bluuebunny/crossref_metadata_2025 huggingface dataset:
Meaningful Acts: Terrorists, Artists, and States
Authors: Torres Sonia
Published: March 2006

Terrorism is not a novelty. As Chomsky points out, the term came into use at the end of the eighteenth century, and referred to violent acts of governments with the intent to ensure popular submission. One need only remember the reign of terror, whose social cement was force and cruelty, in which the Illu‐minist ideals of the French Revolution seemed to have been defeated. In con‐temporary Western societies, terrorism has come to be associated mainly with what Chomsky calls “retail terrorism,” by individuals or groups (as opposed to the “wholesale terrorism” of governments).1 What are the different forms of conceiving the term, in the last quarter of a century? The following dictionary entries on terror/terrorism, as well as the most recurrent definitions provided by terrorism scholars and state institutions, are worthy of highlighting:

Terrorism: System of governing through terror, or by means of violent revolutions.2

Terrorism: 1. Means of coercing, threatening, or influencing other people, or of imposing a will upon them through the systematic deployment of terror; 2. form of political action that combats the established power by violent means.3

Terrorism: 1. The act of terrorizing; use of force or threat to demoralize, intimidate, and subjugate, esp. such use as a political weapon or policy; 2. the demoralization and intimidation produced in this way. Syn. Disorder; lawlessness; murder; nihilism.4

The unlawful use of force or violence against persons or property to intimidate or coerce a government, the civilian population, or any segment thereof, in furtherance of political or social objectives. (FBI)5

Premeditated, politically motivated violence perpetuated against noncombatant targets by subnational groups or clandestine agents, usually intended to influence an audience. (U.S. Department of State)6

Terrorism is a symbolic act designed to influence political behavior by extranormal means, entailing the use or threat of violence.7

Terrorism, in the most widely accepted contemporary usage of the term, is fundamentally and inherently political. It is also ineluctably about power: the pursuit of power, the acquisition of power, and the use of power to achieve political change.8
Christian Peacemaker Teamsasan Alternativeto“Redemptive Violence”1
Authors: Satterwhite James
Published: March 2006

This article examines the theoretical assumptions underlying the creation and activity of the Christian Peacemaker Teams (CPT). It compares CPT with other, similar initiatives, then explores the way in which CPT developed out of an evolving Mennonite peace theology to represent a significant new embodiment of that theology. The article further examines the way in which CPT is meant to embody a nonviolent way of intervention in conflict situations that undercuts the assumption that violence is the only approach that “works” (the “myth of redemptive violence”). Finally, the question is raised as to what sustains CPT persons engaged in nonviolent intervention when often by its very nature such intervention does not bring about im‐mediate, measurable “results”.
Shipping and economic development in nineteenth‐century Ireland1
Authors: SOLAR PETER M.
Published: March 2006

The tonnage of shipping entering and leaving Ireland grew rapidly from the late eighteenth century until the mid‐1870s, after which there was a distinct slowdown. The mid‐nineteenth century was notable for a five‐fold increase in shipping per capita, an indicator of the Irish economy’s increasing commercialization. The slowdown after 1870 would have been even greater without the industrial dynamism of Belfast, Ireland’s leading port from the 1880s. The early and rapid introduction of steamships from the 1820s made possible large‐scale exports of live animals and fresh eggs, products that would account for 60 per cent of agricultural exports and a quarter of total exports by 1910.
Canalization and developmental stability in the Brachyrrhine mouse
Authors: Willmore Katherine Elizabeth , Zelditch Miriam Leah , Young Nathan , Ah‐Seng Andrew , Lozanoff Scott , Hallgrímsson Benedikt
Published: March 2006

The semi‐dominantBrmutation affects presphenoid growth, producing the facial retrognathism and globular neurocranial vault that characterize heterozygotes. We analysed the impact of this mutation on skull shape, comparing heterozygotes to wildtype mice, to determine if the effects are skull‐wide or confined to the sphenoid region targeted by the mutation. In addition, we examined patterns of variability of shape for the skull as a whole and for three regions (basicranium, face and neurocranium). We found that theBrmice differed significantly from wildtype mice in skull shape in all three regions as well as in the shape of the skull as a whole. However, the significant increases in variance and fluctuating asymmetry were found only in the basicranium of mutant mice. These results suggest that the mutation has a significant effect on the underlying developmental architecture of the skull, which produces an increase in phenotypic variability that is localized to the anatomical region in which the mean phenotype is most dramatically affected. These results suggest that the same developmental mechanisms that produce the change in phenotypic mean also produce the change in variance.
Effects of increased nerve growth factor plasma levels on the expression of TrkA and p75NTRin rat testicles
Authors: Levanti M. B. , Germanà A. , de Carlos F. , Ciriaco E. , Vega J. A. , Germanà G.
Published: March 2006

In addition to their well‐known roles within the nervous system, the neurotrophins and their receptors regulate some functions in the reproductive system. In this study we used combined morphological and immunohistochemical techniques to investigate the presence and cellular localization in the rat testicle of the two receptors of nerve growth factor (NGF), i.e. TrkA and p75NTR. Furthermore, to evaluate whether increased plasma levels of NGF affect the ageing process, 4‐methylcathechol (4‐MC), an inductor of NGF synthesis, was administered. Both TrkA and p75NTRwere expressed in rat testicles, but the pattern and intensity of immunoreaction were marginally different between them. In adult rats TrkA was expressed in spermatozoa and spermatids, and p75 was expressed in spermatogonia. In newborn rats TrkA immunoreactivity was found in the Leydig cells, whereas p75 was detected in a cellular layer that surrounds the seminiferous tubules. In adult treated animals the immunoreaction for TrkA and p75NTRwas also localized in the spermatocytes, whereas in newborn treated rats no changes in the pattern of immunoreaction was observed. The present findings suggest a role of the NGF/TrkA/p75 system in the physiology of reproduction, but the practical relevance of this remains to be established.
The functional anatomy of the iliotibial band during flexion and extension of the knee: implications for understanding iliotibial band syndrome
Authors: Fairclough John , Hayashi Koji , Toumi Hechmi , Lyons Kathleen , Bydder Graeme , Phillips Nicola , Best Thomas M. , Benjamin Mike
Published: March 2006

Iliotibial band (ITB) syndrome is a common overuse injury in runners and cyclists. It is regarded as a friction syndrome where the ITB rubs against (and ‘rolls over’) the lateral femoral epicondyle. Here, we re‐evaluate the clinical anatomy of the region to challenge the view that the ITB moves antero‐posteriorly over the epicondyle. Gross anatomical and microscopical studies were conducted on the distal portion of the ITB in 15 cadavers. This was complemented by magnetic resonance (MR) imaging of six asymptomatic volunteers and studies of two athletes with acute ITB syndrome. In all cadavers, the ITB was anchored to the distal femur by fibrous strands, associated with a layer of richly innervated and vascularized fat. In no cadaver, volunteer or patient was a bursa seen. The MR scans showed that the ITB was compressed against the epicondyle at 30° of knee flexion as a consequence of tibial internal rotation, but moved laterally in extension. MR signal changes in the patients with ITB syndrome were present in the region occupied by fat, deep to the ITB. The ITB is prevented from rolling over the epicondyle by its femoral anchorage and because it is a part of the fascia lata. We suggest that it creates the illusion of movement, because of changing tension in its anterior and posterior fibres during knee flexion. Thus, on anatomical grounds, ITB overuse injuries may be more likely to be associated with fat compression beneath the tract, rather than with repetitive friction as the knee flexes and extends.
Structural and functional anatomy of the neck musculature of the dog (Canis familiaris)
Authors: Sharir Amnon , Milgram Joshua , Shahar Ron
Published: March 2006

The morphometric properties and the anatomical relationships of the entire musculature of the canine cervical spine are reported herein. These data were obtained from the dissection of cadavers of six dogs. Total muscle length, muscle weight, fascicle length and angles of pennation were recorded for each muscle comprising the canine cervical spine. Based upon these properties, physiological cross‐section area (PCSA) and architectural index were estimated. When scaled by whole body mass, the values of each of these parameters were found to be similar between all dogs. Muscles that course from the cranial neck to the shoulder girdle or the rib cage (e.g. brachiocephalicus and rhomboideus capitis) were found to have relatively long fascicles and low PCSA values and thus appear to be designed for rapid excursions. By contrast, muscles that primarily support the neck and shoulder against gravitational forces (e.g. serratus ventralis and trapezius) were found to have relatively high PCSA values and short fascicle lengths, and thus have the capacity to generate large forces. Differences of morphometry as well as nomenclature were found between the canine and human neck musculature. Nevertheless, many similarities exist; in particular, both species have similar muscles adapted to force generation or large excursions. We thus conclude that the canine neck may be used as a modelling tool for biomechanical investigations of the human cervical region as long as the differences listed are borne in mind.
Insight into the evolution of avian flight from a new clade of Early Cretaceous ornithurines from China and the morphology of Yixianornis grabaui
Authors: Clarke Julia A. , Zhou Zhonghe , Zhang Fucheng
Published: March 2006

In studies of the evolution of avian flight there has been a singular preoccupation with unravelling its origin. By contrast, the complex changes in morphology that occurred between the earliest form of avian flapping flight and the emergence of the flight capabilities of extant birds remain comparatively little explored. Any such work has been limited by a comparative paucity of fossils illuminating bird evolution near the origin of the clade of extant (i.e. ‘modern’) birds (Aves). Here we recognize three species from the Early Cretaceous of China as comprising a new lineage of basal ornithurine birds. Ornithurae is a clade that includes, approximately, comparatively close relatives of crown clade Aves (extant birds) and that crown clade. The morphology of the best‐preserved specimen from this newly recognized Asian diversity, the holotype specimen of Yixianornis grabaui Zhou and Zhang 2001, complete with finely preserved wing and tail feather impressions, is used to illustrate the new insights offered by recognition of this lineage. Hypotheses of avian morphological evolution and specifically proposed patterns of change in different avian locomotor modules after the origin of flight are impacted by recognition of the new lineage. The complete articulated holotype specimen of Yixianornis grabaui, from the Early Cretaceous Jiufotang Formation of Liaoning Province, in north‐eastern China, arguably the best‐preserved basal ornithurine specimen yet discovered, provides the earliest evidence consistent with the presence of extant avian tail feather fanning.
Homology of the reptilian coracoid and a reappraisal of the evolution and development of the amniote pectoral apparatus
Authors: Vickaryous Matthew K. , Hall Brian K.
Published: March 2006

As in monotreme mammals, the pectoral apparatus of basal (fossil) amniotes includes two coracoid elements, the procoracoid and metacoracoid. Among extant reptiles the metacoracoid has long been assumed lost; this notion is herein challenged. A comprehensive review of data from numerous sources, including the fossil record, experimental embryology, genetic manipulations and an analysis of morphology at the level cell condensations, supports the conclusion that the metacoracoid gives rise to the majority of the reptilian coracoid. By contrast, the reptilian procoracoid remains as a rudiment that is incorporated as a process of the (meta)coracoid and/or the glenoid region of the scapula early during development, prior to skeletogenesis. Application of this integrated approach corroborates and enhances previous work describing the evolution of the pectoral apparatus in mammals. A revised scenario of amniote coracoid evolution is presented emphasizing the importance of considering cell condensations when evaluating the homology of a skeletal complex.
Oestrogen receptor subtype‐specific repression of calpain expression and calpain enzymatic activity in neuronal cells – implications for neuroprotection against Ca2+‐mediated excitotoxicity
Authors: Gamerdinger Martin , Manthey Dieter , Behl Christian
Published: March 2006

Calpains represent a superfamily of Ca2+‐activated cysteine‐proteases, which are important mediators of apoptosis and necrosis. In the brain, m‐calpain and µ‐calpain, the two ubiquitous calpain‐isoforms, are strongly activated in neurones after an excitotoxic Ca2+ influx occurring, for example, during cerebral ischemia. Because oestrogen and its receptors (ERα/ERβ) can exert neuroprotective activity, we investigated their influence on expression of calpains and their endogenous inhibitor, calpastatin. We found that ectopic expression of ERα in human neuroblastoma SK‐N‐MC cells led to a ligand‐independent constitutive down‐regulation of m‐calpain accompanied by an up‐regulation of µ‐calpain expression. Up‐regulation of µ‐calpain was reversed in the presence of oestrogen, which, in turn, could be blocked by co‐treatment with the oestrogen‐receptor antagonist ICI 182 780. Expression of calpastatin was not altered, either in the absence or in the presence of oestrogen. Additional studies revealed that ERα‐expressing cells exhibited decreased calpain enzymatic activity and increased survival when cells were exposed to the Ca2+ ionophore, ionomycin. Since all investigated effects could be observed exclusively in the presence of ERα, but not ERβ, and since the effects are reduced when ERα and ERβ are co‐expressed, our data suggest a novel ER subtype‐specific neuroprotective action by repressing calpain expression and calpain activity under conditions of a massive Ca2+ influx.
The “ins” and “outs” of the high‐affinity choline transporter CHT1
Authors: Ribeiro Fabiola M. , Black Stefanie A. G. , Prado Vania F. , Rylett R. Jane , Ferguson Stephen S. G. , Prado Marco A. M.
Published: March 2006

Maintenance of acetylcholine (ACh) synthesis depends on the activity of the high‐affinity choline transporter (CHT1), which is responsible for the reuptake of choline from the synaptic cleft into presynaptic neurons. In this review, we discuss the current understanding of mechanisms involved in the cellular trafficking of CHT1. CHT1 protein is mainly found in intracellular organelles, such as endosomal compartments and synaptic vesicles. The presence of CHT1 at the plasma membrane is limited by rapid endocytosis of the transporter in clathrin‐coated pits in a mechanism dependent on a dileucine‐like motif present in the carboxyl‐terminal region of the transporter. The intracellular pool of CHT1 appears to constitute a reserve pool of transporters, important for maintenance of cholinergic neurotransmission. However, the physiological basis of the presence of CHT1 in intracellular organelles is not fully understood. Current knowledge about CHT1 indicates that stimulated and constitutive exocytosis, in addition to endocytosis, will have major consequences for regulating choline uptake. Future investigations of CHT1 trafficking should elucidate such regulatory mechanisms, which may aid in understanding the pathophysiology of diseases that affect cholinergic neurons, such as Alzheimer's disease.
Specific regulation of rat glial cell line‐derived neurotrophic factor gene expression by riluzole in C6 glioma cells
Authors: Caumont Anne‐Sophie , Octave Jean‐Noël , Hermans Emmanuel
Published: March 2006

Contrasting with its robust expression during embryogenesis, the glial cell line‐derived neurotrophic factor (GDNF) is repressed in the adult organism. However, rapid induction of this neuronal growth factor is observed following diverse neuronal insults and it is now widely accepted that the control of its expression could constitute a powerful target in neuropharmacology. We investigated the effects of the neuroprotective drug, riluzole, on the GDNF gene expression in glial cells. Exposure of C6 glioma cells to riluzole (1 µm) significantly increased GDNF protein and mRNA levels. Using luciferase reporter gene constructs encoding fragments of the 5′ untranslated region of the rat GDNF gene, we demonstrated that riluzole mediates its effect at the transcription level. Furthermore, luciferase assays revealed the presence of a negative regulatory region within the +343/+587 region of exon 1. This region was shown to contribute to the high sensitivity and specificity of the induction mediated by riluzole in the C6 glioma cell line at pharmacologically relevant concentrations. The effects of riluzole were inhibited by the mitogen‐activated protein kinase extracellular signal‐related kinase (MEK) inhibitor PD 98059. Together, these results indicated that the induction of GDNF release by riluzole in the C6 glioma cells results from the activation of its corresponding gene promoter through a signalling pathway involving MEK activity. This study suggests that the regulation of GDNF gene transcription in glial cells could contribute to the pharmacological properties of riluzole and possibly other neuroprotective drugs.
Gene expression is differentially regulated by neurotransmitters in embryonic neuronal cortical culture
Authors: Ghiani Cristina A. , Lelievre Vincent , Beltran‐Parrazal Luis , Sforza Daniel M. , Malvar Jemily , Smith Desmond J. , Charles Andrew C. , Ferchmin Pedro A. , de Vellis Jean
Published: March 2006

Neurotransmitters and their receptors have been involved in both proper brain development and neurodevelopmental disorders. The role that nicotinic receptors play in immature cortical neurons was initially investigated by gene profiling using Affymetrix DNA arrays. Both short (15 min) and prolonged (18 h) treatments with nicotine did not induce modification in gene expression, whereas a significant down‐regulation of c‐fos protein levels was observed after 18 h treatment. Conversely, a brief treatment with the glutamatergic agonist NMDA triggered up‐regulation of immediate early genes and transcription factors, which remained unaffected by pre‐treatment for 18 h with nicotine. Calcium imaging studies revealed that NMDA activated a sustained increase in intracellular calcium concentration in the majority of neurons, whereas nicotine evoked only a transient calcium increase in a smaller percentage of neurons, suggesting that the calcium signalling response was correlated with activation of gene expression. Nicotine effects on immature cortical neurons perhaps do not require gene regulation but may be still acting on signalling pathways.
High susceptibility of neural stem cells to methylmercury toxicity: effects on cell survival and neuronal differentiation
Authors: Tamm Christoffer , Duckworth Joshua , Hermanson Ola , Ceccatelli Sandra
Published: March 2006

Neural stem cells (NSCs) play an essential role in both the developing embryonic nervous system through to adulthood where the capacity for self‐renewal may be important for normal function of the CNS, such as in learning, memory and response to injury. There has been much excitement about the possibility of transplantation of NSCs to replace damaged or lost neurones, or by recruitment of endogenous precursors. However, before the full potential of NSCs can be realized, it is essential to understand the physiological pathways that control their proliferation and differentiation, as well as the influence of extrinsic factors on these processes. In the present study we used the NSC line C17.2 and primary embryonic cortical NSCs (cNSCs) to investigate the effects of the environmental contaminant methylmercury (MeHg) on survival and differentiation of NSCs. The results show that NSCs, in particular cNSCs, are highly sensitive to MeHg. MeHg induced apoptosis in both models via Bax activation, cytochrome c translocation, and caspase and calpain activation. Remarkably, exposure to MeHg at concentrations comparable to the current developmental exposure (via cord blood) of the general population in many countries inhibited spontaneous neuronal differentiation of NSCs. Our studies also identified the intracellular pathway leading to MeHg‐induced apoptosis, and indicate that NSCs are more sensitive than differentiated neurones or glia to MeHg‐induced cytotoxicity. The observed effects of MeHg on NSC differentiation offer new perspectives for evaluating the biological significance of MeHg exposure at low levels.
Functional and molecular identification of sodium‐coupled dicarboxylate transporters in rat primary cultured cerebrocortical astrocytes and neurons
Authors: Yodoya Etsuo , Wada Miyuki , Shimada Ayumi , Katsukawa Hiromi , Okada Naoki , Yamamoto Akira , Ganapathy Vadivel , Fujita Takuya
Published: March 2006

Na+‐coupled carboxylate transporters (NaCs) mediate the uptake of tricarboxylic acid cycle intermediates in mammalian tissues. Of these transporters, NaC3 (formerly known as Na+‐coupled dicarboxylate transporter 3, NaDC3/SDCT2) and NaC2 (formerly known as Na+‐coupled citrate transporter, NaCT) have been shown to be expressed in brain. There is, however, little information available on the precise distribution and function of both transporters in the CNS. In the present study, we investigated the functional characteristics of Na+‐dependent succinate and citrate transport in primary cultures of astrocytes and neurons from rat cerebral cortex. Uptake of succinate was Na+ dependent, Li+ sensitive and saturable with a Michaelis constant (Kt) value of 28.4 µm in rat astrocytes. Na+ activation kinetics revealed that the Na+ to succinate stoichiometry was 3 : 1 and the concentration of Na+ necessary for half‐maximal transport was 53 mm. Although uptake of citrate in astrocytes was also Na+ dependent and saturable, its Kt value was significantly higher (∼ 1.2 mm) than that of succinate. Unlabeled succinate (2 mm) inhibited Na+‐dependent [14C]succinate (18 µm) and [14C]citrate (4.5 µm) transport completely, whereas unlabeled citrate inhibited Na+‐dependent [14C]succinate uptake more weakly. Interestingly, N‐acetyl‐l‐aspartate, which is the second most abundant amino acid in the nervous system, also completely inhibited Na+‐dependent succinate transport in rat astrocytes. The inhibition constant (Ki) for the inhibition of [14C]succinate uptake by unlabeled succinate, N‐acetyl‐l‐aspartate and citrate was 15.9, 155 and 764 µm respectively. In primary cultures of neurons, uptake of citrate was also Na+ dependent and saturable with a Kt value of 16.2 µm, which was different from that observed in astrocytes, suggesting that different Na+‐dependent citrate transport systems are expressed in neurons and astrocytes. RT–PCR and immunocytochemistry revealed that NaC3 and NaC2 are expressed in cerebrocortical astrocytes and neurons respectively. These results are in good agreement with our previous reports on the brain distribution pattern of NaC2 and NaC3 mRNA using in situ hybridization. This is the first report of the differential expression of different NaCs in astrocytes and neurons. These transporters might play important roles in the trafficking of tricarboxylic acid cycle intermediates and related metabolites between glia and neurons.
Transcranial magnetic stimulation attenuates cell loss and oxidative damage in the striatum induced in the 3‐nitropropionic model of Huntington's disease
Authors: Túnez Isaac , Drucker‐Colín René , Jimena Ignacio , Medina Francisco J. , del Carmen Muñoz Maria , Peña José , Montilla Pedro
Published: March 2006

An investigation was conducted on the effect of transcranial magnetic field stimulation (TMS) on the free radical production and neuronal cell loss produced by 3‐nitropropionic acid in rats. The effects of 3‐nitropropionic acid were evaluated by examining the following changes in: the quantity of hydroperoxides and total radical‐trapping antioxidant potential (TRAP), lipid peroxidation products, protein carbonyl groups, reduced glutathione (GSH) content, glutathione peroxidase (GSH‐Px), catalase and succinate dehydrogenase (SDH) activities; total nitrite and cell death [morphological changes, quantification of neuronal loss and lactate dehydrogenase (LDH) levels]. Our results reveal that 3‐nitropropionic acid induces oxidative and nitrosative stress in the striatum, prompts cell loss and also shows that TMS prevents the harmful effects induced by the acid. In conclusion, the results show the ability of TMS to modify neuronal response to 3‐nitropropionic acid.
Protective effect of a synthetic anti‐oxidant on neuronal cell apoptosis resulting from experimental hypoxia re‐oxygenation injury
Authors: Rayner Ben S. , Duong T. T. Hong , Myers Simon J. , Witting Paul K.
Published: March 2006

Oxidative stress is associated with the pathology of acute and chronic neurodegenerative disease. Cultured neuronal cells exposed to hypoxia‐reoxygenation (H/R) injury, as a model for stroke, yield a burst of reactive oxygen species (ROS) as measured with electron paramagnetic resonance (EPR) spectroscopy in combination with spin trapping. Added superoxide dismutase inhibited spin‐adduct formation verifying that superoxide radical anion was formed in neuronal cells following H/R injury. The intracellular ADP/ATP ratio increased rapidly over the first 5 h following injury and this was due primarily to the decreased cellular pools of ATP, consistent with the notion that H/R promotes mitochondrial dysfunction leading to decreased ATP reserve and increased ROS formation. As an early response to the enhanced oxidative stress, genes encoding for hypoxia‐inducible factor 1‐α (HIF1‐α), inducible haemoxygenase‐1 (HO‐1), and the oxygen‐sensor neuroglobin increased significantly. Up‐regulation of the HO‐1 gene was paralleled by increased HO protein expression and activity. Despite this cellular response, apoptosis increased significantly following H/R injury indicating that the endogenous anti‐oxidant defenses were unable to protect the cells. In contrast, addition of a phenolic anti‐oxidant, bisphenol (BP), prior to H/R injury, inhibited ROS production and gene regulation and significantly decreased neuronal cell apoptosis. Added BP was converted stoichiometrically to the corresponding diphenoquinone indicating the synthetic anti‐oxidant effectively decreased oxidative stress through a radical scavenging mechanism. Together, these data indicate that BP has the potential to act as a neuro‐protective drug.
Capacitative Ca2+ entry is involved in regulating soluble amyloid precursor protein (sAPPα) release mediated by muscarinic acetylcholine receptor activation in neuroblastoma SH‐SY5Y cells
Authors: Kim Jin Hyoung , Choi Sinkyu , Jung Ji‐Eun , Roh Eun‐Jihn , Kim Hwa‐Jung
Published: March 2006

Previous studies have demonstrated that stimulation of phospholipase C‐linked G‐protein‐coupled receptors, including muscarinic M1 and M3 receptors, increases the release of the soluble form of amyloid precursor protein (sAPPα) by α‐secretase cleavage. In this study, we examined the involvement of capacitative Ca2+ entry (CCE) in the regulation of muscarinic acetylcholine receptor (mAChR)‐dependent sAPPα release in neuroblastoma SH‐SY5Y cells expressing abundant M3 mAChRs. The sAPPα release stimulated by mAChR activation was abolished by EGTA, an extracellular Ca2+ chelator, which abolished mAChR‐mediated Ca2+ influx without affecting Ca2+ mobilization from intracellular stores. However, mAChR‐mediated sAPPα release was not inhibited by thapsigargin, which increases basal [Ca2+]i by depletion of Ca2+ from intracellular stores. While these results indicate that the mAChR‐mediated increase in sAPPα release is regulated largely by Ca2+ influx rather than by Ca2+ mobilization from intracellular stores, we further investigated the Ca2+ entry mechanisms regulating this phenomenon. CCE inhibitors such as Gd3+, SKF96365, and 2‐aminoethoxydiphenyl borane (2‐APB), dose dependently reduced both Ca2+ influx and sAPPα release stimulated by mAChR activation, whereas inhibition of voltage‐dependent Ca2+ channels, Na+/Ca2+ exchangers, or Na+‐pumps was without effect. These results indicate that CCE plays an important role in the mAChR‐mediated release of sAPPα.
Interactions between β‐neuregulin and neurotrophins in motor neuron apoptosis
Authors: Ricart Karina , J. Pearson Richard , Viera Liliana , Cassina Patricia , Kamaid Andrés , Carroll Steven L. , Estévez Alvaro G.
Published: March 2006

Neuregulins play a major role in the formation and stabilization of neuromuscular junctions, and are produced by both motor neurons and muscle. Although the effects and mechanism of neuregulins on skeletal muscle (e.g. regulation of acetylcholine receptor expression) have been studied extensively, the effects of neuregulins on motor neurons remain unknown. We report that neuregulin‐1β (NRGβ1) inhibited apoptosis of rat motor neurons for up to 7 days in culture by a phosphatidylinositol 3 kinase‐dependent pathway and synergistically enhanced motor neuron survival promoted by glial‐derived neurotrophic factor (GDNF). However, binding of neurotrophins, including brain‐derived neurotrophic factor (BDNF) and nerve growth factor (NGF), to the p75 neurotrophin receptor (p75NTR) abolished the neuregulin anti‐apoptotic effect on motor neurons. Inhibitors of the c‐Jun N‐terminal kinase (JNK) mitogen‐activated protein kinase prevented motor neuron death caused by co‐incubation of NRGβ1 and BDNF or NGF, as well as by trophic factor deprivation. Motor neuron apoptosis resulting from both trophic factor deprivation and exposure to NRGβ1 plus neurotrophins required the induction of neuronal nitric oxide synthase and peroxynitrite formation. Because motor neurons express both p75NTR and neuregulin erbB receptors during the period of embryonic programmed cell death, motor neuron survival may be the result of complex interactions between trophic and death factors, which may be the same molecules acting in different combinations.
Spatial and temporal relationship between monocyte chemoattractant protein‐1 expression and spinal glial activation following peripheral nerve injury
Authors: Zhang Ji , De Koninck Yves
Published: March 2006

Peripheral nerve injury can induce spinal microglial/astrocyte activation. Substances released by activated glial cells excite spinal nociceptive neurons. Pharmacological disruption of glial activation or antagonism of substances released by activated glia prevent or reverse pain hypersensitivity. It is not known, however, what causes spinal cord glia to shift from a resting to an activated state. In an attempt to understand the potential role of monocyte chemoattractant protein‐1 (MCP‐1) in triggering spinal glial activation and its contribution to the development of neuropathic pain, we investigated the effect of peripheral nerve injury on MCP‐1 expression in dorsal root ganglia (DRG) and the spinal cord, and established its temporal relationship with activation of spinal microglia and astrocytes. We observed that MCP‐1 was induced by chronic constriction of the sciatic nerve in DRG sensory neurons, spinal cord motor neurons and in the superficial dorsal horn, ipsilateral to the injury. Neuronal MCP‐1 induction was followed by surrounding microglial activation. After peaking at day 7 after injury, MCP‐1 levels began to decline rapidly and had returned to baseline by day 150. In contrast, microglial activation peaked by day 14 and declined afterwards to reach a lower, yet significantly raised level beyond day 22 and remained increased until the end of the test period. Astrocyte activation became detectable later, progressed more slowly and also remained increased until the end of the test period, in parallel with a decreased nociceptive threshold. Our results suggest that neuronal MCP‐1 may serve as a trigger for spinal microglial activation, which participates in the initiation of neuropathic pain. Delayed, sustained astrocyte activation may participate with microglia in the persistent phase of pain hypersensitivity.
APPε, the ε‐secretase‐derived N‐terminal product of the β‐amyloid precursor protein, behaves as a type I protein and undergoes α‐, β‐, and γ‐secretase cleavages
Authors: Lefranc‐Jullien Solveig , Sunyach Claire , Checler Frédéric
Published: March 2006

β‐Amyloid peptide accumulates in the brain of patients affected by sporadic or familial forms of Alzheimer's disease. It derives from the proteolytic attacks of the β‐amyloid precursor protein (βAPP) by β‐ and γ‐secretase activities. An additional ε cleavage taking place a few residues C‐terminal to the γ‐site has been reported, leading to the formation of an intracellular fragment referred to as APP intracellular domain C50. This ε cleavage received particular attention because it resembles the S3 Notch cleavage generating Notch intracellular domain. Indeed, APP intracellular domain, like its Notch counterpart, appears to mediate important physiological functions. γ and ε cleavages on βAPP appear spatio‐temporally linked but pharmacologically distinct and discriminable by mutagenesis approaches. As these cleavages could be seen as either deleterious (γ‐site) or beneficial (ε‐site), it appears of most interest to set up models aimed at studying these activities separately, particularly to design specific and bioavailable inhibitors. On the other hand, it is important to respect the topology of the substrates in order to examine physiologically relevant cleavages. Here we describe the obtention of cells overexpressing APPε, the ε‐secretase‐derived N‐terminal fragment of βAPP. Interestingly, this N‐terminal fragment of βAPP was shown by biochemical and immunohistochemical approaches to behave as a genuine membrane‐bound protein. APPε undergoes constitutive and protein kinase C‐regulated α‐secretase cleavages. Furthermore, APPε is targeted by the β‐secretase β‐site APP‐cleaving enzyme and is subsequently cleaved by γ‐secretase. The resulting β‐amyloid peptide production is fully prevented by various γ‐secretase inhibitors. Altogether, our study shows that APPε is a relevant βAPP derivative to study γ‐secretase activities and to design specific inhibitors without facing any rate‐limiting effect of ε‐secretase‐derived cleavage.
Fibroblast growth factor receptor signaling affects development and function of dopamine neurons – inhibition results in a schizophrenia‐like syndrome in transgenic mice
Authors: Klejbor Ilona , Myers Jason M. , Hausknecht Kathy , Corso Thomas D. , Gambino Angelo S. , Morys Janusz , Maher Pamela A. , Hard Robert , Richards Jerry , Stachowiak Ewa K. , Stachowiak Michal K.
Published: March 2006

Developing and mature midbrain dopamine (DA) neurons express fibroblast growth factor (FGF) receptor‐1 (FGFR1). To determine the role of FGFR1 signaling in the development of DA neurons, we generated transgenic mice expressing a dominant negative mutant [FGFR1(TK–)] from the catecholaminergic, neuron‐specific tyrosine hydroxylase (TH) gene promoter. In homozygous th(tk–)/th(tk–) mice, significant reductions in the size of TH‐immunoreactive neurons were found in the substantia nigra compacta (SNc) and the ventral tegmental area (VTA) at postnatal days 0 and 360. Newborn th(tk–)/th(tk–) mice had a reduced density of DA neurons in both SNc and VTA, and the changes in SNc were maintained into adulthood. The reduced density of DA transporter in the striatum further demonstrated an impaired development of the nigro‐striatal DA system. Paradoxically, the th(tk–)/th(tk–) mice had increased levels of DA, homovanilic acid and 3‐methoxytyramine in the striatum, indicative of excessive DA transmission. These structural and biochemical changes in DA neurons are similar to those reported in human patients with schizophrenia and, furthermore, these th(tk–)/th(tk–) mice displayed an impaired prepulse inhibition that was reversed by a DA receptor antagonist. Thus, this study establishes a new developmental model for a schizophrenia‐like disorder in which the inhibition of FGF signaling leads to alterations in DA neurons and DA‐mediated behavior.
Amyloid beta peptide increases DP5 expression via activation of neutral sphingomyelinase and JNK in oligodendrocytes
Authors: Chen Shawei , Lee Jin‐Moo , Zeng Chenbo , Chen Hong , Hsu Chung Y. , Xu Jan
Published: March 2006

There is growing recognition that white matter pathology is a common feature in Alzheimer's disease. We have previously reported that the amyloid beta peptide (Aβ) induces apoptosis in oligodendrocytes (OLG), via activation of neutral sphingomyelinase (nSMase) and resultant generation of ceramide. In the current study, we report that both Aβ and ceramide increased expression of the proapoptotic protein DP5/Hrk (DP5), and release of cytochrome C from mitochondria to cytoplasm in OLGs. We provide evidence that the Jun N‐terminal kinase (JNK) signaling pathway mediates Aβ‐ and ceramide‐induced apoptosis: Both Aβ and ceramide activated JNK phosphorylation, and subsequent AP‐1 DNA binding activity; JNK siRNA decreased AP‐1 DNA binding, DP5 expression and reduced cell death. Furthermore, inhibition of nSMase attenuated Aβ‐induced JNK phosphorylation, AP‐1 DNA binding activity, DP5 expression, and cytochrome C release. Collectively, these results suggest that Aβ‐induced apoptosis involves the sequential activation of nSMase with ceramide generation, JNK activation, AP‐1 DNA binding, and DP5 expression.
Problem of Distinguishing False‐Positive Tests from Acute or Transient Helicobacter pylori Infections
Authors: Nugalieva Zhannat Z. , Opekun Antone R. , Graham David Y.
Published: March 2006

Background:  Reliable detection of acute Helicobacter pylori infections remains problematic. The high prevalence of false‐positive non‐invasive tests in low H. pylori prevalence populations makes identification of acute and transient infections difficult.

Methods:  We explored the use of serum pepsinogens (PG) for diagnosis of acute infection in patients following H. pylori challenge such that the onset of the infection was known. We then compared those findings to a group of children with presumed acute infections defined as a positive urea breath test (UBT) and negative IgG serology.

Results:  We examined the pattern and calculated cut‐off values of PG levels in 18 adult volunteers with known acute H. pylori infection. We then compared the results with sera from nine symptomatic children with presumed acute H. pylori infection and a matched control group of nine children who did not meet criteria for acute H. pylori infection. In acute infection, both PGI and II levels increased following H. pylori infection reaching a peak by 2 weeks post‐infection. The frequency of a positive test defined as a value > mean +2 SD was 17, 71, and 94% at week 1, 2, and 4 post‐infection, respectively. Only one child with presumed acute H. pylori infection had an elevated serum PGI and one had an elevated PGII. Five of the children had follow‐up UBTs and four were negative consistent with the diagnosis of false‐positive UBT. H. pylori infection was confirmed in the child with an elevated PGI level.

Conclusions:  These data suggest that a single positive noninvasive test in populations of low prevalence is most likely a false‐positive result. This suggests that a single positive test requires confirmation preferably using a test that measures a different parameter (e.g., UBT confirmed by stool antigen test). It appears that most “transient”H. pylori infections are diagnosed on the basis of false‐positive tests. PG levels are possible candidates as the confirmatory test.
Comparison of Localized Gastric Mucosa‐Associated Lymphoid Tissue (MALT) Lymphoma with and without Helicobacter pylori Infection
Authors: Akamatsu Taiji , Mochizuki Taro , Okiyama Yoko , Matsumoto Akihiro , Miyabayashi Hideharu , Ota Hiroyoshi
Published: March 2006

Background:  The clinical features and clinical course of Helicobacter pylori‐negative gastric mucosa‐associated lymphoid tissue (MALT) lymphoma are unclear and a treatment strategy has not yet been established.

Aim:  To clarify the clinical differences between H. pylori‐positive and H. pylori‐negative gastric MALT lymphoma, we compared these two types of gastric MALT lymphoma.

Materials and Methods:  Fifty‐seven patients with localized gastric MALT lymphoma were studied. H. pylori infection was present in 41 and absent in 16. Treatment consisted of antibiotic therapy and/or 30 Gy radiation therapy. Response assessment was performed every 3–6 months by esophagogastroduodenoscopy including gathering biopsy samples, endoscopic ultrasonography, clinical examination, and various imaging procedures. The median follow‐up period was 37 months.

Results:  There were no significant differences between H. pylori‐positive and H. pylori‐negative gastric MALT lymphoma patients in terms of sex, age, stage, gross phenotype, affected area of the stomach, or the presence of monoclonality. Complete regression was achieved with antibiotic therapy against H. pylori‐negative gastric MALT lymphoma in one of nine patients (11.1%), compared to 28 of 38 patients (73.7%) with H. pylori‐positive gastric MALT lymphoma (p < .001). Radiation therapy showed high effectiveness for the local control of H. pylori‐negative or antibiotic‐resistant gastric MALT lymphoma (92.9%), although distant recurrence was recognized in three of 14 patients (21.4%). Two of 16 patients (12.5%) with H. pylori‐negative gastric MALT lymphoma died because of the transformation of the disease into diffuse large B‐cell lymphoma. There was a significant difference in both the overall and cause‐specific survival rate between the two groups (p = .038).

Conclusion:  Radiation therapy is the effective treatment for H. pylori‐negative or antibiotic‐resistant localized gastric MALT lymphoma. However, careful systemic follow‐up for distant involvement should be required. Transformation into diffuse large B‐cell lymphoma is thought to be the important cause of death in patients with gastric MALT lymphoma.
Dating metamorphic reactions and fluid flow: application to exhumation of high‐P granulites in a crustal‐scale shear zone, western Canadian Shield
Authors: MAHAN K. H. , GONCALVES P. , WILLIAMS M. L. , JERCINOVIC M. J.
Published: March 2006

The Legs Lake shear zone is a crustal‐scale thrust fault system in the western Canadian Shield that juxtaposes high‐pressure (1.0+ GPa) granulite facies rocks against shallow crustal (< 0.5 GPa) amphibolite facies rocks. Hangingwall decompression is characterized by breakdown of the peak assemblage Grt + Sil + Kfs + Pl + Qtz into the assemblage Grt + Crd + Bt ± Sil + Pl + Qtz. Similar felsic granulite occurs throughout the region, but retrograde cordierite is restricted to the immediate hangingwall of the shear zone. Textural observations, petrological analysis using P–T/P–MH2O phase diagram sections, and in situ electron microprobe monazite geochronology suggest that decompression from peak conditions of 1.1 GPa, c. 800 °C involved several distinct stages under first dry and then hydrated conditions. Retrograde re‐equilibration occurred at 0.5–0.4 GPa, 550–650 °C. Morphology, X‐ray maps, and microprobe dates indicate several distinct monazite generations. Populations 1 and 2 are relatively high yttrium (Y) monazite that grew at 2.55–2.50 Ga and correspond to an early granulite facies event. Population 3 represents episodic growth of low Y monazite between 2.50 and 2.15 Ga whose general significance is still unclear. Population 4 reflects low Y monazite growth at 1.9 Ga, which corresponds to the youngest period of high‐pressure metamorphism. Finally, population 5 is restricted to the hydrous retrograded granulite and represents high Y monazite growth at 1.85 Ga that is linked directly to the synkinematic garnet‐consuming hydration reaction (KFMASH): Grt + Kfs + H2O = Bt + Sil + Qtz. Two samples yield weighted mean microprobe dates for this population of 1853 ± 15 and 1851 ± 9 Ma, respectively. Subsequent xenotime growth correlates with the reaction: Grt + Sil + Qtz + H2O = Crd. We suggest that the shear zone acted as a channel for fluid produced by dehydration of metasediments in the underthrust domain.
Separate or shared metamorphic histories of eclogites and surrounding rocks? An example from the Bohemian Massif
Authors: ŠTÍPSKÁ P. , PITRA P. , POWELL R.
Published: March 2006

Eclogite boudins occur within an orthogneiss sheet enclosed in a Barrovian metapelite‐dominated volcano‐sedimentary sequence within the Velké Vrbno unit, NE Bohemian Massif. A metamorphic and lithological break defines the base of the eclogite‐bearing orthogneiss nappe, with a structurally lower sequence without eclogite exposed in a tectonic window. The typical assemblage of the structurally upper metapelites is garnet–staurolite–kyanite–biotite–plagioclase–muscovite–quartz–ilmenite ± rutile ± silli‐manite and prograde‐zoned garnet includes chloritoid–chlorite–paragonite–margarite, staurolite–chlorite–paragonite–margarite and kyanite–chlorite–rutile. In pseudosection modelling in the system Na2O–CaO–K2O–FeO–MgO–Al2O3–SiO2–H2O (NCKFMASH) using THERMOCALC, the prograde path crosses the discontinuous reaction chloritoid + margarite = chlorite + garnet + staurolite + paragonite (with muscovite + quartz + H2O) at 9.5 kbar and 570 °C and the metamorphic peak is reached at 11 kbar and 640 °C. Decompression through about 7 kbar is indicated by sillimanite and biotite growing at the expense of garnet. In the tectonic window, the structurally lower metapelites (garnet–staurolite–biotite–muscovite–quartz ± plagioclase ± sillimanite ± kyanite) and amphibolites (garnet–amphibole–plagioclase ± epidote) indicate a metamorphic peak of 10 kbar at 620 °C and 11 kbar and 610–660 °C, respectively, that is consistent with the other metapelites. The eclogites are composed of garnet, omphacite relicts (jadeite = 33%) within plagioclase–clinopyroxene symplectites, epidote and late amphibole–plagioclase domains. Garnet commonly includes rutile–quartz–epidote ± clinopyroxene (jadeite = 43%) ± magnetite ± amphibole and its growth zoning is compatible in the pseudosection with burial under H2O‐undersaturated conditions to 18 kbar and 680 °C. Plagioclase + amphibole replaces garnet within foliated boudin margins and results in the assemblage epidote–amphibole–plagioclase indicating that decompression occurred under decreasing temperature into garnet‐free epidote–amphibolite facies conditions. The prograde path of eclogites and metapelites up to the metamorphic peak cannot be shared, being along different geothermal gradients, of about 11 and 17 °C km−1, respectively, to metamorphic pressure peaks that are 6–7 kbar apart. The eclogite–orthogneiss sheet docked with metapelites at about 11 kbar and 650 °C, and from this depth the exhumation of the pile is shared.
The Fallacy of Passive Management Managing for Firesafe Forest Reserves
Authors: Agee James K.
Published: March 2006

The hard lesson that we should take away from the last decade of fire management in drier forests is that a choice to do nothing is a choice of action, not always with a desirable outcome.