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Selective Activation (selective + activation)
Selected AbstractsPathogen-Mimicking MnO Nanoparticles for Selective Activation of the TLR9 Pathway and Imaging of Cancer Cells,ADVANCED FUNCTIONAL MATERIALS, Issue 23 2009Mohammed Ibrahim Shukoor Abstract Here, design of the first pathogen-mimicking metal oxide nanoparticles with the ability to enter cancer cells and to selectively target and activate the TLR9 pathway, and with optical and MR imaging capabilities, is reported. The immobilization of ssDNA (CpG ODN 2006) on MnO nanoparticles is performed via the phosphoramidite route using a multifunctional polymer. The multifunctional polymer used for the nanoparticle surface modification not only affords a protective organic biocompatible shell but also provides an efficient and convenient means for loading immunostimulatory oligonucleotides. Since fluorescent molecules are amenable to photodetection, a chromophore (Rhodamine) is introduced into the polymer chain to trace the nanoparticles in Caki-1 (human kidney cancer) cells. The ssDNA coupled nanoparticles are used to target Toll-like receptors 9 (TLR9) receptors inside the cells and to activate the classical TLR cascade. The presence of TLR9 is demonstrated independently in the Caki-1 cell line by western blotting and immunostaining techniques. The magnetic properties of the MnO core make functionalized MnO nanoparticles potential diagnostic agents for magnetic resonance imaging (MRI) thereby enabling multimodal detection by a combination of MR and optical imaging methods. The trimodal nanoparticles allow the imaging of cellular trafficking by different means and simultaneously are an effective drug carrier system. [source] The brand anchoring effect: A judgment bias resulting from brand awareness and temporary accessibilityPSYCHOLOGY & MARKETING, Issue 4 2009Franz-Rudolf Esch Following the Selective Activation, Reconstruction, and Anchoring (SARA) and consumer-based brand equity models, high awareness brands are expected to serve as anchors for forming impressions of co-branded entities. Comparing the brand personality profiles of fictitious brand alliances with high and low awareness brands, the brand anchoring effect is found in Studies 1 and 2. Moreover, Study 3 shows that the effect generalizes to specific brand characteristics and results from making brand-related information more available. Future research on brand awareness and on the brand anchoring effect is discussed. © 2009 Wiley Periodicals, Inc. [source] Alkene Substituents of Selective Activation of endo-Regioselective Polyepoxide Oxacyclizations.CHEMINFORM, Issue 13 2005Fernando Bravo Abstract For Abstract see ChemInform Abstract in Full Text. [source] Selective activation of the ventrolateral prefrontal cortex in the human brain during active retrieval processingEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 7 2001Genevičve Cadoret Abstract The present study examined the role of the prefrontal cortex in retrieval processing using functional magnetic resonance imaging in human subjects. Ten healthy subjects were scanned while they performed a task that required retrieval of specific aspects of visual information. In order to examine brain activity specifically associated with retrieval, we designed a task that had retrieval and control conditions that were perfectly matched in terms of depth of encoding, decision making and postretrieval monitoring and differed only in terms of whether retrieval was required. In the retrieval condition, based on an instructional cue, the subjects had to retrieve either the particular stimulus that was previously presented or its location. In the control condition, the cue did not instruct retrieval but shared with the instructional cues the function of alerting the subjects of the impending test phase. The comparison of activity between the retrieval and control conditions demonstrated a significant and selective increase in activity related to retrieval processes within the ventrolateral prefrontal cortical region, more specifically within area 47/12. These activity increases were bilateral but stronger in the right hemisphere. The present study by strictly controlling the level of encoding, postretrieval monitoring, and decision making has demonstrated a specific increase in the ventrolateral prefrontal region that could be clearly related to active retrieval processing, i.e. the active selection of particular stored visual representations. [source] Differential phosphorylation of myosin light chain (Thr)18 and (Ser)19 and functional implications in plateletsJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 10 2010T. M. GETZ Summary. Background:, Myosin IIA is an essential platelet contractile protein that is regulated by phosphorylation of its regulatory light chain (MLC) on residues (Thr)18 and (Ser)19 via the myosin light chain kinase (MLCK). Objective:, The present study was carried out to elucidate the mechanisms regulating MLC (Ser)19 and (Thr)18 phosphorylation and the functional consequence of each phosphorylation event in platelets. Results:, Induction of 2MeSADP-induced shape change occurs within 5 s along with robust phosphorylation of MLC (Ser)19 with minimal phosphorylation of MLC (Thr)18. Selective activation of G12/13 produces both slow shape change and comparably slow MLC (Thr)18 and (Ser)19 phosphorylation. Stimulation with agonists that trigger ATP secretion caused rapid MLC (Ser)19 phosphorylation while MLC (Thr)18 phosphorylation was coincident with secretion. Platelets treated with p160ROCK inhibitor Y-27632 exhibited a partial inhibition in secretion and had a substantial inhibition in MLC (Thr)18 phosphorylation without effecting MLC (Ser)19 phosphorylation. These data suggest that phosphorylation of MLC (Ser)19 is downstream of Gq/Ca2+ -dependent mechanisms and sufficient for shape change, whereas MLC (Thr)18 phosphorylation is substantially downstream of G12/13 -regulated Rho kinase pathways and necessary, probably in concert with MLC (Ser)19 phosphorylation, for full contractile activity leading to dense granule secretion. Overall, we suggest that the amplitude of the platelet contractile response is differentially regulated by a least two different signaling pathways, which lead to different phosphorylation patterns of the myosin light chain, and this mechanism results in a graded response rather than a simple on/off switch. [source] Selective activation of the sacral anterior roots for induction of bladder voidingNEUROUROLOGY AND URODYNAMICS, Issue 2 2006Narendra Bhadra Abstract Aim We investigated the efficacy of selective activation of the smaller diameter axons in the sacral anterior roots for electrically induced bladder voiding. Materials and Methods Acute experiments were conducted in five adult dogs. The anterior sacral roots S2 and S3 were implanted bilaterally with tripolar electrodes. Pressures were recorded from the bladder and from the proximal urethra and the external urethral sphincter. A detector and flow meter monitored fluid flow. A complete sacral dorsal rhizotomy was carried out. The effects of two types of pulse trains at 20 Hz were compared; quasitrapezoidal pulses (500 µsec with 500 µsec exponential decay) and interrupted rectangular (100 µsec, 2 sec on/2 sec off). Before rhizotomy, rectangular pulse trains (100 µsec) to activate all fibers were also applied. The experimental design was block randomized before and after rhizotomy. Results Quasitrapezoidal pulses showed block of sphincter activation with average minimum current for maximum suppression of 1.37 mA. All pulse types evoked average bladder pressures above the basal sphincter closure pressure. The pressure patterns in the proximal urethra closely followed the bladder pressures. Before dorsal rhizotomy, stimulation evoked a superadded increase in sphincter pressures with slow rise time. After rhizotomy, the sphincter pressure patterns followed the bladder pressures during selective activation and voiding occurred during stimulation with quasitrapezoidal trains and in between bursts with interrupted rectangular stimulation. Conclusions Selective activation of sacral ventral roots combined with dorsal rhizotomy may provide a viable means of low-pressure continuous voiding in neurological impairment. Neurourol. Urdynam. © 2005 Wiley-Liss, Inc. [source] Regulation of rat mesencephalic GABAergic neurones through muscarinic receptorsTHE JOURNAL OF PHYSIOLOGY, Issue 2 2004François J. Michel Central dopamine neurones are involved in regulating cognitive and motor processes. Most of these neurones are located in the ventral mesencephalon where they receive abundant intrinsic and extrinsic GABAergic input. Cholinergic neurones, originating from mesopontine nuclei, project profusely in the mesencephalon where they preferentially synapse onto local GABAergic neurones. The physiological role of this cholinergic innervation of GABAergic neurones remains to be determined, but these observations raise the hypothesis that ACh may regulate dopamine neurones indirectly through GABAergic interneurones. Using a mesencephalic primary culture model, we studied the impact of cholinergic agonists on mesencephalic GABAergic neurones. ACh increased the frequency of spontaneous IPSCs (151 ± 49%). Selective activation of muscarinic receptors increased the firing rate of isolated GABAergic neurones by 67 ± 13%. The enhancement in firing rate was Ca2+ dependent since inclusion of BAPTA in the pipette blocked it, actually revealing a decrease in firing rate accompanied by membrane hyperpolarization. This inhibitory action was prevented by tertiapin, a blocker of GIRK-type K+ channels. In addition to its excitatory somatodendritic effect, activation of muscarinic receptors also acted presynaptically, inhibiting the amplitude of unitary GABAergic synaptic currents. Both the enhancement in spontaneous IPSC frequency and presynaptic inhibition were abolished by 4-DAMP (100 nm), a preferential M3 muscarinic receptor antagonist. The presence of M3-like receptors on mesencephalic GABAergic neurones was confirmed by immunocytochemistry. Taken together, these results demonstrate that mesencephalic GABAergic neurones can be regulated directly through muscarinic receptors. Our findings provide new data that should be helpful in better understanding the influence of local GABAergic neurones during cholinergic activation of mesencephalic circuits. [source] Differential effects of cannabinoid receptor agonists on regional brain activity using pharmacological MRIBRITISH JOURNAL OF PHARMACOLOGY, Issue 2 2008C-L Chin Background and purpose: Activation of cannabinoid CB1 and/or CB2 receptors mediates analgesic effects across a broad spectrum of preclinical pain models. Selective activation of CB2 receptors may produce analgesia without the undesirable psychotropic side effects associated with modulation of CB1 receptors. To address selectivity in vivo, we describe non-invasive, non-ionizing, functional data that distinguish CB1 from CB2 receptor neural activity using pharmacological MRI (phMRI) in awake rats. Experimental approach: Using a high field (7 T) MRI scanner, we examined and quantified the effects of non-selective CB1/CB2 (A-834735) and selective CB2 (AM1241) agonists on neural activity in awake rats. Pharmacological specificity was determined using selective CB1 (rimonabant) or CB2 (AM630) antagonists. Behavioural studies, plasma and brain exposures were used as benchmarks for activity in vivo. Key results: The non-selective CB1/CB2 agonist produced a dose-related, region-specific activation of brain structures that agrees well with published autoradiographic CB1 receptor density binding maps. Pretreatment with a CB1 antagonist but not with a CB2 antagonist, abolished these activation patterns, suggesting an effect mediated by CB1 receptors alone. In contrast, no significant changes in brain activity were found with relevant doses of the CB2 selective agonist. Conclusion and implications: These results provide the first clear evidence for quantifying in vivo functional selectivity between CB1 and CB2 receptors using phMRI. Further, as the presence of CB2 receptors in the brain remains controversial, our data suggest that if CB2 receptors are expressed, they are not functional under normal physiological conditions. British Journal of Pharmacology (2008) 153, 367,379; doi:10.1038/sj.bjp.0707506; published online 29 October 2007 [source] Simulation of nerve bundle activation by simultaneous multipoint extracellular stimulation with surface electrodesELECTRONICS & COMMUNICATIONS IN JAPAN, Issue 6 2009Hirokazu Takahashi Abstract Neural prostheses for restoring lost functions can benefit from selective activation of nerves. We previously proposed a multipoint gating stimulation, which can selectively activate a desired portion of a nerve bundle, regardless of the density of the electrode. In this paper, we discuss the design of an electrode array and effective strategies to determine the stimulus parameters. Large electrodes were less affected by the relative location of the electrodes and the nodes of Ranvier, suggesting that a rectangular electrode, whose long side along a nerve bundle is longer than the internodal distance (i.e., on the order of 1 mm), would be more effective than a disk electrode. We were able to estimate an appropriate current at each electrode on the basis of a blocking threshold, above which no spike propagation was permitted. For lateral gating stimulation, the gate current should be set above the threshold, while for depthwise gating stimulation, the gate current should be set below the threshold. The spatial resolutions of lateral and depthwise gating stimulation were theoretically estimated to be at least 50 ,m when the grid spacing of the array was 1.2 mm. © 2009 Wiley Periodicals, Inc. Electron Comm Jpn, 92(6): 31,40, 2009; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/ecj.10064 [source] Abnormal substance P release from the spinal cord following injury to primary sensory neuronsEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 1 2000Marzia Malcangio Abstract The neuropeptide substance P (SP) modulates nociceptive transmission within the spinal cord. Normally, SP is uniquely contained in a subpopulation of small-calibre axons (A,- and C-fibres) within primary afferent nerve. However, it has been shown that after nerve transection, besides being downregulated in small axons, SP is expressed de novo in large myelinated A,-fibres. In this study we investigated whether, following peripheral nerve injury, SP was released de novo from the spinal cord after selective activation of A,-fibres. Spinal cords with dorsal roots attached were isolated in vitro from rats 2 weeks following distal sciatic axotomy or proximal spinal nerve lesion (SNL). The ipsilateral dorsal roots were electrically stimulated for two consecutive periods at low- or high-threshold fibre strength, spinal cord superfusates were collected and SP content was determined by radioimmunoassay. SNL, but not axotomized or control rat cords, released significant amounts of SP after selective activation of A,-fibres. Not only do these data support the idea that A, myelinated fibres contribute to neuropathic pain by releasing SP, they also illustrate the importance of the proximity of the lesion to the cell body. [source] Intramolecular Opening of ,-Lactams with Amines as a Strategy Toward Enzymatically or Photochemically Triggered Activation of Lactenediyne ProdrugsEUROPEAN JOURNAL OF ORGANIC CHEMISTRY, Issue 7 2003Luca Banfi Abstract In order to develop a general strategy for selective activation of designed enediyne prodrugs belonging to the "lactenediyne" family, we studied the scope of intramolecular transamidation of simple monocyclic ,-lactams bearing a tethered amine. The effect of substituents, of reaction media, and of the type of tether, on the rate of transamidation is disclosed. The possibility of triggering the transamidation event under mild conditions by the action of suitable enzymes or UV light was demonstrated on model monocyclic ,-lactams. Finally, the strategy of intramolecular opening of the ,-lactam leading to a larger seven-membered ring was employed on a lactenediyne, demonstrating that ring enlargement could unleash the reactivity of the enediyne moiety. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003) [source] Adenosine receptors: promising targets for the development of novel therapeutics and diagnostics for asthmaFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 1 2006Cristina Russo Abstract Interest in the role of adenosine in asthma has escalated considerably since the early observation of its powerful bronchoconstrictor effects in asthmatic but not normal airways. A growing body of evidence has emerged in support of a proinflammatory and immunomodulatory role for the purine nucleoside adenosine in the pathogenic mechanisms of chronic inflammatory disorders of the airways such as asthma. The fact that adenosine enhances mast cell allergen-dependent activation, that elevated levels of adenosine are present in chronically inflamed airways, and that adenosine given by inhalation cause dose-dependent bronchoconstriction in subjects with asthma emphasizes the importance of adenosine in the initiation, persistence and progression of these common inflammatory disorders of the airways. These distinctive features of adenosine have been recently exploited in the clinical and research setting to identify innovative diagnostic applications for asthma. In addition, because adenosine exerts its multiple biological activities by interacting with four adenosine receptor subtypes, selective activation or blockade of these receptors may lead to the development of novel therapies for asthma. [source] Activation and deactivation of periventricular white matter phagocytes during postnatal mouse developmentGLIA, Issue 1 2010Mariya Hristova Abstract Brain microglia are related to peripheral macrophages but undergo a highly specific process of regional maturation and differentiation inside the brain. Here, we examined this deactivation and morphological differentiation in cerebral cortex and periventricular subcortical white matter, the main "fountain of microglia" site, during postnatal mouse development, 0,28 days after birth (P0,P28). Only macrophages in subcortical white matter but not cortical microglia exhibited strong expression of typical activation markers alpha5, alpha6, alphaM, alphaX, and beta2 integrin subunits and B7.2 at any postnatal time point studied. White matter phagocyte activation was maximal at P0, decreased linearly over P3 and P7 and disappeared at P10. P7 white matter phagocytes also expressed high levels of IGF1 and MCSF, but not TNFalpha mRNA; this expression disappeared at P14. This process of deactivation followed the presence of ingested phagocytic material but correlated only moderately with ramification, and not with the extent of TUNEL+ death in neighboring cells, their ingestion or microglial proliferation. Intravenous fluosphere labeling revealed postnatal recruitment and transformation of circulating leukocytes into meningeal and perivascular macrophages as well as into ramified cortical microglia, but bypassing the white matter areas. In conclusion, this study describes strong and selective activation of postnatally resident phagocytes in the P0,P7 subcortical white matter, roughly equivalent to mid 3rd trimester human fetal development. This presence of highly active and IGF1- and MCSF-expressing phagocytes in the neighborhood of vulnerable white matter could play an important role in the genesis of or protection against axonal damage in the fetus and premature neonate. © 2009 Wiley-Liss, Inc. [source] Asymmetric Activation/Deactivation of Racemic Ru Catalysts for Highly Enantioselective Hydrogenation Irrespective of Ketonic Substrates: Molecular Design of Dimethylbinaphthylamine for Enantiomeric Catalysts DiscriminationADVANCED SYNTHESIS & CATALYSIS (PREVIOUSLY: JOURNAL FUER PRAKTISCHE CHEMIE), Issue 1-2 2003Koichi Mikami Abstract Asymmetric activation and deactivation of racemic catalysts are two extremes in asymmetric catalysis. In a combination of these two protocols, higher enantioselectivity can be achieved by maximizing the difference in catalytic activity between the enantiomers of racemic catalysts through selective activation and deactivation of enantiomeric catalysts. 3,3,-Dimethyl-2,2,-diamino-1,1,-binaphthyl (DM-DABN) is thus designed as a chiral poison (deactivator) for complete enantiomer resolution of racemic BINAP-Ru(II) catalysts. The catalyst system of DM-DABN, 1,2-diphenylethylenediamine (DPEN), and racemic BINAP-Ru(II) led to great success in highly enantioselective hydrogenation irrespective of the ketonic substrates. The lower catalytic activity of the BINAP-Ru(II)/DM-DABN complex stems from the electron delocalization from the Ru center to the diamine moiety in contrast to the BINAP-Ru(II)/DPEN complex where the highest electron densities are localized on the Ru-N region. The present ,asymmetric activation/deactivation protocol' can provide a guiding principle for the rational design of a molecule for enantiomeric discrimination between racemic catalysts. [source] NAAG peptidase inhibitor increases dialysate NAAG and reduces glutamate, aspartate and GABA levels in the dorsal hippocampus following fluid percussion injury in the ratJOURNAL OF NEUROCHEMISTRY, Issue 4 2006Chunlong Zhong Abstract Traumatic brain injury (TBI) produces a rapid and excessive elevation in extracellular glutamate that induces excitotoxic brain cell death. The peptide neurotransmitter N -acetylaspartylglutamate (NAAG) is reported to suppress neurotransmitter release through selective activation of presynaptic group II metabotropic glutamate receptors. Therefore, strategies to elevate levels of NAAG following brain injury could reduce excessive glutamate release associated with TBI. We hypothesized that the NAAG peptidase inhibitor, ZJ-43 would elevate extracellular NAAG levels and reduce extracellular levels of amino acid neurotransmitters following TBI by a group II metabotropic glutamate receptor (mGluR)-mediated mechanism. Dialysate levels of NAAG, glutamate, aspartate and GABA from the dorsal hippocampus were elevated after TBI as measured by in vivo microdialysis. Dialysate levels of NAAG were higher and remained elevated in the ZJ-43 treated group (50 mg/kg, i.p.) compared with control. ZJ-43 treatment also reduced the rise of dialysate glutamate, aspartate, and GABA levels. Co-administration of the group II mGluR antagonist, LY341495 (1 mg/kg, i.p.) partially blocked the effects of ZJ-43 on dialysate glutamate and GABA, suggesting that NAAG effects are mediated through mGluR activation. The results are consistent with the hypothesis that inhibition of NAAG peptidase may reduce excitotoxic events associated with TBI. [source] Neuroplastic Changes in the Brain: A Case of Two Successive Adaptive Changes Within the Motor CortexJOURNAL OF NEUROIMAGING, Issue 3 2010Eytan Raz MD ABSTRACT We describe a case of neuroplasticity associated with both arteriovenous malformation (AVM) and stroke, which occurred in two successive events in the same patient. Functional magnetic resonance imaging (fMRI) during right-hand movement in a young man with a left rolandic AVM detected activation of a region corresponding to the left premotor cortex. The AVM was embolized. A few hours after the last embolization session, the patient sustained an ischemic complication in the left subcortical white matter. A second fMRI detected a lower degree of left premotor cortex activation and strong activation of the contralesional right primary motor cortex and bilateral supplementary motor areas. One month later, in association with clinical recovery, the fMRI activation returned to that observed in the first fMRI, ie, selective activation of the ipsilesional left premotor cortex. This is, to our knowledge, the first description of two distinct functional cortical changes determined by an AVM and a stroke within the motor network. [source] G,s protein C -terminal ,-helix at the interface: does the plasma membrane play a critical role in the G,s protein functionality?JOURNAL OF PEPTIDE SCIENCE, Issue 10 2005Stefania Albrizio Abstract The heterotrimeric guanine nucleotide-binding regulatory proteins (G proteins, G,,,) mediate the signalling process of a large number of receptors, known as G protein-coupled receptors. The C -terminal domain of the heterotrimeric G protein ,-subunit plays a key role in the selective activation of G proteins by their cognate receptors. The interaction of this domain can take place at the end of a cascade including several successive conformational modifications. G,s(350,394) is the 45-mer peptide corresponding to the C -terminal region of the G,s subunit. In the crystal structure of the G,s subunit it encompasses the ,4/,6 loop, the ,6 ,-sheet segment and the ,5 helix region. Following a previous study based on the synthesis, biological activity and conformational analysis of shorter peptides belonging to the same G,s region, G,s(350,394) was synthesized and investigated. The present study outlines the central role played by the residues involved in the ,4/,6 loop and ,6/,5 loops in the stabilization of the C -terminal G,s,-helix. H2O/2H2O exchange experiments, and NMR diffusion experiments show interesting evidence concerning the interaction between the SDS micelles and the polypeptide. These data prompt intriguing speculations on the role of the intracellular environment/cellular membrane interface in the stabilization and functionality of the C -terminal G,s region. Copyright © 2005 European Peptide Society and John Wiley & Sons, Ltd. [source] Attenuation of the Stimulant Response to Ethanol is Associated with Enhanced Ataxia for a GABAA, but not a GABAB, Receptor AgonistALCOHOLISM, Issue 1 2009Sarah E. Holstein Background:, The ,-aminobutyric acid (GABA) system is implicated in the neurobiological actions of ethanol, and pharmacological agents that increase the activity of this system have been proposed as potential treatments for alcohol use disorders. As ethanol has its own GABA mimetic properties, it is critical to determine the mechanism by which GABAergic drugs may reduce the response to ethanol (i.e., via an inhibition or an accentuation of the neurobiological effects of ethanol). Methods:, In this study, we examined the ability of 3 different types of GABAergic compounds, the GABA reuptake inhibitor NO-711, the GABAA receptor agonist muscimol, and the GABAB receptor agonist baclofen, to attenuate the locomotor stimulant response to ethanol in FAST mice, which were selectively bred for extreme sensitivity to ethanol-induced locomotor stimulation. To determine whether these compounds produced a specific reduction in stimulation, their effects on ethanol-induced motor incoordination were also examined. Results:, NO-711, muscimol, and baclofen were all found to potently attenuate the locomotor stimulant response to ethanol in FAST mice. However, both NO-711 and muscimol markedly increased ethanol-induced ataxia, whereas baclofen did not accentuate this response. Conclusions:, These results suggest that pharmacological agents that increase extracellular concentrations of GABA and GABAA receptor activity may attenuate the stimulant effects of ethanol by accentuating its intoxicating and sedative properties. However, selective activation of the GABAB receptor appears to produce a specific attenuation of ethanol-induced stimulation, suggesting that GABAB receptor agonists may hold greater promise as potential pharmacotherapies for alcohol use disorders. [source] Molecular basis of platelet activation by an ,IIb,3-CHAMPS peptideJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 2 2009B. GRYGIELSKA Summary.,Background:,A novel method, known as computed helical anti-membrane protein (CHAMP), for the design of peptides that bind with high affinity and selectivity to transmembrane helices was recently described and illustrated using peptides that bind ,IIb- and ,v-integrin subunits, which induce selective activation of integrins ,IIb,3 and ,v,3, respectively [1]. Objectives:,In the present study, we have investigated the ability of an ,IIb-CHAMPS peptide (termed integrin-activatory-peptide or IAP) to stimulate protein tyrosine phosphorylation and aggregation in human and mouse platelets. Methods:,The ability of IAP to stimulate platelet aggregation and dense granule secretion was measured in washed preparations of human and mouse platelets. Samples were taken for measurement of tyrosine phosphorylation. Results:,IAP stimulates robust tyrosine phosphorylation of the tyrosine kinase Syk and the FcR ,-chain, but only weak phosphorylation of PLC,2. Aggregation to low but not high concentrations of IAP is reduced in the presence of the Src kinase inhibitor, PP1, or by inhibitors of the two feedback agonists, ADP and thromboxane A2 (TxA2) suggesting that activation is reinforced by Src kinase-driven release of ADP and TxA2. Unexpectedly, aggregation by IAP is only partially inhibited in human and mouse platelets deficient in integrin ,IIb,3. Further, IAP induces partial aggregation of formaldehyde-fixed platelets. Conclusions:,The present study demonstrates that the ,IIb-CHAMPS peptide induces platelet activation through integrin ,IIb,3-dependent and independent pathways with the former mediating tyrosine phosphorylation of FcR ,-chain and Syk. The use of the ,IIb-CHAMPS peptide to study integrin ,IIb,3 function is compromised by non-integrin-mediated effects. [source] (N)-methanocarba-2MeSADP (MRS2365) is a subtype-specific agonist that induces rapid desensitization of the P2Y1 receptor of human plateletsJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 4 2006D. M. BOURDON Summary., Adenosine diphosphate (ADP) initiates and maintains sustained aggregation of platelets through simultaneous activation of both the Gq -coupled P2Y1 receptor and the Gi -coupled P2Y12 receptor. We recently described the synthesis and P2Y1 receptor-specific agonist activity of (N)-methanocarba-2MeSADP (MRS2365). Consequences of selective activation of the P2Y1 receptor by MRS2365 have been further examined in human platelets. Whereas MRS2365 alone only induced shape change, addition of MRS2365 following epinephrine treatment, which activates the Gi/z -linked, ,2A -adrenergic receptor, resulted in sustained aggregation that was indistinguishable from that observed with ADP. Conversely, the platelet shape change promoted by ADP in the presence of the GPIIb/IIIa antagonist eptifibatide was similar to that promoted by MRS2365. Preaddition of the high affinity P2Y1 receptor antagonist MRS2500 inhibited the effect of MRS2365, whereas addition of MRS2500 subsequent to MRS2365 reversed the MRS2365-induced shape change. Preactivation of the P2Y1 receptor with MRS2365 for 2 min resulted in marked loss of capacity of ADP to induce aggregation as evidenced by a greater than 20-fold rightward shift in the concentration effect curve of ADP. This inhibitory effect of P2Y1 receptor activation was dependent on the concentration of MRS2365 (EC50 = 34 nm). The inhibitory effect of preincubation with MRS2365 was circumvented by activation of the Gq -coupled 5-HT2A receptor suggesting that MRS2365 induces loss of the ADP response as a consequence of desensitization of the Gq -coupled P2Y1 receptor. The time course of MRS2365-induced loss of aggregation response to epinephrine was similar to that observed with ADP. These results further demonstrate the P2Y1 receptor selectivity of MRS2365 and illustrate the occurrence of agonist-induced desensitization of the P2Y1 receptor of human platelets studied in the absence of P2Y12 receptor activation . [source] Diagnosis of toxic shock syndrome by two different systems; clinical criteria and monitoring of TSST-1-reactive T cellsMICROBIOLOGY AND IMMUNOLOGY, Issue 11 2008Yoshio Matsuda ABSTRACT Two methods of TSS diagnosis were evaluated: comparison of symptoms with clinical criteria and monitoring for evidence of selective activation of V,2+ T cells by the causative toxin, TSS toxin-1 (TSST-1). Ten patients with acute and systemic febrile infections caused by Staphylococcus aureus were monitored for increase in TSST-1-reactive V,2+ T cells during their clinical courses. Nine of the ten patients were diagnosed with TSS based on evidence of selective activation of V,2+ T cells by TSST-1; however, clinical symptoms met the clinical criteria for TSS in only six of these nine patients. In the remaining patient, clinical symptoms met the clinical criteria, but selective activation of V,2+ T cells was not observed. Time taken to reach the diagnosis of TSS could be significantly shortened by utilizing the findings from tracing V,2+ T cells. In vitro studies showed that TSST-1- reactive T cells from TSS patients were anergic in the early phase of their illness. Examining selective activation of V,2+ T cells could be a useful tool to supplement clinical criteria for early diagnosis of TSS. [source] German cockroach proteases regulate matrix metalloproteinase-9 in human bronchial epithelial cellsALLERGY, Issue 8 2006K. Page Background:, Matrix metalloproteinases (MMPs) digest extracellular matrix proteins and may play a role in the pathogenesis of bronchial asthma. MMP-9 levels are increased in the bronchoalveolar lavage fluid and sputum of asthmatics compared with that of controls. As exposure to cockroaches is an environmental risk factor for asthma, we sought to investigate the role of German cockroach fecal remnants (frass) on MMP-9 expression. Methods:, Human bronchial epithelial cells (16HBE14o-) and primary normal human bronchial epithelial cells were treated with cockroach frass in the absence or presence of tumor necrosis factor (TNF),. MMP-9 mRNA, protein levels and pro-MMP-9 activity were determined using real-time polymerase chain reaction (PCR), enzyme-linked immunosorbent assay (ELISA) and zymogram assays. Pretreatment of frass with aprotinin abolished protease activity. PD98059, a chemical inhibitor of extracellular signal regulated kinase (ERK), and SLIGKV, an activator of protease-activated receptor (PAR)-2 were also used. AP-1DNA binding was determined by electrophoretic mobility shift assay (EMSA) and ERK phosphorylation by Western blot analysis. Results:, Cockroach frass augmented TNF, -mediated MMP-9 mRNA and protein expression by a mechanism dependent on active serine proteases within frass and not on endogenous endotoxin. Frass increased ERK phosphorylation, and chemical inhibition of ERK attenuated cockroaches' effects on MMP-9. Serine proteases are known to activate the PAR-2 receptor. We found that selective activation of PAR-2 using the peptide SLIGKV augmented TNF, -induced MMP-9 protein levels and increased ERK phosphorylation. Frass and SLIGKV each increased AP-1 translocation and DNA binding. Conclusions:, These data suggest that German cockroach frass contains active serine proteases which augment TNF, -induced MMP-9 expression by a mechanism involving PAR-2, ERK and AP-1. [source] Selective block of external anal sphincter activation during electrical stimulation of the sacral anterior roots in a canine modelNEUROGASTROENTEROLOGY & MOTILITY, Issue 5 2005N. Bhadra Abstract, Our aim was to electrically activate small diameter parasympathetic fibres in the sacral anterior roots, without activating the larger somatic fibres to the external anal sphincter (EAS). Electrodes were implanted on selected roots in five adult dogs. Pressures were recorded from the rectum and EAS. Quasitrapezoidal (Qzt) pulses for selective activation of smaller axons and narrow rectangular (Rct) pulses to activate all fibres were applied. Sphincter block was defined as [(Pmax , Pmin)/Pmax] × 100%. Roots were also tested with 20 Hz trains. In three animals, evacuation of bowel contents was recorded with artificial fecal material. Stimulation with Qzt pulses showed decrease in sphincter recruitment with increasing pulse amplitudes, indicating propagation arrest in the large fibres. The average sphincter suppression was 94.1% in 16 roots implanted. With Qzt pulse trains, the average evoked sphincter pressure was significantly lower than Rct pulses. Evoked rectal pressures were not significantly different. The mean mass of expelled bowel contents of 51.1 g by Qzt trains was significantly higher than that of 14.8 g expelled by Rct trains. Our results demonstrate that this selective stimuli can activate small diameter fibres innervating the distal bowel and result in significant evacuation of rectal contents. [source] Pudendal nerve stimulation evokes reflex bladder contractions in persons with chronic spinal cord injury,,NEUROUROLOGY AND URODYNAMICS, Issue 7 2007Paul B. Yoo Abstract Aims Although electrical stimulation of the pudendal nerve has been shown to evoke reflex micturition-like bladder contractions in both intact and spinalized cats, there is little evidence to suggest that an analogous excitatory reflex exists in humans, particularly those with spinal cord injury (SCI). We present two cases where electrical activation of pudendal nerve afferents was used to evoke excitatory bladder responses. Subjects and Methods A percutaneously placed catheter electrode was used to electrically stimulate the pudendal nerve trunk in two males with SCI. The response was quantified with recorded changes in detrusor pressure and EMG activity of the external anal sphincter. Results In both individuals, frequency specific (f,=,20,50 Hz) activation of the pudendal nerve trunk evoked excitatory bladder contractions that also depended on the stimulus amplitude and bladder volume. Conclusion The results suggest that selective activation of the perineal branches of the pudendal nerve may further augment the excitatory reflex evoked by electrical stimulation. Neurourol. Urodynam. 26:1020,1023, 2007. © 2007 Wiley-Liss, Inc. [source] Selective activation of the sacral anterior roots for induction of bladder voidingNEUROUROLOGY AND URODYNAMICS, Issue 2 2006Narendra Bhadra Abstract Aim We investigated the efficacy of selective activation of the smaller diameter axons in the sacral anterior roots for electrically induced bladder voiding. Materials and Methods Acute experiments were conducted in five adult dogs. The anterior sacral roots S2 and S3 were implanted bilaterally with tripolar electrodes. Pressures were recorded from the bladder and from the proximal urethra and the external urethral sphincter. A detector and flow meter monitored fluid flow. A complete sacral dorsal rhizotomy was carried out. The effects of two types of pulse trains at 20 Hz were compared; quasitrapezoidal pulses (500 µsec with 500 µsec exponential decay) and interrupted rectangular (100 µsec, 2 sec on/2 sec off). Before rhizotomy, rectangular pulse trains (100 µsec) to activate all fibers were also applied. The experimental design was block randomized before and after rhizotomy. Results Quasitrapezoidal pulses showed block of sphincter activation with average minimum current for maximum suppression of 1.37 mA. All pulse types evoked average bladder pressures above the basal sphincter closure pressure. The pressure patterns in the proximal urethra closely followed the bladder pressures. Before dorsal rhizotomy, stimulation evoked a superadded increase in sphincter pressures with slow rise time. After rhizotomy, the sphincter pressure patterns followed the bladder pressures during selective activation and voiding occurred during stimulation with quasitrapezoidal trains and in between bursts with interrupted rectangular stimulation. Conclusions Selective activation of sacral ventral roots combined with dorsal rhizotomy may provide a viable means of low-pressure continuous voiding in neurological impairment. Neurourol. Urdynam. © 2005 Wiley-Liss, Inc. [source] A brighter side of ROS revealed by selective activation of ,-adrenergic receptor subtypesTHE JOURNAL OF PHYSIOLOGY, Issue 16 2010Nora Biary No abstract is available for this article. [source] Rapid activation of Mac-1(CD11b/CD18) molecules on macrophages by a new chemotactic factor ,Gasserokine' produced by Lactobacillus gasseri JCM1131TANIMAL SCIENCE JOURNAL, Issue 5 2002Haruki KITAZAWA ABSTRACT The chemoattractant activity of a new chemotactic factor, ,Gasserokine' produced by Lactobacillus gasseri JCM1131T, has been proposed as a novel immunological function of probiotic lactic acid bacteria. The focus of the present study was to understand the mechanism of the chemotaxis induced by Gasserokine, using activation of an adhesion molecule, Mac-1 (CD11b/CD18) on macrophages. The macrophage chemotaxis to Gasserokine was abolished by preincubation of macrophages with the anti-Mac-1 mAb. Gasserokine induced rapid serine phosphorylation of CD18 molecules within 1 min of stimulation, but the effect was short-lived. Substantial tyrosine phosphorylation was observed in CD18-associated protein of macrophages stimulated by Gasserokine. The tyrosine phosphorylation was confirmed in macrophages stimulated with Gasserokine and also serine/threonine phosphorylation was detected on CD18 molecules by laser microscopy using a double immunostaining method. These results suggest that selective activation of intracellular signaling cascades, such as the mitogen-activated protein kinase pathway, are related to the macrophage chemotaxis induced by Gasserokine. [source] The graphemic/motor frontal area Exner's area revisited,ANNALS OF NEUROLOGY, Issue 4 2009Franck-Emmanuel Roux MD Objective In 1881, Exner first described a "graphic motor image center" in the middle frontal gyrus. Current psycholinguistic models of handwriting involve the conversion of abstract, orthographic representations into motor representations before a sequence of appropriate hand movements is produced. Direct cortical stimulation and functional magnetic resonance imaging (fMRI) were used to study the human frontal areas involved in writing. Methods Cortical electrical stimulation mapping was used intraoperatively in 12 patients during the removal of brain tumors to identify the areas involved in oral language (sentence reading and naming) and writing, and to spare them during surgery. The fMRI activation experiment involved 12 right-handed and 12 left-handed healthy volunteers using word dictation (without visual control) and 2 control tasks. Results Direct cortical electrical stimulation of restricted areas rostral to the primary motor hand area (Brodmann area [BA] 6) impaired handwriting in 6 patients, without disturbing hand movements or oral language tasks. In 6 other patients, stimulation of lower frontal regions showed deficits combining handwriting with other language tasks. fMRI also revealed selective activation during word handwriting in left versus right BA6 depending on handedness. This area was anatomically matched to those areas that affected handwriting on electrical stimulation. Interpretation An area in middle frontal gyrus (BA6) that we have termed the graphemic/motor frontal area supports bridging between orthography and motor programs specific to handwriting. Ann Neurol 2009;66:537,545 [source] S- Thiazolinyl (STaz) Glycosides as Versatile Building Blocks for Convergent Selective, Chemoselective, and Orthogonal Oligosaccharide SynthesisCHEMISTRY - A EUROPEAN JOURNAL, Issue 25 2006Papapida Pornsuriyasak Abstract In the aim of developing new procedures for efficient oligosaccharide assembly, a range of S- thiazolinyl (STaz) glycosides have been synthesized. These novel derivatives were evaluated against a variety of reaction conditions and were shown to be capable of being chemoselectively activated in the armed,disarmed fashion. Moreover, the S- thiazolinyl moiety exhibited a remarkable propensity for selective activation over other common leaving groups. Conversely, a variety of leaving groups could be selectively activated over the STaz moiety, which, in turn, allowed STaz/S- ethyl and STaz/S- phenyl orthogonal approaches. To demonstrate versatility of novel STaz derivatives, a number of oligosaccharide targets have been synthesized in a convergent selective, orthogonal, and chemoselective fashion. [source] | ||||||||||||||||||||||||||||