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Results for “Pathway informed transformer”

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PubMed2001

Mouse plasmacytoma: an experimental model of human multiple myeloma.

BACKGROUND AND OBJECTIVES: There is no ideal animal model for human multiple myeloma (MM). All the models resemble the human disease in some respect, but none of them fulfils all the criteria of a perfect animal model. EVIDENCE AND INFORMATION SOURCES: The pristane oil (2,6,10,12-tetramethylpentadecane)-induced mouse plasmacytoma (MPC) model is the most widely used and accepted model and has provided the most data on plasmacytomagenesis so far. This model gives the opportunity to study the role of c-myc dysregulations, the mechanisms leading to cytogenetic changes involving Ig genes, the role of chronic inflammatory factors, the role of interleukin-6 (IL-6), insulin-like growth factor-I, prostaglandins, as well as signal transduction pathways in the neoplastic process. Therapeutic agents have been successfully tested. Although MPC growth is usually restricted to the peritoneal environment, intraperitoneal injection of MPC cell suspensions can reproduce the disseminated characteristics of the human disease in recipients. The IL-6 transgene and knockout models are important tools for clarifying the role of IL-6 in the pathogenesis of MM. Transgenic mice and retroviral gene transfer facilitate the study of oncogenes in neoplastic transformation. Spontaneous development of plasmacytomas in C57BL/ KaLwRij aging mice has several advantages, mainly because the disseminated growth, the typical bone lesions and renal involvement resemble, in part, the human disease. Furthermore, this model has already proved useful in studies on the effect of bisphosphonate in the treatment of bone disease in MM. The severe combined immunodeficiency (SCID) mouse model is also very attractive. A disseminated-like disease can be reproduced in this model. Multiple osteolytic bone lesions and bone marrow involvement are generated, and conventional drugs applied in the treatment of human multiple myeloma have proven to be effective. Nevertheless, the immune system of SCID mice basically differs from that of a MM patient. PERSPECTIVES: Taken together, all these models have contributed to our understanding of MM, but demonstrate the opportuness of developing a more appropriate model of the human disease.

Animals↗

PubMed2001

The parietal lobe as a sensorimotor interface: a perspective from clinical and neuroimaging data.

Lesion studies show a wide range of sensorimotor functions that can be selectively disturbed in patients with parietal lobe damage. This is illustrated by the selective impairment of unimodal or polymodal sensorimotor transformations in patients with apraxia. These clinically apparent deficits of goal-directed motor behavior are complimented by more subtle sensorimotor transformation disorders such as mirror agnosia and ataxia that can only be disclosed by special tests. Imaging studies further exemplify the prominent role of the parietal cortex as a sensorimotor interface and provide new information about the interrelationship between perception and action. Action observation activates premotor cortex, but parietal cortex is also recruited whenever an action involves objects. This emphasizes the significance of parietal cortex for goal-directed motor behavior. The intact comprehension of the meaning of gestures or of tool use shows the preservation of the cognitive aspects of motor behavior as long as lesions are restricted to the parietal lobe.

Apraxia, Ideomotor↗

PubMed1997

Artificial implementation of auditory neurons: a comparison of biologically motivated models and a new transfer function oriented model.

Auditory perception neurons, also called inner hair cells (IHCs) because of their physical shape, transform the mechanical movements of the basilar membrane into electrical impulses. The impulse coding of the IHC is the main information carrier in the auditory process and is the basis for improvements in cochlear implants as well as for low-rate, high-quality speech processing and compression. This paper compares biologically motivated models (Meddis, Cooke, Payton) with a newly developed model which is transfer function oriented. The new model has only three reservoirs and the parameters can be controlled through five small ROM tables. This model is compared with the often used Meddis model in terms of accuracy, system parameter flexibility, and hardware effort in an FPGA implementation.

Auditory Pathways↗

PubMed2006

Use of multiparameter analysis for Vibrio alginolyticus viable but nonculturable state determination.

BACKGROUND: Vibrio alginolyticus is known to enter into a viable but nonculturable (VBNC) state in response to environmental conditions unfavorable to the growth. Cells in VBNC condition pose a public health threat because they are potentially pathogenic. METHODS: We constructed a pathway for the identification of the most significant variables and the characterization of those variables able to discriminate the groups under investigation. Different parameters measured by the image processing software were chosen as the most representative of V. alginolyticus cell morphology (length index for dimension) and metabolic activity (density profile indexes). To detect relationships between the groups of treatment performed, we carried out a principal components analysis (PCA). RESULTS: The PCA analysis indicated that increasing coccoid shape transformation was related to both metabolic and dimension variations, delineating a well defined graph profile. Indeed, we discovered that specific morphological variations occur when cells in the culturable state pass into VBNC condition, namely comma-shaped culturable bacteria are converted into coccoid-shaped VBNC cells. The results were also supported by scanning electron microscopy analysis. CONCLUSIONS: This technique allows the analysis of a large number of vibrio samples in a short period of time. The obtained multiparameter information may complement genetic/molecular analyses facilitating, in an automatic fashion, further studies to evaluate the potential risk of this pathogen in the environment. It may also be a useful tool for large-scale cell biology studies and high content screening.

Bacterial Physiological Phenomena↗

PubMed2003

Structural study of spirolide marine toxins by mass spectrometry. Part I. Fragmentation pathways of 13-desmethyl spirolide C by collision-induced dissociation and infrared multiphoton dissociation mass spectrometry.

A novel group of toxins, the spirolides, has been investigated by several mass spectrometric (MS) methods to enable structure elucidation and metabolite identification. These macrocyclic compounds, produced by the dinoflagellate Alexandrium ostenfeldii, are a new class of marine phycotoxin with characteristic spiro-linked tricyclic ether and imine moieties. A crude phytoplankton extract has been shown to contain known spirolides and several unknown compounds, present at low yet significant levels. This study has focused on mass spectrometric characterization of the main component of this extract, 13-desmethyl spirolide C. Collision-induced dissociation (CID) spectra were collected on triple-quadrupole and quadrupole linear ion-trap instruments. High-resolution Fourier-transform ion cyclotron resonance MS data revealed the accurate masses of the protonated molecule and the product ions formed by infrared multiphoton dissociation. A fragmentation scheme for this toxin has been proposed to explain the formation of the collision-induced fragments. Charge-remote fragmentations dominate the CID spectra, because there is only one predominantly basic site in this molecule, and prove to be structurally informative. Extensive MS characterization of 13-desmethyl spirolide C will undoubtedly be useful in the characterization of known and unknown spirolides and other related compounds.

Animals↗

PubMed1991

Phosphoinositide 3-kinase: a new effector in signal transduction?

Interest in phosphoinositide 3-kinase (PI 3-kinase) has been fuelled by its identification as a major phosphotyrosyl protein detected in cells following growth factor stimulation and oncogenic transformation. It is found complexed with activated growth factor receptors and non-receptor tyrosine kinases, thus suggesting that it participates in the signal transduction pathways initiated by the activation of tyrosine kinases. PI 3-kinase phosphorylates the 3-position in the inositol ring of the well known inositol phospholipids in vitro giving phosphatidylinositol 3-phosphate, phosphatidylinositol 3,4-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate [PtdIns3P, PtdIns(3,4)P2 and PtdIns(3,4,5)P3], respectively. The cellular levels of PtdIns(3,4)P2 and PtdIns(3,4,5)P3 rapidly increase in circumstances where PI 3-kinase becomes complexed with tyrosine kinases. Accumulation of the same lipids also occurs in platelets and neutrophils following stimulation of G-protein linked alpha-thrombin and chemotactic peptide receptors, respectively, leading to speculation that one or both of these lipids is a new second messenger whose function is not yet known. This review brings together recent information on the isolation, characterization and regulation of PI 3-kinase, the cellular occurrence of 3-phosphorylated inositol phospholipids and possible functions of the PI 3-kinase pathway in cell signalling.

1-Phosphatidylinositol 4-Kinase↗

PubMed2003

The mechanism of action of the tumour suppressor gene PTEN.

Intracellular levels of phosphorylation are regulated by the coordinated action of protein kinases and phosphatases. Disregulation of this balance can lead to cellular transformation. Here we review knowledge of the mechanisms of one protein phosphatase, the tumour suppressor PTEN/MMAC/TEP 1 apropos its role in tumorigenesis and signal transduction. PTEN plays an important role in the phosphatidyl-inositol-3-kinase (PI3-K) pathway by catalyzing degradation of phosphatidylinositol-(3,4,5)-triphosphate generated by PI3-K. This inhibits downstream targets mainly protein kinase B (PKB/Akt), cell survival and proliferation. PTEN contributes to cell cycle regulation by blockade of cells entering the S phase of the cell cycle, and by upregulation of p27(Kip1) which is recruited into the cyclin E/cdk2 complex. PTEN also modulates cell migration and motility by regulation of the extracellular signal-related kinase - mitogen activated protein kinase (ERK-MAPK) pathway and by dephosphorylation of focal adhesion kinase (FAK). We also emphasize the increasingly important role that PTEN has from an evolutionary point of view. A number of PTEN functions have been elucidated but more information is needed for utilization in clinical application and potential cancer therapy.

Animals↗

PubMed1991

Autocrine growth factors and solid tumor malignancy.

The ability of malignant cells to escape the constraint that normally regulate cell growth and differentiation has been a primary focus of attention for investigators of cancer cell biology. An outcome of this attention has been the discovery that the protein products of oncogenes play a role in the activation of growth signal pathways. A second outcome, possibly related to abnormal oncogene expression, has been the discovery that malignant cells frequently show an ability to regulate their own growth by the release of autocrine growth modulatory substances. Most important, the growth of certain malignant cell types has been shown to depend on autocrine growth circuits. A malignant tumor whose continued growth depends on the release of an autocrine growth factor may be vulnerable to treatment with specific receptor antagonists or immunoneutralizing antibodies designed to break the autocrine circuit. Information is rapidly emerging concerning autocrine growth factors in selected human solid tissue malignancy.

Cytokines↗

PubMed1996

Xenobiotics in food. I. Metabolic phthalate degradation.

In conjunction with the programme of monitoring the food contamination by one of the most widely distributed contaminants--phthalic acid esters--the present investigation was focused on the elucidation of metabolic transformations of phthalates in the organism of the rat and humans and on assessment of the phthalate content of beef and pork liver. As a model substance di-(2-ethylhexyl)phthalate was selected. The paper contains new information on the mechanism of metabolic oxidative phthalate degradation in the rat, identifies the structure of intermediary products and suggests a reaction breakdown pattern. The balance of phthalate excretion from experimental animals in faeces and urine was examined, their metabolized ratio was defined and the phthalate load of the decisive parts of the organism was evaluated, i.e. in the liver, kidneys, spleen, brain and muscular tissue. Subsequent monitoring of phthalates in urine of human volunteers exposed only to the natural phthalate intake from contaminated food revealed the presence of some oxidative metabolites in body fluids. It provided also evidence of the possible endogenous formation of 2-ethyl-3-carboxypropylphthalic acid the presence of which may signalize metabolic oxidation by a pathway terminated by possible hepatocellular carcinogenicity of phthalates. The probability of introduction of oxidative phthalate metabolites from meat of domestic animals seems minimal.

Animals↗

PubMed2004

Application of laser capture microdissection and protein microarray technologies in the molecular analysis of airway injury following pollution particle exposure.

Understanding the mechanisms by which various types of air pollution particles (particulate matter, PM) mediate adverse health effects would provide biological plausibility to epidemiological associations of increased rates of morbidity and mortality. The majority of information regarding the means by which PM generates lung injury has been derived from in vitro studies. However, it is unclear as to what extent these mechanisms can be extrapolated to the in vivo situation. Current methods to assess mechanisms of PM-induced lung injury make it difficult to obtain site-specific, sensitive, and comprehensive determinations of cellular and molecular pathology associated with PM-induced injury. In the present study, the ability of laser capture microdissection (LCM) and protein microarray technologies were assessed to examine the effect of residual oil fly ash (ROFA) exposure on airway intracellular signaling pathways and transcription factor activation. Sprague-Dawley rats were intratracheally instilled with 0.5 mg/rat of ROFA. LCM was used to recover airway cells and protein extracts derived from the microdissected airways were analyzed by protein microarray. ROFA exposure increased p-ERK:ERK and p-I kappa B:I kappa B, suggesting changes in cell growth, transformation, and inflammation within the airway. These results are consistent with previously reported in vitro findings, demonstrating for the first time the credibility of applying LCM and protein microarray technologies to assess acute lung injury induced by environmental air pollutants.

Air Pollutants↗

PubMed2004

The oxidation process of Antarctic fish hemoglobins.

Analysis of the molecular properties of proteins extracted from organisms living under extreme conditions often highlights peculiar features. We investigated by UV-visible spectroscopy and X-ray crystallography the oxidation process, promoted by air or ferricyanide, of five hemoglobins extracted from Antarctic fishes (Notothenioidei). Spectroscopic analysis revealed that these hemoglobins share a common oxidation pathway, which shows striking differences from the oxidation processes of hemoglobins from other vertebrates. Indeed, simple exposure of these hemoglobins to air leads to the formation of a significant amount of the low-spin hexacoordinated form, denoted hemichrome. This hemichrome form, which is detected under a variety of experimental conditions, can be reversibly transformed to either carbomonoxy or deoxygenated forms with reducing agents. Interestingly, the spectra of the fully oxidized species, obtained by treating the protein with ferricyanide, show the simultaneous presence of peaks corresponding to different hexacoordinated states, the aquomet and the hemichrome. In order to assign the heme region state of the alpha and beta chains, the air-oxidized and ferricyanide-oxidized forms of Trematomus bernacchii hemoglobin were crystallized. Crystallographic analysis revealed that these forms correspond to an alpha(aquomet)-beta(bishistidyl-hemichrome) state. This demonstrates that the alpha and beta chains of Antarctic fish hemoglobins follow very different oxidation pathways. As found for Trematomus newnesi hemoglobin in a partial hemichrome state [Riccio, A., Vitagliano, L., di Prisco, G., Zagari, A. & Mazzarella, L. (2002) Proc. Natl Acad. Sci. USA99, 9801-9806], the quaternary structures of these alpha(aquomet)-beta(bishistidyl-hemichrome) forms are intermediate between the physiological R and T hemoglobin states. Together, these structures provide information on the general features of this intermediate state.

Animals↗

PubMed1997

Apoptosis and carcinogenesis.

Many tumours are characterised by increased levels of apoptosis. This observation establishes significance for this process in tumour development, but it does little to elucidate the nature of this role, nor does it yield information relevant to the early stages of carcinogenesis. To gain a better understanding of the importance of apoptosis, it has been necessary to create a number of transgenic model systems wherein the apoptotic response has been modified. Using this strategy, a number of genetic lesions have been identified which affect both the apoptotic pathway and predisposition to malignancy. These lesions can operate either directly, by blocking the induction of apoptosis; or indirectly, by increasing the selective pressure for further genetic change. The consequent deregulation of growth control and increase in mutation burden represent two key steps in carcinogenesis, underlining the pivotal role played in tumour suppression by the normal induction of apoptosis.

Apoptosis↗

PubMed2000

[A neuropsychological and functional brain imaging study of visuo-imitative apraxia].

We describe the case of a 58-years-old right-handed women suffering from an occipital-parietal lesion. The administration of a cognitively based assessment tool for limb praxis (Batterie d'Evaluation des Praxies, B.E.P., Peigneux and Van der Linden, 1998) demonstrated bilateral visuo-imitative apraxia. Gesture production was mainly characterised by spatial, errors, and imitation of meaningful gestures was worse than their pantomime on verbal command. Moreover, the imitation of meaningless gestures and their reproduction on a manikin were worse than imitation of their matched meaningful gestures. In a cognitive perspective, adapted from the Rothi et al. (1997) and Goldenberg (1995) contributions to our understanding of limb praxis, this configuration of performance suggests deficits occurring at multiple levels. On one hand, it suggests either access difficulties or alteration of the output praxicon, i.e., the lexicon for visuo-kinesthetic engrams of meaningful gestures. On the other hand, the simultaneous deficit for meaningless gesture reproduction on the subject's own body and on a manikin favors an alteration of the structural descriptions of the human body (i.e., human body knowledge), underlying the mental transposition processes occurring between the visual analysis of a meaningless gestural configuration and its effective reproduction on oneself or on a manikin, thus contradicting the classic view of a direct pathway linking visual analysis and motor planning in meaningless gesture imitation. Finally, due to the output praxicon deficit, imitation of meaningful gestures is partly processed in the same way as meaningless gestures (also impaired in this case), leading to an interference effect between both degraded memory-based and visually-transposed traces, which account for imitation of meaningful gestures being worse than their pantomime on verbal command. We also assess regional cerebral metabolism using positron emission tomography (PET). Comparison with 41 healthy subjects (SPM96) demonstrated a statistically significant hypometabolism in the left intraparietal sulcus and superior parietal lobule, and in the right dorsal prestriate cortex. These results, together with a review of the other studies of visuo-imitative apraxia, suggest that the left intraparietal sulcus may be associated with access or integration of information from the output praxicon. The left superior parietal and the right dorsal prestriate deficits functionally impaired a bilateral dorsal network implied in the mental transformations of the body, thus suggesting that these mental transformations are underlined by knowledge of the human body, which may subsequently explain the deficit for the reproduction of meaningless and meaningful configurations.

Aged↗

PubMed1997

Separate channels for visuomotor transformations in the pigeon.

Since the discovery of two parallel visual systems in humans and primates there has been much speculation about their functions. One prominent current model, suggesting independent processing of visual information for perception and action, is supported by neuroanatomical, electrophysiological, neurobehavioral, and human clinical data. Furthermore, studies of visuomotor behavior in amphibians and non-primate mammals indicate that neural processing of action-related behavior is mediated by separate neuronal channels thus suggesting an evolutionary principle in the organization of visuomotor behavior. If such an evolutionary principle operates it should also apply to birds. I will present and discuss behavioral and behavioral physiological evidence that action-related behavior in pigeons like pecking, grasping and control of gaze is controlled via separate neuronal channels subserving visuomotor functions.

Amphibians↗

PubMed2004

[Transforming and transmitting auditory information].

A mechanism of transforming and transmitting auditory information has been introduced taking into consideration the course of occurrences on molecular level in auditory cell itself. Physical energy of the sound wave is changed into bioelectric energy of the inside of the auditory cell owing to the generated electrochemical gradient. The change of the cell membrane potential which has been caused by the energy of the sound wave influences the change of the calcium level in the cell and at a further stage energetistic processes, enzymatic proteins activity and also it regulates the exocytosis of the mediator. The relationship between the generation of the transmitter and its secretion, and the stimulation of the auditory cell has been discussed. The role of afferent and efferent innervation in the generation of the fast and slow contraction of auditory cells has been noticed. Other phenomena accompanying the process of hearing have also been noticed. They are: Coding information, pre- and post-synaptic inhibition, facilitation of impulse transmission along nervous pathways, collateral inhibition, convergence and divergence. The mechanism of stimulating the receptors in the other senses has been described. A hypothesis has been put forward about the possibility of existence of a mechanism activating ionic canals of the cell membrane of auditory cells other than purely mechanical one connected with tip-links. The mechanism mentioned above may be based on inducing conformational changes of canal proteins, especially potassium canals, by the energy of the sound wave. There is a probability that there exist sound sensitive molecules in the ear as just as there exist light sensitive molecules in the organ of sight. The ability of basement membrane to transmit auditory information, especially on the verge of auditory threshold has been questioned.

Animals↗

PubMed2004

Ontological integration of data models for cell signaling pathways by defining a factor of causality called 'signal'.

Databases have collected masses of information concerning cell signaling pathways that includes information on pathways, molecular interactions as well as molecular complexes. However we have no general data model to represent comprehensive properties of cell signaling pathways, so that this type of information has been represented by two different data models that we call 'binary relation' and 'state transition'. The disagreement between the existing models derives from lack of consensus about a factor of causality in reactions in cell signaling pathways, which is often called 'signal'. We developed an ontology named CSNO (Cell Signaling Networks Ontology) based on device ontology. As device ontology is a research product of knowledge engineering, CSNO is the first application of it to biological knowledge. CSNO defines the factor of causality called 'signal', offers an integrative viewpoint for the two different data models, explicates intrinsic distinctions between signaling and metabolic pathways, and eliminates ambiguity from representation of complex molecules.

Cell Physiological Phenomena↗

PubMed2003

Rival penalized competitive learning (RPCL): a topology-determining algorithm for analyzing gene expression data.

DNA arrays have become the immediate choice in the analysis of large-scale expression measurements. Understanding the expression pattern of genes provide functional information on newly identified genes by computational approaches. Gene expression pattern is an indicator of the state of the cell, and abnormal cellular states can be inferred by comparing expression profiles. Since co-regulated genes, and genes involved in a particular pathway, tend to show similar expression patterns, clustering expression patterns has become the natural method of choice to differentiate groups. However, most methods based on cluster analysis suffer from the usual problems (i) dead units, and (ii) the problem of determining the correct number of clusters (k) needed to classify the data. Selecting the k has been an open problem of pattern recognition and statistics for decades. Since clustering reveals similar patterns present in the data, fixing this number strongly influences the quality of the result. While there is no theoretical solution to this problem, the number of clusters can be decided by a heuristic clustering algorithm called rival penalized competitive learning (RPCL). We present a novel implementation of RPCL that transforms the correct number of clusters problem to the tractable problem of clustering based on the degree of similarity. This is biologically significant since our implementation clusters functionally co-regulated genes and genes that present similar patterns of expression. This new approach reveals potential genes that are co-involved in a biological process. This implementation of the RPCL algorithm is useful in differentiating groups involved in concerted functional regulation and helps to progressively home into patterns, which are closely similar.

Algorithms↗

PubMed2006

G proteins in drug screening: from analysis of receptor-G protein specificity to manipulation of GPCR-mediated signalling pathways.

Seven transmembrane G protein coupled receptors (7TM GPCRs) represent one of the largest gene familes in the human genome. Because of the size of the GPCR family, their proven history of being valuable targets for small molecule drug design, the fact that the absolute number of GPCRs that are targets for current medicines represents only a small fraction of the total encoded by the human genome, and that ligands for GPCRs do not have to enter the cell to exert their function, it is very likely that GPCRs will remain major targets for the pharmaceutical industry in the foreseeable future. Despite recent evidence indicating that GPCRs can provide information to cells, that does not require activation of G proteins ("signaling at zero G"), most of the GPCRs known to date function via interaction with and activation of heterotrimeric (alphabetagamma) G proteins. Thus, assay systems translating ligand modulation of GPCRs into G protein-dependent intracellular responses are a key component of both basic research and the drug discovery process. This article will review the current knowledge and recent progress in understanding molecular aspects of specific receptor-G protein recognition. It will also highlight how the knowledge generated by such studies can be transformed into assay systems for GPCR drug discovery.

Animals↗