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Results for “Enhancer mapping”

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At least 937 records · Page 52Linked to original sources

PubMed1996

Treatment of vascular smooth muscle cells with antisense phosphorothioate oligodeoxynucleotides directed against p42 and p44 mitogen-activated protein kinases abolishes DNA synthesis in response to platelet-derived growth factor.

We have investigated the requirement for mitogen-activated protein (MAP) kinase in the stimulation of DNA synthesis by platelet-derived growth factor (PDGF) in rat aortic smooth muscle cells using a phosphorothioate-modified oligodeoxy-nucleotide (ODN) to deplete MAP kinase. Treatment for 72 h with MAP kinase antisense ODN directed against both the p42 and p44 isoforms of MAP kinase abolished the expression of MAP kinase and reduced agonist-stimulated MAP kinase activity by approx. 95%. The scrambled control ODN was without effect, but the sense control ODN slightly enhanced the expression of both isoforms. Abolition of MAP kinase activity by antisense ODN treatment prevented angiotensin II- and PDGF-stimulated activation of p90 ribosomal S6 kinase activity, but did not affect activation of MAP kinase kinase. In addition, antisense ODN pretreatment reduced PDGF-stimulated [3H]thymidine incorporation to < 5% of control, and decreased basal incorporation by approx. 90%. In contrast, basal [3H]thymidine incorporation was enhanced approx. 60% by control sense ODN treatment. These results indicate an obligatory role for MAP kinase in the activation of a number of early events in mitogenesis, including DNA synthesis, in vascular smooth muscle cells.

Animals↗

PubMed2006

PIASxalpha differentially regulates the amplitudes of transcriptional responses following activation of the ERK and p38 MAPK pathways.

Activation of the MAP kinase pathways leads to changes in gene expression profiles through direct targeting of transcription factors and their coregulators. Here we identify PIASxalpha as a key regulator that determines the differential response of the transcription factor Elk-1 to the ERK and the stress-activated p38 MAP kinase pathways. While PIASxalpha functions as a coactivator to facilitate SUMO and HDAC-2 removal from Elk-1 in response to ERK pathway activation, PIASxalpha acts in the opposite manner to inhibit HDAC-2 and SUMO loss following stress-activated MAP kinase pathway signaling. Thus, PIASxalpha either enhances or dampens down the activation of Elk-1 target genes, depending on the pathway activated. p38 MAP kinase-mediated PIASxalpha phosphorylation allows it to switch between these two alternative modes of operation. Thus, PIASxalpha acts as a key signal integrator that permits different responses from the same transcription factor, depending on the signaling pathway that is activated.

Anisomycin↗

PubMed1988

Effect of vasopressin on atrial natriuretic peptide release and renal function in dogs.

To assess the effect of arginine vasopressin (AVP) and 1-deamino-8-D-AVP (DDAVP) on atrial natriuretic peptide (ANP) release, renal water and electrolyte excretion, and cardiovascular function, AVP and DDAVP were administered at a dose of 10 ng.kg-1.min-1 iv for 30 min into anesthetized dogs receiving saline infusion at a rate of 1 ml.kg-1.min-1 (n = 12). In the control study, saline was infused alone (n = 6). AVP potentiated the plasma ANP response to an increase in plasma volume produced by saline infusion, increased mean arterial blood pressure (MAP), and exaggerated the natriuresis and kaliuresis. DDAVP did not potentiate the increase in plasma ANP but enhanced the natriuresis without any rise in MAP. Saline alone increased plasma ANP as well as sodium and potassium excretion with no changes in MAP. Inulin and p-aminohippuric acid clearances did not change during these studies. The results suggest that in hydrated dogs, AVP may increase ANP release and arterial blood pressure via the vasopressor activity of AVP and potentiate the natriuresis and kaliuresis, but the increased ANP may play little role in the natriuresis.

Animals↗

PubMed2000

Conformational mapping of the N-terminal segment of surfactant protein B in lipid using 13C-enhanced Fourier transform infrared spectroscopy.

Synthetic peptides based on the N-terminal domain of human surfactant protein B (SP-B1-25; 25 amino acid residues; NH2-FPIPLPYCWLCRALIKRIQAMIPKG) retain important lung activities of the full-length, 79-residue protein. Here, we used physical techniques to examine the secondary conformation of SP-B1-25 in aqueous, lipid and structure-promoting environments. Circular dichroism and conventional, 12C-Fourier transform infrared (FTIR) spectroscopy each indicated a predominate alpha-helical conformation for SP-B1-25 in phosphate-buffered saline, liposomes of 1-palmitoyl-2-oleoyl phosphatidylglycerol and the structure-promoting solvent hexafluoroisopropanol; FTIR spectra also showed significant beta- and random conformations for peptide in these three environments. In further experiments designed to map secondary structure to specific residues, isotope-enhanced FTIR spectroscopy was performed with 1-palmitoyl-2-oleoyl phosphatidylglycerol liposomes and a suite of SP-B1-25 peptides labeled with 13C-carbonyl groups at either single or multiple sites. Combining these 13C-enhanced FTIR results with energy minimizations and molecular simulations indicated the following model for SP-B1-25 in 1-palmitoyl-2-oleoyl phosphatidylglycerol: beta-sheet (residues 1-6), alpha-helix (residues 8-22) and random (residues 23-25) conformations. Analogous structural motifs are observed in the corresponding homologous N-terminal regions of several proteins that also share the 'saposin-like' (i.e. 5-helix bundle) folding pattern of full-length, human SP-B. In future studies, 13C-enhanced FTIR spectroscopy and energy minimizations may be of general use in defining backbone conformations at amino acid resolution, particularly for peptides or proteins in membrane environments.

Carbon Radioisotopes↗

PubMed2006

Cerebral perfusion mapping using a robust and efficient method for deconvolution analysis of dynamic contrast-enhanced images.

Dynamic contrast-enhanced (DCE) imaging using MRI or CT is emerging as a promising tool for diagnostic imaging of cerebral disorders and the monitoring of tumor response to treatment. In this study, we present a robust and efficient deconvolution method based on a linearized model of the impulse residue function, which allows for the mapping of functional cerebral parameters such as cerebral blood flow, volume, mean transit time, and permeability. Monte Carlo simulation studies were performed to study the accuracy and stability of the proposed method, before applying it to clinical study cases of patients with cerebral tumors imaged using DCE CT. Functional parameter maps generated using the proposed method revealed the locations of the cerebral tumors and were found to be of sufficiently good clarity for marked regional differences in tissue vascularity and permeability to be assessed. In particular, tumor visualization and delineation were found to be better on the parameter maps that were indicative of the breakdown of the blood-brain barrier.

Adenoma↗

PubMed2003

Antihypertensive effects of the essential oil of Alpinia zerumbet and its main constituent, terpinen-4-ol, in DOCA-salt hypertensive conscious rats.

The present study investigated the hypotensive responses to intravenous (i.v.) treatment with the essential oil of Alpinia zerumbet (EOAZ) and its main constituent, terpinen-4-ol (Trp-4-ol), in the experimental model of deoxycorticosterone-acetate (DOCA)-salt hypertensive rat. In both DOCA-salt hypertensive and uninephrectomized, normotensive rats, i.v. bolus injections of EOAZ (1-20 mg/kg) or Trp-4-ol (1-10 mg/kg) decreased mean aortic pressure (MAP) in a dose-related manner. However, hypotensive responses to Trp-4-ol were significantly greater than those evoked by the same doses of EOAZ (1-10 mg/kg). Treatment with DOCA-salt significantly enhanced the maximal percentage decreases in MAP evoked by EOAZ or Trp-4-ol. Likewise, both maximal percentage and absolute decreases in MAP elicited by i.v. injection of the ganglion blocker, hexamethonium (30 mg/kg), were significantly greater in DOCA-salt hypertensive than in control rats. In DOCA-salt hypertensive rats, neither hexamethonium (30 mg/kg, i.v.) nor methylatropine (1 mg/kg, i.v.) pretreatment affected the enhancement of EOAZ-induced hypotension. These results show that i.v. treatment with either EOAZ or Trp-4-ol dose-dependently decreases blood pressure in conscious DOCA-salt hypertensive rats, and this action is enhanced when compared with uninephrectomized controls. This enhancement could be related mainly to an increase in EOAZ-induced vascular smooth muscle relaxation rather than to enhanced sympathetic nervous system activity in this hypertensive model. The data further support our previous hypothesis that hypotensive effects of EOAZ are partially attributed to the actions of Trp-4-ol.

Alpinia↗

PubMed1998

High-resolution functional magnetic resonance imaging of the rat brain: mapping changes in cerebral blood volume using iron oxide contrast media.

Contrast-enhanced magnetic resonance imaging was used to produce high-resolution activation maps reflecting local changes in cerebral blood volume after a simple sensory stimulus. Activation of the forelimb region of the somatosensory cortex was performed in alpha-chloralose-anaesthetized rats with an electrical stimulus (5 V, 3 Hz) delivered through needle electrodes placed subcutaneously on the left forelimb. A gradient echo magnetic resonance imaging sequence, sensitive to changes in the relative amount of deoxyhemoglobin within the cerebral vasculature, produced a 4.05%+/-1.69% increase in signal intensity. This effect was enhanced with an injection of an intravascular iron oxide contrast agent (Combidex, Advanced Magnetics), resulting in a 9.11%+/-1.52% decrease in signal intensity.

Animals↗

PubMed1999

On the application of susceptibility-weighted ultra-fast low-angle RARE experiments in functional MR imaging.

The applicability of displaced, split-echo, and phase-cycled variants of the blood oxygenation level-dependent (BOLD) sensitized ultra-fast low-angle rapid acquisition and relaxation enhancement (UFLARE) technique for the mapping of brain function are examined in functional magnetic resonance imaging (fMRI) experiments at high magnetic field strength (3 T). Activation maps are presented for visual and motor-sensory activation. For the visual studies the range of the stimulation-associated signal intensity changes is 5-7% in voxels containing mainly gray matter and 10-15% in voxels dominated by larger vessels. The motor studies reveal signal changes of 5-10% in the primary motor cortex and in the supplementary motor area. For gray matter, T2* increases from 31.2 +/- 1.5 msec under baseline conditions to 33.0 +/- 1.5 msec during periods of visual stimulation. The results clearly demonstrate that T2*-weighted UFLARE is a robust and reliable method for detection of brain activation. The relative pros and cons of displaced, split-echo, and phase-cycled T2*-sensitized UFLARE versions are discussed for fMRI applications. Since the susceptibility weighting can be freely adjusted from zero upward, the UFLARE variants used are particularly suitable for functional examinations in regions with poor magnetic field homogeneity and at high magnetic field strengths.

Brain↗

PubMed2002

Dynamic oxygen-enhanced MRI reflects diffusing capacity of the lung.

The purpose of this study was to demonstrate the feasibility of dynamic oxygen-enhanced MRI in a clinical setting. We hypothesized that dynamic oxygen enhancement can reflect the regional diffusing capacity of the lung. Ten patients with pulmonary emphysema and seven healthy volunteers were examined with a respiratory-synchronized inversion recovery single-shot turbo spin-echo sequence (TR = 3200-5000 ms, TE = 16 ms, TI = 720 ms, ETS = 4 ms) following 100% oxygen inhalation, using a 1.5 T whole-body scanner. Maximum mean relative enhancement ratios calculated by averaging six defined regions of interest (ROIs) in both lungs were statistically compared between healthy volunteers and patients, and were correlated with diffusing lung capacity (%DL(CO)). In patients with pulmonary emphysema, maximum mean relative enhancement ratios were significantly decreased compared to those in healthy volunteers (P = 0.0008). Maximum mean relative enhancement ratio had excellent correlation with % DL(C0) (r(2) = 0.83). Dynamic oxygen-enhanced MRI may reflect the diffusing capacity of the lung; therefore, imaging of oxygen enhancement with MRI may provide maps of the diffusing capacity.

Adult↗

PubMed2000

Translocation of HSP27 to sarcomere induced by ischemic preconditioning in isolated rat hearts.

We investigated the role of the 27-kDa heat shock protein (HSP27) in cardiac protection using Langendorff-perfused rat hearts. After preconditioning (a single episode of 5 min global ischemia followed by 5 min of reperfusion), HSP27 redistributed from the cytosol to the sarcomere and recovery of the contractile function, after 40 min of global ischemia and 50 min of reperfusion, was significantly enhanced. Both SB203580, a p38 MAP kinase inhibitor, and bisindolylmaleimide I, a protein kinase C inhibitor, prevented the effects of preconditioning. Both 2-chloro-N(6)-cyclopentyladenosine (adenosine A1 agonist) and anisomycin (activator of p38 MAP kinase and c-jun N-terminal kinase) mimicked preconditioning. These results suggest that activation of protein kinase C followed by activation of p38 MAP kinase elicits translocation of HSP27 to the sarcomere, a process which may be involved in the cardioprotective mechanism afforded by ischemic preconditioning in rat heart.

Animals↗

PubMed1994

Functions of the v-Src protein tyrosine kinase.

The peripheral non-receptor tyrosine kinase oncoprotein, v-Src, has pleiotropic effects. It is a mitogen for quiescent cells, substituting for both competence and progression factor-mediated signals but it also induces cellular morphological transformation. We are dissecting the activities of v-Src by studying mutant proteins, including those with temperature sensitive (ts) effects, in different cellular backgrounds. Activation of a ts v-Src kinase rapidly increases activity of both the transcription factor, AP-1, and MAP kinase, an enzyme that enhances AP-1 activity by both phosphorylation of c-Jun and increased c-fos transcription; the relative contribution of these two events depends on the cells in which v-Src is expressed. Transient early AP-1 activation requires proper location of v-Src at the cell periphery and it is essential for mitogenesis. It is not, however, sufficient for entry into S-phase, there being a second need for v-Src later in G1. Transformation by v-Src does not require AP-1 activation but seems linked to events at the cell periphery, notably phosphorylation of proteins that bind to the v-Src SH3 domain such as the p85 subunit of PI-3 kinase.

Animals↗

PubMed1994

Quantitation of peritumoural oedema and the effect of steroids using NMR-relaxation time imaging and blood-brain barrier analysis.

A new method of in vivo quantitation of peritumoural brain oedema using NMR relaxation time imaging (T1-maps) and Gd-DTPA-enhanced Blood-Tumour-Barrier (BTB) analysis is presented. The method is based on image pixel histogram analysis and a fast imaging method combined with arterial [Gd-DTPA]-measurement. The method was applied in 26 brain tumour patients, studied prior to--and 1, 3 and 7 days after initiation of dexamethasone. Oedema resorption rate following dexamethasone treatment was almost equal in glioblastomas and metastases, mean T1 being reduced by ca. 12% in 7 days. In meningiomas no significant changes in peritumoural oedema could be detected. Simultaneous BTB-analysis was obtained in 4 patients showing correlation between oedema resorption in vivo and reduction of BTB transport rate constant Ki after 7 days of steroid treatment. This method is a powerful tool in quantitation and monitoring of brain oedema in vivo, as both steroid influence on oedema resorption and on BTB-defect can be monitored simultaneously.

Blood-Brain Barrier↗

PubMed1988

A topographic background symmetry display for comparison with routine EEG.

We describe a new approach for assessing EEG background symmetry by topographic display of spectral band amplitude. Asymmetry is expressed as a percentage in much the same way that routine EEG symmetry comparisons are made. Spectral graphs of each channel are simultaneously displayed to facilitate interpretation. This method enhances the use of topographic mapping as an adjunct to conventional EEG interpretation.

Brain Mapping↗

PubMed1991

Vectors containing infrequently cleaved restriction sites for use in BAL 31 nuclease-assisted and end-label-mediated analysis of cloned DNA fragments.

Cloning vectors derived from plasmids pUC8 and pUC18 and phage M13mp10 were constructed so as to have multiple cloning sites (MCS) flanked by the recognition/cleavage sites for the Sfi I and Not I restriction nucleases. Cleavage of vectors containing cloned DNA fragments with either of the infrequently cleaving Sfi I or Not I endonucleases will usually yield linear DNAs cleaved only at the corresponding site in the MCS, so that the cloned insert can be degraded unidirectionally by the duplex exonuclease activity of the BAL 31 nucleases until an amount equal to the length of the vector has been degraded. The ends of the above constructs resulting from cleavage with Not I or Sfi I can readily be labeled, with labeling at only the terminus of the cloned DNA available for the Sfi I site. The BAL 31 nuclease-mediated procedures enhance a previous technique for mapping of restriction enzyme fragments, allow for localization of sequences in cloned segments for which a probe is available, and improve a method for sequencing cloned inserts through the production of sets of nested unidirectional deletions from either end of the parent cloned fragment. The advantages of end-label-mediated restriction site mapping using the above vectors over existing such procedures are also demonstrated.

Bacteriophages↗

PubMed1997

Changes of behavior and monoamine metabolites in the rat brain after repeated methamphetamine administration: effects of duration of repeated administration.

1. The authors studied the mechanism of the reverse-tolerance phenomenon caused by long-term administration of central stimulant drugs. Methamphetamine(MAP) was chronically administered to rats, and the reverse-tolerance phenomenon was studied in terms of behavioral changes and changes in monoamine metabolites, the latter being examined by in vivo microdialysis of the extracellular compartment of the corpus-striatum. The authors also studied [3H]SCH23390 and [3H]spiperone binding to striatal membranes after chronic MAP administration. 2. MAP(4 mg/kg) or saline was administered intraperitoneally once daily to male rats. In Groups 1 and 2, 10 and 30 injections of MAP were given, respectively. In Groups 3 and 4, animals received 10 and 30 injections of saline as controls. One week after the final injection, all rats were challenged with 4 mg/kg MAP. 3. Groups 1 and 2 displayed more intense stereotypy than Groups 3 and 4, indicating that behavioral sensitization had been achieved in the former. Dopamine(DA) levels increased rapidly in response to MAP challenge in all groups, with the increases in Groups 1 and 2 being more marked than that in Groups 3 and 4. Group 1 showed greater persistence and a higher rate of DA increase than Group 2. 4. The number of D1 and D2 dopamine receptors did not change after the repeated MAP administration. 5. The rate of increase in DA release induced by MAP was dependent on the duration of repeated administration, and there was no correlation between the intensity of stereotypy and the rate of increase in DA release induced by MAP. These findings suggest that enhancement in DA release is unlikely to be the sole cause of behavioral sensitization.

Animals↗

PubMedDate not supplied

Data visualization during the early stages of drug discovery.

Multidimensional compound optimization is a new paradigm in the drug discovery process, yielding efficiencies during early stages and reducing attrition in the later stages of drug development. The success of this strategy relies heavily on understanding this multidimensional data and extracting useful information from it. This paper demonstrates how principled visualization algorithms can be used to understand and explore a large data set created in the early stages of drug discovery. The experiments presented are performed on a real-world data set comprising biological activity data and some whole-molecular physicochemical properties. Data visualization is a popular way of presenting complex data in a simpler form. We have applied powerful principled visualization methods, such as generative topographic mapping (GTM) and hierarchical GTM (HGTM), to help the domain experts (screening scientists, chemists, biologists, etc.) understand and draw meaningful decisions. We also benchmark these principled methods against relatively better known visualization approaches, principal component analysis (PCA), Sammon's mapping, and self-organizing maps (SOMs), to demonstrate their enhanced power to help the user visualize the large multidimensional data sets one has to deal with during the early stages of the drug discovery process. The results reported clearly show that the GTM and HGTM algorithms allow the user to cluster active compounds for different targets and understand them better than the benchmarks. An interactive software tool supporting these visualization algorithms was provided to the domain experts. The tool facilitates the domain experts by exploration of the projection obtained from the visualization algorithms providing facilities such as parallel coordinate plots, magnification factors, directional curvatures, and integration with industry standard software.

Drug Design↗

PubMed2006

Imaging study of vibrational predissociation of the HCl-acetylene dimer: pair-correlated distributions.

The state-to-state predissociation dynamics of the HCl-acetylene dimer were studied following excitation in the asymmetric C-H (asym-CH) stretch and the HCl stretch. Velocity map imaging (VMI) and resonance enhanced multiphoton ionization (REMPI) were used to determine pair-correlated product energy distributions. Different vibrational predissociation mechanisms were observed for the two excited vibrational levels. Following excitation in the of the asym-CH stretch fundamental, HCl fragments in upsilon = 0 and j = 4-7 were observed and no HCl in upsilon = 1 was detected. The fragments' center-of-mass (c.m.) translational energy distributions were derived from images of HCl (j = 4-7), and were converted to rotational state distributions of the acetylene co-fragment by assuming that acetylene is generated with one quantum of C-C stretch (nu(2)) excitation. The acetylene pair-correlated rotational state distributions agree with the predictions of the statistical phase space theory, restricted to acetylene fragments in 1nu(2). It is concluded that the predissociation mechanism is dominated by the initial coupling of the asym-CH vibration to a combination of C-C stretch and bending modes in the acetylene moiety. Vibrational energy redistribution (IVR) between acetylene bending and the intermolecular dimer modes leads to predissociation that preserves the C-C stretch excitation in the acetylene product while distributing the rest of the available energy statistically. The predissociation mechanism following excitation in the Q band of the dimer's HCl stretch fundamental was quite different. HCl (upsilon = 0) rotational states up to j = 8 were observed. The rovibrational state distributions in the acetylene co-fragment derived from HCl (j = 6-8) images were non-statistical with one or two quanta in acetylene bending vibrational excitation. From the observation that all the HCl(j) translational energy distributions were similar, it is proposed that there exists a constraint on conversion of linear to angular momentum during predissociation. A dimer dissociation energy of D(0) = 700 +/- 10 cm(-1) was derived.

Acetylene↗

PubMed2001

Effects of caffeine and high ambient temperature on haemodynamic and body temperature responses to dynamic exercise.

Caffeine can enhance mean arterial blood pressure (MAP) and attenuate forearm blood flow (FBF) and forearm vascular conductance (FVC) during exercise in thermal neutral conditions without altering body temperature. During exercise at higher ambient temperatures, where a greater transfer of heat from the body core to skin would be expected, caffeine-induced attenuation of FBF (i.e. cutaneous blood flow) could attenuate heat dissipation and increase body temperature (T(re)). We hypothesized that during exercise at an ambient temperature of 38 degrees C, caffeine increases MAP, and attenuates FBF and FVC such that T(re) is increased. Eleven caffeine-naive, active men, were studied at rest and during exercise after ingestion of a placebo or 6 mg kg(-1) of caffeine. MAP, heart rate (HR), FBF, FVC, T(re) skin temperature (T(sk)) and venous lactate concentrations (lactate) were assessed sequentially during rest at room temperature, after 45 min of exposure to an ambient temperature of 38 degrees C, and during 35 min of submaximal cycling. Heat exposure caused increases in MAP, FBF, FVC and T(sk) that were not altered by caffeine. HR, T(re), and lactate were unaffected. During exercise, only MAP (95 +/- 2 vs. 102 +/- 2 mmHg), HR (155 +/- 10 vs. 165 +/- 10 beats min(-1)), and lactate (2.0 +/- 0.4 vs. 2.3 +/- 0.4 mmol l(-1)) were increased by caffeine. These data indicate that increases in cutaneous blood flow during exercise in the heat are not reduced by caffeine. This may be because of activation of thermal reflexes that cause cutaneous vasodilation capable of offsetting caffeine-induced reductions in blood flow. Caffeine-induced increases in lactate, MAP and HR during exercise suggest that this drug and high ambient temperatures increase production of muscle metabolites that cause reflex cardiovascular responses.

Adult↗