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Increased PI (increased + pi)
Selected AbstractsPathogenic T cells in murine lupus exhibit spontaneous signaling activity through phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathwaysARTHRITIS & RHEUMATISM, Issue 4 2003Florin Niculescu Objective To determine the activation status of two cytoplasmic signaling pathways, phosphatidylinositol 3-kinase (PI 3-kinase) and the mitogen-activated protein kinase (MAPK) family. Methods We studied the pathogenic CD4+ T cells that drive disease in the parent-into-F1 mouse model of lupus-like chronic graft-versus-host disease (GVHD). We determined immunoprecipitated kinase activity for PI 3-kinase and MAPK members (Raf-1, extracellular signal,regulated kinase 1 [ERK-1], c-Jun N-terminal kinase 1 [JNK-1], and p38 MAPK) from either unfractionated splenocytes or purified donor CD4+ T cells. Uninjected normal mice served as negative controls, and acute GVHD mice served as positive controls. Results Compared with negative controls, unfractionated splenocyte kinase activity from chronic GVHD mice was significantly increased for PI 3-kinase and JNK-1, but not for Raf-1, p38 MAPK, or ERK-1. Increased PI 3-kinase and JNK-1 activity was also seen in acute GVHD splenocytes, as was increased Raf-1 and p38 MAPK activity. The pattern of increased PI 3-kinase and JNK-1 activity seen in unfractionated chronic GVHD splenocytes was also seen in isolated donor, but not host, CD4+ T cells from chronic GVHD mice, indicating that donor CD4+ T cell signaling activity accounted for at least a portion of the activity observed in unfractionated splenocytes. Increased ERK-1 activity was not seen in either donor or host CD4+ T cells. This pattern of cytoplasmic signaling pathway in donor CD4+ T cells was associated with increased T cell receptor membrane signaling activation (Lck and Fyn phosphorylation) and increased transcription activation (phosphorylation of inhibitor of nuclear factor ,B), confirming the biologic significance of these observations. Conclusion The pathogenic T cells driving disease in this murine model exhibit activation in the form of spontaneous cytoplasmic signaling pathway activity that can be detected without in vitro restimulation and involves a T cell,specific (PI 3-kinase) and a nonspecific stress/cytokine pathway (JNK-1). These results raise the possibility that a full characterization of the signaling pathways active in pathogenic lupus T cells might lead to new therapeutic targets. [source] Preoperative Electrocardiographic Risk Assessment of Atrial Fibrillation After Coronary Artery Bypass GraftingJOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 12 2004Ph.D., YI GANG M.D. Introduction: This study evaluated the role of surface ECG in assessment of risk of new-onset atrial fibrillation (AF) after coronary artery bypass grafting surgery (CABG). Methods and Results: One hundred fifty-one patients (126 men and 25 women; age 65 ± 10 years) without a history of AF undergoing primary elective and isolated CABG were studied. Standard 12-lead ECGs and P wave signal-averaged ECG (PSAE) were recorded 24 hours before CABG using a MAC VU ECG recorder. In addition to routine ECG measurements, two P wave (P wave complexity ratio [pCR]; P wave morphology dispersion [PMD]) and six T wave morphology descriptors (total cosine R to T [TCRT]; T wave morphology dispersion of ascending and descending part of the T wave [aTMD and dTMD], and others), and three PSAE indices (filtered P wave duration [PD]; root mean square voltage of terminal 20 msec of averaged P wave [RMS20]; and integral of P wave [Pi]) were investigated. During a mean hospital stay of 7.3 ± 6.2 days after CABG, 40 (26%) patients developed AF (AF group) and 111 remained AF-free (no AF group). AF patients were older (69 ± 9 years vs 64 ± 10 years, P = 0.005). PD (135 ± 9 msec vs 133 ± 12 msec, P = NS) and RMS20 (4.5 ± 1.7 ,V vs 4.0 ± 1.6 ,V, P = NS) in AF were similar to that in no AF, whereas Pi was significantly increased in AF (757 ± 230 ,Vmsec vs 659 ± 206 ,Vmsec, P = 0.007). Both pCR (32 ± 11 vs 27 ± 10) and PMD (31.5 ± 14.0 vs 26.4 ± 12.3) were significantly greater in AF (P = 0.012 and 0.048, respectively). TCRT (0.028 ± 0.596 vs 0.310 ± 0.542, P = 0.009) and dTMD (0.63 ± 0.03 vs 0.64 ± 0.02, P = 0.004) were significantly reduced in AF compared with no AF. Measurements of aTMD and three other T wave descriptors were similar in AF and no AF. Significant variables by univariate analysis, including advanced age (P = 0.014), impaired left ventricular function (P = 0.02), greater Pi (P = 0.012), and lower TCRT (P = 0.007) or dTMD, were entered into multiple logistic regression models. Increased Pi (P = 0.038), reduced TCRT (P = 0.040), and lower dTMD (P = 0.014) predicted AF after CABG independently. In patients <70 years, a linear combination of increased pCR and lower TCRT separated AF and no AF with a sensitivity of 74% and specificity of 62% (P = 0.005). Conclusion: ECG assessment identifies patients vulnerable to AF after CABG. Combination of ECG parameters assessed preoperatively may play an important role in predicting new-onset AF after CABG. [source] The influence of mating system on the intensity of parent,offspring conflict in primatesJOURNAL OF EVOLUTIONARY BIOLOGY, Issue 3 2005T. A. F. LONG Abstract An evolutionary conflict of interest exists between parents and their offspring over the partitioning of parental investment (PI) among siblings. When the direct fitness benefits to offspring of increased PI, outweigh the inclusive fitness costs from lost future sibling fitness, selection should favour the evolution of offspring selfishness over altruism. In theory, this conflict is heightened when females are not strictly monogamous, as current offspring should be less altruistic towards future half-siblings than they would be towards full-siblings. Using data collected on foetal growth rate (representing prenatal PI) in primates, I test the prediction from theory that the resolution of the parent-offspring conflict will be closer to the offspring's evolutionary optima in polyandrous species than in more monandrous species. Using phylogenetic comparative analysis, and controlling for allometry, I show that offspring are able to obtain more PI when the probability of future full-siblings decreases, and that this is most pronounced in taxa where there is the opportunity for direct foetal access to the maternal bloodstream. These results support the hypothesis that the resolution of prenatal PI conflict is influenced by both a species' mating system and by its placental structure. [source] Cerebral Hemodynamics Changes During Retrograde Brain Perfusion in DogsJOURNAL OF NEUROIMAGING, Issue 2 2001Alexander Y. Razumovsky PhD ABSTRACT The objective of this study was to examine cerebral hemodynamics changes during hypothermic circulatory arrest (HCA) with and without retrograde cerebral perfusion (RCP). Thirteen colony-bred hound dogs were placed on cardiopulmonary bypass (CPB) and cooled to 18°C. Five dogs underwent 2 hours of HCA without RCP and 8 with RCP. The animals were then rewarmed on CPB until normothermic and weaned. Cerebral blood flow velocity (CBFV) and Gosling Pulsatility Index (PI) in the middle cerebral artery (MCA) were studied using transcranial Doppler (TCD) ultrasound. At baseline and during pre- and postarrest CPB, there was anterograde direction of blood flow in the MCA. During HCA with RCP, there was retrograde direction of blood flow in the MCA. There was no difference in CBFV between pre-, during, and postarrest CPB in the group with RCP; however, there was significantly increased CBFV during postarrest CPB in the group without RCP compared to the dogs with RCP. Later, at 3 hours after postarrest CPB, there was decreased CBFV in all animals accompanied by increased PI (2.4 ± 0.4 and 2.2 ± 0.6 for animals with RCP and without RCP, respectively) and abnormal TCD waveform changes including decreased diastolic compartment and sharp systolic peak. During hypothermic circulatory arrest, RCP provides CBFV in the MCA comparable to MCA CBFV during CPB. HCA dogs without RCP showed immediate hyperemia on reperfusion. The decreased CBFV and increased PI at 1 hour after postarrest CPB could be an indicator of progressive ischemic injury due to the increased intracranial pressure despite the implementation of RCP. [source] A mutant form of PTEN linked to autismPROTEIN SCIENCE, Issue 10 2010Roberta E. Redfern Abstract The tumor suppressor, phosphatase, and tensin homologue deleted on chromosome 10 (PTEN), is a phosphoinositide (PI) phosphatase specific for the 3-position of the inositol ring. PTEN has been implicated in autism for a subset of patients with macrocephaly. Various studies identified patients in this subclass with one normal and one mutated PTEN gene. We characterize the binding, structural properties, activity, and subcellular localization of one of these autism-related mutants, H93R PTEN. Even though this mutation is located at the phosphatase active site, we find that it affects the functions of neighboring domains. H93R PTEN binding to phosphatidylserine-bearing model membranes is 5.6-fold enhanced in comparison to wild-type PTEN. In contrast, we find that binding to phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) model membranes is 2.5-fold decreased for the mutant PTEN in comparison to wild-type PTEN. The structural change previously found for wild-type PTEN upon interaction with PI(4,5)P2, is absent for H93R PTEN. Consistent with the increased binding to phosphatidylserine, we find enhanced plasma membrane association of PTEN-GFP in U87MG cells. However, this enhanced plasma membrane association does not translate into increased PI(3,4,5)P3 turnover, since in vivo studies show a reduced activity of the H93R PTEN-GFP mutant. Because the interaction of PI(4,5)P2 with PTEN's N-terminal domain is diminished by this mutation, we hypothesize that the interaction of PTEN's N-terminal domain with the phosphatase domain is impacted by the H93R mutation, preventing PI(4,5)P2 from inducing the conformational change that activates phosphatase activity. [source] Pathogenic T cells in murine lupus exhibit spontaneous signaling activity through phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathwaysARTHRITIS & RHEUMATISM, Issue 4 2003Florin Niculescu Objective To determine the activation status of two cytoplasmic signaling pathways, phosphatidylinositol 3-kinase (PI 3-kinase) and the mitogen-activated protein kinase (MAPK) family. Methods We studied the pathogenic CD4+ T cells that drive disease in the parent-into-F1 mouse model of lupus-like chronic graft-versus-host disease (GVHD). We determined immunoprecipitated kinase activity for PI 3-kinase and MAPK members (Raf-1, extracellular signal,regulated kinase 1 [ERK-1], c-Jun N-terminal kinase 1 [JNK-1], and p38 MAPK) from either unfractionated splenocytes or purified donor CD4+ T cells. Uninjected normal mice served as negative controls, and acute GVHD mice served as positive controls. Results Compared with negative controls, unfractionated splenocyte kinase activity from chronic GVHD mice was significantly increased for PI 3-kinase and JNK-1, but not for Raf-1, p38 MAPK, or ERK-1. Increased PI 3-kinase and JNK-1 activity was also seen in acute GVHD splenocytes, as was increased Raf-1 and p38 MAPK activity. The pattern of increased PI 3-kinase and JNK-1 activity seen in unfractionated chronic GVHD splenocytes was also seen in isolated donor, but not host, CD4+ T cells from chronic GVHD mice, indicating that donor CD4+ T cell signaling activity accounted for at least a portion of the activity observed in unfractionated splenocytes. Increased ERK-1 activity was not seen in either donor or host CD4+ T cells. This pattern of cytoplasmic signaling pathway in donor CD4+ T cells was associated with increased T cell receptor membrane signaling activation (Lck and Fyn phosphorylation) and increased transcription activation (phosphorylation of inhibitor of nuclear factor ,B), confirming the biologic significance of these observations. Conclusion The pathogenic T cells driving disease in this murine model exhibit activation in the form of spontaneous cytoplasmic signaling pathway activity that can be detected without in vitro restimulation and involves a T cell,specific (PI 3-kinase) and a nonspecific stress/cytokine pathway (JNK-1). These results raise the possibility that a full characterization of the signaling pathways active in pathogenic lupus T cells might lead to new therapeutic targets. [source] | ||||||||||