bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pricing in International Markets: a “Small‐country” Benchmark
Authors: Parsley David C. 
Published: July 2004

AbstractThe paper studies export pricing to market (PTM) in a “small‐country” context using a panel of disaggregated exports from Hong Kong since 1992. Conventional wisdom is that PTM is commonplace—except for US exports. This study provides a benchmark by which to interpret the puzzling behavior of US export prices. Empirically, Hong Kong's export price behavior is comparable to that of the US. This similarity reinforces the idea that PTM behavior is also a function of home market conditions and the ability to price discriminate across markets. There is little evidence of differences in PTM across Hong Kong's export destinations.
Up‐regulation of Na+–Ca2+ exchange activity by interferon‐γ in cultured rat microglia
Authors: Nagano Takayuki , Kawasaki Yasushi , Baba Akemichi , Takemura Motohiko , Matsuda Toshio 
Published: July 2004

AbstractThe Na+–Ca2+ exchanger (NCX) plays a role in regulating intracellular Ca2+ concentration, but little is known about NCX in microglia. We examined mRNA expression of NCX isoforms in cultured rat microglia and the effect of interferon‐γ (IFN‐γ) on NCX activity. RT–PCR showed that all of the known NCX isoforms, NCX1–3, are expressed in cultured microglia. Ouabain and monensin increased 45Ca2+ uptake and intracellular Ca2+ concentration in microglia, suggesting the presence of NCX activity in the reverse mode. Treatment with IFN‐γ (100 U/mL) caused a biphasic increase in NCX activity. The transient increase in NCX activity by IFN‐γ for 1 h was blocked by the protein kinase C (PKC) inhibitors, staurosporine and GF109203X, and the tyrosine kinase inhibitor, herbimycin A. The delayed increase in NCX activity by IFN‐γ for 24 h was blocked by the protein synthesis inhibitor cycloheximide and actinomycin D. Treatment with IFN‐γ for 24 h increased NCX mRNA and protein levels. The increase in NCX activity and NCX protein by IFN‐γ for 24 h was blocked by staurosporine, GF109203X, herbimycin A and the extracellular signal‐regulated kinase inhibitor, PD98059. These findings suggest that NCX is up‐regulated by IFN‐γ in a biphasic manner in microglia. Moreover, PKC and tyrosine kinase are involved in the up‐regulation of NCX and the extracellular signal‐regulated protein kinase is also involved in the delayed increase in NCX activity.
Presenilin‐directed inhibitors of γ‐secretase trigger caspase 3 activation in presenilin‐expressing and presenilin‐deficient cells
Authors: Alves da Costa Cristine , Ayral Erwan , Hernandez Jean‐François , St George‐Hyslop Peter , Checler Frédéric 
Published: July 2004

AbstractThe amyloid β peptide (Aβ) is generated by subsequent cleavages by β‐ and γ‐secretases. Therefore, these two enzymes are putative therapeutic targets to prevent Aβ production, and hopefully to slow down or even stop the Alzheimer's disease (AD) neurodegenerative process. Several studies have revealed that γ‐secretase hydrolyses other important substrates besides β‐amyloid precursor protein (βAPP) thus adding another level of complexity to designing fully AD‐specific interfering drugs. Here we demonstrate that three distinct presenilin‐directed γ‐secretase inhibitors as well as JLK compounds indirectly potentiate caspase 3 activity, the effector caspase of the apoptotic cascade. Thus, inhibitors were shown to drastically stimulate caspase 3 activity in wild‐type mice blastocyst‐derived and fibroblast cells. Interestingly, some of these inhibitors known to interact with presenilins also trigger caspase activation in presenilin‐deficient cells. However, inhibitors do not affect recombinant caspase 3 activity, indicating that the effect on this enzyme was indirect. Furthermore, we established that caspase 3 activation was not due to an effect of γ‐secretase inhibitors on calpains, a family of proteolytic enzymes able to modulate caspase 3 activity. Altogether, our data demonstrate that presenilin‐directed γ‐secretase inhibitors affect caspase 3 activity in a presenilin‐independent manner. Therefore, as presenilin‐dependent γ‐secretase activity is not specific for βAPP and because its inhibitors clearly affect other vital cell functions, care should be taken in considering ‘γ‐secretase’ inhibitors as putative therapeutic tools to interfere with AD pathology.
Atorvastatin‐induced activation of Alzheimer's α secretase is resistant to standard inhibitors of protein phosphorylation‐regulated ectodomain shedding
Authors: Parvathy S. , Ehrlich Michelle , Pedrini Steve , Diaz Nichole , Refolo Lorenzo , Buxbaum Joseph D. , Bogush Alexey , Petanceska Suzana , Gandy Sam 
Published: July 2004

AbstractStudies of metabolism of the Alzheimer amyloid precursor protein (APP) have focused much recent attention on the biology of juxta‐ and intra‐membranous proteases. Release or ‘shedding’ of the large APP ectodomain can occur via one of two competing pathways, the α‐ and β‐secretase pathways, that are distinguished both by subcellular site of proteolysis and by site of cleavage within APP. The α‐secretase pathway cleaves within the amyloidogenic Aβ domain of APP, precluding the formation of toxic amyloid aggregates. The relative utilization of the α‐ and β‐secretase pathways is controlled by the activation of certain protein phosphorylation signal transduction pathways including protein kinase C (PKC) and extracellular signal regulated protein kinase [ERK/mitogen‐activated protein kinase (MAP kinase)], although the relevant substrates for phosphorylation remain obscure. Because of their apparent ability to decrease the risk for Alzheimer disease, the effects of statins (HMG CoA reductase inhibitors) on APP metabolism were studied. Statin treatment induced an APP processing phenocopy of PKC or ERK activation, raising the possibility that statin effects on APP processing might involve protein phosphorylation. In cultured neuroblastoma cells transfected with human Swedish mutant APP, atorvastatin stimulated the release of α‐secretase‐released, soluble APP (sAPPα). However, statin‐induced stimulation of sAPPα release was not antagonized by inhibitors of either PKC or ERK, or by the co‐expression of a dominant negative isoform of ERK (dnERK), indicating that PKC and ERK do not play key roles in mediating the effect of atorvastatin on sAPPα secretion. These results suggest that statins may regulate α‐secretase activity either by altering the biophysical properties of plasma membranes or by modulating the function of as‐yet unidentified protein kinases that respond to either cholesterol or to some intermediate in the cholesterol metabolic pathway. A ‘phospho‐proteomic’ analysis of N2a cells with and without statin treatment was performed, revealing changes in the phosphorylation state of several protein kinases plausibly related to APP processing. A systematic evaluation of the possible role of these protein kinases in statin‐regulated APP ectodomain shedding is underway.
AMPA protects cultured neurons against glutamate excitotoxicity through a phosphatidylinositol 3‐kinase‐dependent activation in extracellular signal‐regulated kinase to upregulate BDNF gene expression
Authors: Wu Xuan , Zhu Daming , Jiang Xueying , Okagaki Peter , Mearow Karen , Zhu Guanshan , McCall Sherman , Banaudha Krishna , Lipsky Robert H. , Marini Ann M. 
Published: July 2004

AbstractThe signal transduction and molecular mechanisms underlying α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionate (AMPA)‐mediated neuroprotection are unknown. In the present study, we determined a major AMPA receptor‐mediated neuroprotective pathway. Exposure of cerebellar granule cells to AMPA (500 µm) + aniracetam (1 µm), a known blocker of AMPA receptor desensitization, evoked an accumulation of brain‐derived neurotropic factor (BDNF) in the culture medium and enhanced TrkB‐tyrosine phosphorylation following the release of BDNF. AMPA also activated the src‐family tyrosine kinase, Lyn, and the downstream target of the phosphatidylinositol 3‐kinase (PI3‐K) pathway, Akt. Extracellular signal regulated kinase (ERK), a component of the mitogen‐activated protein kinase (MAPK) pathway, was also activated. K252a, a selective inhibitor of neurotrophin signaling, blocked the AMPA‐mediated neuroprotection. The involvement of BDNF release in protecting neurons by AMPA was confirmed using a BDNF‐blocking antibody. AMPA‐mediated neuroprotection is blocked by PP1, an inhibitor of src family kinases, LY294002, a PI3‐K inhibitor, or U0126, a MAPK kinase (MEK) inhibitor. Neuroprotective concentrations of AMPA increased BDNF mRNA levels that was blocked by the AMPA receptor antagonist, 1,2,3,4‐tetrahydro‐6‐nitro‐2,3‐dioxo‐benzo[f]quinoxaline‐7‐sulfonamide (NBQX). The increase in BDNF gene expression appeared to be the downstream target of the PI3‐K‐dependent activation of the MAPK cascade since MEK or the PI3‐K inhibitor blocked the AMPA receptor‐mediated increase in BDNF mRNA. Thus, AMPA receptors protect neurons through a mechanism involving BDNF release, TrkB receptor activation, and a signaling pathway involving a PI3‐K dependent activation of MAPK that increases BDNF expression.
Intracellular lithium and cyclic AMP levels are mutually regulated in neuronal cells
Authors: Montezinho L. P. , B. Duarte C. , Fonseca C. P. , Glinka Y. , Layden B. , Mota de Freitas D. , Geraldes C. F. G. C. , Castro M. M. C. A. 
Published: July 2004

AbstractIn this work, we studied the effect of intracellular 3′,5′‐cyclic adenosine monophosphate (cAMP) on Li+ transport in SH‐SY5Y cells. The cells were stimulated with forskolin, an adenylate cyclase activator, or with the cAMP analogue, dibutyryl‐cAMP. It was observed that under forskolin stimulation both the Li+ influx rate constant and the Li+ accumulation in these cells were increased. Dibutyryl‐cAMP also increased Li+ uptake and identical results were obtained with cortical and hippocampal neurons. The inhibitor of the Na+/Ca2+ exchanger, KB‐R7943, reduced the influx of Li+ under resting conditions, and completely inhibited the effect of forskolin on the accumulation of the cation. Intracellular Ca2+ chelation, or inhibition of N‐type voltage‐sensitive Ca2+ channels, or inhibition of cAMP‐dependent protein kinase (PKA) also abolished the effect of forskolin on Li+ uptake. The involvement of Ca2+ on forskolin‐induced Li+ uptake was confirmed by intracellular free Ca2+ measurements using fluorescence spectroscopy. Exposure of SH‐SY5Y cells to 1 mm Li+ for 24 h increased basal cAMP levels, but preincubation with Li+, at the same concentration, decreased cAMP production in response to forskolin. To summarize, these results demonstrate that intracellular cAMP levels regulate the uptake of Li+ in a Ca2+‐dependent manner, and indicate that Li+ plays an important role in the homeostasis of this second messenger in neuronal cells.
Effects of NGF on acetylcholine, acetyl‐CoA metabolism, and viability of differentiated and non‐differentiated cholinergic neuroblastoma cells
Authors: Szutowicz Andrzej , Madziar Beata , Pawełczyk Tadeusz , Tomaszewicz Maria , Bielarczyk Hanna 
Published: July 2004

AbstractNerve growth factor (NGF) is a peptide displaying multiple cholinotropic activities. The aim of this work was to explain mechanisms of the positive and negative effects of NGF on phenotypic properties and viability of cholinergic cells. To discriminate these effects we used two p75NTRreceptor‐positive lines of cholinergic neuroblastoma cells, SN56 and T17 that are devoid of or express high affinity NGF (TrkA) receptors, respectively. cAMP and retinoic acid caused differentiation of both cell lines. In addition to the morphologic maturation, the increase of choline acetyltransferase activity, acetylcholine, Ca and cytoplasmic acetyl‐CoA levels and decrease of mitochondrial acetyl‐CoA and cell viability were observed. NGF caused similar effects in non‐differentiated T17 cells but had no influence on non‐differentiated SN56 cells. On the contrary, in both cAMP/all‐trans‐retinoic acid (RA) differentiated cell lines, NGF resulted in a similar suppression of cholinergic phenotype along with an increase of mitochondrial acetyl‐CoA and cell susceptibility to nitric oxide and amyloid‐β25–35. These effects of NGF were prevented by an antibody against the p75NTRreceptor. Data indicate that: (i) positive cholinotrophic effects of NGF required activation of both TrkA and p75NTRreceptors; (ii) cAMP/RA‐evoked differentiation inhibited NGF effects mediated by TrkA receptors and activated its p75NTR‐dependent suppressing influences and (iii) a differentiation‐evoked decrease of mitochondrial acetyl‐CoA and an elevation of mitochondrial Ca could augment impairment of cholinergic neurons by neurotoxic signals.
Metalloendopeptidase EC3.4.24.15 is constitutively released from the exofacial leaflet of lipid rafts in GT1‐7 cells
Authors: Jeske Nathaniel A. , Glucksman Marc J. , Roberts James L. 
Published: July 2004

AbstractMetalloendopeptidase EC3.4.24.15 (EP24.15) is a physiologically important neuropeptide‐degrading enzyme involved in the metabolism of multiple neuropeptides. The mechanism of release of EP24.15 from neuronal cells is multimodal, being both constitutive and stimulatable. Previous studies have characterized stimulated EP24.15 secretion, yet little is understood concerning constitutive release of the peptidase. Utilizing the mouse hypothalamic neuronal GT1‐7 cell line, we demonstrate that EP24.15 exists within lipid rafts in the plasma membrane, and that the enzyme is localized to the exofacial leaflet of lipid rafts. Further, we have found that biotinylated EP24.15 on the extracellular surface is released into the cell media in a fashion similar to constitutive release. In addition, classical and non‐classical secretion pathway inhibitors were employed to understand the release of EP24.15 into surrounding cell media. The non‐classical secretion inhibitor glyburide, a blocker of ATP‐sensitive K+ channels, decreased the amount of constitutively released EP24.15 in cell media of GT1‐7 cells. With these data, we conclude that EP24.15 association with lipid rafts on the extracellular surface precedes constitutive release of the peptidase into the extracellular milieu for its action on neuropeptides.
Nomifensine amplifies subsecond dopamine signals in the ventral striatum of freely‐moving rats
Authors: Robinson Donita L. , Wightman R. Mark 
Published: July 2004

AbstractThe present experiment examined the effect of the dopamine transporter blocker nomifensine on subsecond fluctuations in dopamine concentrations, or dopamine transients, in the nucleus accumbens and olfactory tubercle. Extracellular dopamine was measured in real time using fast‐scan cyclic voltammetry at micron‐dimension carbon fibers in freely‐moving rats. Dopamine transients occurred spontaneously throughout the ventral striatum in the absence of apparent sensory input or change in behavioral response. The frequency of dopamine transients increased at the presentation of salient stimuli to the rat (food, novel odors and unexpected noises). Administration of 7 mg/kg nomifensine amplified spontaneous dopamine transients by increasing both amplitude and duration, consistent with its known action at the dopamine transporter and emphasizing the dopaminergic origin of the signals. Moreover, nomifensine increased the frequency of detected dopamine transients, both during baseline conditions and at the presentation of stimuli, but more profoundly in the nucleus accumbens than in the olfactory tubercle. This difference was not explained by nomifensine effects on the kinetics of dopamine release and uptake, as its effects on electrically‐evoked dopamine signals were similar in both regions. These findings demonstrate the heterogeneity of dopamine transients in the ventral striatum and establish that nomifensine elevates the tone of rapid dopamine signals in the brain.
Effects of phosphorylation by protein kinase A on binding of catecholamines to the human tyrosine hydroxylase isoforms
Authors: Sura Giri R. , Daubner S. Colette , Fitzpatrick Paul F. 
Published: July 2004

AbstractTyrosine hydroxylase (TyrH), the catalyst for the key regulatory step in catecholamine biosynthesis, is phosphorylated by cAMP‐dependent protein kinase A (PKA) on a serine residue in a regulatory domain. In the case of the rat enzyme, phosphorylation of Ser40 by PKA is critical in regulating the enzyme activity; the effect of phosphorylation is to relieve the enzyme from inhibition by dopamine and dihydroxyphenylalanine (DOPA). There are four isoforms of human tyrosine hydroxylase (hTyrH), differing in the size of an insertion after Met30. The effects of phosphorylation by PKA on the binding of DOPA and dopamine have now been determined for all four human isoforms. There is an increase of about two‐fold in the Kd value for DOPA for isoform 1 upon phosphorylation, from 4.4 to 7.4 µm; this effect decreases with the larger isoforms such that there is no effect of phosphorylation on the Kd value for isoform 4. Dopamine binds more much tightly, with Kd values less than 3 nm for all four unphosphorylated isoforms. Phosphorylation decreases the affinity for dopamine at least two orders of magnitude, resulting in Kd values of about 0.1 µm for the phosphorylated human enzymes, due primarily to increases in the rate constant for dissociation of dopamine. Dopamine binds about two‐fold less tightly to the phosphorylated isoform 1 than to the other three isoforms. The results extend the regulatory model developed for the rat enzyme, in which the activity is regulated by the opposing effects of catecholamine binding and phosphorylation by PKA. The small effects on the relatively high Kd values for DOPA suggest that DOPA levels do not regulate the activity of hTyrH.
Professional stereotyping and interprofessional education
Authors: Mandy Anne , Milton Carl , Mandy Philip 
Published: July 2004

AbstractEffective interprofessional working is considered to be essential for optimum healthcare delivery. Interprofessional rivalry, tribalism and stereotypes are known to exist within healthcare professions and detract from effective health delivery. Limited literature is available that reports undergraduate healthcare students’ stereotypical perceptions of each other. Stereotypes in relation to interprofessional education are commonly explained through the Contact Hypothesis Theory, the Realistic Conflict Theory, or the Social Identity Theory. The aim of this study was to investigate undergraduate physiotherapy and podiatry students’ stereotypes of each other's professions before and after a semester of interprofessional education. Stereotypes were measured using the Health Team Stereotype Scale. Results indicated that both professional groups had stereotypical perceptions of each other prior to any education, which were reinforced as a result of the education. The results support the Social Identity Theory, which explains intergroup discrimination and describes an interpersonal–intergroup continuum. The timing of the interprofessional education may be critical to reducing such an effect.
Common heterozygous hemochromatosis gene mutations are risk factors for inflammation and fibrosis in chronic hepatitis C
Authors: Geier Andreas , Reugels Michael , Weiskirchen Ralf , Wasmuth Hermann E. , Dietrich Christoph G. , Siewert Elmar , Gartung Carsten , Lorenzen Johann , Bosserhoff Anja K. , Brügmann Marc , Gressner Axel M. , Matern Siegfried , Lammert Frank 
Published: July 2004

Abstract:  Background: Chronic hepatitis C is frequently associated with increased hepatic iron stores. It remains controversial whether heterozygous mutations of hemochromatosis genes affect fibrosis progression. Therefore our aim was to assess associations between HFE mutations and hepatic inflammation and stage of fibrosis in German hepatitis C patients.Methods: Liver biopsies from 166 patients were scored for inflammatory activity (A0–4) and hepatic fibrosis (F0–4). Gene mutations were determined by LightCycler, restriction fragment length polymorphism analysis, or direct sequencing.Results: The frequencies of common HFE mutations C282Y and H63D are 4.2% and 21.3%, whereas the recently described S65C substitution and the Y250X mutation in the transferrin receptor 2 gene are very rare. In regression analysis, heterozygous carriers of C282Y or H63D mutations display significantly (P<0.05) higher inflammatory activities and more advanced fibrosis than patients without mutations. For C282Y heterozygous patients, the odds ratios for marked inflammatory activity (A2–4) and advanced liver fibrosis or cirrhosis (F2–4) are 4.9 and 4.6, respectively, compared with patients carrying homozygous wild‐type alleles. C282Y mutations are associated with significantly (P<0.05) increased serum iron and aminotransferase levels, whereas H63D heterozygotes display higher transferrin saturation, serum iron, and ferritin concentrations compared to wild‐type (P<0.01).Conclusions: Common heterozygous hemochromatosis mutations are associated with higher grades of inflammation and more severe hepatic fibrosis. Our findings support a role of HFE mutations as primary risk factors for fibrogenesis and disease progression in chronic hepatitis C.
Characteristics of murine histidinaemia and its potential for genetic manipulation
Authors: Mellor N. , Themis M. , Selden C. , Jones M. , Hodgson H. J. F. 
Published: July 2004

Abstract: Background: Histidinaemia is an autosomal recessive disorder affecting the hepatic enzyme histidine ammonia lyase (histidase) resulting in elevated plasma and urinary histidine and is prototypic of a series of hepatic cytosolic enzyme defects.Aims: To characterise the physiology of murine histidinaemia with respect to histidine excretion and catabolism, and explore the potential for manipulating cellular and whole body histidase metabolism by gene transfer.Materials and Methods: We studied his/his mice which have a G to A substitution in the gene encoding histidase, using both in vitro transduction of isolated hepatocytes by lipofection with wild‐type histidase cDNA, and in vivo transduction of whole liver using a retroviral construct.Results and Conclusion: Histidase cDNA expression restored histidase activity in vivo and in vitro towards normal levels, demonstrated both at the cellular level and by whole body metabolic studies, establishing the potential of this model for the development of new gene therapeutic approaches.
Tissue collection, transport and isolation procedures required to optimize human hepatocyte isolation from waste liver surgical resections. A multilaboratory study
Authors: Richert Lysiane , Alexandre Eliane , Lloyd Tom , Orr Samantha , Viollon‐Abadie Catherine , Patel Rakhee , Kingston Shaun , Berry David , Dennison Ashley , Heyd Bruno , Mantion Georges , Jaeck Daniel 
Published: July 2004

Abstract: Background: The European Center for Validation of Alternative Methods (ECVAM) has funded a prevalidation study in three laboratories (France, USA and UK) on the use of human hepatocyte cultures to predict cytochrome P‐450 induction.Aims and Methods: As first stage of this prevalidation study, the purpose of the present work was to set criteria for optimization and harmonization of hepatocyte isolation from human tissue among laboratories to establish a routine procedure. This was achieved by combining and/or comparing the data generated by the two independent European laboratories (France and UK).Results: The results confirmed that surgical waste material is a valuable source for obtaining high quality hepatocytes under certain pre‐, intra‐ and post‐operative conditions: cell yield of viable hepatocytes was not significantly affected by age and sex of patients, nor indications for resection, steatosis or cholestasis. Cold ischeamia up to 5 hours did not influence viable cell yield allowing transport of material.Conclusion: The use of biopsy sizes between 50–100 g, cannulation with 2–4 cannulae, digestion with collagenase‐containing digestion medium at a flow rate of 25 ml/cannula for 20 minutes, with cut surface being glued in order to reform Glisson's capsule, should optimize the total yield of viable human hepatocytes obtained per preparation of waste liver surgical resecitons.