawal reflex system encodes error signals to the cerebellum through some of the spino-olivo cerebellar pathways, the modular concept is, in fact, a key to understanding sensory processing in higher order motor systems as well. Developmental studies indicate that each module is a self-organising circuitry that uses sensory feedback on muscle contractions to adjust its synaptic organisation. Furthermore, these studies suggest that the spontaneous movements during development, by providing structured sensory information related to movement pattern of single muscles and body shape, are instrumental in shaping the sensorimotor transformation in the spinal cord. These findings and their implications for the understanding of higher motor functions and their clinical aspects will be discussed.

Animals↗

PubMed2004

Unraveling human tumor suppressor pathways: a tale of the INK4A locus.

Research on tumor suppressors has for a long time run on two tracks: analysis of the mutations found in human tumor material, and active genetic manipulation in mice. As primary human cells were not easily amenable to genetic alterations, the proof to designate a suspected gene as a tumor suppressor was often by generation of knockout mice and analysis of their phenotypes. In this way, a vast amount of information has been gathered on the actions of major players in carcinogenesis. However, it has recently become apparent that there are major differences in the requirements for oncogenic transformation between human and mouse cells. Among these are the expression of hTERT, SV40 small t, and the response to Ras induced growth arrest by the tumor suppressor pathways involving p53, pRb and the INK4A locus. The potential contribution of these tumor suppressors to the prevention of transformation of human cells can now begin to be unraveled by the recent emergence of novel RNA interference genetic tools.

Animals↗

PubMed2006

The role of the NKG2D receptor for tumor immunity.

Natural killer (NK) cells have originally been identified based on their capacity to kill transformed cells in a seemingly non-specific fashion. Over the last 15 years, knowledge on receptor ligand systems used by NK cells to specifically detect transformed cells has been accumulating rapidly. One of these receptor ligand systems, the NKG2D pathway, has received particular attention, and now serves as a paradigm for how the immune system is able to gather information about the health status of autologous host cells. In addition to its significance on NK cells, NKG2D, as well as other NK cell receptors, play significant roles on T cells. This review aims at summarizing recent insights into the regulation of NKG2D function, the control over NKG2D ligand expression and the role of NKG2D in tumor immunity. Finally, we will discuss first attempts to exploit NKG2D function to improve immunity to tumors.

Animals↗

PubMed1998

The blooming of grass flower development.

The past half decade has provided a wealth of information concerning the molecular and genetic control of floral organ and meristem identity in dicotyledonous plants. Comparatively little is understood about these processes in grass species in spite of the importance that these species play in human agriculture. The isolation of grass genes that are homologous to dicot floral homeotic genes in combination with recent advances in reverse genetic technology and improvements in cereal transformation opens the door for understanding molecular mechanisms of grass flower development. Such information will also focus attention on the evolutionary relationships between grass and dicot flowers and the degree to which the developmental pathways leading to reproductive organ development in divergent angiosperms have utilized conserved mechanisms.

Cloning, Molecular↗

PubMed1978

Transport and transportation pathways of hazardous chemicals from solid waste disposal.

To evaluate the impact of hazardous chemicals in solid wastes on man and other organisms, it is necessary to have information about amounts of chemical present, extent of exposure, and chemical toxicity. This paper addresses the question of organism exposure by considering the major physical and biological transport pathways and the physicochemical and biochemical transformations that may occur in sediments, soils, and water. Disposal of solid wastes in both terrestrial and oceanic environments is considered. Atmospheric transport is considered for emissions from incineration of solid wastes and for wind resuspension of particulates from surface waste deposits. Solid wastes deposited in terrestrial environments are subject to leaching by surface and ground waters. Leachates may then be transported to other surface waters and drinking water aquifers through hydrologic transport. Leachates also interact with natural organic matter, clays, and microorganisms in soils and sediments. These interactions may render chemical constituents in leachates more or less mobile, possibly change chemical and physical forms, and alter their biological activity. Oceanic waste disposal practices result in migration through diffusion and ocean currents. Surface area-to-volume ratios play a major role in the initial distributions of chemicals in the aquatic environment. Sediments serve as major sources and sinks of chemical contaminants. Food chain transport in both aquatic and terrestrial environments results in the movement of hazardous chemicals from lower to higher positions in the food web. Bioconcentration is observed in both terrestrial and aquatic food chains with certain elements and synthetic organics. Bioconcentration factors tend to be higher for synthetic organics, and higher in aquatic than in terrestrial systems. Biodilution is not atypical in terrestrial environments. Synergistic and antagonistic actions are common occurrences among chemical contaminants and can be particularly important toxicity considerations in aquatic environments receiving runoff from several terrestrial sources.

Animals↗

PubMed2007

Expression profiling and lung cancer development.

Recent lung cancer research has been directed to using molecular approaches to facilitate early diagnosis, to identify clinically relevant biological factors associated with histologic heterogeneity, and to identify novel therapeutic agents. This research takes advantage of technical advances that allow rapid high throughput assays to interrogate the genome, proteome, and epigenome. In this review of gene expression profiling in lung carcinogenesis, we will focus upon recent advances in the understanding of malignant transformation of lung epithelial cells and of lung cancer differentiation and progression. These studies have provided important information about the genomic alterations of tobacco smoke-associated airway field carcinogenesis and about the developmental pathways that mediate lung tumor invasion and histologic differentiation in response to injury.

Adenocarcinoma↗

PubMed2006

Sonic hedgehog signaling in forebrain development and its interactions with pathways that modify its effects.

During the development of the nervous system and other organs in the embryo, a limited set of master signaling pathways are used repeatedly for induction, patterning and growth. Among these, the Sonic hedgehog (Shh) pathway is crucial for the development of many structures in the brain. How the context-specific interplay between these various signaling pathways produces distinct temporal and spatial outcomes is not clear. Resolving this problem is a major goal in the study of cell and organ development. Here, we focus on signaling events during dorso-ventral patterning of the embryonic forebrain in vertebrates. In particular, we discuss the role of the Shh pathway in this process and on its interactions with the FGF, retinoic acid and Nodal pathways and other information cascades that modify its effects.

Animals↗

PubMed1976

Retinotectal system of the tortoise, Testudo horsfieldi, Gray (morpho-functional study in the norm and after enucleation).

The optic nerve and mesencephalic optic centre (tectum opticum, TO) of the tortoise, Testudo horsfieldi, Gray, in the norm and after the enucleation have been studies using Golgi's method, electron microscopy and the electrophysiological technique. The optic nerve comprises about 400,000 fibres represented by two classes of axons: myelinated (10%) and unmyelinated (90%). The diameters of the former vary within 0.3-3 mum, of the latter within 0.3-1.1 mum. The neurogramms of the optic nerve contain two components corresponding to the two rates of conduction through different groups of fibres (1.3 musec and 0.5 musec). The stratified synaptic organization of the TO has been investigated. The optic terminals are shown to join in complex synaptic formations at certain levels of the upper layers of the TO (Strata I, II and III). The process of degeneration in the optic system of Testudo is drastically stretched in time. It was demonstrated by the electrophysiological control that the TO potentials induced in response to the nerve stimulation were not registered any longer only 6-6.5 months after the enucleation. Certain groups of retinal fibres of the optic nerve and their terminals in the TO are shown to degenerate differently and asynchronously. Earlier unknown types of destructive changes of the terminals (vesicular, neurofilamentous, glycogen and others) are described. It is suggested that the different types of degeneration of the optic fibres and their terminals are the result of possible biochemical heterogeneity of the retinal ganglious cells. The comparison of the terms and types of degeneration of different groups of nervous fibres in the optic nerve and their terminals in the TO has revealed some correlations suggesting that the myelinated optic fibres produce nervous terminals degenerating by the "dark" type, whereas the unmyelinated optic axons may be subdivided into several groups, each producing nervous terminals subjected to a definite type of destruction ("clear", "vesicular", "neurofilamentous" etc.). The localization of certain groups of therminals at certain levels of the cortical plate of the TO confirms the electrophysiological data on the stratified organization of the retino-tectal projections in the TO of lower vertebrates. It has been shown by the comparison of the results obtained with those reported for Emys orbicularis, L. that the two species have marked differences in the morpho-functional characteristics of the retino-tectal system, neuronic composition of the TO, the character of destructive changes of the terminals after the enucleation and the component composition of polysynaptic complexes and glomerules. Probably these differences may come from the peculiarities of the perception and transformation of visual information in the species.

Animals↗

PubMed1975

[Changes in the receptive field of pigeon tectum neurons subjected to vestibular and acoustic stimulation].

The changes in the receptive fields of neurons in the deep layers of the tectum opticum were studied as induced by labyrinthine and sound stimulation. Variations in the size of the receptive field, the particular direction of sensitive cells movement, duration of the reaction and amount of impulses in it were found. The results obtained and data from the literature allow one to suggest an active role of tectum opticum in the transformation of signals from the retina depending on the kind of information from other sensory systems.

Animals↗

PubMed1998

Molecular biology of the MEN2 gene.

Cancer is a genetic disease caused by 'gain of function' mutations of oncogenes and 'loss of function' mutations of tumour suppressors and of genes involved in DNA repair mechanisms. The RET gene encodes a tyrosine kinase receptor for molecules belonging to the glial cell line-derived neurotrophic factor (GDNF) family. RET is a paradigmatic example of how different mutations of a single gene can lead to different neoplastic phenotypes. Indeed, gene rearrangements, often caused by chromosomal inversions, activate the oncogenic potential of RET in a fraction of human thyroid papillary carcinomas. On the other hand, different point mutations activate RET in familial multiple endocrine neoplasia syndromes familial medullary thyroid carcinoma (FMTC), MEN-2A and MEN-2B. Little information is so far available on the biochemical mechanisms by which the potent transforming and mitogenic signals of RET are delivered to the nucleus. However, recent data indicate coupling to the Shc-Ras-MAPK pathway as a necessary step in RET signal transduction.

Carcinoma, Papillary↗

PubMed2003

TGF-beta1 causes airway fibrosis and increased collagen I and III mRNA in mice.

BACKGROUND: Subepithelial collagen and extracellular matrix protein deposition are important pathophysiological components of airway remodelling in chronic asthma. Animal models based on the local reaction to antigens show structural alterations in the airway submucosal region and provide important information regarding disease pathophysiology. We describe a murine model of peribronchial fibrosis using intratracheally instilled transforming growth factor (TGF)-beta(1) in BALB/C mice that facilitates a mechanistic approach to understanding the cellular and molecular pathways leading to airway fibrosis. METHODS: BALB/C mice were intratracheally instilled with either TGF-beta(1) or buffered saline. Airway fibrosis was assessed by light microscopy, hydroxyproline content, and polymerase chain reaction (PCR) for collagen I and III on microdissected airway samples. The lysyl oxidase inhibitor beta-aminoproprionitrile (BAPN) was administered to TGF-beta(1) treated mice to block airway collagen deposition. Airway hyperresponsiveness was also measured after treatment with TGF-beta(1). RESULTS: During the 7 days after administration of TGF-beta(1) the mice developed increased subepithelial collagen which could be blocked by BAPN. Increased mRNAs for collagen types I and III were seen in microdissected airways 1 week after TGF-beta(1), and significantly increased total collagen was found in the airways 4 weeks after TGF-beta(1). A detectable increase in airway hyperreactivity occurred. CONCLUSIONS: This new model should facilitate detailed study of airway remodelling that occurs in the absence of detectable cellular inflammation, and allow examination of the functional consequences of a major structural alteration in the conducting airways uncomplicated by inflammatory cell influx.

Aminopropionitrile↗

PubMedDate not supplied

[Thalamocortical dynamics: how do the thalamus and the neocortex communicate during the processing of information?].

INTRODUCTION AND DEVELOPMENT: The thalamus is the gateway to the neocortex. Most of the information that reaches the neocortex is transmitted through thalamocortical fibres. The neocortex, in turn, sends massive feedback to the thalamus through corticothalamic fibres. The sensory input reaches the thalamus by means of the primary sensory fibres. When the properties of these pathways are explored, they are found to present specific response characteristics. These studies have generally been conducted during anaesthesia or other quiescent states. Yet when the properties of these synaptic connections are explored in the active states typical of information processing, their responses are substantially different. CONCLUSION: These changes appear to be necessary to set the pathways of the thalamocortical system in a state of sensory input processing and, therefore, could account for the transformations that take place in order to sustain attentional and perceptive processes.

Action Potentials↗

PubMed2000

Analysis of gene expression by microarrays: cell biologist's gold mine or minefield?

The development of DNA microarrays to study simultaneously the level of mRNA expressed from thousands of genes offers great promise to cell biologists. Microarrays can be used to gain detailed information about transcriptional changes involved in a specific pathway, potentially leading to the identification of novel components of the signalling system. They can also be used to obtain a fingerprint of the transcriptional status of the cell under a given condition, which may be useful for characterising the pathways used in response to novel stimuli. The use of microarrays will generate huge amounts of expression data, contributing to the transformation of biology from a data-poor to a data-rich science. Whether this leads to real advances in the understanding of cell biological problems will depend on the development of methodologies, both in experimental biology and in bioinformatics, that allow meaningful knowledge to be extracted from all this information.

Eukaryotic Cells↗

PubMed2006

BMP signaling in the cartilage growth plate.

Transforming growth factor-beta (TGF-beta) superfamily members play diverse roles in all aspects of cartilage development and maintenance. It is well established that TGF-betas and bone morphogenetic proteins (BMPs) play distinct roles in the growth plate. This chapter discusses key experiments and experimental approaches that have revealed these roles, and progress toward the identification of previously unsuspected roles. Current understanding of the mechanisms by which different TGF-beta and BMP pathways exert their functions is discussed. Finally attempts to utilize this information to promote cartilage regeneration, and important issues for future research, are outlined.

Animals↗