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941.
It is hypothesized that anterior cingulate cortex (ACC) function may be disrupted in psychopathy. Since ACC is considered the generator of the error-related negativity (ERN), we expected the ERN to be sensitive to the degree of psychopathy among violent offenders. EEG was collected while offenders and controls responded to a standard letter flanker task and to a face flanker task that required discrimination between angry and fearful expressions. Offenders were as accurate as controls on the letter flanker task but made more errors in emotion discrimination on the face flanker task. ERNs elicited by letter flanker errors did not differ across groups but were markedly reduced in the offenders in the face flanker condition. These effects were related to the degree of psychopathy within the offender group. Source modelling of the ERN also indicated an atypical response for psychopaths when error monitoring required the discrimination of affectively based information. 相似文献
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Harris EJ Miller NR Bamber JC Evans PM Symonds-Tayler JR 《Physics in medicine and biology》2007,52(18):5683-5703
Three-dimensional (3D) soft tissue tracking is of interest for monitoring organ motion during therapy. Our goal is to assess the tracking performance of a curvilinear 3D ultrasound probe in terms of the accuracy and precision of measured displacements. The first aim was to examine the depth dependence of the tracking performance. This is of interest because the spatial resolution varies with distance from the elevational focus and because the curvilinear geometry of the transducer causes the spatial sampling frequency to decrease with depth. Our second aim was to assess tracking performance as a function of the spatial sampling setting (low, medium or high sampling). These settings are incorporated onto 3D ultrasound machines to allow the user to control the trade-off between spatial sampling and temporal resolution. Volume images of a speckle-producing phantom were acquired before and after the probe had been moved by a known displacement (1, 2 or 8 mm). This allowed us to assess the optimum performance of the tracking algorithm, in the absence of motion. 3D speckle tracking was performed using 3D cross-correlation and sub-voxel displacements were estimated. The tracking performance was found to be best for axial displacements and poorest for elevational displacements. In general, the performance decreased with depth, although the nature of the depth dependence was complex. Under certain conditions, the tracking performance was sufficient to be useful for monitoring organ motion. For example, at the highest sampling setting, for a 2 mm displacement, good accuracy and precision (an error and standard deviation of <0.4 mm) were observed at all depths and for all directions of displacement. The trade-off between spatial sampling, temporal resolution and size of the field of view (FOV) is discussed. 相似文献
945.
Doppel induces degeneration of cerebellar Purkinje cells independently of Bax 总被引:1,自引:0,他引:1 下载免费PDF全文
Dong J Li A Yamaguchi N Sakaguchi S Harris DA 《The American journal of pathology》2007,171(2):599-607
Doppel (Dpl) is a prion protein paralog that causes neurodegeneration when expressed ectopically in the brain. To investigate the cellular mechanism underlying this effect, we analyzed Dpl-expressing transgenic mice in which the gene for the proapoptotic protein Bax had been deleted. We found that Bax deletion does not alter either clinical symptoms or Purkinje cell degeneration in Dpl transgenic mice. In addition, we observed that degenerating Purkinje cells in these animals do not display DNA fragmentation or caspase-3 activation. Our results suggest that non-Bax-dependent pathways mediate the toxic effects of Dpl in Purkinje cells, highlighting a possible role for nonapoptotic mechanisms in the death of these neurons. 相似文献
946.
Central role of protein kinase Cepsilon in constitutive activation of ERK1/2 and Rac1 in the malignant cells of hairy cell leukemia 下载免费PDF全文
Slupsky JR Kamiguti AS Harris RJ Cawley JC Zuzel M 《The American journal of pathology》2007,170(2):745-754
We have previously identified the presence of Ras/Raf-independent constitutive activation of extracellular signal-regulated kinase (ERK) in the hairy cells (HCs) of hairy cell leukemia. The aim of the present study was to characterize the signaling components involved in this activation and their relationship to the reported activation of Rac1. We found that both Rac1 and ERK activation in HCs are downstream of active Src and protein kinase C (PKC). Inhibition with toxin B showed that Rac1 plays no role in ERK activation in HCs. However, toxin B inhibited p60src and the Rac1-GEF Vav, demonstrating a positive feedback/activation of p60src by Rac1. Treatment with specific small interfering RNA for various PKC isoforms, or with PKC isoform-specific inhibitors, demonstrated a central role for PKCepsilon in the constitutive activation of Rac1 and ERK in HCs. PKCepsilon and active ERK were mutually associated and co-localized with mitochondria in HCs. Furthermore, active PKCepsilon was nitrated on tyrosine, pointing to a reactive oxygen species-dependent mechanism of activation. By being involved in activation of ERK and Rac1, PKCepsilon plays roles in both the survival of HCs and in the cytoskeletal dynamics responsible for the distinctive morphology and tissue homing of these cells. Our study therefore describes novel aspects of signaling important for the pathogenesis of hairy cell leukemia. 相似文献
947.
Sisodiya SM Thompson PJ Need A Harris SE Weale ME Wilkie SE Michaelides M Free SL Walley N Gumbs C Gerrelli D Ruddle P Whalley LJ Starr JM Hunt DM Goldstein DB Deary IJ Moore AT 《Journal of medical genetics》2007,44(6):373-380
Background
The genetic basis of variation in human cognitive abilities is poorly understood. RIMS1 encodes a synapse active‐zone protein with important roles in the maintenance of normal synaptic function: mice lacking this protein have greatly reduced learning ability and memory function.Objective
An established paradigm examining the structural and functional effects of mutations in genes expressed in the eye and the brain was used to study a kindred with an inherited retinal dystrophy due to RIMS1 mutation.Materials and methods
Neuropsychological tests and high‐resolution MRI brain scanning were undertaken in the kindred. In a population cohort, neuropsychological scores were associated with common variation in RIMS1. Additionally, RIMS1 was sequenced in top‐scoring individuals. Evolution of RIMS1 was assessed, and its expression in developing human brain was studied.Results
Affected individuals showed significantly enhanced cognitive abilities across a range of domains. Analysis suggests that factors other than RIMS1 mutation were unlikely to explain enhanced cognition. No association with common variation and verbal IQ was found in the population cohort, and no other mutations in RIMS1 were detected in the highest scoring individuals from this cohort. RIMS1 protein is expressed in developing human brain, but RIMS1 does not seem to have been subjected to accelerated evolution in man.Conclusions
A possible role for RIMS1 in the enhancement of cognitive function at least in this kindred is suggested. Although further work is clearly required to explore these findings before a role for RIMS1 in human cognition can be formally accepted, the findings suggest that genetic mutation may enhance human cognition in some cases.A genetic contribution to variation in human intelligence is well established, but the identities of the genes responsible remain elusive. Many mutations are associated with impaired cognition:1 no definite genetic causes of enhanced cognition are established,2 and there are no known cognition‐enhancing “gain‐of‐function” mutations in genes otherwise associated with cognitive impairment. Therapeutic possibilities deriving from the discovery of any such genes or variants are potentially important: cognitive decline reduces the quality of life,3 and low intelligence test scores are associated with increased morbidity and shorter life‐span.4 Accelerated evolution of genes subserving neurodevelopment figures in molecular explanations of the advance of the human nervous system: many of the identified genes regulate brain size and behaviour, some encoding critical synaptic proteins.5To identify genes influencing human brain development and function, including cognitive function, we use a paradigm evaluating cerebral structure and function in individuals with known mutations in genes co‐expressed in the lineage‐sharing eye and brain, ascertained by their obvious ocular phenotype, but in whom a neurological phenotype was not fully appreciated. Using this paradigm, we demonstrated roles for the genes PAX6, PITX2, SOX2 and OTX2 in human brain development, cognitive function and memory.6,7,8,9,10,11We now report on the functional and structural effects of mutation in the eye‐ and brain‐expressed gene RIMS1, through the study of individuals from a family already reported to have retinal dystrophy caused by RIMS1 mutation.12,13 To our knowledge, this is the only family so far reported with such a mutation: the eye phenotype is homogeneous in the family, and has been documented in detail.13 The orthologous murine Rim1α encodes a synaptic active‐zone protein necessary for preserving the normal probability of synaptic neurotransmitter release and for long‐term presynaptic potentiation.14,15Rim1α is also expressed in retinal ribbon synapses.16 Mice lacking Rim1α protein show severely impaired learning and memory.17 In our kindred, RIMS1 mutation (Arg844His) causes a late‐onset dominantly inherited cone–rod dystrophy (CORD7; OMIM 603649), leading to varying degrees of visual loss starting from the third decade onwards.13 Because RIMS1/Rim1α is also expressed in the brain, we hypothesised that this RIMS1 mutation would produce a structural and functional neurological phenotype. 相似文献948.
Owen RE Sinclair E Emu B Heitman JW Hirschkorn DF Epling CL Tan QX Custer B Harris JM Jacobson MA McCune JM Martin JN Hecht FM Deeks SG Norris PJ 《Journal of immunological methods》2007,326(1-2):93-115
Although cryopreservation of peripheral blood mononuclear cells (PBMC) is a commonly used technique, the degree to which it affects subsequent functional studies has not been well defined. Here we demonstrate that long-term cryopreservation has detrimental effects on T cell IFN-gamma responses in human immunodeficiency virus (HIV) infected individuals. Long-term cryopreservation caused marked decreases in CD4(+) T cell responses to whole proteins (HIV p55 and cytomegalovirus (CMV) lysate) and HIV peptides, and more limited decreases in CD8(+) T cell responses to whole proteins. These losses were more apparent in cells stored for greater than one year compared to less than six months. CD8(+) T cell responses to peptides and peptide pools were well preserved. Loss of both CD4(+) and CD8(+) T cell responses to CMV peptide pools were minimal in HIV-negative individuals. Addition of exogenous antigen presenting cells (APC) did not restore CD4(+) T cell responses to peptide stimulation and partially restored T cell IFN-gamma responses to p55 protein. Overnight resting of thawed cells did not restore T cell IFN-gamma responses to peptide or whole protein stimulation. A selective loss of phenotypically defined effector cells did not explain the decrement of responses, although cryopreservation did increase CD4(+) T cell apoptosis, possibly contributing to the loss of responses. These data suggest that the impact of cryopreservation should be carefully considered in future vaccine and pathogenesis studies. In HIV-infected individuals short-term cryopreservation may be acceptable for measuring CD4(+) and CD8(+) T cell responses. Long-term cryopreservation, however, may lead to the loss of CD4(+) T cell responses and mild skewing of T cell phenotypic marker expression. 相似文献
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