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Results for “Pathway informed transformer”

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At least 271 records · Page 15Linked to original sources

PubMed1991

Muscle fatigue: conduction or mechanical failure?

It is well documented that repeated voluntary activity or electrical stimulation of skeletal muscle results in a decline in force production or power output. However, the precise physiological causes of "muscle fatigue" are not yet well understood. It is conceivable that the mechanism(s) may lie either in the conduction of action potentials in the central and peripheral nervous systems or in the transformation of the electrical event into mechanical force production by the muscle itself. In fact, none of the components of the electrical pathway from generation of impulses in the brain to their conduction over the neuron and the excitable membranes of the muscle can as yet be ruled out as potential contributors to the fatigue process. Relative to that on conduction failure, more information exists concerning the possibility that a defect in the excitation contraction coupling process in skeletal muscle, e.g., intracellular acidosis, inadequate supply of energy for contraction, or a disruption in Ca2+ homeostasis may also be significant in compromising force production following sustained activity. Despite this, the amount of conflicting data derived from these experiments has hindered the resolution of this question. In the future more attention must be given to such issues as the type of activity used to elicit fatigue and the fiber composition of the muscles studied. This is imperative as these factors clearly impact the nature of correlations between the biochemical and physiological events in muscle that are required to support prospective fatigue mechanisms.

Animals↗

PubMed1982

Replication and expression of a bacterial--mitochondrial hybrid plasmid in the fungus Podospora anserina.

Hybrid plasmids consisting of the bacterial plasmid pBR322 and plasmid-like DNA (pl DNA) sequences from the fungus Podospora anserina are not only able to replicate in Escherichia coli but also in the fungus. This was proved by both biophysical and biological evidence involving buoyant density profiles, DNA.DNA hybridization, and restriction analysis--all confirming that pl DNA behaves as a true plasmid. During its amplification in P. anserina, the hybrid plasmid does not lose its prokaryotic coding capacity as shown after retransfer and subsequent cloning in E. coli. P. anserina is able to express both the eukaryotic and the prokaryotic genetic information of the hybrid plasmid because the occurrence of senescence and the production of beta-lactamase could be shown in experiments involving specific hybrid plasmids. In the same systems, it was possible to demonstrate that a hybrid plasmid containing, instead of pl DNA, a pl DNA homologous region of native mtDNA also could function as a true plasmid. This hybrid plasmid contained about 25% of the genetic information pl DNA, which corresponds to about 6% of the genetic information of mtDNA. Thus, the data show that hybrid plasmids may be used to shuttle genetic information between P. anserina and E. coli. hence, through the use of a mtDNA replicon, as evidenced by the pl DNA of P. anserina, another pathway in genetic engineering is established.

DNA Replication↗

PubMed1989

The order of schizophrenic thought.

Analysis of schizophrenic thought disorder reveals structures and regulatory processes that govern its phenotypic expressions. In particular, the three primary variants of this thought disorder--combinative thinking, drive-dominated thinking, and loss of reality testing--can be viewed in terms of thematic structures. Schizophrenic communication is characterized by an affective rule-governing process that channels information into case-grammar thematic structures. The author elaborates an earlier proposal that transformational grammar subunits should be identified and modeled to schizophrenic thought and explicates the use of these specific structures and processes. He then suggests clinical interventions and future research applications.

Afferent Pathways↗

PubMed2005

Identification of neutrophil gelatinase-associated lipocalin (NGAL) as a discriminatory marker of the hepatocyte-secreted protein response to IL-1beta: a proteomic analysis.

The liver is the major source of proteins used throughout the body for various functions. Upon injury or infection, an acute phase response (APR) is initiated in the liver that is primarily mediated by inflammatory cytokines such as interleukin-1beta (IL-1beta) and interleukin-6. Among others, the APR is characterized by an altered protein synthetic profile. We used two-dimensional gel electrophoresis to study the dynamics of changes in protein synthesis in hepatocytes exposed to these inflammatory cytokines. Protein profiles were quantified using image analysis and further analyzed using multivariate statistical methods. Our results indicate that IL-1beta and IL-6 each induces secreted protein responses with distinct dynamics and dose-dependence. Parallel stimulation by IL-1beta and IL-6 results in a protein pattern indistinguishable from the IL-1beta pattern, indicating a dominant effect of IL-1beta over IL-6 at the doses tested. Multidimensional scaling (MDS) of correlation distances between protein secretion levels revealed two protein pairs that are robustly co-secreted across the various cytokine stimulation conditions, suggesting shared regulatory pathways. Finally, we also used multivariate alternating conditional expectation (MACE) to identify transformation functions that discriminated the cytokine-stimulated and untreated hepatocyte-secreted protein profiles. Our analysis indicates that the expression of neutrophil gelatinase-associated lipocalin (NGAL) was sufficient to discriminate between IL-1beta and IL-6 stimulation. The combination of proteomics and multivariate analysis is expected to provide new information on the cellular regulatory networks involved in generating specific cellular responses.

Acute-Phase Proteins↗

PubMed2002

Analysis of the aspartic acid metabolic pathway using mutant genes.

Amino acid metabolism is a fundamental process for plant growth and development. Although a considerable amount of information is available, little is known about the genetic control of enzymatic steps or regulation of several pathways. Much of the information about biochemical pathways has arisen from the use of mutants lacking key enzymes. Although mutants were largely used already in the 60's, by bacterial and fungal geneticists, it took plant research a long time to catch up. The advance in this area was rapid in the 80's, which was followed in the 90's by the development of techniques of plant transformation. In this review we present an overview of the aspartic acid metabolic pathway, the key regulatory enzymes and the mutants and transgenic plants produced for lysine and threonine metabolism. We also discuss and propose a new study of high-lysine mutants.

Aspartate Kinase↗

PubMed1996

The brain specific Ras exchange factor CDC25 Mm: modulation of its activity through Gi-protein-mediated signals.

CDC25Mm is a mouse guanine nucleotide exchange factor specific for Ras, exclusively expressed in the brain. We used a reporter gene containing a Ras-responsive fos-promoter in order to gain information on the role played by this exchange factor in signal transduction. Transient expression of CDC25Mm in CHO cells activates Ras. Moreover serum, but not insulin, can upregulate the response mediated by CDC25Mm and this modulation requires that the CDC25Mm maintains its N-terminal region. NIH3T3 fibroblasts, stably overexpressing this exchange factor, show a partially transformed phenotype, suggesting that the Ras-dependent pathway is constitutively active. In these cells serum and lysophosphatidic acid (LPA) stimulate Ras activity above the basal level while PDGF does not. Both serum and LPA-induced Ras activations in CDC25Mm overexpressing cells can be completely inhibited by pertussis toxin. Moreover, these responses are strongly reduced by coexpression of a truncated version of CDC25Mm lacking the C-terminal catalytic portion. This construct behaves in a dominant negative manner suggesting that it may compete with CDC25Mm by sequestering in an unproductive way signalling components activated by these factors. The data presented indicate that CDC25Mm does not participate in connecting tyrosine kinase receptors with Ras, while it could mediate Ras activation induced by pertussis toxin sensitive Gi-coupled receptors.

3T3 Cells↗

PubMed1996

The Engrailed-2 homeobox gene and patterning of spinocerebellar mossy fiber afferents.

The mouse Engrailed-2 gene, En-2, appears to be involved in cerebellar pattern formation. Homozygous null mutants for En-2 have abnormal foliation patterns in the posterior half of the cerebellum and there are changes in Purkinje and granule cell gene expression in some posterior folia, possibly reflecting changes in cell identity. We have examined the distribution of spinocerebellar mossy fiber terminals in homozygous En-2hd null mutants to determine if En-2 is involved in regulating the pattern of afferent connectivity in the cerebellum. Spinocerebellar mossy fiber terminals were labeled following WGA-HRP injections in the lumbar region of 5 homozygous En-2hd mutants and 4 heterozygous controls. The distribution of spinocerebellar mossy fiber terminals was consistently altered in lobules VIII and IX of the En-2hd mutants. The principal changes were a reduction in the number of mossy fiber terminal fields in the dorsal aspect of lobule VIII and the dorsal midline field in lobule IX was fused into a single compartment. The results suggest that the deletion of En-2 expression does not transform lobule identity, at least with respect to afferent fiber positional information cues. However, the changes in foliation and afferent connectivity in the En-2 mutant support a broad role for the En-2 gene in cerebellar patterning.

Afferent Pathways↗

PubMed2005

Identification of candidate genes associated with salivary adenoid cystic carcinomas using combined comparative genomic hybridization and oligonucleotide microarray analyses.

Adenoid cystic carcinoma (ACC) of the salivary gland often has a variable clinical course with a poor prognosis. To investigate DNA copy number aberrations associated with ACCs, we compared comparative genome hybridization data from ACCs (n = 6) with other types of salivary gland tumors such as adenocarcinomas (n = 3) and pleomorphic adenomas (n = 6). While 15 gain loci (1q32, 6p25, 6q21-q24, 7q11.2, 7q31, 10q11.2, 11p12-q12, 12q13, 12q14, 13q24, 16p13.3-13.2, 18p11.3, 18q23, 19q13.4, and Xq28) were detected, no DNA loss locus was evident. To examine the expression status of genes on the ACC-associated loci, transcriptional measurements of approximately 38000 human genes then were monitored using Affymetrix U133 Plus 2.0 GeneChips. A total of 4431 genes were found differentially expressed by at least two-fold between ACCs and normal salivary glands. Of them, 3162 genes were up-regulated and 1269 genes were down-regulated in ACCs. After obtaining locus information about the RNA transcripts from the Affymetrix database, we found 262 ACC-associated genes with increased expression on ACC-associated loci. To investigate functional network and gene ontology, the 262 genes were analyzed using Ingenuity Pathway Analysis Tool. The function with the highest P value was a cancer-related function (P = 2.52e-4 to 4.71e-2). In addition, we identified pituitary tumor-transforming gene 1 and transformation related protein 63 genes that were up-regulated by increasing DNA copy number and modulated expression of oncogenes. These results suggested that the combination of copy number and gene expression profiling provides an improved strategy for gene identification in salivary gland ACCs.

Adenocarcinoma↗

PubMed2001

Prostaglandin inhibitors and the chemoprevention of noncolonic malignancy.

Much has been learned about the role of NSAIDs as cancer preventives through epidemiologic and experimental studies. The pathways of carcinogenesis in the gastrointestinal tract are initiated by many different genetic, environmental, infective, and lifestyle factors. It is possible that the final common pathway of all these malignancies may have some common features. It is conceivable that head and neck, esophageal, gastric, and colorectal epithelial carcinogenesis all are influenced by or require COX-2 up-regulation as a step toward transformation. Intuitively, it is possible that selective COX-2 inhibitors may have a preventive role in all these epithelial malignancies. Today's challenge is to translate this information into clinical trials to define what role, if any, COX inhibition might play in the prevention of these malignancies.

Adenocarcinoma↗

PubMedDate not supplied

Information content in organic molecules: reaction pathway analysis via Brownian processing.

Carbon chemistry offers infinite possibilities for molecules as information carriers. Moreover, there is no boundary on the number of ways in which a carrier's information can change via a chemical reaction. Organic reaction pathways thus pose new types of informatic variables which compel characterization using Brownian methods. We apply the tools of the preceding paper to these variable types for select reactions and classes. Along the way, geometric descriptors are formulated which complement the structure graph sequences of chemistry texts and journals. In addition, the statistical structure underpinning carbon transformations is explored more deeply. Overall, this work brings to light several informatic principles of organic reactions. Knowledge of these can assist in synthetic designs on both large- and small-scales. Brownian methods are able to address the pathway structures of all organic reactions: those reported in the literature, explored in the lab, or in the developmental stage.

Journal Article↗

PubMed2003

BSD: the Biodegradative Strain Database.

The Biodegradative Strain Database (BSD) is a freely-accessible, web-based database providing detailed information on degradative bacteria and the hazardous substances that they degrade, including corresponding literature citations, relevant patents and links to additional web-based biological and chemical data. The BSD (http://bsd.cme.msu.edu) is being developed within the phylogenetic framework of the Ribosomal Database Project II (RDPII: http://rdp.cme.msu.edu/html) to provide a biological complement to the chemical and degradative pathway data of the University of Minnesota Biocatalysis/Biodegradation Database (UM-BBD: http://umbbd.ahc.umn.edu). Data is accessible through a series of strain, chemical and reference lists or by keyword search. The web site also includes on-line data submission and user survey forms to solicit user contributions and suggestions. The current release contains information on over 250 degradative bacterial strains and 150 hazardous substances. The transformation of xenobiotics and other environmentally toxic compounds by microorganisms is central to strategies for biocatalysis and the bioremediation of contaminated environments. However, practical, comprehensive, strain-level information on biocatalytic/biodegradative microbes is not readily available and is often difficult to compile. Similarly, for any given environmental contaminant, there is no single resource that can provide comparative information on the array of identified microbes capable of degrading the chemical. A web site that consolidates and cross-references strain, chemical and reference data related to biocatalysis, biotransformation, biodegradation and bioremediation would be an invaluable tool for academic and industrial researchers and environmental engineers.

Bacteria↗

PubMed2026

Genetic diversity and molecular mechanisms in hypertrophic cardiomyopathy: toward personalized therapy.

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac muscle disorder, yet contemporary genomic and mechanistic research still lacks a cohesive model explaining how diverse genetic architectures give rise to heterogeneous phenotypes. This review synthesizes advances across sarcomeric and nonsarcomeric mutations, including intermediate-effect variants, polygenic modifiers, and ancestry-dependent sources of variant misclassification to elucidate how these factors govern disease penetrance and clinical expression. It critically evaluates how genetic diversity intersects with key molecular pathways, including sarcomeric hypercontractility, calcium dysregulation, mitochondrial energy deficiency, and transforming growth factor-β (TGF-β) and protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling, to drive hypertrophic and fibrotic remodeling. Emerging mechanism-based therapies, such as myosin inhibition, allele-specific silencing, clustered regularly interspaced short palindromic repeats (CRISPR)-based correction, and metabolic modulation, are examined with respect to their capacity to modify upstream molecular drivers rather than downstream hemodynamic consequences. Persistent challenges, including variants of uncertain significance classification, ancestry-biased databases, inequitable access to genetic testing, and unresolved safety concerns for gene-based therapies, are critically assessed as major barriers to precision-medicine integration. By linking genetic architecture, molecular pathogenesis, and targeted interventions, this review advances a contemporary, mechanistically grounded framework that informs both individualized management and future research directions. Future research should prioritize pathway-specific therapeutics, functional and mechanistic validation of emerging variants, deeper physiologic phenotyping to refine disease modeling, and accelerate translation throughout the continuum of HCM pathophysiology.

Humans↗

PubMed1978

Glioblastoma multiforme: morphology and biology.

Glioblastoma multiforme, representing about 50% of all gliomas, encompasses a group of intrinsic tumours of the brain in later years (age peak around 50 years), the morphological hallmarks of which are an ensemble of variations in tumour cell and tissue structure featuring its biological malignancy. Glioblastoma, while sometimes appearing as a distinct "primary" tumour type, is usually accepted as an extreme manifestation of anaplasia and dedifferentiation of glia, mostly astrocytic. The astrocytic nature of most glioblastomas has been confirmed by ultrastructural studies and progressive differentiation of tumours maintained in organotypic tissue culture. Reproducible experimental models are particularly induced by oncogenic RNA (oncorna) viruses. The cell kinetic parameters are similar to those of other solid malignant tumours except for a comparatively low growth fraction of glioblastoma. The frequent occurrence of giant cells as well as of regressive changes with necrosis and vascular responses are indirect (secondary) indicators of malignancy which coincide with histochemical (enzymatic anisochronia) and biochemical data (lower level of glia specific S100 protein than in differentiated gliomas). Vascular proliferation, a characteristic feature of glioblastoma, may occasionally progress to sarcomatous transformation with development of gliosarcomas (mixed glial-mesenchymal tumours). While dissemination of glioblastoma through the cerebrospinal pathways is not uncommon, extraneural distant metastatic spread is rare, and usually observed after craniotomy. The results of modern neuro-oncology support the pathogenetic view that glioblastoma results from neoplastic transformation of glial elements with continuing dedifferentiation. This transformation can be experimentally induced by various factors including oncogenic DNA (oncorna) viruses by using a reverse transcriptase, while there is indirect evidence for an oncorna-virus information in human glioblastoma. The significance of immunological factors in the pathogenesis of brain tumours and in the course of neoplastic transformation of glia is not yet understood, but both morphological and immunological data are in favour of a cell mediated immunological reaction against tumour-specific antibodies. Since immunological factors and changes in cytokinetics are apparently active after the transformed tumour cells proliferate, all available therapeutic methods, including radiation, chemotherapy, and immunotherapy of glioblastoma only influence the final stages of neoplastic development with clinical manifestation of the tumour. In spite of modern combination and multimodality therapy schemes the prognosis of glioblastoma is still poor.

Adult↗

PubMed1999

Recognition hypermnesia with repeated trials: initial evidence for the alternative retrieval pathways hypothesis.

The alternative retrieval pathways (ARP) hypothesis of hypermnesia is here proposed. This hypothesis predicts hypermnesia (net improvements in recall or recognition after initial learning) whenever alternative retrieval pathways are provided leading to the original episodic trace. Initial evidence for this hypothesis was obtained in two experiments testing a non-obvious prediction of its format transformation assumption, namely that hypermnesia would be obtained in recognition and would not occur in recall if the former, but not the latter, condition requires obligatory format transformations between item encoding and retrieval. In the first experiment the same participants, exposed to identical items and having analogous encoding and retrieval conditions, showed recognition and did not show recall hypermnesia. With a between-participant design, the second experiment replicated the recognition hypermnesia findings, using a different recognition procedure and three instead of two test trials, whereas recall hypermnesia remained absent. Results are discussed comparing the heuristic value of ARP hypothesis to that of other current theories. It is concluded that recognition hypermnesia using individual words and pictures is a reliable phenomenon, provided ceiling effects can be prevented, and access to the original episodic information takes place using alternative retrieval pathways.

Adult↗

PubMed1995

An illusory transformation in a model of optic flow processing.

We present results from computer simulations of a biologically plausible model of heading detection in the visual motion pathway of higher mammals. These simulations are closely related to a recently discovered visual illusion in optic flow processing in humans. The model reproduces the results described for humans and suggests a possible explanation, namely that humans interpret the illusory stimuli in terms of egomotion. It provides further indication that the visual system makes use of visual information to cope with eye movement effects in dealing with optic flow.

Algorithms↗

PubMedDate not supplied

Analysis of cellular phosphoproteins by two-dimensional gel electrophoresis: applications for cell signaling in normal and cancer cells.

Two-dimensional (2-D) gel electrophoresis has been used to map proteins from various cell types in an effort to eventually link such maps to the sequencing of the entire human genome. While this analysis indicates the cellular disposition and expression of proteins, another application of 2-D gels, the analysis of phosphoproteins, can provide much information as to the assembly and "wiring" of the signal transduction circuits within cells which appear to be enervated by phosphate exchange. The preparation and separation of 32P-labeled proteins is described, as well as various analytical methods, including: the variety of gel systems available for specialist types of analyses, comparing 33P- and 32P-labeling of proteins, imaging techniques, phosphoamino analysis, phosphopeptide separation, identifying the amino acid groups that are phosphorylated, and the identification of phosphoproteins on 2-D gels by immunoprecipitation, corunning of purified proteins, comparative mapping and microsequencing, and by Western blotting. Examples (in brackets) are given of applications in which 2-D phosphogels can be applied, which offer advantages over other techniques. These include: (i) identifying in vivo substrates for kinases (protein kinase C activated by phorbol myristate acetate), (ii) investigating cytokine signaling pathways (tumor necrosis factor and interleukin-1), (iii) investigating the effects of drugs on signaling pathways (okadaic acid, menadione and cyclooxygenase inhibitors), (iv) characterization of specific phosphoproteins (heat-shock protein Hsp27 and stathmin), (v) comparing normal and transformed cells (MRC-5 human lung fibroblasts and their SV-40-transformed counterparts, MRC-5 SV1 cells), (vi) purifying phosphoproteins, (vii) investigating the relationship of protein phosphorylation to stages in the cell cycle (stathmin), (viii) investigating protein/protein interactions, (ix) mapping in vitro kinase substrates (protein kinase C, protein kinase A, and mitogen activated protein kinase activated protein kinase 2), and (x) locating and identifying cellular phosphatases (Hsp27 phosphatase). It is possible that the mapping of phosphoproteins can be linked to other 2-D gel databases and that information derived from these can be used in the future to better understand the signaling mechanisms of normal and cancerous cells.

Amino Acid Sequence↗

PubMed2002

Efficient coding of natural sounds.

The auditory system encodes sound by decomposing the amplitude signal arriving at the ear into multiple frequency bands whose center frequencies and bandwidths are approximately exponential functions of the distance from the stapes. This organization is thought to result from the adaptation of cochlear mechanisms to the animal's auditory environment. Here we report that several basic auditory nerve fiber tuning properties can be accounted for by adapting a population of filter shapes to encode natural sounds efficiently. The form of the code depends on sound class, resembling a Fourier transformation when optimized for animal vocalizations and a wavelet transformation when optimized for non-biological environmental sounds. Only for the combined set does the optimal code follow scaling characteristics of physiological data. These results suggest that auditory nerve fibers encode a broad set of natural sounds in a manner consistent with information theoretic principles.

Animals↗

PubMedDate not supplied

Consecutive silver staining and autoradiography of 35S and 32P-labeled cellular proteins: application for the analysis of signal transducing pathways.

The methodology for the simultaneous analysis of protein synthesis concomitant with protein phosphorylation/dephosphorylation is described. The technique consists of metabolic labeling of rat liver epithelial (RLE) cells with [32P]orthophosphate and [35S]methionine, performing two-dimensional polyacrylamide gel electrophoresis (2-D PAGE) of the mixed samples, followed by silver staining and subsequent autoradiography of the dried silver stained 2-D PAGE electrophoretograms using two films placed back-to-back. The first film, which is positioned in direct contact with the dried silver-stained gel, visualized both exposure to 35S and 32P while the second film recorded exposure to only 32P due to the differential energy levels of the two isotopes. The juxta-positioning of the silver-stained images with the two autoradiographic film images permits the unambiguous mapping of the phosphorylated polypeptides back to their corresponding silver-stained and methionine-labeled counterparts. This strategy provides quantitative information utilizing both silver staining (measure of constitutive levels of protein expression) and metabolic labeling to measure rates of protein synthesis and/or degradation and phosphorylation and/or dephosphorylation using [35S]methionine and [32P]orthophosphate, respectively. We have utilized this methodology for the in vitro analysis of transforming growth factor type beta 1 (TGF-beta 1)-mediated signal transduction in RLE cells and have identified three nuclear polypeptides, 1 (pI 4.95/M(r) 97 kDa), 2 (5.00/85 kDa) and 3 (4.90/84 kDa) whose phosphorylation status is rapidly and transiently modulated by TGF-beta 1. The methodology described should have wide applications in studies where it is desirous to measure protein synthesis and/or degradation concomitant with signal transduction pathways involving protein phosphorylation.

Animals↗