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Results for “Pathway informed transformer”

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PubMed2000

Xenopus Xenf: an early endodermal nuclear factor that is regulated in a pathway distinct from Sox17 and Mix-related gene pathways.

We report a novel zygotic gene encoding a Xenopus endodermal nuclear factor, Xenf. Expression of Xenf starts at the late blastula stages and is decreased after gastrulation. Xenf shows no structural homology to any known proteins. When GFP-tagged Xenf is overexpressed in Xenopus cells, Xenf protein is localized to the nucleus, associating closely with the chromosomes. In animal cap assays, Xenf expression is strongly activated by mRNA injection of Vg1 and VegT, maternal vegetal genes that can induce endodermal differentiation. In contrast, Xenf is not induced by endoderm-inducing zygotic transcription factors such as Sox17 and Mix-related genes. In turn, Xenf does not activate expression of Sox17, Mixer or Milk. Thus, Xenf is regulated by maternal vegetal positional information in a parallel manner to Sox17 and Mix-related gene pathways.

Amino Acid Sequence↗

PubMed1999

A direct demonstration of both structure and function in the visual system: combining diffusion tensor imaging with functional magnetic resonance imaging.

The relationships between functional activation patterns and the structural properties of brain pathways have not been widely studied. The recently developed magnetic resonance imaging technique of diffusion tensor imaging (DTI) allows a full characterization of water molecule mobility in three dimensions, providing new structural information that is not available from other in vivo imaging techniques. The directional bias of diffusion (anisotropy) may be derived from the diffusion tensor, and is related to fiber tract integrity and orientation. Since DTI and functional magnetic resonance imaging (fMRI) both require rapid (generally echoplanar) imaging it is possible to obtain geometrically matched images from the two modalities. fMRI and DTI were combined in a visual system study using photic stimulation to demonstrate the feasibility of combining the two methods and to investigate the structural properties of activated regions compared to the white matter tracts. Blood oxygenation level-dependent (BOLD) fMRI activation maps were directly overlayed upon fractional anisotropy (FA) maps, avoiding registration and spatial transformation by carefully matching acquisition parameters. Activated regions had lower FA than optic radiation white matter, supporting the hypothesis that most BOLD signal change occurs within the relatively isotropic cortical grey matter. The combination of these modalities in future studies may provide further insights into relationships between brain structure and function in both health and disease.

Adult↗

PubMed2004

An update on the molecular genetics of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is associated with multiple risk factors and is believed to arise from preneoplastic lesions, usually in the background of cirrhosis. Extensive studies on HCC and its precursors have demonstrated complex and heterogeneous genetic or chromosomal abnormalities along the way from preneoplastic lesions to HCCs. These genetic abnormalities include loss of heterozygosity, microsatellite instability, gene alterations, and aberrant global gene expression profiles. Although some genetic alterations involving the p53 family, Rb family, and Wnt pathways are particularly important in the development of HCCs, the molecular pathogenesis of HCC differs with etiology in some extent. Recent studies using DNA microarray technique have identified some unique gene expression profiles in hepatitis B virus (HBV)- and hepatitis C virus (HCV)-associated HCCs. Gene expression profiling also allows people to distinguish HCCs from normal tissue or preneoplastic lesions and to evaluate metastatic or recurrent potentials. These unique genes or gene products associated with malignant transformation and recurrent or metastatic potentials may serve as molecular markers for early diagnosis, prediction of prognosis, and responsiveness to therapy. To date, information that has accumulated for the past several decades is still incomplete, and we still are faced with a great challenge in deciphering the molecular mechanisms of HCCs.

Aflatoxins↗

PubMed2000

Thermal-Dependent dehydration process and intramolecular cyclization of lisinopril dihydrate in the solid state.

The pathway of dehydration and intramolecular cyclization of lisinopril dihydrate in the solid state was investigated using differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and a combination of thermal analyzer with Fourier transform infrared microspectroscopy (thermal FT-IR microscopic system). The results indicate that the dehydration from the solid-state lisinopril dihydrate had a two-step process from dihydrate to monohydrate at 76 degrees C and then from monohydrate to anhydrate at 99-101 approximately C, which could be clearly observed from the above three methods. Only the thermal FT-IR microscopic system could give vital information on diketopiperazine (DKP) formation via intramolecular cyclization in anhydrous lisinopril. A new peak at 1670 cm(-1) assigned to the carbonyl band of DKP formation was clearly evidenced. The water of reaction byproduct was liberated at a temperature >157 degrees C and appeared on the IR spectra near 3200-3400 cm(-1). Moreover, the peak at 1574 cm(-1) assigned to carboxylate shifted to 1552 cm(-1) due to the DKP formation. The peak at 1670 cm(-1) related to the DKP formation changed slightly in intensity from 147 degrees C and significantly near 157 degrees C. DSC and TGA methods were poor for use in supplying information on DKP formation in lisinopril. The thermal FT-IR microscopic system is useful from the view point that it can quickly and directly show the solid-state stability of drug.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed2005

Auditory thalamocortical transformation: structure and function.

Communicative, predatory, and reproductive behaviors rely on the auditory thalamocortical system, a key nexus that combines, transforms, and distributes virtually all acoustic information relevant to survival. The rules of connectivity for this complex network, both anatomically and functionally, are only beginning to be uncovered. Although the auditory thalamocortical system shares many features with other modalities, its connectivity and information processing principles differ from those of other modalities in many ways. Some physiological and anatomical bases for these differences are the subject of this review.

Animals↗

PubMedDate not supplied

Independent component analysis of temporal sequences subject to constraints by lateral geniculate nucleus inputs yields all the three major cell types of the primary visual cortex.

Information maximization has long been suggested as the underlying coding strategy of the primary visual cortex (V1). Grouping image sequences into blocks has been shown by others to improve agreement between experiments and theory. We have studied the effect of temporal convolution on the formation of spatiotemporal filters--that is, the analogues of receptive fields--since this temporal feature is characteristic to the response function of lagged and non-lagged cells of the lateral geniculate nucleus. Concatenated input sequences were used to learn the linear transformation that maximizes the information transfer. Learning was accomplished by means of principal component analysis and independent component analysis. Properties of the emerging spatiotemporal filters closely resemble the three major types of V1 cells: simple cells with separable receptive field, simple cells with non-separable receptive field, and complex cells.

Action Potentials↗

PubMed2002

Brain oscillations, medium spiny neurons, and dopamine.

1. The striatum is part of a multisynaptic loop involved in translating higher order cognitive activity into action. The main striatal computational unit is the medium spiny neuron, which integrates inputs arriving from widely distributed cortical neurons and provides the sole striatal output. 2. The membrane potential of medium spiny neurons' displays shifts between a very negative resting state (down state) and depolarizing plateaus (up states) which are driven by the excitatory cortical inputs. 3. Because striatal spiny neurons fire action potentials only during the up state, these plateau depolarizations are perceived as enabling events that allow information processing through cerebral cortex-basal ganglia circuits. In vivo intracellular recording techniques allow to investigate simultaneously the subthreshold behavior of the medium spiny neuron membrane potential (which is a "reading" of distributed patterns of cortical activity) and medium spiny neuron firing (which is an index of striatal output). 4. Recent studies combining intracellular recordings of striatal neurons with field potential recordings of the cerebral cortex illustrate how the analysis of the input-output transformations performed by medium spiny neurons may help to unveil some aspects of information processing in cerebral cortex-basal ganglia circuits, and to understand the origin of the clinical manifestations of Parkinson's disease and other neurologic and neuropsychiatric disorders that result from alterations in dopamine-dependent information processing in the cerebral cortex-basal ganglia circuits.

Action Potentials↗

PubMed2005

The spatial organization of lipid synthesis in the yeast Saccharomyces cerevisiae derived from large scale green fluorescent protein tagging and high resolution microscopy.

The localization pattern of proteins involved in lipid metabolism in the yeast Saccharomyces cerevisiae was determined using C-terminal green fluorescent protein tagging and high resolution confocal laser scanning microscopy. A list of 493 candidate proteins ( approximately 9% of the yeast proteome) was assembled based on proteins of known function in lipid metabolism, their interacting proteins, proteins defined by genetic interactions, and regulatory factors acting on selected genes or proteins. Overall 400 (81%) transformants yielded a positive green fluorescent protein signal, and of these, 248 (62% of the 400) displayed a localization pattern that was not cytosolic. Observations for many proteins with known localization patterns were consistent with published data derived from cell fractionation or large scale localization approaches. However, in many cases, high resolution microscopy provided additional information that indicated that proteins distributed to multiple subcellular locations. The majority of tagged enzymes localized to the endoplasmic reticulum (91), but others localized to mitochondria (27), peroxisomes (17), lipid droplets (23), and vesicles (53). We assembled enzyme localization patterns for phospholipid, sterol, and sphingolipid biosynthetic pathways and propose a model, based on enzyme localization, for concerted regulation of sterol and sphingolipid metabolism that involves shuttling of key enzymes between endoplasmic reticulum, lipid droplets, vesicles, and Golgi.

Biomarkers↗

PubMed1997

Expression of transferrin receptors in endothelial cells transfected by electroporation.

Transferrin is the primary iron-binding protein in the plasma. Transferrin receptors (TfR) were detected in brain and liver endothelial cells (EC); however, little information exists about their intracellular routes. To detect the EC structures involved in TfR biosynthetic and endocytotic pathways, cultured aortic EC were transfected with the plasmid pSR alpha containing a construct encoding the human TfR, to which horseradish peroxidase (HRP) was anchored as reporter molecule. Since EC are difficult to be transfected, we tried different techniques, and two forms of the plasmid (circular and linearized), of which the electroporation method and the linearized plasmid were the most efficient in producing stable cell lines. Transfected cells were selected with geneticin, and the expression of TfR-HRP tested by cytochemistry. The stable transformants preserved the general characteristics of EC. At the ultrastructural level, TfR-HRP was associated with the nuclear envelope, rough endoplasmic reticulum, Golgi complex and adjacent secretory vesicles, cytoplasmic vesicles of various sizes (50-130 nm diameter), endosomes, plasma membrane, plasmalemmal pits, and a fraction of plasmalemmal vesicles. The intensity of the reaction product varied, suggesting a different concentration of TfR, in specific organelles. For example, (i) a gradient of HRP-reaction product was found within the Golgi cisternae, (ii) the plasmalemmal pits were more intensely stained than the adjacent plasma membrane, and (iii) the vesicle membrane was decorated stronger than the endosomal membrane (to which it fuses). A striking feature was the coexistence within the same EC of two vesicle populations (or subtypes): some containing TfR-HRP, whereas others lack the receptor. Quantitative data indicated a stronger expression of TfR in confluent cells (approximately 8-fold higher) than in EC at 2 days after plating; a significant decrease (approximately 9-fold) of TfR was found in postconfluent transfectants. Together, the data demonstrate that (i) after electroporation of EC, the stable lines maintain the characteristics of native cells; (ii) the newly synthesized TfR is located in variable concentration within the organelles involved in endocytosis and exocytosis, and (iii) the expression of TfR-HRP is particularly high in confluent cells.

Animals↗

PubMed2003

Smad3: a key player in pathogenetic mechanisms dependent on TGF-beta.

Transforming growth factor-beta (TGF-beta), a key player in a large variety of physiological and disease processes, signals through transmembrane receptor serine/threonine kinases to activate novel signaling intermediates called Smad proteins, which then modulate transcription of target genes. We have utilized mice with a targeted deletion of Smad3, one of two homologous proteins involved in signaling from TGF-beta/activin, to investigate the function of this particular pathway in transducing such effects of TGF-beta. The dramatic results of the absence of Smad3 on parameters of healing of cutaneous wounds, such as reepithelialization and influx of inflammatory cells, as well as on fibrosis as modeled by radiation fibrosis of skin in mice, suggest that signaling flux through Smad3 is critical for chemotactic activity of TGF-beta, inhibitory effects of TGF-beta on keratinocyte proliferation and migration, and chemoattraction and elaboration of extracellular matrix by fibroblasts in fibrotic diseases. We recently identified a novel molecule, TLP for TRAP-1-like protein, which selectively interferes with Smad3 signaling, and are currently investigating whether levels of this protein might be altered in disease to change the relative flow of information from Smad2 and Smad3.

Animals↗

PubMed2003

Ultraviolet radiation and cutaneous malignant melanoma.

Recent years have seen a steady rise in the incidence of cutaneous malignant melanoma worldwide. Although it is now appreciated that the key to understanding the process by which melanocytes are transformed into malignant melanoma lies in the interplay between genetic factors and the ultraviolet (UV) spectrum of sunlight, the nature of this relation has remained obscure. Recently, prospects for elucidating the molecular mechanisms underlying such gene-environment interactions have brightened considerably through the development of UV-responsive experimental animal models of melanoma. Genetically engineered mice and human skin xenografts constitute novel platforms upon which to build studies designed to elucidate the pathogenesis of UV-induced melanomagenesis. The future refinement of these in vivo models should provide a wealth of information on the cellular and genetic targets of UV, the pathways responsible for the repair of UV-induced DNA damage, and the molecular interactions between melanocytes and other skin cells in response to UV. It is anticipated that exploitation of these model systems will contribute significantly toward the development of effective approaches to the prevention and treatment of melanoma.

Animals↗

PubMed1999

Synthetic pathways of gallbladder mucosal prostanoids: the role of cyclooxygenase-1 and 2.

Acute cholecystitis is associated with increased gallbladder prostanoid formation and the inflammatory changes and prostanoid increases can be inhibited by nonsteroidal anti-inflammatory agents. Recent information indicates that prostanoids are produced by two cyclooxygenase (COX) enzymes, COX-1 and COX-2. The purpose of this study was to determine the COX enzymatic pathway in gallbladder mucosal cells involved in the production of prostanoids stimulated by inflammatory agents. Human gallbladder mucosal cells were isolated from cholecystectomy specimens and maintained in cell culture and studied in comparison with cells from a well differentiated gallbladder mucosal carcinoma cell line. COX enzymes were evaluated by Western immunoblotting and prostanoids were measured by ELISA. Unstimulated and stimulated cells were exposed to specific COX-1 and COX-2 inhibitors. In both normal and transformed cells constitutive COX-1 was evident and in gallbladder cancer cells lysophosphatidyl choline (LPC) induced the formation of constitutive COX-1 enzyme. While not detected in unstimulated normal mucosal cells and cancer cells, COX-2 protein was induced by both lipopolysaccharide (LPS) and LPC. Unstimulated gallbladder mucosal cells and cancer cells produced prostaglandin E2 (PGE2) and prostacyclin (6-keto prostaglandin F1alpha, 6-keto PGF1alpha) continuously. In freshly isolated normal gallbladder mucosal cells, continuously produced 6 keto PGF1alpha was inhibited by both COX-1 and COX-2 inhibitors while PGE2 levels were not affected. Both LPS and LPC stimulated PGE2 and 6 keto PGF1alpha formation were blocked by COX-2 inhibitors in freshly isolated, normal human gallbladder mucosal cells and in the gallbladder cancer cells. The prostanoid response of gallbladder cells stimulated by proinflammatory agents is inhibited by COX-2 inhibitors suggesting that these agents may be effective in treating the pain and inflammation of gallbladder disease.

6-Ketoprostaglandin F1 alpha↗

PubMed2005

VAV1: a new target in pancreatic cancer?

Pancreatic ductal adenocarcinoma (PDA) is arguably the most lethal malignancy in the United States. Despite the identification of many molecular alterations in PDA, this information has not translated into effective therapeutic strategies to date. A recent report in Cancer Cell (Fernandez-Zapico et al, Cancer Cell 2005, 7:39-49) reveals an unexpected role for the hematopoietic-specific RhoGEF VAV1 in pancreatic tumorigenesis, where ectopic expression of VAV1 as a result of promoter demethylation was identified in the majority of established cell lines and PDA tissue samples. Importantly, VAV1 expression was functionally required for optimal proliferation, transformation and survival of pancreatic cancer cell lines. This study provides the first evidence of VAV1 promoter demethylation as an event in cancer progression, suggesting that aberrant signaling pathways driven by VAV1 are potential therapeutic targets in PDA.

Animals↗

PubMed1993

Targeting of pro-opiomelanocortin to the regulated secretory pathway may involve cooperation between different protein domains.

The structure of pro-opiomelanocortin (POMC) can be divided into three main domains: an NH2-terminal domain formed by the NH2-terminal glycopeptide and the joining peptide, a central domain corresponding to the adrenocorticotropin sequences and a COOH-terminal domain containing the beta-lipotropin sequences. Expression of POMC in neuroendocrine cell lines such as the mouse neuroblastoma Neuro2A cells results in its targeting to the regulated secretory pathway of these cells. Intracellular targeting of proteins along non default pathways are widely believed to involve the recognition of specific structural features by a sorting machinery. To understand the nature of the signal involved in targeting prohormone to the regulated secretory pathway, we have constructed mutants of POMC in which sequences from the NH2-terminal, the central and the COOH-terminal domains were deleted and examined the sorting of these mutant POMC molecules in Neuro2A cells by immunofluorescence and immunoelectron microscopy. Our results indicate that POMC NH2-terminal glycopeptide or beta-LPH domain do not contain sufficient information for targeting to the regulated pathway since these peptides are not sorted to secretory vesicles when expressed in Neuro2A cells: Similarly, the ACTH domain does not contain essential targeting information since POMC mutants lacking these sequences were sorted to secretory vesicles. Mutant POMCs containing the sequences of more than one of the main protein domains were, however, correctly targeted to the regulated secretory pathway. Our results indicate that POMC is not targeted to the regulated secretory pathway through recognition of a unique continuous 'molecular address'.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗

PubMed2006

Information processing in the olfactory systems of insects and vertebrates.

Insects and vertebrates separately evolved remarkably similar mechanisms to process olfactory information. Odors are sampled by huge numbers of receptor neurons, which converge type-wise upon a much smaller number of principal neurons within glomeruli. There, odor information is transformed by inhibitory interneuron-mediated, cross-glomerular circuit interactions that impose slow temporal structures and fast oscillations onto the firing patterns of principal neurons. The transformations appear to improve signal-to-noise characteristics, define odor categories, achieve precise odor identification, extract invariant features, and begin the process of sparsening the neural representations of odors for efficient discrimination, memorization, and recognition.

Animals↗

PubMed1992

Fatigue-induced changes in diaphragmatic afferents and cortical activity in the cat.

The rationale for the present study was to test the hypothesis that changes in phrenic sensory activity during diaphragmatic fatigue may modify the transmission of phrenic afferent action potentials to the cortex and also the spontaneous EEG activity. This was performed in anesthetized cats. Diaphragmatic fatigue was produced by intermittent direct muscle stimulation for a 30 min period. Diaphragmatic metaboreceptors (tonically active afferents) and mechanoreceptors (phasic phrenic activity) were identified by their activation by intraarterial lactic acid injection or their discharge in phase with diaphragmatic contraction, respectively. Cortical phrenic evoked potentials (CPEPs) and spontaneous EEG activity were recorded from the left sensorimotor area. Diaphragmatic failure was shown from the 10th minute of stimulation. Then, the activity of tonic phrenic afferents increased markedly whereas, in parallel, the phasic discharge of mechanoreceptors decreased progressively. This was associated with progressive lengthening in onset and peak latencies of CPEPs. The main EEG changes (visual and fast Fourier transform analysis) were characterized by a transient increased energy in the delta frequency band during the first minutes of the fatigue run, followed by decreased energy in the theta frequency band after 11-25 min of stimulation. Denervation of the diaphragm suppressed the EEG changes during the fatigue run. The present observations suggest that the cortical integration of sensory information from the diaphragm may be altered during fatigue.

Afferent Pathways↗

PubMed1986

A temporal-processing mechanism for all species?

Certain species of anurans and electric fish detect amplitude modulations as a means of identifying conspecifics and foreign objects, respectively. This paper provides an account of the similarities between the electrosensory and auditory systems in terms of the mechanisms by which this temporal information is analyzed. Both animals employ a temporal filtering mechanism in this analysis. The transformation from a periodicity coding of amplitude modulations by the peripheral nervous system to a temporal-filter analysis in the central nervous system appears to be present in a number of different animals, ranging from crickets to cats. The possibility of a similar temporal filtering mechanism in humans and its role in perception are discussed.

Animal Communication↗

PubMed2003

Structure of curcumin in complex with lipoxygenase and its significance in cancer.

Scientific research provides documented evidence that fatty acid metabolites have profound impact on carcinogenesis. Intervention into dioxygenase pathways might therefore effect development, metastasis and progression of many types of cancers. This work delivers the first 3D structural data and explains how curcumin interacts with the fatty acid metabolizing enzyme, soybean lipoxygenase. Curcumin binds to lipoxygenase in a non-competitive manner. Trapped in that complex, it undergoes photodegradation in the X-rays, but utilizes enzyme catalytic ability to form the peroxy complex Enz-Fe-O-O-R as 4-hydroperoxy-2-methoxy-phenol, that later transforms into 2-methoxycyclohexa-2,5-diene-1,4-dione. Our observations about this radiation and time-dependent inhibition add new information to the role that curcumin might play in cancer prevention and treatment.

Animals↗