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Results for “Pathway informed transformer”

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PubMed2004

A systematic approach to simulating metabolism in computational toxicology. I. The TIMES heuristic modelling framework.

Designing biologically active chemicals and managing their risks requires a holistic perspective on the chemical-biological interactions that form the basis of selective toxicity. The balance of therapeutic and adverse outcomes for new drugs and pesticides is managed by shaping the probabilities for transport, metabolism, and molecular initiating events. For chemicals activated as well as detoxified by metabolism, selective toxicity may be considered in terms of relative probabilities, which shift dramatically across species as well as within a population, depending on many factors. The complexity in toxicology that results from metabolism has been troublesome in QSAR research because the parent structure is less relevant to predicting ultimate effects and finding reference species/conditions for metabolic rates seems hopeless. Even the complexity of comparative xenobiotic metabolism itself seems paradoxical in light of the evidence of highly conserved catabolic processes across species. Clearly, predicting the role of metabolism in selective toxicity and adverse health outcomes requires a probabilistic framework for deterministic models as well as the many factors shaping the metabolic probability distributions under specific conditions. This paper presents a tissue metabolism simulator (TIMES), which uses a heuristic algorithm to generate plausible metabolic maps from a comprehensive library of biotransformations and abiotic reactions and estimates for system-specific transformation probabilities. The transformation probabilities can be calibrated to specific reference conditions using transformation rate information from systematic testing. In the absence of rate data, a combinatorial algorithm is used to translate known metabolic maps taken from reference systems into best-fit transformation probabilities. Finally, toxicity test data itself can be used to shape the transformation probabilities for toxicity pathways in which the metabolic activation is the rate-limiting process leading to a toxic effect. The conceptual approach for metabolic simulation will be presented along with practical uses in forecasting plausible activated metabolites.

Animals↗
PubMed1994

How does the brain know the body is sick? New approaches to an old problem in medicine.

The physiological significance of a widespread distribution of lymphoid cells throughout most of the organ systems in the body is thought to represent the general tissue requirement for protection and vigilance against foreign invaders and certain other disease states. More recently, this distribution has also been viewed as a group of immune system transducers capable of extending the sensory capabilities of the central nervous system. The information monitors the internal state of the body in relation to the external environment including potential invaders, malignant transformations of body cells, and certain other disease-causing agents. This kind of information is clearly on a sensory scale or wavelength not otherwise available to the central nervous system. The information consists of chemical messengers rather than energy, which is monitored by sensory pathways that have been conceptualized and studied over a much longer period of time.

Brain↗
PubMed1999

Protein kinases: which one is the memory molecule?

Encoding of new experiences is likely to induce activity-dependent modifications in the brain. Studies in organisms far apart on the phylogenetic scale have shown that similar, sometimes identical, signal transduction pathways subserve plasticity in neuronal systems, and they may play pivotal roles in the formation of long-term memories. It has become evident that phosphorylation/dephosphorylation reactions are critical for the initiation of cellular mechanisms that embody, retain and modify information in neural circuits. Although physiological investigations on synaptic plasticity have had a major impact, we have concentrated our review on behavioural studies that provide direct or indirect evidence for a role of kinases in mechanisms underlying memory formation. From these, it appears that the learning event induces activation of a variety of kinases with specific time courses. For instance, the calcium/calmodulin-dependent protein kinase II seems to participate in an early phase of memory formation. Apparently, activation of both protein tyrosine kinases and mitogen-activated protein kinases is required for much longer and may thus have a particular function during transformation from short-term into long-term memory. Quite different time courses appear for protein kinase C (PKC) and protein kinase A (PKA), which may function at two different time points, shortly after training and again much later. This suggests that PKC and PKA might play a role at early and late stages of memory formation. However, we have considered some examples showing that these signalling pathways do not function in isolation but rather interact in an intricate intracellular network. This is indicative of a more complex contribution of each kinase to the fine tuning of encoding and information processing. To decipher this complexity, pharmacological, biochemical and genetic investigations are more than ever necessary to unravel the role of each kinase in the syntax of learning and memory formation.

Animals↗
PubMed1998

Clonality Studies in the Analysis of Adrenal Medullary Proliferations: Application Principles and Limitations.

Clonality remains as the hallmark of neoplasms. A dual genetic approach using markers nonrelated (e.g., X-chromosome inactivation assays) and related to the malignant transformation (such as loss of heterozygosity analyses of tumor-suppressor genes) would provide useful clonality information from early and advanced tumor stages, respectively. Tumor progression and clonal selection would result in genetic instability and heterogeneous expression of those molecular markers related to the malignant pathway. Therefore, only the coexistence of multiple genetic abnormalities would support the clonal nature as an expression of convergent cell selection. Considering those facts, the currently available evidence on tumorigenesis and clonality in the adrenal medulla can be summarized as follows: 1. Multistep tumorigenesis defines the evolution of pheochromocytomas, as evidenced by the presence of several genetic alterations. 2. Both the significant association of nonrandom genetic alterations (specially 1p and 22q interstitial deletions) and the topographic accumulation of genetic deletions at the peripheral tumor compartment support a convergent clone selection for these neoplasms. 3. Although many genetic loci show nonrandom abnormalities, the most frequently involved locates on chromosome 1p regardless of genetic tumor background (sporadic or inherited predisposition). 4. Most pheochromocytomas should begin as monoclonal proliferations that do not always correlate with histopathologic features, particularly in inherited tumor syndromes. 5. Early histopathologic stages, described as adrenal medullary hyperplasias, are defined by hyperproliferative features in animal models and monoclonal patterns in the adrenal nodules from patients with MEN-2a.

Journal Article↗
PubMed2001

Shape representation in area V4: position-specific tuning for boundary conformation.

Visual shape recognition in primates depends on a multi-stage pathway running from primary visual cortex (V1) to inferotemporal cortex (IT). The mechanisms by which local shape signals from V1 are transformed into selectivity for abstract object categories in IT are unknown. One approach to this issue is to investigate shape representation at intermediate stages in the pathway, such as area V4. We studied 109 V4 cells that appeared sensitive to complex shape in preliminary tests. To achieve a more complete picture of shape representation in V4, we tested each cell with a set of 366 stimuli, constructed by systematically combining convex and concave boundary elements into closed shapes. Using this large, diverse stimulus set, we found that all the cells in our sample responded to a wide variety of shapes and did not appear to encode any single type of global shape. However, for most cells the shapes evoking strongest responses were characterized by a consistent type of boundary conformation at a specific position within the stimulus. For example, a given cell might be tuned for shapes containing concave curvature at the right, with other parts of the shape having little or no effect on responses. Many cells were tuned for more complex boundary configurations (e.g., a convex angle adjacent to a concave curve). We quantified this kind of shape tuning with Gaussian functions on a curvature x position domain. These tuning functions fit the neural responses much better than tuning functions based on edge or axis orientation. Thus individual V4 cells appear to encode moderately complex boundary information at specific locations within larger shapes. This finding suggests that, at intermediate stages in the V1-IT transformation, complex objects are represented at least partly in terms of the configurations and positions of their contour components.

Animals↗
PubMed1997

Role of focal adhesion proteins in signal transduction and oncogenesis.

The focal adhesion is a structure that is formed when a cell comes into contact with the extracellular matrix. Originally, the focal adhesion was thought to only provide structural support for the actin-based cytoskeleton of the cell. However, the last decade has yielded considerable information linking various protein components of the focal adhesion to signal transduction pathways. Examples of focal adhesion proteins include the catalytically active p125FAK, SH2-containing tensin, and the multifunctional LIM domain-containing paxillin. The interactions of focal adhesion proteins may be altered after cellular transformation. This review details how certain focal adhesion proteins are associated in cellular signaling as well as transformation. The importance of various GTP-binding proteins in interacting with and forming the focal adhesion, and the influence they have on neoplastic transformation, are discussed. A key feature of this review is how oncogenes and their respective oncoproteins affect the focal adhesion. Classically, v-src transformation of adherent cells has been studied to characterize focal adhesions, namely, because of the distinct morphological changes that occur in the focal adhesion concomitantly with src transformation. Similarly, the BCR/ABL oncogene, which causes chronic myelogenous leukemia, leads to adhesion defects and can alter the properties of focal adhesion proteins. Thus, we describe some of the relevant interactions between the focal adhesion and the Src and BCR/ABL oncoproteins, respectively.

Animals↗
PubMed2004

The supramammillary area: its organization, functions and relationship to the hippocampus.

The supramammillary area of the hypothalamus, although small in size, can have profound modulatory effects on the hippocampal formation and related temporal cortex. It can control hippocampal plasticity and also has recently been shown to contain cells that determine the frequency of hippocampal rhythmical slow activity (theta rhythm). We review here its organization and anatomical connections providing an atlas and a new nomenclature. We then review its functions particularly in relation to its links with the hippocampus. Much of its control of behaviour and its differential activation by specific classes of stimuli is consistent with a tight relationship with the hippocampus. However, its ascending connections involve not only caudal areas of the cortex with close links to the hippocampus but also reciprocal connections with more rostral areas such as the infralimbic and anterior cingulate cortices. These latter areas appear to be the most rostral part of a network that, via the medial septum, hippocampus and lateral septum, is topographically mapped into the hypothalamus. The supramammillary area is thus diffusely connected with areas that control emotion and cognition and receives more topographically specific return information from areas that control cognition while also receiving ascending information from brain stem areas involved in emotion. We suggest that it is a key part of a network that recursively transforms information to achieve integration of cognitive and emotional aspects of goal-directed behaviour.

Animals↗
PubMed2000

Genetic screens in mammalian cells by enhanced retroviral mutagens.

Genetic approaches such as retrovirus-mediated mutagenesis and cDNA expression libraries have contributed greatly to our understanding of signal transduction in mammalian cells. However, previously described methods for retroviral insertional mutagenesis are hindered by low mutagenesis rates and difficulties in cloning mutated genes. cDNA expression library methods are usually cell-type dependent and bias towards abundant and short messages. With the near completion of the genome projects, alternative genetic methods are needed where large numbers of genes can be more easily isolated and biochemically studied. We have developed a novel retrovirus-mediated genetic screening method in cultured cells. To achieve efficient and regulated mutagenesis, we constructed Enhanced Retroviral Mutagen (ERM) vectors that contained several engineered sequences (e.g., an ERM Tag and a splice donor) controlled by a tetracycline-responsive promoter. Endogenous genes can thus be randomly activated and tagged in a conditional system. NIH3T3 cells were used to screen for focus-forming genes using the ERM strategy. We showed that these added sequences increased the screening efficiency by >10-fold, and allowed more direct identification of the genes targeted. Sequence analysis of approximately 10% of the >600 focus clones recovered revealed both known oncogenes and novel factors such as protein kinases and GTP/GDP exchange proteins. The ERM strategy should help to facilitate large-scale gene identification in diverse pathways and integrate both genetic (with the completion of the genome projects) and functional information more readily.

3T3 Cells↗
PubMed2000

A mathematical analysis of the characteristics of the system connecting the cerebellar ventral paraflocculus and extraoculomotor nucleus of alert monkeys during upward ocular following responses.

Movements of the visual scene evoke short-latency ocular-following-responses (OFR). Many studies suggest that a neural pathway containing the cerebellar-ventral-paraflocculus (VPFL) mediates OFR. The relationship between eye movement and simple-spike firing in the VPFL during OFR has been studied in detail using an inverse dynamics approach. The relationship between eye movement and cell firing in the extraoculomotor nucleus (MN) has already been reported. However, no studies have examined the information transformation that occurs between the VPFL and the MN during OFR. In this paper, using an inverse dynamics approach, we derive a transfer function that represents the characteristics of the structure connecting the VPFL and the MN during upward OFR. This structure appears to contain a kind of neural integrator, which constructs eye-velocity-and-position information from eye-acceleration-and-velocity information. We propose a diagram for the neural integration commonly at work during all types of upward eye movement. This is a closed-loop circuit containing a low-pass filter. The low-pass filter can construct eye-velocity-and-position information from an eye-acceleration-velocity-position command similar to the final motor command used commonly for all upward eye movements. Anatomical and electrophysiological data suggest that the vestibular nuclei-interstitial nucleus of Cajal-vestibular nuclei loop might perform such neural integration.

Action Potentials↗
PubMed1999

Signal transduction, cell cycle regulatory, and anti-apoptotic pathways regulated by IL-3 in hematopoietic cells: possible sites for intervention with anti-neoplastic drugs.

Over the past decade, there has been an exponential increase in our knowledge of how cytokines regulate signal transduction, cell cycle progression, differentiation and apoptosis. Research has focused on different biochemical and genetic aspects of these processes. Initially, cytokines were identified by clonogenic assays and purified by biochemical techniques. This soon led to the molecular cloning of the genes encoding the cytokines and their cognate receptors. Determining the structure and regulation of these genes in normal and malignant hematopoietic cells has furthered our understanding of neoplastic transformation. Furthermore, this has allowed the design of modified cytokines which are able to stimulate multiple receptors and be more effective in stimulating the repopulation of hematopoietic cells after myelosuppressive chemotherapy. The mechanisms by which cytokines transduce their regulatory signals have been evaluated by identifying the involvement of specific protein kinase cascades and their downstream transcription factor targets. The effects of cytokines on cell cycle regulatory molecules, which either promote or arrest cell cycle progression, have been more recently examined. In addition, the mechanisms by which cytokines regulate apoptotic proteins, which mediate survival vs death, are being elucidated. Identification and characterization of these complex, interconnected pathways has expanded our knowledge of leukemogenesis substantially. This information has the potential to guide the development of therapeutic drugs designed to target key intermediates in these pathways and effectively treat patients with leukemias and lymphomas. This review focuses on the current understanding of how hematopoietic cytokines such as IL-3, as well as its cognate receptor, are expressed and the mechanisms by which they transmit their growth regulatory signals. The effects of aberrant regulation of these molecules on signal transduction, cell cycle regulatory and apoptotic pathways in transformed hematopoietic cells are discussed. Finally, anti-neoplastic drugs that target crucial constituents in these pathways are evaluated.

Animals↗
PubMed2001

The dynamics of molecular networks: applications to therapeutic discovery.

Recent advances in biomedical research, genomics and bioinformatics have given the pharmaceutical and biotechnology industries new promises and expectations: providing effective cures for complex diseases, discovering and prioritizing drug targets more efficiently, eliminating toxic and ineffective compounds earlier and delivering the right drug therapy to the appropriate patients. Ultimately, the biomedical information generated today must be transformed into integrated predictive models that can be consulted for decision-making in drug discovery, efficacy and toxicity screening and individualized therapy. Here we describe how models that capture different aspects of network dynamics can be generated and applied in disease pathway identification, drug screening, diagnostics and individualized therapy.

Journal Article↗
PubMed1999

Genes to remember.

It has been known for several decades that the formation of long-term memory requires gene expression. In recent years, the use of genetic and molecular approaches has led to the identification and characterization of genes and molecules that play a fundamental role in the biological mechanisms underlying learning and memory. From these studies, it appears that molecules and molecular mechanisms essential for the process of memory have been conserved throughout evolution. The cyclic AMP (cAMP)-dependent activation pathway and a cAMP-dependent cascade of gene expression have been shown to be essential for memory formation in Aplysia californica, Drosophila melanogaster and rodents. Moreover, members of the transcription factor family cAMP response element binding proteins (CREBs) seem to represent key molecules for transforming incoming information into long-term memory. Here, we review the studies showing that conserved molecules and biological mechanisms are engaged in simple and complex forms of memory.

Animals↗
PubMedDate not supplied

[The functional coupling of the mechanisms for the selection of significant signals and the motor reactions they induce].

The data are described in favour of forming the integrative image of the significant signals in the mammalian brain. This image is created as a summary of the significant at this moment information, selected in the specialized areas of the cortex. The hypothesis is founded on the investigations of the cortico-striatal interrelations. They suggest that the results of the cortical analysis, which are dispersed through the specialized cortical fields, enter the striatum via the corticofugal pathways and transform into an integrative form in its neuronal network. The experimental data show that the striatal activity recorded during instrumental behaviour does not contain motor programs or commands, but reflects the peculiarity of the sensory environment, in which the movements are realized.

Animals↗
PubMedDate not supplied

In vivo metabolism of isoxicam in rats, dogs, and monkeys.

Isoxicam is a long half-life nonsteroidal anti-inflammatory agent which undergoes extensive metabolism prior to elimination in animals and man. The major route of isoxicam transformation is hydroxylation of the methylisoxazole functionality to form hydroxymethylisoxicam, and cleavage of its benzothiazine moiety to give an oxoacetic acid metabolite. The metabolic pathway for scission of the benzothiazine moiety to the oxoacetic acid metabolite and to other potential metabolites is not known. To gain additional information on the metabolic fate of isoxicam, 14C-isoxicam labeled on the N-methyl group was administered to rats, dogs, and monkeys with urine and feces collected for metabolic profiling and identification. Identified as new metabolites of isoxicam were an open-ring sulfonamide, N-methylsaccharin, and saccharin. The formation of these metabolites suggests that isoxicam undergoes direct oxidative scission of its benzothiazine ring at carbon atom 3 to generate the observed open-ring sulfonamide, N-methylsaccharin, and oxoacetic acid metabolites.

Animals↗
PubMed2006

Electrostatic calculations for assignment of infrared difference bands to carboxyl groups getting protonated during protein reactions.

Fourier transform infrared (FTIR) difference spectroscopy is predestined to monitor the protonation of carboxyl groups during protein reactions, making glutamic and aspartic amino acids unique to follow proton pathways. The absorption of the corresponding vibrations are clearly distinguishable from the absorption of other amino acids. However, the assignment to specific groups within the protein needs additional information, e.g., from induced spectral changes due to isotopic labeling or mutation. Here, the capability of electrostatic calculations to assign IR difference bands to specific carboxyl groups getting protonated is demonstrated by the ion pump mechanism of the sarcoplasmic reticulum Ca(2+)-ATPase. Active Ca(2+) transport is coupled to the hydrolysis of ATP. Two Ca(2+) ions are transported per ATP hydrolysed and two or three H(+) ions are countertransported. FTIR difference spectra show that during the Ca(2+) release step, carboxyl groups become protonated. Multiconformation continuum electrostatic calculations (MCCE) have been carried out to determine the equilibrium distribution of residue ionization and side chain conformation in dependence of pH. Available structural X-ray data from the calcium-bound and the calcium-free state allows us to simulate the transition between the two states monitored in the IR difference spectra. Exemplarily for Asp 800, ligand of both calcium ions, it is shown that MCCE calculations can identify this specific Asp to contribute to the IR bands and therefore to take part in the proton countertransport of the Ca(2+)-ATPase. In addition, an energy analysis can be performed to understand what interactions shift the pK(a).

Binding Sites↗
PubMed1996

Genomic instability induced by ionizing radiation.

Genomic instability is characterized by the increased rate of acquisition of alterations in the mammalian genome. These changes encompass a diverse set of biological end points including karyotypic abnormalities, gene mutation and amplification, cellular transformation, clonal heterogeneity and delayed reproductive cell death. The loss of stability of the genome is becoming accepted as one of the most important aspects of carcinogenesis, and the numerous genetic changes associated with the cancer cell implicate genomic stability as contributing to the neoplastic phenotype. Multiple metabolic pathways govern the accurate duplication and distribution of DNA to progeny cells; other pathways maintain the integrity of the information encoded by DNA and regulate the expression of genes during growth and development. For each of these functions, there is a normal baseline frequency at which errors occur, leading to spontaneous mutations and other genomic anomalies. This review summarizes the current status of knowledge about radiation-induced genomic instability. Those events and processes likely to be involved in the initiation and perpetuation of the unstable phenotype, the potential role of epigenetic factors in influencing the onset of genomic instability, and the delayed effects of cellular exposure to ionizing radiation are discussed.

Animals↗
PubMed1998

Herpes simplex virus type 2: unique biological properties include neoplastic potential mediated by the PK domain of the large subunit of ribonucleotide reductase.

The prevalence of herpes simplex virus type 2 (HSV-2) infections in the US has increased approximately 30%. Like HSV-1, which causes facial lesions, HSV-2 causes symptomatic lesions (at genital sites) and establishes latent infections of the sensory ganglia. However, the two viruses are biologically distinct, suggesting that they possess unique functions which are mediated by different viral genes. Unlike HSV-1, HSV-2 is a tumor virus. It causes neoplastic transformation of cultured human cells and tumors in animals. The oncogene is at the 5'-terminal of a chimeric gene that also codes for the large subunit of viral ribonucleotide reductase (RR1). It was captured from the cell and it codes for a novel growth factor receptor serine-threonine protein kinase (PK) the minimal genetic information of which can adapt to a relatively wide functional diversity due to the flexibile use of additional and alternate catalytic sites and protein interaction motifs which are organized in an efficient, almost superimposed fashion. By contrast to other growth factor receptor serine-threonine kinases studied so far, the HSV-2 oncoprotein (RR1 PK) activates the RAS signaling pathway, thereby providing a biological bridge to the tyrosine growth factor receptor kinases. Expression of the oncogene is required for neoplastic transformation and tumor growth in vivo is inhibited by antisense inhibition of oncogene expression. The virus conserved the captured oncogene because it provides a biological advantage for its survival. In cultured cells, RR1 PK is required for viral IE gene transcription. In vivo, RR1 PK is likely to be involved in latency reactivation.

Cell Transformation, Neoplastic↗