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Simultaneous Activation (simultaneous + activation)
Selected AbstractsRegiospecific Synthesis of 4-Deoxy- D - threo -hex-3-enopyranosides by Simultaneous Activation,Elimination of the Talopyranoside Axial 4-OH with the NaH/Im2SO2 System: Manifestation of the Stereoelectronic EffectEUROPEAN JOURNAL OF ORGANIC CHEMISTRY, Issue 23 2006Emanuele Attolino Abstract A new and high-yielding method for the regioselective preparation of 4-deoxy- and 2,4-dideoxy-2-acetamido-,- D - threo -hex-3-enopyranosides has been developed. The process involves a simultaneous activation,elimination of the OH-4 group of ,- D -talopyranosides and 2-acetamido-2-deoxy-,- D -talopyranosides, mediated by the NaH/N,N,-sulfuryldiimidazole system at ,30 °C. The same reaction applied on the analogous ,- D -galactopyranosides takes place without any regioselectivity, affording mixtures of hex-3- and hex-4-enopyranosides. In the case of the methyl 2,3,6-tri- O -benzyl-,- D -talo- and ,- D -galactopyranosides, the corresponding 4- O -imidazylates can be isolated by quenching the reactions at ,30 °C. Upon warming these crude products to room temperature, the ,- talo -4- O -imidazylate gives the corresponding hex-3-eno derivative in very high yield, but its ,- galacto analogue gives the hex-4-enopyranoside enol ether in poor yield. The different regiochemical outcome between the talo and the galacto series has been attributed to the stereoelectronic effect exerted, exclusively in talo -configured compounds, by the axially disposed C-2 electronegative substituent, which selectively accelerates the breaking of the antiperiplanar C(3),H bond. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006) [source] ChemInform Abstract: Synthesis of Thioesters by Simultaneous Activation of Carboxylic Acids and Alcohols Using PPh3/NBS with Benzyltriethylammonium Tetrathiomolybdate as the Sulfur Transfer Reagent.CHEMINFORM, Issue 12 2010Purushothaman Gopinath Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a "Full Text" option. The original article is trackable via the "References" option. [source] Activation of receptors negatively coupled to adenylate cyclase is required for induction of long-term synaptic depression at Schaffer collateral-CA1 synapsesDEVELOPMENTAL NEUROBIOLOGY, Issue 3 2006Linda A. Santschi Abstract Chemical LTD (CLTD) of synaptic transmission is triggered by simultaneously increasing presynaptic [cGMP] while inhibiting PKA. Here, we supply evidence that class II, but not III, metabotropic glutamate receptors (mGluRs), and A1 adenosine receptors, both negatively coupled to adenylate cyclase, play physiologic roles in providing PKA inhibition necessary to promote the induction of LTD at Schaffer collateral-CA1 synapses in hippocampal slices. Simultaneous activation of group II mGluRs with the selective agonist (2S,2,R,3,R)-2-(2,,3,-dicarboxy-cyclopropyl) glycine (DCGIV; 5 ,M), while raising [cGMP] with the type V phosphodiesterase inhibitor, zaprinast (20 ,M), resulted in a long-lasting depression of synaptic strength. When zaprinast (20 ,M) was combined with a cell-permeant PKA inhibitor H-89 (10 ,M), the need for mGluR IIs was bypassed. DCGIV, when combined with a "submaximal" low frequency stimulation (1 Hz/400 s), produced a saturating LTD. The mGluR II selective antagonist, (2S)-alpha-ethylglutamic acid (EGLU; 5 ,M), blocked induction of LTD by prolonged low frequency stimulation (1 Hz/900 s). In contrast, the mGluR III selective receptor blocker, (RS)-a-Cyclopropyl-[3- 3H]-4-phosphonophenylglycine (CPPG; 10 ,M), did not impair LTD. The selective adenosine A1 receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX; 100 nM), also blocked induction of LTD, while the adenosine A1 receptor agonist N6 -cyclohexyl adenosine (CHA; 50 nM) significantly enhanced the magnitude of LTD induced by submaximal LFS and, when paired with zaprinast (20 ,M), was sufficient to elicit CLTD. Inhibition of PKA with H-89 rescued the expression of LTD in the presence of either EGLU or DPCPX, confirming the hypothesis that both group II mGluRs and A1 adenosine receptors enhance the induction of LTD by inhibiting adenylate cyclase and reducing PKA activity. © 2005 Wiley Periodicals, Inc. J Neurobiol, 2006 [source] Simultaneous activation of JAK1 and JAK2 confers IL-3 independent growth on Ba/F3 pro-B cellsJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 2 2005Huei-Mei Huang Abstract JAK1 and JAK2 are tyrosine kinases involved in the regulation of cell proliferation, differentiation, and survival. These proteins may play a key role in mediating the effects of the cytokine IL-3 on hematopoietic cells. IL-3 induces tyrosine phosphorylation of both JAK1 and JAK2. However, it is not clear whether the activation of JAK1, JAK2, or both is sufficient to confer factor-independent growth in IL-3 dependent cells. To address this issue, fusion proteins CD16/CD7/JAK (CDJAK), comprised of a CD16 extracellular domain, a CD7 transmembrane domain, and a JAK cytoplasmic region (either a wild-type JAK or a dominant negative mutant of JAK) were constructed. We established several Ba/F3 derivatives that stably overexpress the conditionally active forms of either CDJAK1, CDJAK2, or both these fusion proteins. In this study, the autophosphorylation of CDJAK1 or CDJAK2 was induced by crosslinking with anti-CD16 antibody. We demonstrated that, like their wild-type counterparts, CDJAK1 and CDJAK2 were preassociated with the IL-3 receptor beta and alpha subunits, respectively. Furthermore, the simultaneous activation of both CDJAK1 and CDJAK2 fusion proteins, but not either one alone, led to the tyrosine phosphorylation of the IL-3 receptor beta subunit, the activation of downstream signaling molecules, including STAT5, Akt, and MAPK, and the conferring of factor-independent growth to IL-3-dependent Ba/F3 cells. Coexpression of dominant negative mutants CDJAK1KE or CDJAK2KE with wild type CDJAK2 or CDJAK1, respectively, inhibited these activation activities. These results suggest that JAK1 and JAK2 must work cooperatively and not independently and that their actions are dependent on having normal kinase activity to trigger downstream signals leading to IL-3 independent proliferation and survival of Ba/F3 cells. © 2005 Wiley-Liss, Inc. [source] When is high-Ca2+ microdomain required for mitochondrial Ca2+ uptake?,ACTA PHYSIOLOGICA, Issue 1 2009A. Spät Abstract Ca2+ release from IP3 -sensitive stores in the endoplasmic reticulum (ER) induced by Ca2+ -mobilizing agonists generates high-Ca2+ microdomains between ER vesicles and neighbouring mitochondria. Here we present a model that describes when such microdomains are required and when submicromolar [Ca2+] is sufficient for mitochondrial Ca2+ uptake. Mitochondrial Ca2+ uptake rate in angiotensin II-stimulated H295R adrenocortical cells correlates with the proximity between ER vesicles and the mitochondrion, reflecting the uptake promoting effect of high-Ca2+ peri-mitochondrial microdomains. Silencing or inhibition of p38 mitogen-activated protein kinase (MAPK) or inhibition of the novel isoforms of protein kinase C enhances mitochondrial Ca2+ uptake and abolishes the positive correlation between Ca2+ uptake and ER-mitochondrion proximity. Inhibition of protein phosphatases attenuates mitochondrial Ca2+ uptake and also abolishes its positive correlation with ER-mitochondrion proximity. We postulate that during IP3 -induced Ca2+ release, Ca2+ uptake is confined to ER-close mitochondria, because of the simultaneous activation of the protein kinases. Attenuation of Ca2+ uptake prevents Ca2+ overload of mitochondria and thus protects the cell against apoptosis. On the other hand, all the mitochondria accumulate Ca2+ at a non-inhibited rate during physiological Ca2+ influx through the plasma membrane. Membrane potential is higher in ER-distant mitochondria, providing a bigger driving force for Ca2+ uptake. Our model explains why comparable mitochondrial Ca2+ signals are formed in response to K+ and angiotensin II (equipotent in respect to global cytosolic Ca2+ signals), although only the latter generates high-Ca2+ microdomains. [source] Both Fc,RIV and Fc,RIII are essential receptors mediating type II and type III autoimmune responses via FcR,-LAT-dependent generation of C5aEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 12 2009Shahzad N. Syed Abstract Fc,RIV is a relatively new IgG Fc receptor (Fc,R) that is reported to contribute to the pathogenesis of autoimmune diseases, although its specific role in relation to Fc,RIII, complement and IgG2 subclasses remains uncertain. Here we define Fc,RIV on macrophages as a receptor for soluble IgG2a/b complexes but not for cellular bound IgG2a and show that simultaneous activation of Fc,RIV and Fc,RIII is critical to mediate certain type II/III autoimmune responses. Fc,RIII-deficient mice display compensatory enhanced Fc,RIV expression, are protected from lung inflammation after deposition of IgG complexes, and show reduced sensitivity to IgG2a/b-mediated hemolytic anemia, indicating that increased Fc,RIV alone is not sufficient to trigger these diseases in the absence of Fc,RIII. Importantly, however, blockade of Fc,RIV is also effective in inhibiting phagocytosis and cytokine production in IgG2b-induced anemia and acute lung injury, processes that display a further dependence on C5a anaphylatoxin receptor. Using gene deletion and functional inhibition studies, we found that Fc,RIII and Fc,RIV are each essential to trigger an FcR,-linker for activation of T-cell-dependent signal that drives C5a production in the Arthus reaction. Together, the results demonstrate a combined requirement for Fc,RIII and Fc,RIV in autoimmune injury, and identify the linker for activation of T cells adaptor as an integral component of linked Fc,R and C5a anaphylatoxin receptor activation to generate inflammation. [source] Corticospinal control of antagonistic muscles in the catEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 6 2007Christian Ethier Abstract We recently suggested that movement-related inter-joint muscle synergies are recruited by selected excitation and selected release from inhibition of cortical points. Here we asked whether a similar cortical mechanism operates in the functional linking of antagonistic muscles. To this end experiments were done on ketamine-anesthetized cats. Intracortical microstimulation (ICMS) and intramuscular electromyographic recordings were used to find and characterize wrist, elbow and shoulder antagonistic motor cortical points. Simultaneous ICMS applied at two cortical points, each evoking activity in one of a pair of antagonistic muscles, produced co-contraction of antagonistic muscle pairs. However, we found an obvious asymmetry in the strength of reciprocal inhibition; it was always significantly stronger on physiological extensors than flexors. Following intravenous injection of a single bolus of strychnine, a cortical point at which only a physiological flexor was previously activated also elicited simultaneous activation of its antagonist. This demonstrates that antagonistic corticospinal neurons are closely grouped, or intermingled. To test whether releasing a cortical point from inhibition allows it to be functionally linked with an antagonistic cortical point, one of three GABAA receptor antagonists, bicuculline, gabazine or picrotoxin, was injected iontophoretically at one cortical point while stimulation was applied to an antagonistic cortical point. This coupling always resulted in co-contraction of the represented antagonistic muscles. Thus, antagonistic motor cortical points are linked by excitatory intracortical connections held in check by local GABAergic inhibition, with reciprocal inhibition occurring at the spinal level. Importantly, the asymmetry of cortically mediated reciprocal inhibition would appear significantly to bias muscle maps obtained by ICMS in favor of physiological flexors. [source] Regiospecific Synthesis of 4-Deoxy- D - threo -hex-3-enopyranosides by Simultaneous Activation,Elimination of the Talopyranoside Axial 4-OH with the NaH/Im2SO2 System: Manifestation of the Stereoelectronic EffectEUROPEAN JOURNAL OF ORGANIC CHEMISTRY, Issue 23 2006Emanuele Attolino Abstract A new and high-yielding method for the regioselective preparation of 4-deoxy- and 2,4-dideoxy-2-acetamido-,- D - threo -hex-3-enopyranosides has been developed. The process involves a simultaneous activation,elimination of the OH-4 group of ,- D -talopyranosides and 2-acetamido-2-deoxy-,- D -talopyranosides, mediated by the NaH/N,N,-sulfuryldiimidazole system at ,30 °C. The same reaction applied on the analogous ,- D -galactopyranosides takes place without any regioselectivity, affording mixtures of hex-3- and hex-4-enopyranosides. In the case of the methyl 2,3,6-tri- O -benzyl-,- D -talo- and ,- D -galactopyranosides, the corresponding 4- O -imidazylates can be isolated by quenching the reactions at ,30 °C. Upon warming these crude products to room temperature, the ,- talo -4- O -imidazylate gives the corresponding hex-3-eno derivative in very high yield, but its ,- galacto analogue gives the hex-4-enopyranoside enol ether in poor yield. The different regiochemical outcome between the talo and the galacto series has been attributed to the stereoelectronic effect exerted, exclusively in talo -configured compounds, by the axially disposed C-2 electronegative substituent, which selectively accelerates the breaking of the antiperiplanar C(3),H bond. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006) [source] Prevotella intermedia lipopolysaccharide stimulates release of tumor necrosis factor-, through mitogen-activated protein kinase signaling pathways in monocyte-derived macrophagesFEMS IMMUNOLOGY & MEDICAL MICROBIOLOGY, Issue 2 2007Sung-Jo Kim Abstract The purpose of this study was to investigate the effects of lipopolysaccharide from Prevotella intermedia, a major cause of inflammatory periodontal disease, on the production of tumor necrosis factor (TNF)-, and the expression of TNF-, mRNA in differentiated THP-1 cells, a human monocytic cell line. The potential involvement of the three main mitogen-activated protein kinase (MAPK) signaling pathways in the induction of TNF-, production was also investigated. Lipopolysaccharide from P. intermedia ATCC 25611 was prepared by the standard hot phenol,water method. THP-1 cells were incubated in the medium supplemented with phorbol myristate acetate to induce differentiation into macrophage-like cells. It was found that P. intermedia lipopolysaccharide can induce TNF-, mRNA expression and stimulate the release of TNF-, in differentiated THP-1 cells without additional stimuli. Treatment of the cells with P. intermedia lipopolysaccharide resulted in a simultaneous activation of three MAPKs [extracellular signal-related kinase 1/2 (ERK1/2), c-Jun N-terminal kinase 1/2 (JNK1/2) and p38]. Pretreatment of the cells with MAPK inhibitors effectively suppressed P. intermedia lipopolysaccharide-induced TNF-, production without affecting the expression of TNF-, mRNA. These data thus provided good evidence that the MAPK signaling pathways are required for the regulation of P. intermedia lipopolysaccharide-induced TNF-, synthesis at the level of translation more than at the transcriptional level. [source] DNA bending and looping in the transcriptional control of bacteriophage ,29FEMS MICROBIOLOGY REVIEWS, Issue 5 2010Ana Camacho Abstract Recent studies on the regulation of phage ,29 gene expression reveal new ways to accomplish the processes required for the orderly gene expression in prokaryotic systems. These studies revealed a novel DNA-binding domain in the phage main transcriptional regulator and the nature and dynamics of the multimeric DNA,protein complex responsible for the switch from early to late gene expression. This review describes the features of the regulatory mechanism that leads to the simultaneous activation and repression of transcription, and discusses it in the context of the role of the topological modification of the DNA carried out by two phage-encoded proteins working synergistically with the DNA. [source] A gene-alteration profile of human lung cancer cell lines,HUMAN MUTATION, Issue 8 2009Raquel Blanco Abstract Aberrant proteins encoded from genes altered in tumors drive cancer development and may also be therapeutic targets. Here we derived a comprehensive gene-alteration profile of lung cancer cell lines. We tested 17 genes in a panel of 88 lung cancer cell lines and found the rates of alteration to be higher than previously thought. Nearly all cells feature inactivation at TP53 and CDKN2A or RB1, whereas BRAF, MET, ERBB2, and NRAS alterations were infrequent. A preferential accumulation of alterations among histopathological types and a mutually exclusive occurrence of alterations of CDKN2A and RB1 as well as of KRAS, epidermal growth factor receptor (EGFR), NRAS, and ERBB2 were seen. Moreover, in non-small-cell lung cancer (NSCLC), concomitant activation of signal transduction pathways known to converge in mammalian target of rapamycin (mTOR) was common. Cells with single activation of ERBB2, PTEN, or MET signaling showed greater sensitivity to cell-growth inhibition induced by erlotinib, LY294002, and PHA665752, respectively, than did cells featuring simultaneous activation of these pathways, underlining the need for combined therapeutic strategies in targeted cancer treatments. In conclusion, our gene-alteration landscape of lung cancer cell lines provides insights into how gene alterations accumulate and biological pathways interact in cancer. Hum Mutat 30,1,8, 2009. © 2009 Wiley-Liss, Inc. [source] Simultaneous activation of JAK1 and JAK2 confers IL-3 independent growth on Ba/F3 pro-B cellsJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 2 2005Huei-Mei Huang Abstract JAK1 and JAK2 are tyrosine kinases involved in the regulation of cell proliferation, differentiation, and survival. These proteins may play a key role in mediating the effects of the cytokine IL-3 on hematopoietic cells. IL-3 induces tyrosine phosphorylation of both JAK1 and JAK2. However, it is not clear whether the activation of JAK1, JAK2, or both is sufficient to confer factor-independent growth in IL-3 dependent cells. To address this issue, fusion proteins CD16/CD7/JAK (CDJAK), comprised of a CD16 extracellular domain, a CD7 transmembrane domain, and a JAK cytoplasmic region (either a wild-type JAK or a dominant negative mutant of JAK) were constructed. We established several Ba/F3 derivatives that stably overexpress the conditionally active forms of either CDJAK1, CDJAK2, or both these fusion proteins. In this study, the autophosphorylation of CDJAK1 or CDJAK2 was induced by crosslinking with anti-CD16 antibody. We demonstrated that, like their wild-type counterparts, CDJAK1 and CDJAK2 were preassociated with the IL-3 receptor beta and alpha subunits, respectively. Furthermore, the simultaneous activation of both CDJAK1 and CDJAK2 fusion proteins, but not either one alone, led to the tyrosine phosphorylation of the IL-3 receptor beta subunit, the activation of downstream signaling molecules, including STAT5, Akt, and MAPK, and the conferring of factor-independent growth to IL-3-dependent Ba/F3 cells. Coexpression of dominant negative mutants CDJAK1KE or CDJAK2KE with wild type CDJAK2 or CDJAK1, respectively, inhibited these activation activities. These results suggest that JAK1 and JAK2 must work cooperatively and not independently and that their actions are dependent on having normal kinase activity to trigger downstream signals leading to IL-3 independent proliferation and survival of Ba/F3 cells. © 2005 Wiley-Liss, Inc. [source] Vibrational spectral studies and the non-linear optical properties of a novel NLO material L -prolinium tartrateJOURNAL OF RAMAN SPECTROSCOPY, Issue 12 2006L. Padmaja Abstract Vibrational spectral analysis of the novel non-linear optical (NLO) material, L -prolinium tartrate (LPT) was carried out using NIR-FT-Raman and FT-IR spectroscopy. The density functional theoretical (DFT) computations have been performed at B3LYP/6,31G (d) level to derive equilibrium geometry, vibrational wavenumbers, intensities and first hyperpolarizability. The reasonable NLO efficiency, predicted for the first time in this novel compound, has been confirmed by Kurtz,Perry powder second-harmonic generation (SHG) experiments. The charge-transfer interaction between the pyrrolidine ring and the carbonyl group of the tartrate anion through the intramolecular ionic hydrogen bonds is confirmed by the simultaneous activation of ring modes in IR and Raman spectra. The splitting of the ring-breathing mode, pseudo-rotational ring puckering modes and the NH2 modes of the pyrrolidine ring lead to the conclusion that the pyrrolidine ring adopts a conformation intermediate between the envelope (bent) form and the half-chair (twisted) form, resulting in the lowering of symmetry from C2 to Cs. The lowering of the methylenic stretching wavenumbers and the enhancement of the stretching intensities suggest the existence of the electronic effects of back-donation in LPT. The positional disorder of the pyrrolidine ring, the presence of blue-shifting H-bonds as well as other non-bonded interactions in LPT, low frequency H-bond vibrations and the role of intramolecular charge transfer and the hydrogen bonds in making the molecule NLO active have been analysed on the basis of the vibrational spectral features. Copyright © 2006 John Wiley & Sons, Ltd. [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] Antagonistic expression of hepatitis C virus and alpha interferon in lymphoid cells during persistent occult infectionJOURNAL OF VIRAL HEPATITIS, Issue 8 2007T. N. Q. Pham Summary., Detection of residual HCV in individuals with SVR after treatment of CHC can be significantly heightened by analyzing ex vivo mitogen-activated T and B lymphocytes and applying sensitive nucleic acid amplification assays. However, it remained unknown if synergistic activation of lymphocytes and monocytes would further augment HCV detection, if viral replication becomes universally upregulated in treated cells, and if examining sequential sera and lymphoid cells would improve detection of occult infection. Using paired sera and lymphoid cells collected 1 year apart from 17 individuals with normal liver enzymes for up to 72 months after SVR, it was found that simultaneous activation of lymphocytes and monocytes enhanced identification of silent HCV infection and revealed that in some cases monocytes were the principal immune cell type where HCV persisted. Testing of serial samples further increased detection of occult infection. Ultimately, by combining the above two approaches, all individuals with SVR were found to be silent carriers of HCV. Clonal sequencing revealed HCV variations in sera and lymphoid cells and evolution of viral genomes confirming ongoing virus replication. Surprisingly, similar to those with CHC, naive lymphoid cells from some individuals carried ,103 HCV copies/,g total RNA. HCV loads in naive lymphoid cells predetermined the outcome of ex vivo stimulation with respect to upregulation or inhibition of HCV replication. HCV RNA levels in occult infection were inversely proportional to the expression of IFN, and IFN-inducible MxA, but not to IFN, or tumour necrosis factor , in naive and mitogen-treated lymphoid cells. [source] Reentry Within the Cavotricuspid Isthmus: An Isthmus Dependent CircuitPACING AND CLINICAL ELECTROPHYSIOLOGY, Issue 8 2005YANFEI YANG Background: We describe a new cavotricuspid isthmus (CTI) circuit. Methods: This study includes 8 patients referred for atrial flutter (AFL) ablation whose tachycardia circuit was confined to the septal CTI and the os of the coronary sinus (CSOS) region. Entrainment mapping was performed within the CTI, CSOS, and other right atrial annular sites (tricuspid annulus (TA)). Electroanatomic mapping was available in 2 patients. Results: Sustained AFL occurred in all patients with mean tachycardia cycle length (TCL) of 318 ± 54 (276 , 420) ms. During tachycardia, fractionated or double potentials were recorded at either the septal CTI and/or the region of CSOS in all, and concealed entrainment with post-pacing interval (PPI) , TCL , 25 ms occurred in this area; but manifest entrainment with PPI > TCL was demonstrated from the anteroinferior CTI and other annular sites in 7/8 patients. In one, tachycardia continued with conduction block at the anteroinferior CTI during ablation. Up to three different right atrial activation patterns (identical TCL) were observed. The tachycardia showed a counterclockwise (CCW) pattern in 6, a clockwise pattern in 2, and simultaneous activation of both low lateral right atrium and septum in 5. Electroanatomic mapping was available in 2, showing an early area arising from the septal CTI in 1, and a CCW activation sequence along the TA in another. Radiofrequency application to the septal CTI terminated tachycardia in 4, and tachycardia no longer inducible in all. Conclusions: We describe a tachycardia circuit confined to the septal CTI/CSOS region, and hypothesize that this circuit involves slow conduction within the CTI and around the CSOS, which acts as a central obstacle. [source] Mouse models of gastric tumors: Wnt activation and PGE2 inductionPATHOLOGY INTERNATIONAL, Issue 9 2010Hiroko Oshima Accumulating evidence has suggested that cooperation of oncogenic activation and the host responses is important for cancer development. In gastric cancer, activation of Wnt signaling appears to be a major oncogenic pathway that causes tumorigenesis. In the chronic gastritis caused by Helicobacter pylori infection, cyclooxigenase-2 induces prostaglandin E2 (PGE2) biosythesis, which plays an important role in tumorigenesis. We constructed a series of mouse models and investigated the role of each pathway in the gastric tumorigenesis. Wnt activation in gastric epithelial cells suppresses differentiation, and induces development of preneoplastic lesions. On the other hand, induction of the PGE2 pathway in gastric mucosa induces development of spasmolytic polypeptide-expressing metaplasia (SPEM), which is a possible preneoplastic metaplasia. Importantly, simultaneous activation of Wnt and PGE2 pathways leads to dysplastic gastric tumor development. Moreover, induction of the PGE2 pathway also promotes gastric hamartoma development when bone morphogenetic protein (BMP) signaling is suppressed. These results indicate that alteration in the Wnt or BMP signaling impairs epithelial differentiation, and the PGE2 pathway accelerates tumor formation regardless of the types of oncogenic pathways. We review the phenotypes and gene expression profiles of the respective models, and discuss the cooperation of oncogenic pathways and host responses in gastric tumorigenesis. [source] AMPA-sst2 somatostatin receptor interaction in rat hypothalamus requires activation of nmda and/or metabotropic glutamate receptors and depends on intracellular calciumTHE JOURNAL OF PHYSIOLOGY, Issue 1 2003Stéphane Peineau Modulation of glutamatergic transmission by neuropeptides is an essential aspect of neuronal network activity. Activation of the hypothalamic somatostatin sst2 receptor subtype by octreotide decreases AMPA glutamate responses, indicating a central link between a neurohormonal and neuromodulatory peptide and the main hypothalamic fast excitatory neurotransmitter. In mediobasal hypothalamic slices, sst2 activation inhibits the AMPA component of glutamatergic synaptic responses but is ineffective when AMPA currents are pharmacologically isolated. In mediobasal hypothalamic cultures, the decrease of AMPA currents induced by octreotide requires a concomitant activation of sst2 receptors with either NMDA and/or metabotropic glutamate receptors. This modulation depends on changes in intracellular calcium concentration induced by calcium flux through NMDA receptors or calcium release from intracellular stores following metabotropic glutamate receptor activation. These results highlight an unusual regulatory mechanism in which the simultaneous activation of at least three different types of receptor is necessary to allow somatostatin-induced modulation of fast synaptic glutamatergic transmission in the hypothalamus. [source] The effect of vibration on pain during local anaesthesia injectionsAUSTRALIAN DENTAL JOURNAL, Issue 2 2009E Nanitsos Abstract Background:, The "gate control" theory suggests pain can be reduced by simultaneous activation of nerve fibres that conduct non-noxious stimuli. This study investigated the effects of vibration stimuli on pain experienced during local anaesthetic injections. Methods:, In a preliminary study, subjects were asked to rate anticipated and actual pain from regional anaesthetic injections in the oral cavity. A second study compared, within subjects, pain from injections with and without a simultaneous vibration stimulus. Both infiltration and block anaesthetic injection techniques were assessed. In each subject, two similar injections were given and with one, a vibration stimulus was randomly allocated. Injection pain was assessed by visual analogue scale and McGill pain descriptors. Results:, Both infiltration and block injections were painful (mean anticipated intensity: 31.25, actual: 17.82 mm on 100 mm scale). Pain intensity with and without vibration was 12.9 mm (range 0,67) and 22.2 mm (range 0,83) respectively (p = 0.00005, paired T-test), and this effect was seen with both infiltration (p = 0.032) and block anaesthetic (p = 0.0001) injection subgroups. Furthermore, compared to no vibration-stimulus injections, injections with vibration resulted in less pain descriptors chosen (p = 0.004), and the descriptors had a lower pain rating (p = 0.001). Conclusions:, The results suggest that vibration can be used to decrease pain during dental local anaesthetic administration. [source] Simultaneous signalling through c-mpl, c-kit and CXCR4 enhances the proliferation and differentiation of human megakaryocyte progenitors: possible roles of the PI3-K, PKC and MAPK pathwaysBRITISH JOURNAL OF HAEMATOLOGY, Issue 1 2001Hitoshi Minamiguchi We assessed the effect of signalling through CXCR4 on the proliferation and differentiation of human megakaryocytic progenitor cells (CFU-Meg) in the presence or absence of stem cell factor (SCF) and/or thrombopoietin (TPO), using peripheral blood-derived CD34+IL-6R, cells as a target. TPO alone induced a significant number of CFU-Meg colonies. Although stromal cell-derived factor-1 (SDF-1) or SCF alone did not support CFU-Meg colony formation, these factors had a synergistic effect on CFU-Meg colony formation in the presence of TPO. The combination of SDF-1, SCF and TPO induced twice as many CFU-Meg colonies as TPO alone. To investigate the mechanism of this synergistic action, we examined the effects of various protein kinase inhibitors on CFU-Meg colony formation. LY294002 and GF109203X (inhibitors of PI3-K and PKC respectively) completely or partially inhibited this synergistic action. In contrast, a MEK inhibitor (PD98059) did not inhibit CFU-Meg colony formation. It significantly increased the higher ploidy classes (16N to 64N) of megakaryocytes supported by TPO, TPO + SCF, TPO + SDF-1, and TPO + SCF + SDF-1, whereas it abolished the effect of SDF-1 on the increase of higher ploidy classes of megakaryocytes supported by TPO. These results suggest that MAPK may negatively or positively regulate the nuclear maturation of megakaryocytes, known as endomitosis. In the presence of PD98059, proplatelet formation (PPF) was significantly augmented, suggesting that the MAPK pathway may also inhibit the initiation of PPF. In conclusion, simultaneous activation of three signals through c-mpl, c-kit and CXCR4 can induce the in vitro proliferation and differentiation of CFU-Meg, and SDF-1 is a potentiator of human megakaryocytopoiesis. [source] Role of gp130-mediated signalling pathways in the heart and its impact on potential therapeutic aspectsBRITISH JOURNAL OF PHARMACOLOGY, Issue S1 2008P Fischer IL-6-type cytokines bind to plasma membrane receptor complexes containing the common signal transducing receptor chain gp130 that is ubiquitously expressed in most tissues including the heart. The two major signalling cascades activated by the gp130 receptor, SHP2/ERK and STAT pathways, have been demonstrated to play important roles in cardiac development, hypertrophy, protection and remodelling in response to physiological and pathophysiological stimuli. Experimental data, both in vivo and in vitro, imply beneficial effects of gp130 signalling on cardiomyocytes in terms of growth and survival. In contrast, it has been reported that elevated serum levels of IL-6 cytokines and gp130 proteins are strong prognostic markers for morbidity and mortality in patients with heart failure or after myocardial infarction. Moreover, it has been shown that the local gp130 receptor system is altered in failing human hearts. In the present review, we summarize the basic principles of gp130 signalling, which requires simultaneous activation of STAT and ERK pathways under the tight control of positive and negative intracellular signalling modulators to provide a balanced biological outcome. Furthermore, we highlight the key role of the gp130 receptor and its major downstream effectors in the heart in terms of development and regeneration and in response to various physiological and pathophysiological stress situations. Finally, we comment on tissue-specific diversity and challenges in targeted pharmacological interference with components of the gp130 receptor system. British Journal of Pharmacology (2008) 153, S414,S427; doi:10.1038/bjp.2008.1; published online 4 February 2008 [source] REFLEXLY EVOKED COACTIVATION OF CARDIAC VAGAL AND SYMPATHETIC MOTOR OUTFLOWS: OBSERVATIONS AND FUNCTIONAL IMPLICATIONSCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 12 2006Julian FR Paton SUMMARY 1The purpose of the present review is to highlight the pattern of activity in the parasympathetic and sympathetic nerves innervating the heart during their reflex activation. 2We describe the well-known reciprocal control of cardiac vagal and sympathetic activity during the baroreceptor reflex, but point out that this appears to be the exception rather than the rule and that many other reflexes reviewed herein (e.g. peripheral chemoreceptor, nociceptor, diving response and oculocardiac) involve simultaneous coactivation of both autonomic limbs. 3The heart rate response during simultaneous activation of cardiac autonomic outflows is unpredictable because it does not simply reflect the summation of opposing influences. Indeed, it can result in bradycardia (peripheral chemoreceptor, diving and corneal), tachycardia (nociceptor) and, in some circumstances, can predispose to malignant arrhythmias. 4We propose that this cardiac autonomic coactivation may allow greater cardiac output during bradycardia (increased ventricular filling time and stronger contraction) than activation of the sympathetic limb alone. This may be important when pumping blood into a constricted vascular tree, such as is the case during the peripheral chemoreceptor reflex and the diving response. [source] Speed, Accuracy, and Serial Order in Sequence ProductionCOGNITIVE SCIENCE - A MULTIDISCIPLINARY JOURNAL, Issue 1 2007Peter Q. Pfordresher The production of complex sequences like music or speech requires the rapid and temporally precise production of events (e.g., notes and chords), often at fast rates. Memory retrieval in these circumstances may rely on the simultaneous activation of both the current event and the surrounding context (Lashley, 1951). We describe an extension to a model of incremental retrieval in sequence production (Palmer & Pfordresher, 2003) that incorporates this logic to predict overall error rates and speed,accuracy trade-offs, as well as types of serial ordering errors. The model,assumes that retrieval of the current event is influenced by activations of surrounding events. Activations of surrounding events increase over time, such that both the accessibility of distant events and overall accuracy increases at slower production rates. The model's predictions were tested in an experiment in which pianists performed unfamiliar music at 8 different tempi. Model fits to speed,accuracy data and to serial ordering errors support model predictions. Parameter fits to individual data further suggest that working memory contributes to the retrieval of serial order and overall accuracy is influenced in addition by motor dexterity and domain-specific skill. [source] | ||||||||||||||||