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Results for “Pathway informed transformer”

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PubMed2004

Underlying principles of visual shape selectivity in posterior inferotemporal cortex.

Object perception depends on shape processing in the ventral visual pathway, which in monkeys culminates in inferotemporal cortex (IT). Here we provide a description of fundamental quantitative principles governing neural selectivity for complex shape in IT. By measuring responses to large, parametric sets of two-dimensional (2D) silhouette shapes, we found that neurons in posterior IT (Brodmann's areas TEO and posterior TE) integrate information about multiple contour elements (straight and curved edge fragments of the type represented in lower-level areas) using both linear and nonlinear mechanisms. This results in complex, distributed response patterns that cannot be characterized solely in terms of example stimuli. We explained these response patterns with tuning functions in multidimensional shape space and accurately predicted neural responses to the widely varying shapes in our stimulus set. Integration of contour element information in earlier stages of IT represents an important step in the transformation from low-level shape signals to complex object representation.

Action Potentials↗

PubMed2000

Mapping of statistical physics to information theory with application to biological systems.

The problem of achieving a mapping of formalisms in statistical physics and theoretical biology to information theory is discussed using an example for canonical ensembles. We extend the meaning of the Handscomb Monte-Carlo method to a general recipe for the transformation from a "configuration" space to a "sentence" space. The ensemble of "sentences" and its corresponding source uncertainty function are introduced. A possible mapping procedure based on a generalization of the Handscomb representation is described. For a biological illustration, we present a way to introduce a pathway representation to describe metabolic processes in living systems.

Animals↗

PubMed1999

Calcium-induced activation of a mutant G-protein-coupled receptor causes in vitro transformation of NIH/3T3 cells.

The calcium-sensing receptor (CaR) is a G-protein-coupled receptor that is widely expressed, has tissue-specific functions, and regulates cell growth. Activating mutations of this receptor cause autosomal dominant hypocalcemia, a syndrome characterized by hypocalcemia and hypercalciuria. The identification of a family with an activating mutation of the CaR (Thr151Met) in which hypocalcemia cosegregates with several unusual neoplasms led us to examine the transforming effects of this mutant receptor. Transfection of NIH/3T3 cells with the mutant but not the normal receptor supported colony formation in soft agar at subphysiologic calcium concentrations. The mutant CaR causes a calcium-dependent activation of the extracellular signal-regulated protein kinase (ERK) 1/2 and Jun-N-terminal kinase/stress-activated (JNK/ SAPK) pathways, but not P38 MAP kinase. These findings contribute to a growing body of information suggesting that this receptor plays a role in the regulation of cellular proliferation, and that aberrant activation of the mutant receptor in this family may play a role in the unusual neoplastic manifestations.

3T3 Cells↗

PubMed2005

Protein targeting into plastids: a key to understanding the symbiogenetic acquisitions of plastids.

Recent progress in molecular phylogenetics has proven that photosynthetic eukaryotes acquired plastids via primary and secondary endosymbiosis and has given us information about the origin of each plastid. How a photosynthetic endosymbiont became a plastid in each group is, however, poorly understood, especially for the organisms with secondary plastids. Investigating how a nuclear-encoded plastid protein is targeted into a plastid in each photosynthetic group is one of the most important keys to understanding the evolutionary process of symbiogenetic plastid acquisition and its diversity. For organisms which originated through primary endosymbiosis, protein targeting into plastids has been well studied at the molecular level. For organisms which originated through secondary endosymbiosis, molecular-level studies have just started on the plastid-targeted protein-precursor sequences and the targeting pathways of the precursors. However, little information is available about how the proteins get across the inner two or three envelope membranes in organisms with secondary plastids. A good in vitro protein-import system for isolated plastids and a cell transformation system must be established for each group of photosynthetic eukaryotes in order to understand the mechanisms, the evolutionary processes and the diversity of symbiogenetic plastid acquisitions in photosynthetic eukaryotes.

Biological Evolution↗

PubMed1992

Gene conversion in Neisseria gonorrhoeae: evidence for its role in pilus antigenic variation.

Antigenic variation of gonococcal pili results from the unidirectional transfer of genetic information from variant-encoding partial pilin genes to an active expression locus. Two potential mechanisms that may result in the observed alterations of gene linkage and organization are conversion and transformation. To determine the relative contributions of these two distinct pathways of recombination to pilus variation, gonococcal strains carrying defined frameshift, missense, and nonsense mutations within the pilin expression locus were constructed. Reversion to a piliated state required correction of the lesions and provided a simple means of scoring productive recombination and antigenic variation. Examination of the mutants revealed a lack of correspondence between the frequencies with which they could be transformed (10(-6) per recipient) and the incidence with which they gave rise to revertants (greater than 10(-4) per colony-forming unit per generation). Further, the rates of reversion demonstrated by these mutants were not altered by growth in the presence of DNase I, conditions that abolished intercellular transfer of chromosomal markers during cultivation. Through the use of a pilin mutant in which a frameshift mutation encompassed the introduction of a restriction endonuclease site, the symmetry of recombination that resulted in reversion could be scored by Southern hybridization. In all cases examined, the DNA alterations responsible for pilin variation were nonreciprocal events. The results favor the model that productive pilin gene rearrangements in gonococci arise by gene conversion.

Amino Acid Sequence↗

PubMed2001

Dynamical encoding by networks of competing neuron groups: winnerless competition.

Following studies of olfactory processing in insects and fish, we investigate neural networks whose dynamics in phase space is represented by orbits near the heteroclinic connections between saddle regions (fixed points or limit cycles). These networks encode input information as trajectories along the heteroclinic connections. If there are N neurons in the network, the capacity is approximately e(N-1)!, i.e., much larger than that of most traditional network structures. We show that a small winnerless competition network composed of FitzHugh-Nagumo spiking neurons efficiently transforms input information into a spatiotemporal output.

Action Potentials↗

PubMed1993

Oncogenes and expression of endogenous lectins and glycoconjugates.

It is now well established that malignant transformation of eucaryotic cells is concomitant with typical alterations of glycosylation and the expression pattern of endogenous lectins. In parallel, oncogene transfection studies revealed a correlation between the expression of some of these genes, the transformed state and perhaps metastasis. These observations lead to the idea that oncogenes may control the expression of enzymes involved in the biosynthetic pathway of cell membrane glycoconjugates and the expression of endogenous lectins. Indeed, several contributions have shown that cells upon transfection with activated oncogenes of the ras family become invasive and/or metastatic and have their membrane glycoproteins modified. Information on the molecular mechanism of this postulated oncogene regulation is still lacking. Because of the diversity of the functions of oncogene-encoded proteins, further experiments dealing with other activated oncogenes may help in deciphering the regulation of expression of glycoconjugates and endogenous lectins together with their functions.

Animals↗

PubMed2002

Two-dimensional femtosecond spectroscopy.

The simplest two-dimensional (2D) spectra show how excitation with one (variable) frequency affects the spectrum at all other frequencies, thus revealing the molecular connections between transitions. Femtosecond 2D Fourier transform (2D FT) spectra are more flexible and share some of the remarkable properties of their conceptual parent, 2D FT nuclear magnetic resonance. When 2D FT spectra are experimentally separated into real absorptive and imaginary refractive parts, the time resolution and frequency resolution can both reach the uncertainty limit set for each resonance by the sample itself. Coherent four-level contributions to the signal provide new molecular phase information, such as relative signs of transition dipoles. The nonlinear response can be picked apart by selecting a single coherence pathway (e.g., specifying the relative signs of energy level difference frequencies during different time intervals as in the photon echo). Because molecules are frozen on the femtosecond timescale, femtosecond 2D FT experiments can separate a distribution of instantaneous molecular environments and intramolecular geometries as inhomogeneous broadening. This review provides an introduction to two-dimensional Fourier transform experiments exploiting second- and third-order vibrational and electronic nonlinearities.

Journal Article↗

PubMed2003

Parallel colour-opponent pathways to primary visual cortex.

The trichromatic primate retina parses the colour content of a visual scene into 'red/green' and 'blue/yellow' representations. Cortical circuits must combine the information encoded in these colour-opponent signals to reconstruct the full range of perceived colours. Red/green and blue/yellow inputs are relayed by the lateral geniculate nucleus (LGN) of thalamus to primary visual cortex (V1), so understanding how cortical circuits transform these signals requires understanding how LGN inputs to V1 are organized. Here we report direct recordings from LGN afferent axons in muscimol-inactivated V1. We found that blue/yellow afferents terminated exclusively in superficial cortical layers 3B and 4A, whereas red/green afferents were encountered only in deeper cortex, in lower layer 4C. We also describe a distinct cortical target for 'blue-OFF' cells, whose afferents terminated in layer 4A and seemed patchy in organization. The more common 'blue-ON' afferents were found in 4A as well as lower layer 2/3. Chromatic information is thus conveyed to V1 by parallel, anatomically segregated colour-opponent systems, to be combined at a later stage of the colour circuit.

Animals↗

PubMed2002

New concepts in selenium chemoprevention.

This article highlights some recent advances in selenium cancer chemoprevention research. It has been well documented that the chemical transformation of selenium to a monomethylated metabolite is an important step in achieving cancer prevention. Studies with the rat mammary carcinogenesis model suggested that methylselenocysteine (MSC), a good precursor for generating methylselenol endogenously, is able to block clonal expansion of premalignant lesions in the mammary gland. This finding supports the notion that selenium intervenes at an early stage of carcinogenesis. In addition to decreasing cell proliferation of the transformed colonies in vivo, MSC also enhances apoptosis. These same cellular responses are replicated with human premalignant breast cells grown in culture. cDNA microarray analysis indicated that selenium affects a multitude of molecular targets. Based on this information, a number of signaling pathways are proposed that could potentially provide insight into how selenium might block cell cycle progression and induce cell death.

Animals↗

PubMed1997

Role of intracellular pH in proliferation, transformation, and apoptosis.

Both cellular proliferation and apoptosis (programmed cell death) have been claimed to be modulated, perhaps even triggered by, changes in intracellular pH. In this review, we summarize the evidence that gave rise to these hypotheses. To facilitate a critical appraisal of the existing data, we briefly review the main pathways involved in cytosolic pH homeostasis and their regulation by mitogens and by apoptosis-inducing agents. The information available at present suggests that cytosolic pH plays a permissive role in cellular growth and proliferation, but is neither a trigger nor an essential step in the mitogenic signal transduction cascade. Concerning apoptosis, it is clear that lowering the pH in vitro can activate DNase II. However, the evidence linking cytosolic acidification with DNA degradation in vivo is presently not convincing. We conclude that the cytosolic pH, an essential physiological parameter that is tightly controlled by multiple, complementary, or redundant systems, is unlikely to play a role in signalling either cell growth or death.

Apoptosis↗

PubMed2006

Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis.

The tumour-suppressor phosphatase with tensin homology (PTEN) is the most important negative regulator of the cell-survival signalling pathway initiated by phosphatidylinositol 3-kinase (PI3K). Although PTEN is mutated or deleted in many tumours, deregulation of the PI3K-PTEN network also occurs through other mechanisms. Crosstalk between the PI3K pathways and other tumorigenic signalling pathways, such as those that involve Ras, p53, TOR (target of rapamycin) or DJ1, can contribute to this deregulation. How does the PI3K pathway integrate signals from numerous sources, and how can this information be used in the rational design of cancer therapies?

Animals↗

PubMed2000

Focal adhesion kinase, Rap1, and transcriptional induction of vascular endothelial growth factor.

BACKGROUND: Signals from a cell's environment are sensed by receptors, which activate pathways that, in turn, transmit the signals to the nucleus, informing decisions on growth, angiogenesis, and other cell functions. Transcription of vascular endothelial growth factor (VEGF), a potent angiogenic factor, can be induced by cell-cell contact. In the current work, we sought to determine if this induction is dependent on transformation of cells to a malignant phenotype and subsequently to determine which signaling molecules mediate activation of VEGF transcription. METHODS: Normal and transformed prostate epithelial cell lines were examined at various cell densities to simulate the effect of increased cell contact on expression of VEGF messenger RNA. Transformed cells were also cotransfected with a VEGF promoter-reporter construct and with constructs that express dominant negative or activated versions of signal transduction proteins hypothesized to be involved in the cell-cell contact process, and reporter activity was assessed at various cell densities. All P values are two-sided. RESULTS: Direct cell-cell contact, but not extracellular matrix components, resulted in transcriptional activation of a VEGF promoter-reporter construct in malignant (P<.0001) but not in nonmalignant (P =.37) prostate cells. This process was mediated via a mitogen-activated protein kinase (MAPK); it required the activity of focal adhesion kinase (FAK), Rap1, and Raf and was Ras independent. In addition, transcriptional activation of a Ras-sensitive Elk-1 chimeric reporter by cell-cell contact suggests that Rap1 is a key factor in regulating the specificity of convergent MAPK-signaling pathways arising from different upstream extracellular stimuli. CONCLUSIONS: Cell contact induction of VEGF transcription via FAK and Rap1 provides a novel Ras-independent, but transformation-dependent, mechanism for stimulus-specific regulation of tumor VEGF expression via MAPK.

Blotting, Northern↗

PubMed2004

From cells to tissues: fluorescence confocal microscopy in the study of histological samples.

Our knowledge of the genetic mechanisms controlling cell proliferation and differentiation usually originates from in vitro cultured cell line models. However, the definition of the molecular switches involved in control of homeostasis and the understanding of the changes occurring in neoplastic transformation require looking at single cells as the components of a complex tissue network. Histological examination of tissue samples can gain a substantial amount of information from high-resolution fluorescence analysis. In particular, confocal microscopy can help in the definition of functional pathways using multiparameter analysis. In this report, we present acquisition and analysis procedures to obtain high-resolution data from tissue sections. Confocal microscopy coupled to computational restoration, statistical evaluation of spatial correlations, and morphological analysis over large tissue areas were applied to colorectal samples providing a molecular fingerprint of the biological differences inferred from classical histological examination.

Animals↗

PubMed2006

Gene and protein expression in the myometrium in pregnancy and labor.

Microarray technologies widen our comprehension of the major structural and metabolic transformations which affect the myometrium from the very beginning of pregnancy until parturition. The results are coherent with the mass of information which was accumulated previously, primarily on the basis of studies of selected critical factors. They highlight the activation of precise signaling pathways, some of which may have been previously under evaluated. The remodelling and maturation processes that the myometrium undergoes in pregnancy appear clearly as phenomena which last during the full course of gestation. Comparatively, the onset of labor is perhaps the phenomenon which remains the least well described by these methods of analysis. Nevertheless, genomic studies constitute a necessary first step of orientation and help establishing new links between the generic signaling pathways that are activated during the normal or pathological gestation. These studies also represent an indicative step that will have to be paralleled, in the future, with the results of the systematic proteomic analysis of the myometrium.

Animals↗

PubMed2001

Studies of all-trans-retinal as a photooxidizing agent.

The photophysical properties of all-trans-retinal (RAL) have been extensively studied because of the importance of the retinoids in the visual process. However, little information is available regarding the participation of RAL in photochemical transformations such as photoxidation. RAL is one of several native chromophores that have been suggested to act as photosensitizers of damage in the human retina, and this damage would likely occur through oxidative pathways. Time-resolved and steady state techniques have been used to examine the photoreactivity of RAL toward several suitable substrates. The lifetime of the RAL triplet excited state is observed to decrease with increasing concentration of the well-known electron and hydrogen atom donors, 2,3,5,6-tetramethyl-1,4-phenylenediamine (DAD), hydroquinone (HQ), methylhydroquinone (MHQ), 2,3-dimethylhydroquinone (DMHQ) and trimethylhydroquinone (TMHQ), although the bimolecular rate constants for the reaction are much less than that of diffusion controlled (2.9 x 10(7) M-1 s-1, 1.2 x 10(5) M-1 s-1, 1.2 x 10(5) M-1 s-1, 1.5 x 10(5) M-1 s-1 and 1.6 x 10(6) M-1 s-1, for DAD, HQ, MHQ, DMHQ and TMHQ, respectively). In the presence of the donors, new absorptions grow concomitant with the decay of the triplet excited state, and for DAD and TMHQ, the observed spectra are similar to the spectra of p-phenylenediamine and TMHQ radicals. Irradiation of RAL in argon-saturated methanol results in fairly efficient photobleaching of RAL and in the formation of two new compounds having absorption spectra that are shifted below 300 nm. Irradiation of RAL in argon-saturated acetonitrile also results in photobleaching of RAL, but the reaction proceeds at a slower rate.

Humans↗

PubMed2003

The role of connective tissue growth factor, a multifunctional matricellular protein, in fibroblast biology.

Connective tissue growth factor (CTGF, CCN2), a member of the CCN family of proteins, is a cysteine-rich proadhesive matricellular protein that plays an essential role in the formation of blood vessels, bone, and connective tissue. As expression of this protein is potently induced by transforming growth factor-beta (TGFbeta), it has been hypothesized that CTGF mediates several of the downstream actions of TGFbeta. In particular, CTGF is profibrotic, as CTGF is overexpressed in fibrotic disease and synergizes with TGFbeta to promote sustained fibrosis in vivo. Over the last several years, key data regarding the developmental role and structure and function relationship of CTGF have emerged. In addition, increased information concerning the mechanisms underlying the control of CTGF expression in normal and fibrotic cells and the signal transduction pathways through which CTGF acts on cells has been uncovered. This review summarizes the current state of knowledge regarding CTGF biology.

Animals↗

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↗