bluuebunny/crossref_metadata_2025 huggingface dataset:
The origin and evolution of human pathogens
Authors: Groisman Eduardo A. , Casadesús Josep
Published: March 2005

What are the genetic origins of human pathogens? An international group of scientists discussed this topic at a workshop that took place in late October 2004 in Baeza (Spain). Focusing primarily on bacterial pathogens, they examined the role that pathogenicity islands and bacteriophages play on determining the virulence properties that distinguish closely related members of a given species, such as host range and tissue specificity. They also discussed an instance in which closely related bacterial species differ in the production of a cell surface modification mediating resistance to an antibiotic as a result of the disparate regulation of homologous genes. In certain pathogens, genes normally carrying out housekeeping functions may adopt new functions, whereas in other organisms, genes that respond to stresses associated with non‐host environments are silenced during infection to prevent the expression of products that interfere with the normal colonization process. The adaptive behaviour of certain pathogens relies on gene variation at certain loci that by virtue of containing polymeric repeats in regulatory or coding regions, can generate variants that may or may not express products that modify the cell surface of the organism. The meeting also addressed the properties of ORFan genes, which have no homologues in the sequence databases, as well as the creation of genes de novo by duplication and divergence.
Efficacy of magnifying chromoendoscopy for the differential diagnosis of colorectal lesions
Authors: Sano Yasushi , Saito Yutaka , Fu Kuang‐I , Matsuda Takahisa , Uraoka Toshio , Kobayashi Nozomu , Ito Hiroaki , Machida Hirohisa , Iwasaki Junko , Emura Fabian , Hanafusa Masao , Yoshino Takayuki , Kato Shigeharu , Fujii Takahiro
Published: March 2005

Magnifying chromoendoscopy is an exciting new tool and offers detailed analysis of the morphological architecture of mucosal crypt orifices. In this review, we principally show the efficacy of magnifying chromoendoscopy for the differential diagnosis of colorectal lesions such as prediction between non‐neoplastic lesions and neoplastic ones, and distinction between endoscopically treatable early invasive cancers and untreatable cancers based on a review of the literature and our experience at two National Cancer Centers in Japan. Overall diagnostic accuracy by conventional view, chromoendoscopy and chromoendoscopy with magnification ranged from 68% to 83%, 82% to 92%, and 80% to 96%, respectively, and diagnostic accuracy of accessing the stage of early colorectal cancer using magnifying colonoscopy was over 85%. Although the reliability depends on the skill in magnifying observation, widespread applications of the magnification technique could influence the indications for biopsy sampling during colonoscopy and the indication for mucosectomy. Moreover, the new detailed images seen with magnifying chromoendoscopy are the beginning of a new period in which new optical developments, such as narrow band imaging system, endocytoscopy system, and laser‐scanning confocal microscopy, will allow a unique look at glandular and cellular structures.
Evaluation of clinical features of ischemic colitis: Comparison between young and elderly
Authors: Tohda Gen , Higashi Seiju , Sumiyoshi Ken‐Ichi , Sakumoto Hitoshi , Kato Chikako , Kane Teruyuki
Published: March 2005

Background: It has been thought that ischemic colitis is caused by vascular and intestinal factors. Although elderly patients with arteriosclerosis are more susceptible to ischemic colitis, many young patients suffering ischemic colitis are also reported. The present study aimed to clarify the relationship between arteriosclerosis and ischemic colitis, and to evaluate various risk factors for ischemic colitis.

Methods: We compared the clinical features of patients with ischemic colitis (54 cases) and control patients without ischemic colitis (86 cases), all diagnosed by colonoscopy. Subjects were classified into a young group (60 cases) under 60 years of age, and an elderly group (80 cases) of over 60 years. The degree of arteriosclerosis was measured by pulse wave velocity (PWV) level, and the effects of vascular and intestinal factors in the development of ischemic colitis were evaluated using multivariate analytical models.

Results: In the elderly group, the PWV level was significantly higher in ischemic colitis patients than in the controls. By analyzing with multivariate analytical models, a high level of PWV and underlying diseases related to arteriosclerosis were thought to be risk factors for ischemic colitis in the elderly group. In the young group, intestinal factors such as irregular bowel movement, which is often seen in irritable bowel syndrome, habitual constipation, and prior history of an abdominal operation, were thought to be contributors to ischemic colitis.

Conclusion: These findings suggest that intestinal factors in younger patients and vascular factors in more elderly patients are the primary contributors in the development of ischemic colitis.
Endoscopic variceal ligation of patients with liver cirrhosis and cirrhosis accompanied by hepatocellular carcinoma
Authors: Khien Vu Van , Bang Mai Hong , Lac Bui Van , Uemura Masayuki , Nouso Kazuhiro , Taketa Kazuhisa
Published: March 2005

Background:  Rupture of esophageal varices with severe gastrointestinal hemorrhage is one of the most serious complications of liver cirrhosis (LC) and hepatocellular carcinoma (HCC) complicating LC. The present study looks at the success of hemostasis in LC and LC accompanied by HCC, the success of breaking the varices cluster and the rate of rebleeding in patients of LC subject to emergency ligation and prophylactic ligation.

Methods: Seventy‐five patients were divided into three groups. Group 1: 30 patients with LC accompanied by HCC with digestive bleeding; group 2: 30 patients with LC with digestive bleeding; and group 3: 15 patients with LC with high risk of digestive bleeding from esophageal varices (with no medical history of digestive bleeding). Success of hemostasis 72 h after endoscopic variceal ligation (EVL) was that patients did not vomit blood nor produce black feces. The effectiveness of EVL for iradication of the variceal cluster was classified into three levels: good, fairly good and poor.

Results: The hemostasis success in group 1 (LC accompanied by HCC) and group 2 (LC with digestive bleeding due to esophageal varices) was 73.3% and 93.4%, respectively. The success of breaking the varix cluster in group 2 (LC) and group 3 (LC with high risk of digestive bleeding and treated by prophylactic ligation) was 73.3% and 80%, respectively. The rate of rebleeding in group 2 and group 3 after 1 year was 20% and 13.3%, respectively.

Conclusion: Endoscopic variceal ligation is a good technique for variceal hemostasis and eradication of the esophageal varices cluster.
Relationship between histopathological features and type V pit pattern determined by magnifying videocolonoscopy in early colorectal carcinoma
Authors: Oka Shiro , Tanaka Shinji , Nagata Shinji , Ito Masanori , Kitadai Yasuhiko , Shimamoto Fumio , Yosihara Masaharu , Chayama Kazuaki
Published: March 2005

Background: The aim of the present study was to clarify the relationship between the histopathological features and type V pit pattern of early colorectal carcinoma.

Methods: We examined the relationship between the type V pit pattern subtypes, the depth of submucosal invasion and the degrees of desmoplastic reaction, residual pit density and destruction of the intervening membrane between pits on the tumor surface in 135 cases of early colorectal carcinoma. The examinations involved magnifying videoendoscopy with indigo carmine dye spraying and crystal violet staining. The pit patterns were classified as one of two grades (VI, VN), and VN was further divided into three subtypes (A, B and C). The data obtained were evaluated by χ2 test, with significance accepted at < 0.05% for each analysis.

Results: There were 64 VI, 24 VN‐A, 28 VN‐B and 19 VN‐C lesions. The incidence of massive submucosal invasion (sm2, sm3) was significantly higher in VN‐B and VN‐C lesions than in VI and VN‐A lesions (P < 0.05). Among VN pit pattern lesions, depth of submucosal invasion of VN‐B and VN‐C lesions was significantly greater than that of VN‐A lesions (P < 0.01). The incidence of severe desmoplastic reaction in VN‐B and VN‐C lesions was significantly greater than that in VI lesions (P < 0.01). The incidence of severe desmoplastic reaction in VN‐C lesions was significantly greater than that in VN‐A lesions (P < 0.05). The incidence of low residual pit density in VN‐C lesions was significantly greater than that in all other type V lesions. The incidence of mild to moderate and severe destruction of the intervening membrane between pits in VN lesions was significantly higher than that in VI lesions.

Conclusions: Type V pit pattern subclassification is useful for predicting the depth of submucosal invasion in early colorectal carcinomas. The type V pit pattern subtypes are related to the degrees of desmoplastic reaction, the residual pit density and destruction of the intervening membrane between pits on the tumor surface.
Distinct properties of functional KCC2 expression in immature mouse hippocampal neurons in culture and in acute slices
Authors: Khirug Stanislav , Huttu Kristiina , Ludwig Anastasia , Smirnov Sergei , Voipio Juha , Rivera Claudio , Kaila Kai , Khiroug Leonard
Published: March 2005

A hallmark in the development of GABAergic neurotransmission is the switch in GABAA‐mediated responses from depolarizing to hyperpolarizing. This occurs due to a gradual decrease in the intracellular concentration of chloride caused by the functional expression of the neuron‐specific K‐Cl cotransporter KCC2. Whether a mere increase in the amount of KCC2 protein is the rate‐limiting step in vivo, or a further activation of the otherwise nonfunctional cotransporter is required, is not clear. Imposing a fixed Cl– load via patch pipette we measured the resultant somato‐dendritic gradients in reversal potential of GABAergic currents to determine the time course of functional maturation of KCC2‐mediated Cl– extrusion in two preparations: cultured mouse hippocampal neurons plated at embryonic day 17 and CA1 pyramidal cells in acute slices. We found that in immature neurons in both preparations the gradient is initially small or not detectable. It undergoes an abrupt increase at around days 13–14 in culture, while a more gradual increase occurs between postnatal days 5–14 in slices. Consistent with the presence of a nonfunctional form of KCC2 in immature hippocampal neurons grown in culture, application of the broad‐spectrum kinase inhibitor staurosporine produces a rapid and potent up‐regulation of KCC2 function in these cultured neurons, but not in neonatal slices. Taken together with our previously published data, these results indicate that the functional activity of KCC2 in vivo parallels the developmental expression of the protein, whereas cultured neurons require an additional activation step (mimicked by staurosporine) for KCC2 to become functional.
A combination drug therapy improves cognition and reverses gene expression changes in a mouse model of Huntington's disease
Authors: Morton A. Jennifer , Hunt Mark J. , Hodges Angela K. , Lewis Paul D. , Redfern Amanda J. , Dunnett Stephen B. , Jones Lesley
Published: March 2005

Huntington's disease is a genetic disease caused by a single mutation. It is characterized by progressive movement, emotional and cognitive deficits. R6/2 mice transgenic for exon 1 of the HD gene with 150+ CAG repeats have a progressive neurological phenotype, including deterioration in cognitive function. The mechanism underlying the cognitive deficits in R6/2 mice is unknown, but dysregulated gene expression, reduced neurotransmitter levels and abnormal synaptic function are present before the cognitive decline becomes pronounced. Our goal here was to ameliorate the cognitive phenotype in R6/2 mice using a combination drug therapy (tacrine, moclobemide and creatine) aimed at boosting neurotransmitter levels in the brain. Treatment from 5 weeks of age prevented deterioration in two different cognitive tasks until at least 12 weeks. However, motor deterioration continued unabated. Microarray analysis of global gene expression revealed that many genes significantly up‐ or down‐regulated in untreated R6/2 mice had returned towards normal levels after treatment, though a minority were further dysregulated. Thus dysregulated gene expression was reversed by the combination treatment in the R6/2 mice and probably underlies the observed improvements in cognitive function. Our study shows that cognitive decline caused by a genetic mutation can be slowed by a combination drug treatment, and gives hope that cognitive symptoms in HD can be treated.
The relationship between V6 and PO in macaque extrastriate cortex
Authors: Galletti Claudio , Gamberini Michela , Kutz Dieter F. , Baldinotti Ivan , Fattori Patrizia
Published: March 2005

The cerebral cortex of three macaque monkeys, electrophysiologically studied in chronic preparations in order to recognize functionally the medial parieto‐occipital area V6, was reconstructed using the software CARET. Locations of cells recorded from area V6 (n = 553) and from neighbouring cortical areas V2/V3 and V6A (n = 1341) were displayed on surface‐based reconstructions of individual brains, and on a surface‐based atlas of the macaque cerebral cortex. Results show that area V6 occupies the ventral part and fundus of the parieto‐occipital sulcus, as well as the ventral part of the precuneate cortex. V6 borders areas V2/V3 posteriorly and laterally, and area V6A anteriorly. The visualization of individual cases on a common template (atlas), and the use of atlas datasets, allowed us to compare data coming from different individuals and different laboratories. In particular, a comparison of the location and extent of the medial parieto‐occipital areas V6 and PO indicates that area PO occupies different locations according to different authors but in general includes parts of both areas V6 and V6A. We therefore suggest that the term V6 is a more appropriate designation of the visuotopically‐organized area located on the anterior wall of the parieto‐occipital sulcus.
A modified MPTP treatment regime produces reproducible partial nigrostriatal lesions in common marmosets
Authors: Iravani Mahmoud M. , Syed Emilie , Jackson Michael J. , Johnston Louisa C. , Smith Lance A. , Jenner Peter
Published: March 2005

Standard MPTP treatment regimens in primates result in > 85% destruction of nigral dopaminergic neurons and the onset of marked motor deficits that respond to known symptomatic treatments for Parkinson's disease (PD). The extent of nigral degeneration reflects the late stages of PD rather than events occurring at its onset. We report on a modified MPTP treatment regimen that causes nigral dopaminergic degeneration in common marmosets equivalent to that occurring at the time of initiation of motor symptoms in man. Subcutaneous administration of MPTP 1 mg/kg for 3 consecutive days caused a reproducible 60% loss of nigral tyrosine hydroxylase (TH)‐positive cells, which occurred mainly in the calbindin‐D28k‐poor nigrosomes with a similar loss of TH‐immunoreactivity (TH‐ir) in the caudate nucleus and the putamen. The animals showed obvious motor abnormalities with reduced bursts of activity and the onset of motor disability. However, the loss of striatal terminals did not reflect early PD because a greater loss of TH‐ir occurred in the caudate nucleus than in the putamen and a marked reduction in TH‐ir occurred in striatal patches compared to the matrix. Examination of striatal fibres following a partial MPTP lesion showed a conspicuous increase in the number and the diameter of large branching fibres in the putaminal and to some extent caudatal matrix, pointing to a possible compensatory sprouting of dopaminergic terminals. In addition, these partially lesioned animals did not respond to acute treatment with L‐DOPA. This primate partial lesions model may be useful for examining potential neuroprotective or neurorestorative agents for PD.
Inhibition of restraint stress‐induced neural and behavioural activation by endogenous cannabinoid signalling
Authors: Patel Sachin , Roelke Craig T. , Rademacher David J. , Hillard Cecilia J.
Published: March 2005

The role of endocannabinoid (eCB) signalling in restraint stress‐induced neuronal activation was studied. Male mice exposed to 30 min of restraint exhibit increased Fos protein within prefrontal cortex (PFC), lateral septum (LS), nucleus accumbens (Acb) and medial amygdala. SR141716 (2 mg/kg) itself had no effect on Fos but pretreatment with SR141716 significantly potentiated restraint‐induced Fos expression in cingulate, LS and Acb. SR141716 also significantly increased the time spent in active escape behaviours during the restraint. In restraint‐habituated mice (mice exposed to four previous restraint episodes), the fifth restraint exposure resulted in decreased expression of active escape behaviours compared to the first exposure and only induced Fos protein in the central and medial amygdala. Administration of SR141716 prior to the fifth restraint episode resulted in greater potentiation of restraint‐induced Fos induction than the first; significant increases occurred within all regions of PFC examined, LS and Acb. Brain regional eCB content was measured immediately after restraint. N‐arachidonylethanolamine content within the amygdala was significantly decreased after both restraint episodes. 2‐Arachidonylglycerol content was significantly increased in both the limbic forebrain and amygdala after the fifth restraint but not the first. Restraint had no effect on cerebellar eCB content. These data suggest that eCB activation of CB1 receptors opposes the behavioural and neuronal responses to aversive stimuli. Because repeated homotypic stress increased both limbic 2‐AG and resulted in a greater effect of SR141716 on limbic Fos expression, we hypothesize that increased CB1 receptor activity contributes to the expression of habituation to homotypic stress.
Neurons in monkey visual cortex detect lines defined by coherent motion of dots
Authors: Peterhans E. , Heider B. , Baumann R.
Published: March 2005

Form perception from coherent motion is an important aspect of vision. Representations of one‐, two‐ and three‐dimensional forms have been found at various stages of cortical processing using random‐dot stimuli, whereas representations of biological objects like a walking human being concentrate at higher stages of processing. The perception of biological objects can be induced by sparse dot stimuli that consist of a few dots that mark the joints of the human body [G. Johansson (1973) Percept. Psychophys., 14, 201–211]. In the present study, we aimed to investigate whether neurons in early visual areas that respond to bars and edges defined by luminance contrast also signal bar‐like objects from sparse dot stimuli. We studied single neurons with rows of 3–24 dots that were either collinear or scattered within a rectangular form. These dots were moved coherently on a uniform or dotted background, and human observers perceived them as rigid rods or other bar‐like objects. We found neurons in the visual cortex of the awake, behaving monkey that responded to these stimuli and were sensitive to the orientation of these objects as for conventional bars or edges. Stimulus conditions that failed to induce these percepts in human observers also evoked weaker responses or none in these neurons. We found these neurons with increasing frequency in areas V1, V2 and V3/V3A. The results suggest that the visual cortex not only detects biological objects, but also lines and other bar‐like objects from sparse dot stimuli, and that this function evolves at an early stage of processing.
Divergence and convergence of thalamocortical projections to premotor and supplementary motor cortex: a multiple tracing study in the macaque monkey
Authors: Morel Anne , Liu Jian , Wannier Thierry , Jeanmonod Daniel , Rouiller Eric M.
Published: March 2005

The premotor cortex of macaque monkeys is currently subdivided into at least six different subareas on the basis of structural, hodological and physiological criteria. To determine the degree of divergence/convergence of thalamocortical projections to mesial [supplementary motor area (SMA)‐proper and pre‐SMA] and lateral (PMd‐c, PMd‐r, PMv‐c and PMv‐r) premotor (PM) subareas, quantitative analyses were performed on the distribution of retrograde labelling after multiple tracer injections in the same animal. The results demonstrate that all PM and SMA subareas receive common inputs from several thalamic nuclei, but the relative contribution of these nuclei to thalamocortical projections differs. The largest difference occurs between subareas of SMA, with much greater contribution from the mediodorsal (MD) and area X, and a smaller contribution from the ventral lateral anterior (VLa) and ventral part of the ventral lateral posterior (VLpv) to pre‐SMA than to SMA‐proper. In PM, differences between subareas are less pronounced; in particular, all receive a significant contribution from MD, the ventral anterior (VApc) and area X. However, there are clear gradients, such as increasing projections from MD to rostral, from VLa and VLpv to caudal, and from dorsal VLp (VLpd) to dorsal premotor subareas. Intralaminar nuclei provide widespread projections to all premotor subareas. The degree of overlap between thalamocortical projections varies among different PM and SMA subareas and different sectors of the thalamus. These variations, which correspond to different origin and topography of thalamocortical projections, are discussed in relation to functional organizations at thalamic and cortical levels.
Stabilizing effects of extracellular ATP on synaptic efficacy and plasticity in hippocampal pyramidal neurons
Authors: Martín Eduardo D. , Buño Washington
Published: March 2005

The role of adenosine triphosphate (ATP) as a neurotransmitter and extracellular diffusible messenger has recently received considerable attention because of its possible participation in the regulation of synaptic plasticity. However, the possible contribution of extracellular ATP in maintaining and regulating synaptic efficacy during intracellular ATP depletion is understudied. We tested the effects of extracellular ATP on excitatory postsynaptic currents (EPSCs) evoked in CA1 pyramidal neurons by Schaffer collateral stimulation. In the absence of intracellular ATP, EPSC rundown was neutralized when a low concentration of ATP (1 µm) was added to the extracellular solution. Adenosine and ATP analogues did not prevent the EPSC rundown. The P2 antagonists piridoxal‐5′‐phosphate‐azophenyl 2′,4′‐disulphonate (PPADS) and reactive blue‐2, and the P1 adenosine receptor antagonist 8‐cyclopentyltheophylline (CPT) had no detectable effects in cells depleted of ATP. However, the protective action of extracellular ATP on synaptic efficacy was blocked by extracellular application of the protein kinase inhibitors K252b and staurosporine. In contrast, K252b and staurosporine per se did not interfere with synaptic transmission in ATP loaded cells. Without intracellular ATP, bath‐applied caffeine induced a transient (< 35 min) EPSC potentiation that was transformed into a persistent long‐term potentiation (> 80 min) when 1 µm ATP was added extracellularly. An increased probability of transmitter release paralleled the long‐term potentiation induced by caffeine, suggesting that it originated presynaptically. Therefore, we conclude that extracellular ATP may operate to maintain and regulate synaptic efficacy and plasticity in conditions of abnormal intracellular ATP depletion by phosphorylation of a surface protein substrate via activation of ecto‐protein kinases.
Modulation of synaptic transmission in neocortex by network activities
Authors: Crochet Sylvain , Chauvette Sylvain , Boucetta Sofiane , Timofeev Igor
Published: March 2005

Neocortical neurons integrate inputs from thousands of presynaptic neurons that fire in vivo with frequencies that can reach 20 Hz. An important issue in understanding cortical integration is to determine the actual impact of presynaptic firing on postsynaptic neuron in the context of an active network. We used dual intracellular recordings from synaptically connected neurons or microstimulation to study the properties of spontaneous and evoked single‐axon excitatory postsynaptic potentials (EPSPs) in vivo, in barbiturate or ketamine−xylazine anaesthetized cats. We found that active states of the cortical network were associated with higher variability and decrease in amplitude and duration of the EPSPs owing to a shunting effect. Moreover, the number of apparent failures markedly increased during active states as compared with silent states. Single‐axon EPSPs in vivo showed mainly paired‐pulse facilitation, and the paired‐pulse ratio increased during active states as compare to silent states, suggesting a decrease in release probability during active states. Raising extracellular Ca2+ concentration to 2.5–3.0 mm by reverse microdialysis reduced the number of apparent failures and significantly increased the mean amplitude of individual synaptic potentials. Quantitative analysis of spontaneous synaptic activity suggested that the proportion of presynaptic activity that impact at the soma of a cortical neuron in vivo was low because of a high failure rate, a shunting effect and probably dendritic filtering. We conclude that during active states of cortical network, the efficacy of synaptic transmission in individual synapses is low, thus safe transmission of information requires synchronized activity of a large population of presynaptic neurons.
Brief exposure to NMDA produces long‐term protection of cerebellar granule cells from apoptosis
Authors: Xifro Xavier , Malagelada Cristina , Miñano Alfredo , Rodríguez‐Álvarez José
Published: March 2005

Cerebellar granule cells (CGCs) require excitatory inputs to survive during their postnatal migration from the external to the internal granule cell layers. The lack of innervation of mossy fibres induces CGC death by apoptosis. In vitro, CGCs die by apoptosis in the presence of physiological concentrations of KCl (5 mm or K5) but they survive in the presence of depolarizing concentrations of KCl (25 mm or K25) or N‐methyl‐d‐aspartate (NMDA) by a mechanism dependent on calcium influx. The addition of NMDA or K25, for only 24 h, to immature CGCs cultures [2 days in vitro (DIV)] was able to produce a remarkable and long‐term protection until 8 DIV. Moreover, our data show that NMDA and K25‐mediated long‐lasting protection was related to an inhibition of caspase‐3 activity. By using different protein kinase inhibitors, we have shown that the inhibition of caspase‐3 activation by NMDA was dependent on the activation of tyrosine kinases and phosphatidylinositol 3‐kinase (PI3‐kinase). Moreover, an impairment in NMDA‐mediated neuroprotection and caspase‐3 inhibition was observed when the action of brain‐derived neurotrophic factor (BDNF) was blocked. By contrast, K25‐mediated neuroprotection was BDNF‐independent and was mediated by a mitogen‐activated protein kinase‐ and PI3‐kinase‐dependent inhibition of caspase‐3.
PDE10A inhibition reverses subchronic PCP‐induced deficits in attentional set‐shifting in rats
Authors: Rodefer Joshua S. , Murphy Emily R. , Baxter Mark G.
Published: March 2005

Persistent suppression of N‐methyl‐d‐aspartate (NMDA) receptor function produces enduring structural changes in neocortical and limbic regions in a pattern similar to changes reported in schizophrenia. This similarity suggests that chronic NMDA receptor antagonism in animals may represent a useful model of neurobiological and related cognitive deficits in schizophrenia. Schizophrenia is associated with impairments in frontal lobe‐dependent cognitive functions, including working memory and attentional shifting. Deficits in attention and executive function have not been well characterized in animal models of schizophrenia using chronic NMDA receptor antagonist administration. We investigated whether subchronic systemic administration of the NMDA receptor antagonist phencyclidine (PCP) to rats followed by a drug washout period would produce enduring cognitive deficits on an attentional set‐shifting task. The task is functionally analogous to a sensitive test of frontal function in humans and non‐human primates. Subchronic PCP administration selectively impaired extradimensional shift learning without affecting other discrimination or reversal tasks. Moreover, acute treatment with the PDE10A inhibitor papaverine immediately prior to testing attenuated the PCP‐induced deficits in extradimensional shift learning across a range of doses. These data suggest that subchronic PCP administration may model effectively some of the cognitive deficits that are observed in schizophrenia, and that PDE10A inhibition may be an effective therapeutic route to improve executive function deficits associated with schizophrenia.
SHORT COMMUNICATIONS: Increases in extracellular levels of 5‐HT and dopamine in the basolateral, but not in the central, nucleus of amygdala induced by aversive stimulation of the inferior colliculus
Authors: Macedo Carlos Eduardo , Martinez Raquel Chacon Ruiz , De Souza Silva Maria Angélica , Brandão Marcus Lira
Published: March 2005

Consistent evidence has shown that dopamine release in the prefrontal cortex is increased by electrical stimulation of the inferior colliculus (IC) as unconditioned stimulus. Recent reports have also demonstrated that inactivation of the basolateral nucleus of the amygdala (BLA) with muscimol enhances the behavioural consequences of the aversive stimulation of the IC and reduces the dopamine release in the prefrontal cortex. Moreover, neurotoxic lesions of the BLA enhance whereas those of the central nucleus of the amygdala (CeA) reduce the aversiveness of the electrical stimulation of the IC. Based on these findings the present study examined the effects of the electrical stimulation of the IC on the extracellular levels of serotonin and dopamine in the BLA and CeA. To this end, rats implanted with a stimulation electrode in the IC also bore a microdialysis probe in the BLA or CeA for determination of the release of dopamine and serotonin. IC electrical stimulation at the freezing and escape thresholds increased the levels of serotonin (≈ 70%) and dopamine (≈ 60%) in the BLA related to the basal values. Similarly, the metabolites DOPAC and 5‐HIAA increased in a parallel fashion in BLA. No significant changes could be detected in these biogenic amines and metabolites in CeA following IC aversive stimulation. These findings point to a differential role of serotonergic and dopaminergic mechanisms of the BLA and CeA in the setting up of adaptive responses to fear states generated at the inferior colliculus level.
Purkinje cell loss affects differentially the execution, acquisition and prepulse inhibition of skeletal and facial motor responses in Lurcher mice
Authors: Porras‐García Elena , Cendelin Jan , Domínguez‐del‐Toro Eduardo , Vožeh František , Delgado‐García José M.
Published: March 2005

Adult heterozygous Lurcher mice show a degeneration of almost all Purkinje cells and 90% of the granular cells of the cerebellum, resulting in ataxia or general deficits in motor coordination. These mice are therefore an excellent model for studying the role of the cerebellar cortex in motor performance, including the acquisition of new motor abilities. The performance of 3‐month‐old Lurcher mice was studied in various behavioural (fall, horizontal bar, rotating cylinder, and ladder), spatial orientation (water maze) and associative learning (eyelid classical conditioning) tasks and compared with that of wild‐type mice. Behavioural tasks indicated a deficit for motor abilities in Lurcher mice but with some adaptation to the tests and improvement in performance. Wild‐type and Lurcher mice performed swimming equally, but the latter learned the task significantly more slowly than the former. The late component of reflex blinks was smaller in amplitude and had a longer latency in Lurcher mice than in controls. Learning curves for Lurcher mice during classical conditioning of eyelid responses were similar to controls, but the amplitude of the learned response in Lurcher mice was significantly lower. The startle response to a severe tone was similar in both control and Lurcher mice but the latter were unable to produce prepulse inhibition. These results suggest that the cerebellar cortex is not indispensable for the performance of this complete set of skeletal and facial tasks, or for the acquisition of new motor abilities, but it is for the appropriate execution and adjustment of any of these motor activities.
The Dimensionality of Right‐Wing Authoritarianism: Lessons from the Dilemma between Theory and Measurement
Authors: Funke Friedrich
Published: March 2005

The RWA Scale (Altemeyer, 1981,1988,1996) is commonly regarded as the best measure of right‐wing authoritarianism. The one‐dimensional instrument assesses the covariation of three attitudinal clusters: authoritarian submission, authoritarian aggression, and conventionalism. The incongruence between the implicit conceptual dimensionality on the one hand and methodological operationalization on the other makes room for discussion about whether it would be advantageous to measure the 3 facets of RWA separately. I rely on three arguments: (1) confirmatory factor analyses showing that three‐dimensional scales fit the data better than the conventional one‐dimensional practice; (2) the dimensions showing a considerable interdimension discrepancy in their capability to explain validation criteria; and (3) the dimensions showing an intradimensional discrepancy which is dependent upon the research question. The argumentation is illustrated by empirical evidence from several Web‐based studies among German Internet users.
Authoritarianism as a Group Phenomenon
Authors: Stellmacher Jost , Petzel Thomas
Published: March 2005

A model of authoritarianism on a group level of analysis based on Duckitt's concept of authoritarianism is presented. This conceptualization is called group authoritarianism (GA), which is defined as the belief about the appropriate relationship that should exist between groups and their individual members. The process model of group authoritarianism connects traditional authoritarianism theories with the Social Identity Approach. According to this model group‐authoritarianism reflects the situation‐specific activation of an authoritarian disposition in group contexts. Thus, group authoritarianism provides a perspective according to which personality characteristics and general psychological mechanisms described by Social‐Identity Theory (SIT) and Self‐Categorization Theory (SCT) interact in predicting intergroup hostility and intergroup discrimination. This article describes the development of a group authoritarianism scale as well as an experimental study that tests the main assumption of the group authoritarianism process model. The results confirm the reliability and validity of the group authoritarianism scales and the main hypothesis of the group authoritarianism model.
Authoritarianism and Social Dominance in Western and Eastern Europe: The Importance of the Sociopolitical Context and of Political Interest and Involvement
Authors: Duriez Bart , Van Hiel Alain , Kossowska Malgorzata
Published: March 2005

The present study tests whether the magnitude of the relation between Right‐Wing Authoritarianism (RWA) and Social Dominance Orientation (SDO) is stable across and within cultures, whether their differential relations with value orientations and sociopolitical attitudes remain stable in spite of these possible differences, and whether their differential relations point to a different genesis. For these purposes, two student samples (total N = 684), three adult samples (total N = 553), and a political activist sample (N = 69) were gathered in Belgium, and one adult sample (N = 235) was collected in Poland. Both cross‐ and intracultural differences in the strength of the RWA‐SDO relation emerged. These can be attributed to specificities in sociopolitical context and differences in political socialization, interest, and involvement. In spite of these fluctuations, in the strength of the RWA‐SDO relation, regression analyses revealed high stability of the relation between RWA‐SDO and sociopolitical attitudes, and mediation analyses supported the hypothesis of their different genesis.
Ascent-Based Monte Carlo Expectation– Maximization
Authors: Caffo Brian S. , Jank Wolfgang , Jones Galin L.
Published: March 2005

The expectation–maximization (EM) algorithm is a popular tool for maximizing likelihood functions in the presence of missing data. Unfortunately, EM often requires the evaluation of analytically intractable and high dimensional integrals. The Monte Carlo EM (MCEM) algorithm is the natural extension of EM that employs Monte Carlo methods to estimate the relevant integrals. Typically, a very large Monte Carlo sample size is required to estimate these integrals within an acceptable tolerance when the algorithm is near convergence. Even if this sample size were known at the onset of implementation of MCEM, its use throughout all iterations is wasteful, especially when accurate starting values are not available. We propose a data-driven strategy for controlling Monte Carlo resources in MCEM. The algorithm proposed improves on similar existing methods by recovering EM's ascent (i.e. likelihood increasing) property with high probability, being more robust to the effect of user-defined inputs and handling classical Monte Carlo and Markov chain Monte Carlo methods within a common framework. Because of the first of these properties we refer to the algorithm as ‘ascent-based MCEM’. We apply ascent-based MCEM to a variety of examples, including one where it is used to accelerate the convergence of deterministic EM dramatically.
Scaling Limits for the Transient Phase of Local Metropolis–Hastings Algorithms
Authors: Christensen Ole F. , Roberts Gareth O. , Rosenthal Jeffrey S.
Published: March 2005

The paper considers high dimensional Metropolis and Langevin algorithms in their initial transient phase. In stationarity, these algorithms are well understood and it is now well known how to scale their proposal distribution variances. For the random-walk Metropolis algorithm, convergence during the transient phase is extremely regular—to the extent that the algo-rithm's sample path actually resembles a deterministic trajectory. In contrast, the Langevin algorithm with variance scaled to be optimal for stationarity performs rather erratically. We give weak convergence results which explain both of these types of behaviour and practical guidance on implementation based on our theory.
Model Determination for Categorical Data With Factor Level Merging
Authors: Dellaportas Petros , Tarantola Claudia
Published: March 2005

We deal with contingency table data that are used to examine the relationships between a set of categorical variables or factors. We assume that such relationships can be adequately described by the cond‘itional independence structure that is imposed by an undirected graphical model. If the contingency table is large, a desirable simplified interpretation can be achieved by combining some categories, or levels, of the factors. We introduce conditions under which such an operation does not alter the Markov properties of the graph. Implementation of these conditions leads to Bayesian model uncertainty procedures based on reversible jump Markov chain Monte Carlo methods. The methodology is illustrated on a 2×3×4 and up to a 4×5×5×2×2 contingency table.
Regularization and Variable Selection Via the Elastic Net
Authors: Zou Hui , Hastie Trevor
Published: March 2005

We propose the elastic net, a new regularization and variable selection method. Real world data and a simulation study show that the elastic net often outperforms the lasso, while enjoying a similar sparsity of representation. In addition, the elastic net encourages a grouping effect, where strongly correlated predictors tend to be in or out of the model together. The elastic net is particularly useful when the number of predictors (p) is much bigger than the number of observations (n). By contrast, the lasso is not a very satisfactory variable selection method in the p≫n case. An algorithm called LARS-EN is proposed for computing elastic net regularization paths efficiently, much like algorithm LARS does for the lasso.
14‐3‐3 epsilon modulates the stimulated secretion of endopeptidase 24.15
Authors: Carreño Flávia R. , Goñi Camila N. , Castro Leandro M. , Ferro Emer S.
Published: March 2005

Endopeptidase 24.15 (ep24.15: EC3.4.24.15), a secreted protein involved in peptide metabolism, is unusual in that it does not contain a signal peptide sequence. In this work, we describe the physical interaction between ep24.15 and 14‐3‐3 epsilon, one isoform of a family of ubiquitous phosphoserine/threonine‐scaffold proteins that organizes cell signaling and is involved in exocytosis. The interaction between ep24.15 and 14‐3‐3 epsilon increased following phosphorylation of ep24.15 at Ser644 by protein kinase A (PKA). The co‐localization of ep24.15 and 14‐3‐3 epsilon was increased by exposure of HEK293 cells (human embryonic kidney cells) to forskolin (10 µm). Overexpression of 14‐3‐3 epsilon in HEK293 cells almost doubled the secretion of ep24.15 stimulated by A23187 (7.5 µm) from 10%[1.4 ± 0.24 AFU/(min 106 cells)] to 19%[2.54 ± 0.24 AFU/(min 106 cells)] (p < 0.001) of the total intracellular enzyme activity. Treatment with forskolin had a synergistic effect on the A23187‐stimulated secretion of ep24.15 that was totally blocked by the PKA inhibitor KT5720. The ep24.15 point mutation S644A reduced the co‐localization of ep24.15 and 14‐3‐3 in stably transfected HEK293 cells. Indeed, secretion of the ep24.15 S644A mutant from these cells was only slightly stimulated by A23187 and insensitive to forskolin, in contrast to that of the wild type enzyme. Together, these data suggest that prior interaction with 14‐3‐3 is an important step in the unconventional stimulated secretion of ep24.15.
Dopamine D1 receptor interaction with arrestin3 in neostriatal neurons
Authors: Macey Tara A. , Liu Yong , Gurevich Vsevolod V. , Neve Kim A.
Published: March 2005

Dopamine D1 receptor interactions with arrestins have been characterized using heterologously expressed D1 receptor and arrestins. The purpose of this study was to investigate the interaction of the endogenous D1 receptor with endogenous arrestin2 and 3 in neostriatal neurons. Endogenous arrestin2 and 3 in striatal homogenates bound to the C‐terminus of the D1 receptor in a glutathione‐S‐transferase (GST) pulldown assay, with arrestin3 binding more strongly. The D1 C‐terminus and, to a lesser extent, the third cytoplasmic loop also bound purified arrestin2 and 3. In neostriatal neurons, 2, 5, and 20 min agonist treatment increased the colocalization of the D1 receptor and arrestin3 immunoreactivity without altering the colocalization of the D1 receptor and arrestin2. Further, agonist treatment for 5 and 20 min caused translocation of arrestin3, but not arrestin2, to the membrane. The binding of arrestin3, but not arrestin2, to the D1 receptor was increased as assessed by coimmunoprecipitation after agonist treatment for 5 and 20 min. Agonist treatment of neurons induced D1 receptor internalization (35–45%) that was maximal within 2–5 min, a time‐course similar to that of the increase in colocalization of the D1 receptor with arrestin3. These data indicate that the D1 receptor preferentially interacts with arrestin3 in neostriatal neurons.
Up‐regulation of neuropeptide Y levels and modulation of glutamate release through neuropeptide Y receptors in the hippocampus of kainate‐induced epileptic rats
Authors: Silva Ana P. , Xapelli Sara , Pinheiro Paulo S. , Ferreira Raquel , Lourenço Joana , Cristóvão Armando , Grouzmann Eric , Cavadas Cláudia , Oliveira Catarina R. , Malva João O.
Published: March 2005

Kainate‐induced epilepsy has been shown to be associated with increased levels of neuropeptide Y (NPY) in the rat hippocampus. However, there is no information on how increased levels of this peptide might modulate excitation in kainate‐induced epilepsy. In this work, we investigated the modulation of glutamate release by NPY receptors in hippocampal synaptosomes isolated from epileptic rats. In the acute phase of epilepsy, a transient decrease in the efficiency of NPY and selective NPY receptor agonists in inhibiting glutamate release was observed. Moreover, in the chronic epileptic hippocampus, a decrease in the efficiency of NPY and the Y2 receptor agonist, NPY13‐36, was also found. Simultaneously, we observed that the epileptic hippocampus expresses higher levels of NPY, which may account for an increased basal inhibition of glutamate release. Consistently, the blockade of Y2 receptors increased KCl‐evoked glutamate release, and there was an increase in Y2 receptor mRNA levels 30 days after kainic acid injection, suggesting a basal effect of NPY through Y2 receptors. Taken together, these results indicate that an increased function of the NPY modulatory system in the epileptic hippocampus may contribute to basal inhibition of glutamate release and control hyperexcitability.
Multiple pathways of apolipoprotein E signaling in primary neurons
Authors: Hoe Hyang‐Sook , Harris D. Christopher , Rebeck G. William
Published: March 2005

Apolipoprotein E is a genetic risk factor for Alzheimer's disease, and the apoE protein is associated with β‐amyloid deposits in Alzheimer's disease brain. We examined signaling pathways stimulated by apoE in primary neurons in culture. ApoE and an apoE‐derived peptide activated several intracellular kinases, including prominently extracellular signal‐regulated kinase 1/2 (ERK1/2). ERK1/2 activation by apoE was blocked by an inhibitor of the low‐density lipoprotein receptor family, the specific NMDA glutamate receptor antagonist MK 801 and other calcium channel blockers. Activation of apoE receptors also induced tyrosine phosphorylation of Dab1, an adaptor protein of apoE receptors, but experiments in Dab1 knockout neurons demonstrated that Dab1 was not necessary for ERK activation. In contrast, apoE treatment of primary neurons decreased activation of c‐Jun N‐terminal kinase, a kinase that interacts with another apoE receptor adaptor protein, c‐Jun N‐terminal kinase‐interacting protein. This change also depended on interactions with the low‐density lipoprotein receptor family but was independent of calcium channels. c‐Jun N‐terminal kinase deactivation by apoE was blocked by γ‐secretase inhibitors and pertussis toxin. These results demonstrate that apoE affects several signaling cascades in neurons: increased disabled phosphorylation, activation of the ERK1/2 pathway (dependent on calcium influx via the NMDA receptor) and inhibition of the c‐Jun N‐terminal kinase 1/2 pathway (dependent on γ‐secretase and G proteins).