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Results for “Pathway informed transformer”

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PubMed2001

PCR techniques for clonality assays.

Clonal overgrowths represent the hallmark of neoplastic proliferations, and their demonstration has been proved useful clinically for the diagnosis of malignant lymphomas based on the detection of specific and dominant immunoglobulin and/or T-cell receptor gene rearrangements. Nonrandom genetic alterations can also be used to test clonal expansions and the clonal evolution of neoplasms, especially analyzing hypervariable deoxyribonucleic acid (DNA) regions from patients heterozygous for a given marker. These tests rely basically on the demonstration of loss of heterozygosity (LOH) resulting from either hemizygosity (nonrandom interstitial DNA deletions) or homozygosity of mutant alleles observed in neoplasms. LOH analyses identify clonal expansions of a tumor cell population, and point to monoclonal proliferation when multiple and consistent LOH are demonstrated. Based on the methylation-related inactivation of one X chromosome in female subjects, X-linked markers (e.g., androgen receptor gene) will provide clonality information using LOH analyses after DNA digestion with methylation-sensitive restriction endonucleases. Therefore, both non-X-linked and X-linked analyses give complementary information, related and not related to the malignant transformation pathway respectively. Applied appropriately, these tools can establish the clonal evolution of tumor cell populations (tumor heterogeneity), identify early relapses, distinguish recurrent tumors from other metachronic neoplasms, and differentiate field transformation from metastatic tumor growths in synchronic and histologically identical neoplasms.

Clone Cells↗

PubMed1991

A graph-theoretic approach to modeling metabolic pathways.

The metabolic pathways of medazepam, oxazepam, and diazepam were modeled using graph-theoretic transforms which are incorporable into computer-assisted metabolic analysis programs. The information, represented in the form of a graph-theoretic transform kit, which was obtained from these pathways was then used to predict the metabolites of other benzodiazepine compounds. The transform kits gave statistically significant predictions with respect to a statistical method for evaluating the performance of the transform kits.

Anti-Anxiety Agents↗

PubMed1996

The metabolic pathway collection from EMP: the enzymes and metabolic pathways database.

The Enzymes and Metabolic Pathways database (EMP) is an encoding of the contents of over 10 000 original publications on the topics of enzymology and metabolism. This large body of information has been transformed into a queryable database. An extraction of over 1800 pictorial representations of metabolic pathways from this collection is freely available on the World Wide Web. We believe that this collection will play an important role in the interpretation of genetic sequence data, as well as offering a meaningful framework for the integration of many other forms of biological data.

Animals↗

PubMed2001

Transmission in autonomic ganglia.

The activity of airway smooth muscle, glands and vasculature is under tonic control by the autonomic nervous system. Information regarding the function and state of the airway (e.g. blood flow, temperature, oxygen levels, movement, irritants, inflammation, etc.) is relayed to the central nervous system (CNS) in the form of action potentials carried by sensory nerves. This input is integrated at many levels in the CNS and this information is ultimately transformed into coded action potentials carried by various preganglionic nerve pathways from the CNS to peripheral clusters of neurons referred to as autonomic ganglia. In the autonomic ganglia the CNS-derived action potentials cause the release of neurotransmitter(s) at a synapse between the preganglionic nerve terminal and the principal ganglion neuron. The fact that synaptic transmission exists makes the ganglion neuron the final site of integration in this complex reflex pathway. Whether this transmission of information from the CNS occurs, by activating the autonomic ganglion neuron and consequently the effector organ, depends on neurochemical, anatomical, and electrophysiological factors within the ganglion that is the subject of this review.

Animals↗

PubMed2001

Neural correlates of visuomotor associations. Spatial rules compared with arbitrary rules.

A green button may be the target of a movement, or it may instruct the opening of an adjacent door. In the first case, its spatial configuration serves to guide the hand, whereas in the second case its colour allows a decision between alternative courses of action. This study contrasts these two categories of visuomotor transformation. Our goal was to test the hypothesis that visual information can influence the motor system through different, task-dependent pathways. We used positron emission tomography (PET) to measure human brain activity during the performance of two tasks requiring the transformation of visual stimuli to motor responses. The stimuli instructed either a spatially congruent grasping movement or an arbitrarily associated hand movement. The experimental design emphasised preparatory- over movement-related activity. We expected ventral parieto-precentral regions to contribute to the visuomotor transformations underlying grasping movements, and fronto-striatal circuitry to contribute to the selection of actions on the basis of associative rules. We found that selecting between alternative courses of action on the basis of associative rules specifically involved ventral prefrontal, striatal and dorsal precentral areas. Conversely, spatially congruent grasping movements evoked specific differential responses in ventral precentral and parietal regions. The results suggest that visual information can flow through the dorsal system to determine how actions are performed, but that fronto-striatal loops are involved in specifying which action should be performed in the current context.

Adult↗

PubMed2003

Differential expression of three distinct potassium currents in the ventral cochlear nucleus.

In the ventral cochlear nucleus (VCN), neurons transform information from auditory nerve fibers into a set of parallel ascending pathways, each emphasizing different aspects of the acoustic environment. Previous studies have shown that VCN neurons differ in their intrinsic electrical properties, including the K+ currents they express. In this study, we examine these K+ currents in more detail using whole cell voltage-clamp techniques on isolated VCN cells from adult guinea pigs at 22 degrees C. Our results show a differential expression of three distinct K+ currents. Whereas some VCN cells express only a high-threshold delayed-rectifier-like current (IHT), others express IHT in combination with a fast inactivating current (IA) and/or a slow-inactivating low-threshold current (ILT). IHT, ILT, and IA, were partially blocked by 1 mM 4-aminopyridine. In contrast, only ILT was blocked by 10-100 nM dendrotoxin-I. A surprising finding was the wide range of levels of ILT, suggesting ILT is expressed as a continuum across cell types rather than modally in a particular cell type. IA, on the other hand, appears to be expressed only in cells that show little or no ILT, the Type I cells. Boltzmann analysis shows IHT activates with 164 +/- 12 (SE) nS peak conductance, -14.3 +/- 0.7 mV half-activation, and 7.0 +/- 0.5 mV slope factor. Similar analysis shows ILT activates with 171 +/- 22 nS peak conductance, -47.4 +/- 1.0 mV half-activation, and 5.8 +/- 0.3 mV slope factor.

4-Aminopyridine↗

PubMed1995

[Gene structure and transformation mechanism of HTLV-I].

HTLV-I is the etiological agent of the adult T cell leukemia. HTLV-I genome contains the novel pX region in addition to the genes common to all retroviruses. Tax, encoded at the pX region, may play a central role in cellular transformation, however, little information is available on the mechanism. Tax transactivates transcription through three different pathways, namely, CRE, kB motif and CArG box mediated pathways. In ras cooperative focus formation in REF, transcriptional activation through the CArG box seems to play an important role, although transcription through the CRE pathway plays a central role in tax-mediated transformation of Rat-2 cells. These results suggest that the mechanism of transformation by tax varies with the cell type and/or the property of transformation.

Animals↗

PubMed2002

The TGF-beta family: signaling pathways, developmental roles, and tumor suppressor activities.

Intercellular communication is a critical process for all multicellular organisms, and communication among cells is required for proper embryonic development and adult physiology. Members of the Transforming Growth Factor-beta (TGF-beta) family of secreted proteins communicate information between cells via a complex signaling pathway, and family members are capable of inducing a wide range of cellular responses. The purpose of this review is to provide the reader with a broad introduction to our current understanding of three aspects of the TGF-beta family. These are the molecular mechanisms utilized by TGF-beta signaling pathways, the developmental roles played by TGF-beta family members in a variety of species, and the growing list of cancers in which various TGF-beta signaling pathways display tumor suppressor activity.

Animals↗

PubMed2003

[Safety improvement through implementation of clinical pathways].

In Japan the clinical path (or critical path) is attracting attention as a tool for the improvement of healthcare in terms of optimization of informed consent, development of a team approach in healthcare, transformation of the healthcare system into a patient-centered pattern, economizing on medical resources, etc. As clinical pathways can contribute to the reduction of medical errors and the early detection of abnormalities, they are also very effective in promoting patient safety. Important aspects of risk management include gathering and analyzing past incident reports and establishing countermeasures; they imply that each individual health professional, including each physician and nurse, improve their medical knowledge with regard to risk management and that health professionals improve their communication skills and share as much information as possible. In addition, it is imperative for risk management to standardize medical care, streamline the components of healthcare, and avoid unnecessary tests and treatment measures. Clinical pathways are remarkably useful for all of these goals. Another important consideration is the fact that patients and their relatives can promptly identify irregularities arising from deviations from clinical path stipulations. Clinical pathways are highly useful with regard to risk management.

Critical Pathways↗

PubMed1987

Cyclin (PCNA, auxiliary protein of DNA polymerase delta) is a central component of the pathway(s) leading to DNA replication and cell division.

Cyclin, also known as PCNA or the auxiliary protein of mammalian DNA polymerase delta, is a stable cell cycle regulated (synthesized mainly in S-phase) nuclear protein of apparent Mr 36,000 whose rate of synthesis correlates directly with the proliferative state of normal cultured cells and tissues. Cyclin (PCNA) is absent or present in very low amounts in normal non-dividing cells and tissues, but it is synthesized in variable amounts by proliferating cells of both normal and transformed origin. All available information indicates that this ubiquitous and tightly regulated DNA replication protein is a central component of the pathway(s) leading to DNA replication and cell division.

Animals↗

PubMed2000

Transformation from temporal to rate coding in a somatosensory thalamocortical pathway.

The anatomical connections from the whiskers to the rodent somatosensory (barrel) cortex form two parallel (lemniscal and paralemniscal) pathways. It is unclear whether the paralemniscal pathway is directly involved in tactile processing, because paralemniscal neuronal responses show poor spatial resolution, labile latencies and strong dependence on cortical feedback. Here we show that the paralemniscal system can transform temporally encoded vibrissal information into a rate code. We recorded the representations of the frequency of whisker movement along the two pathways in anaesthetized rats. In response to varying stimulus frequencies, the lemniscal neurons exhibited amplitude modulations and constant latencies. In contrast, paralemniscal neurons in both thalamus and cortex coded the input frequency as changes in latency. Because the onset latencies increased and the offset latencies remained constant, the latency increments were translated into a rate code: increasing onset latencies led to lower spike counts. A thalamocortical loop that includes cortical oscillations and thalamic gating can account for these results. Thus, variable latencies and effective cortical feedback in the paralemniscal system can serve the processing of temporal sensory cues, such as those that encode object location during whisking. In contrast, fixed time locking in the lemniscal system is crucial for reliable spatial processing.

Afferent Pathways↗

PubMed1996

Cell cycle expression of p53 protein, c-Myc gene product and tyrosine-phosphorylation level determined by image analysis in human breast cancer cells.

OBJECTIVE: To investigate the cell cycle expression of p53 protein, c-myc gene product and tyrosine phosphorylation level in human breast cancer cells. STUDY DESIGN: Using a multifluorescence imaging procedure, the concentration per cell in different phases of the cell cycle can be evaluated by analyzing the bivariate contour plot of DNA content versus antigen concentration. RESULTS: Low fluorescence intensity was observed in the G0/G1 phase for the three markers. The analysis of individual cells demonstrated that approximately 10% of cells were negative. During the G1/S transition, the fluorescence intensity of the three antigens increased rapidly. However, after the mild S-phase, the increase of c-myc was more marked than the tyrosine phosphorylation level, whereas p53 protein remained stable, with a slight tendency to decrease. CONCLUSION: This study confirmed that the p53 protein and c-myc gene product could perform a regulatory function in G1/S transition and, consequently, may play an important role in malignant transformation. Like-wise, the variations of tyrosine kinase activity were linked to cellular progression throughout the cell cycle and could be a useful marker of alteration in the growth-factor signaling pathway. Thus, the multifluorescence imaging procedure may provide useful information on the mechanisms of the cell cycle and on malignant transformation.

Antibody Specificity↗

PubMed2000

Obstacles to the prediction of estrogenicity from chemical structure: assay-mediated metabolic transformation and the apparent promiscuous nature of the estrogen receptor.

Information on structure-activity relationships (SAR) and pathways of metabolic activation would facilitate the preliminary screening of chemicals for estrogenic potential. Published crystallographic studies of the estrogen receptor (ER) imply an essential role of the two hydroxyl groups on estradiol (17beta-E(2)) for its binding to ER. The influence of these hydroxyl groups on ER binding and estrogenicity was evaluated by the study of 17beta-E(2) with one or both of these hydroxyl groups removed (17beta-desoxyestradiol and 3, 17beta-bisdesoxyestradiol, respectively). 6-Hydroxytetralin (17beta-E(2) with its C- and D-rings removed) and other synthetic estrogens were also studied. The estrogenicity assays comprised a yeast ER-mediated transcription assay, mammalian cell transcription assays incorporating either ER alpha or ER beta, and the immature rat uterotrophic assay. With the exception of 6-hydroxytetralin in the uterotrophic assay, all the chemicals were active in all the assays. Hydroxylation of the two desoxy compounds to estradiol was shown to occur in immature female rats, but metabolism was not implicated in the responses observed in the ER-binding and yeast systems. It is concluded that the 3-hydroxyl and 17beta-hydroxyl groups of 17beta-E(2) are not absolute requirements for estrogenicity. It would therefore be of value to the derivation of SAR for estrogenicity were the crystal structure of the bisdesoxy-E(2)/ER complex to be evaluated.

Animals↗

PubMed2004

A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway.

Signal transduction pathways are modular composites of functionally interdependent sets of proteins that act in a coordinated fashion to transform environmental information into a phenotypic response. The pro-inflammatory cytokine tumour necrosis factor (TNF)-alpha triggers a signalling cascade, converging on the activation of the transcription factor NF-kappa B, which forms the basis for numerous physiological and pathological processes. Here we report the mapping of a protein interaction network around 32 known and candidate TNF-alpha/NF-kappa B pathway components by using an integrated approach comprising tandem affinity purification, liquid-chromatography tandem mass spectrometry, network analysis and directed functional perturbation studies using RNA interference. We identified 221 molecular associations and 80 previously unknown interactors, including 10 new functional modulators of the pathway. This systems approach provides significant insight into the logic of the TNF-alpha/NF-kappa B pathway and is generally applicable to other pathways relevant to human disease.

Animals↗

PubMed1997

Control of the circannual rhythm of reproduction by melatonin in the ewe.

Annual variations in day length are responsible for seasonal changes in reproductive activity in sheep. However, in constant photoperiodic conditions, ewes express an endogenous rhythm characterized by alternations of reproductive activity and quiescence that are not synchronized among animals. Thus, the main role of photoperiod in the natural environment appears to be the synchronization of this endogenous rhythm. Photoperiodic information is processed through a complex nervous and endocrine pathway to modulate reproductive activity. Light information perceived at the level of the retina is transformed through neural processing into an endocrine signal by the pineal gland: the nocturnal increase in melatonin release. Recent studies strongly suggest that melatonin has a hypothalamic target to modulate the reproductive neuroendocrine axis. Most LHRH perikarya are located in the preoptic area, but this region is devoid of melatonin receptors, and microimplants of melatonin placed in the preoptic area do not effect LHRH release. Thus, melatonin influences LHRH neurones indirectly and must involve interneurons. Good evidence now exists to demonstrate that a population of dopaminergic neurons with axons projecting to the median eminence is one of these interneurons.

Animals↗

PubMed2005

Cell signaling: from beginning to end.

The Connections Maps database and the graphical Web interface at Science's STKE for accessing the data represent an emerging Web-based tool through which researchers in cell signaling can share their knowledge with the scientific community. This tool provides a mechanism by which researchers, students, and clinicians can transform information about interactions between biomolecules into knowledge about a cellular process. In 2005, new Pathways were added to the Connections Maps database and several of the existing Pathways were updated.

Cooperative Behavior↗

PubMed1995

Tracking microbial populations effective in reducing exposure.

Microbial ecology provides the link between basic biochemical and molecular studies on toxicity reduction by microbial metabolism and environmental studies that determine exposure. This link provides the ability to determine which microorganisms are responsible for the actual transformations in nature, thereby establishing how predictive the laboratory pathway, kinetic, regulatory, and enzyme mechanistic information is for nature. This information can be important to the rate of toxicant removal, the type and concentration of intermediate product(s), and the identification of conditions that limit effective toxicant removal. Nucleic acid-based methods now provide the main means to track important biodegrading populations. Examples of these methods are given that illustrate tracking a biodegrading microbe injected into an aquifer, following community succession in a toluene-degrading fluidized bed reactor, aiding the isolation from nature of novel biodegrading organisms, and rapidly characterizing the extent of microbial diversity in an aquifer stimulated to co-metabolize trichloroethene.

Biodegradation, Environmental↗

PubMed1997

Ornithine decarboxylase overexpression in mouse 10T1/2 fibroblasts: cellular transformation and invasion.

BACKGROUND: Ornithine decarboxylase (ODC) plays a pivotal role in the synthesis of polyamines, a group of chemical compounds that are essential for cell growth. Recent reports have shown that ODC overexpression may be involved in malignant transformation of immortalized NIH 3T3 cells. We have demonstrated that ODC-overproducing mouse breast cancer cells are more invasive in vitro than control cells. However, little information is available concerning the relationship between ODC overexpression, tumor invasion, and metastasis and the signal transduction pathways involved in ODC-induced transformation and invasion. PURPOSE: Our purpose was twofold: 1) to determine whether ODC overexpression is directly involved in tumor cell invasion and 2) to determine whether ODC overexpression induces mitogen-activated protein (MAP) kinase activities that are associated with cell growth and transformation. METHODS: We transfected C3H clone 8 mouse 10T1/2 fibroblasts with an expression vector that carries a complementary DNA encoding rat ODC. Neomycin-resistant cells that overproduced ODC (4-6.5 times the control levels) were isolated. The transformed phenotype of these cells was determined by assessing colony formation and anchorage-independent growth in soft agar. The invasiveness of the cells was studied by means of an invasion assay that used Matrigel-coated filters in Boyden chambers. The MAP kinase activity of the cells was assayed by an in-gel kinase assay, using myelin basic protein as the substrate. RESULTS: Overexpression of ODC induced not only cell transformation and anchorage-independent growth in soft agar but also invasiveness through a Matrigel-coated filter. The ODC-overproducing transfectants showed enhanced MAP kinase activity that paralleled the magnitude of cell invasiveness. CONCLUSIONS: ODC plays a pivotal role not only in cell transformation but also in cancer cell invasion. ODC overexpression enhanced MAP kinase activity. IMPLICATIONS: Our results demonstrate a connection between the polyamine/ODC and the MAP kinase signal transduction pathways and suggest that MAP kinase may play a pivotal role in ODC-induced cell transformation and invasion.

Animals↗