bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mutational Spectrum and Linkage Disequilibrium Patterns at the Ornithine Transcarbamylase Gene (OTC)
Authors: Azevedo L. , Soares P. A. , Quental R. , Vilarinho L. , Teles E. L. , Martins E. , Diogo L. , Garcia P. , Cenni B. , Wermuth B. , Amorim A. 
Published: March 2006

SummaryOrnithine transcarbamylase (OTC; EC 2.1.3.3) is a hepatic enzyme involved in ammonia elimination via the urea cycle. Since the sequence of the OTC gene was reported many types of mutations continue to be found in OTC deficiency patients, continuing to increase the already wide mutational spectrum known for this gene. In this study we present the clinical, biochemical and molecular features of thirteen late‐onset OTC deficiency patients. Mutations were identified in all these patients, among which six were novel point substitutions (L59R, A137P, L148S, Y176L, L186P, and K210N) and one was a 2‐bp deletion at exon 4 (341‐342delAA). In addition, a de novo genomic deletion of maternal origin encompassing exons 1 to 5 was also identified by the analysis of LD patterns using intragenic polymorphic markers. This work exemplifies the potential value of population genetic studies for the detection of large deletions.
Standardized Subsets of the HGDP‐CEPH Human Genome Diversity Cell Line Panel, Accounting for Atypical and Duplicated Samples and Pairs of Close Relatives
Authors: Rosenberg Noah A. 
Published: March 2006

SummaryThe HGDP‐CEPH Human Genome Diversity Cell Line Panel is a widely‐used resource for studies of human genetic variation. Here, pairs of close relatives that have been included in the panel are identified. Together with information on atypical and duplicated samples, the inferred relative pairs suggest standardized subsets of the panel for use in future population‐genetic studies.
The Genetic Structure of Human Populations Studied Through Short Insertion‐Deletion Polymorphisms
Authors: Bastos‐Rodrigues Luciana , Pimenta Juliana R. , Pena Sergio D. J. 
Published: March 2006

SummaryIn a landmark study Rosenberg et al. (2002) analyzed human genome diversity with 377 microsatellites in the HGDP‐CEPH Genome Diversity Panel and reported that the populations were structured into five geographical regions: America, Sub‐Saharan Africa, East Asia, Oceania and a cluster composed of Europe, the Middle East and Central Asia. They also observed that the within‐population component accounted for 93–95%, and that the among‐regions portion was only 3.6%, of the total genetic variance. We have also studied the HGDP‐CEPH Diversity Panel (1064 individuals from 52 populations) with a set of 40 biallelic slow‐evolving short insertion‐deletion polymorphisms (indels). We confirmed the partition of worldwide diversity into five genetic clusters that correspond to major geographic regions. Using the indels we have also disclosed an among‐regions component of genetic variance considerably larger (12.1%) than had been estimated using microsatellites. Our study demonstrates that a set of 40 well‐chosen biallelic markers is sufficient for the characterization of human population structure at the global level.
Post‐translational regulation of EAAT2 function by co‐expressed ubiquitin ligase Nedd4‐2 is impacted by SGK kinases
Authors: Boehmer Christoph , Palmada Monica , Rajamanickam Jeyaganesh , Schniepp Roman , Amara Susan , Lang Florian 
Published: March 2006

AbstractThe human excitatory amino acid transporter (EAAT)2 is the major glutamate carrier in the mammalian CNS. Defective expression of the transporter results in neuroexcitotoxicity that may contribute to neuronal disorders such as amyotrophic lateral sclerosis (ALS). The serum and glucocorticoid inducible kinase (SGK) 1 is expressed in the brain and is known to interact with the ubiquitin ligase Nedd4‐2 to modulate membrane transporters and ion channels. The present study aimed to investigate whether SGK isoforms and the related kinase, protein kinase B (PKB), regulate EAAT2. Expression studies in Xenopus oocytes demonstrated that glutamate‐induced inward current (IGLU) was stimulated by co‐expression of SGK1, SGK2, SGK3 or PKB. IGLU is virtually abolished by Nedd4‐2, an effect abrogated by additional co‐expression of either kinase. The kinases diminish the effect through Nedd4‐2 phosphorylation without altering Nedd4‐2 protein abundance. SGKs increase the transporter maximal velocity without significantly affecting substrate affinity. Similar to glutamate‐induced currents, [3H] glutamate uptake and cell surface abundance of the transporter were increased by the SGK isoforms and down‐regulated by the ubiquitin ligase Nedd4‐2. In conclusion, all three SGK isoforms and PKB increase EAAT2 activity and plasma membrane expression and thus, may participate in the regulation of neuroexcitability.
Granulocyte‐colony stimulating factor is neuroprotective in a model of Parkinson's disease
Authors: Meuer Katrin , Pitzer Claudia , Teismann Peter , Krüger Carola , Göricke Bettina , Laage Rico , Lingor Paul , Peters Kerstin , Schlachetzki Johannes C. M. , Kobayashi Kazuto , Dietz Gunnar P. H. , Weber Daniela , Ferger Boris , Schäbitz Wolf‐Rüdiger , Bach Alfred , Schulz Jörg B. , Bähr Mathias , Schneider Armin , Weishaupt Jochen H. 
Published: March 2006

AbstractWe have recently shown that the hematopoietic Granulocyte‐Colony Stimulating Factor (G‐CSF) is neuroprotective in rodent stroke models, and that this action appears to be mediated via a neuronal G‐CSF receptor. Here, we report that the G‐CSF receptor is expressed in rodent dopaminergic substantia nigra neurons, suggesting that G‐CSF might be neuroprotective for dopaminergic neurons and a candidate molecule for the treatment of Parkinson's disease. Thus, we investigated protective effects of G‐CSF in 1‐methyl‐4‐phenylpyridinium (MPP+)‐challenged PC12 cells and primary neuronal midbrain cultures, as well as in the mouse 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) model of Parkinson's disease. Substantial protection was found against MPP+‐induced dopaminergic cell death in vitro. Moreover, subcutaneous application of G‐CSF at a dose of 40 μg/Kg body weight daily over 13 days rescued dopaminergic substantia nigra neurons from MPTP‐induced death in aged mice, as shown by quantification of tyrosine hydroxylase‐positive substantia nigra cells. Using HPLC, a corresponding reduction in striatal dopamine depletion after MPTP application was observed in G‐CSF‐treated mice. Thus our data suggest that G‐CSF is a novel therapeutic opportunity for the treatment of Parkinson's disease, because it is well‐tolerated and already approved for the treatment of neutropenic conditions in humans.
Maturation and maintenance of cholinergic medial septum neurons require glucocorticoid receptor signaling
Authors: Guijarro Christian , Rutz Susanne , Rothmaier Katharina , Turiault Marc , Zhi Qixia , Naumann Thomas , Frotscher Michael , Tronche Francois , Jackisch Rolf , Kretz Oliver 
Published: March 2006

SummaryGlucocorticoids have been shown to influence trophic processes in the nervous system. In particular, they seem to be important for the development of cholinergic neurons in various brain regions. Here, we applied a genetic approach to investigate the role of the glucocorticoid receptor (GR) on the maturation and maintenance of cholinergic medial septal neurons between P15 and one year of age by using a mouse model carrying a CNS‐specific conditional inactivation of the GR gene (GRNesCre). The number of choline acetyltransferase and p75NTR immuno‐positive neurons in the medial septum (MS) was analyzed by stereology in controls versus mutants. In addition, cholinergic fiber density, acetylcholine release and cholinergic key enzyme activity of these neurons were determined in the hippocampus. We found that in GRNesCre animals the number of medial septal cholinergic neurons was significantly reduced during development. In addition, cholinergic cell number further decreased with aging in these mutants. The functional GR gene is therefore required for the proper maturation and maintenance of medial septal cholinergic neurons. However, the loss of cholinergic neurons in the medial septum is not accompanied by a loss of functional cholinergic parameters of these neurons in their target region, the hippocampus. This pinpoints to plasticity of the septo‐hippocampal system, that seems to compensate for the septal cell loss by sprouting of the remaining neurons.
Regulation of astrocytic glutamate transporter expression by Akt: evidence for a selective transcriptional effect on the GLT‐1/EAAT2 subtype
Authors: Li Li‐Bin , Toan Shuy Vang , Zelenaia Olga , Watson Deborah J. , Wolfe John H. , Rothstein Jeffrey D. , Robinson Michael B. 
Published: March 2006

AbstractIn the nervous system, astrocytes express different ratios of the two glial glutamate transporters, glutamate transporter subtype 1 (GLT‐1) and glutamate/aspartate transporter (GLAST), but little is known about the signaling pathways that independently regulate their expression. Treatment with dibutyryl‐cAMP, epidermal growth factor (EGF) or other growth factors both induces expression of GLT‐1 and increases expression of GLAST in astrocyte cultures. The induction of GLT‐1 is correlated with morphological and biochemical changes that are consistent with astrocyte maturation. Pharmacological studies suggest that phosphatidylinositol 3‐kinase (PI‐3K) and the nuclear transcription factor‐κB (NF‐κB) may be involved in the induction of GLT‐1 expression. In several signaling systems Akt, also known as protein kinase B (PKB), functions downstream of PI‐3K. In these present studies we used lentiviral vectors engineered to express dominant‐negative (DN), constitutively active (CA), or null variants of Akt to study the possible involvement of Akt in the regulation of GLT‐1. Expression of DN‐Akt attenuated the EGF‐dependent induction of GLT‐1. Expression of CA‐Akt caused a dose‐ and time‐dependent increase in GLT‐1 protein, increased GLT‐1 mRNA levels, increased dihydrokainate‐sensitive (presumably GLT‐1 mediated) transport activity, and caused a change in astrocyte morphology to a more stellate shape, but had no effect on GLAST protein levels. Finally, the expression of CA‐Akt increased the expression of a reporter construct containing a putative promoter fragment from the human homolog of GLT‐1, called EAAT2. From these studies, we conclude that Akt induces the expression of GLT‐1 through increased transcription and that Akt can regulate GLT‐1 expression without increasing GLAST expression in astrocytes.
Dopamine release is severely compromised in the R6/2 mouse model of Huntington's disease
Authors: Johnson Michael A. , Rajan Vignesh , Miller Charles E. , Wightman R. Mark 
Published: March 2006

AbstractRecently, alterations in dopamine signaling have been implicated in Huntington's disease. In this work, dopamine release and uptake was measured in striatal slices from the R6/2 transgenic mouse model of Huntington's disease using fast‐scan cyclic voltammetry at carbon‐fiber microelectrodes. Dopamine release in brain slices from 6‐week‐old R6/2 mice is substantially reduced (53% of wild type), while dopamine uptake is unaffected. In agreement with this, R6/2 mice injected with the dopamine uptake inhibitor cocaine exhibited a blunted motor activity response (54% of wild type). At 10 weeks of age, an even more dramatic motor activity decrease in response to cocaine injection (21% of wild type) was observed. Moreover, the pre‐drug activity of 10‐week‐old R6/2 mice was significantly reduced (by 37%) compared with 6‐week‐old R6/2 mice. Striatal dopamine release decreased with age, indicating that progressive alterations in dopaminergic pathways may affect motor activity. The inhibition constants of cocaine and methamphetamine (METH) determined in brain slices differed little between genotype or age group, suggesting that the decreased responses to cocaine and METH arise from compromised dopamine release rather than differences in uptake or drug action. Collectively, these data demonstrate (i) a reduction in the ability of dopamine terminals to release dopamine and (ii) the importance of this attenuation of release on the motor symptoms of Huntington's disease.
Translational event mediates differential production of tumor necrosis factor‐α in hyaluronan‐stimulated microglia and macrophages
Authors: Wang Mei‐Jen , Kuo Jon‐Son , Lee Wen‐Wen , Huang Hsin‐Yi , Chen Wu‐Fu , Lin Shinn‐Zong 
Published: March 2006

AbstractRecent evidence has demonstrated that hyaluronan synthase 2 mRNA is up‐regulated after brain ischemia. After a cerebral ischemic event, microglia and macrophages are the major inflammatory cells and are activated by hyaluronan (HA). However, it is unclear how these cells compare with regard to HA responsiveness. We show here that peritoneal macrophages and RAW 264.7 macrophages produced more than five‐ and 10‐fold more tumor necrosis factor‐α (TNF‐α) than primary microglia and BV‐2 microglia, respectively. Antibody blockade study showed that CD44, Toll‐like receptor‐4 receptor and the receptor for HA‐mediated motility were responsible for HA‐induced TNF‐α release. Furthermore, HA induced higher levels of phosphorylated MAPK in RAW 264.7 cells when compared with BV‐2 cells. HA‐mediated TNF‐α production required p38 MAPK, extracellular‐regulated kinase and c‐Jun N‐terminal kinase phosphorylation in both cell types. The levels of HA‐induced TNF‐α mRNA expression in BV‐2 cells were only twofold lower compared with RAW 264.7 cells, suggesting that a translational event is involved in the differential production of TNF‐α. Western blot analysis revealed that HA treatment resulted in more rapid phosphorylation of eukaryotic initiation factor 4E‐binding protein 1 (4E‐BP1) and more effective dissociation of 4E‐BP1 from eukaryotic initiation factor 4E in RAW 264.7 cells than in BV‐2 cells. Additionally, HA‐induced phosphorylation of 4E‐BP1 was dependent on MAPK signaling, indicating that RAW 264.7 cells exhibited higher levels of hyperphosphorylated 4E‐BP1 possibly due to the overactivation of MAPK. The results suggest that resident microglia and blood‐derived monocytes/macrophages exhibit differential sensitivities in response to extracellular mediators after brain ischemia.
Differential metabolic adaptation to acute and long‐term hypoxia in rat primary cortical astrocytes
Authors: Véga Céline , R. Sachleben Leroy , Gozal David , Gozal Evelyne 
Published: March 2006

AbstractBrain astrocytes provide structural and metabolic support to surrounding cells during ischemia. Glucose and oxygen are critical to brain function, and glucose uptake and metabolism by astrocytes are essential to their metabolic coupling to neurons. To examine astrocyte metabolic response to hypoxia, cell survival and metabolic parameters were assessed in rat primary cortical astrocytes cultured for 3 weeks in either normoxia or in either 1 day or 3 weeks sustained hypoxia (5% O2). Although cell survival and proliferation were not affected by the mildly hypoxic environment, substantial differences in glucose consumption and lactate release after either acute or prolonged hypoxia suggest that astrocyte metabolism may contribute to their adaptation. Hypoxia over a period of 1 day increased glucose uptake, lactate release, and glucose transporter 1 (GLUT1) and monocarboxylate transporter 1 (MCT1) expression, whereas hypoxia over a period of 3 weeks resulted in a decrease of all parameters. Furthermore, increased glucose uptake at 1 day of hypoxia was not inhibited by cytochalasin B suggesting the involvement of additional glucose transporters. We uncovered hypoxia‐regulated expression of sodium‐dependent glucose transporters (SGLT1) in astrocytes indicating a novel adaptive strategy involving both SGLT1 and GLUT1 to regulate glucose intake in response to hypoxia. Overall, these findings suggest that although increased metabolic response is required for the onset of astrocyte adaptation to hypoxia, prolonged hypoxia requires a shift to an energy conservation mode. These findings may contribute to the understanding of the relative tolerance of astrocytes to hypoxia compared with neurons and provide novel therapeutic strategies aimed at maintaining brain function in cerebral pathologies involving hypoxia.
Chronic depolarization stimulates norepinephrine transporter expression via catecholamines
Authors: Habecker Beth A. , Willison Breanne D. , Shi Xiao , Woodward William R. 
Published: March 2006

AbstractChronic depolarization increases norepinephrine (NE) uptake and expression of the norepinephrine transporter (NET) in sympathetic neurons, but the mechanisms are unknown. Depolarization of sympathetic neurons stimulates catecholamine synthesis, and several studies suggest that NET can be regulated by catecholamines. It is not clear if the depolarization‐induced increase in NET is because of nerve activity per se, or is secondary to elevated catecholamines. To determine if induction of NET mRNA was a result of increased catecholamines, we used pharmacological manipulations to (i) inhibit tyrosine hydroxylase activity in neurons depolarized with 30 mmKCl, thereby preventing increased catecholamines, or (ii) stimulate tyrosine hydroxylase activity in the absence of depolarization. Inhibiting the depolarization‐induced increase in catecholamines prevented the up‐regulation of NET mRNA, but did not block the increase in tyrosine hydroxylase (TH) mRNA. Furthermore, stimulating catecholamine production in the absence of depolarization elevated NE uptake, NET protein, and NET mRNA in sympathetic neurons. Similarly, elevating endogenous catecholamines in SK‐N‐BE(2)M17 neuroblastoma cells increased NE uptake and NET expression. These data suggest that chronic depolarization of sympathetic neurons induces NET expression through increasing catecholamines, and that M17 neuroblastoma cells provide a model system in which to investigate catechol regulation of NET expression.
Puromycin‐purified rat brain microvascular endothelial cell cultures exhibit improved barrier properties in response to glucocorticoid induction
Authors: Calabria Anthony R. , Weidenfeller Christian , Jones Angela R. , De Vries Helga E. , Shusta Eric V. 
Published: March 2006

Abstract In vitro blood–brain barrier (BBB) models using primary rat brain microvessel endothelial cells (BMEC) are often hampered by a lack of culture purity and poor barrier properties. To address these problems, the translation inhibitor puromycin was used to purify rat BMEC cultures. BMEC purities of 99.8% were routinely attained using puromycin treatment, and this technique proved to be far superior to other purification methods of similar difficulty. In contrast to cultures without puromycin treatment, purity of puromycin‐treated cultures was unaffected by initial seeding density. Next, rat BMEC monolayer transendothelial electrical resistance (TEER) was increased by glucocorticoid treatment with either corticosterone (CORT) or hydrocortisone (HC), and a corresponding decrease in monolayer permeability to small molecules was observed. Importantly, cultures treated with both puromycin and glucocorticoid attained significantly higher TEER values (CORT 168 ± 13 Ω × cm2; HC 218 ± 66 Ω × cm2) than those treated by the glucocorticoid alone (CORT 57 ± 5 Ω × cm2; HC 70 ± 2 Ω × cm2). Glucocorticoid induction resulted in BMEC morphological changes that accompanied the increases in TEER, and BMEC tight junctions exhibited improved integrity as visualized by the localization of tight junction proteins zonula occluden‐1, occludin and claudin‐5. The combined use of puromycin and glucocorticoid therefore provides an in vitro system that is well suited for molecular level BBB investigations.
Evidence that caspase‐1 is a negative regulator of AMPA receptor‐mediated long‐term potentiation at hippocampal synapses
Authors: Lu Chengbiao , Wang Yue , Furukawa Katsutoshi , Fu Weiming , Ouyang Xin , Mattson Mark P. 
Published: March 2006

AbstractBest known for their pivotal role in a form of programmed cell death called apoptosis, caspases may also function in more subtle physiological processes. Caspases are present in synapses and dendrites of neurons where they can be activated in response to glutamate receptor stimulation and calcium influx. Here we tested the hypothesis that caspase‐1 plays a role in modulating long‐term potentiation (LTP) at hippocampal synapses. We provide evidence that caspase‐1 plays a role in regulating α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptor‐mediated calcium influx and synaptic plasticity in the hippocampus. LTP of excitatory postsynaptic potentials at CA1 synapses was significantly enhanced when hippocampal slices were treated with either a pan‐caspase inhibitor or a selective inhibitor of caspase‐1, but not by an inhibitor of caspase‐6. Inhibition of caspase‐1 significantly enhanced the AMPA current‐mediated component of LTP without affecting the N‐methyl‐d‐aspartate current‐mediated component. Calcium responses to AMPA were enhanced in hippocampal neurons treated with a caspase‐1 inhibitor suggesting that caspase‐1 normally functions to reduce AMPA receptor‐mediated calcium influx. These findings suggest that, by selectively reducing AMPA currents and calcium influx, caspase‐1 functions as a negative regulator of LTP at hippocampal synapses.
NFκB in neurons? The Uncertainty Principle in neurobiology
Authors: Massa Paul T. , Aleyasin Hossein , Park David S. , Mao Xianrong , Barger Steven W. 
Published: March 2006

AbstractNuclear factor κB (NFκB) is a dynamically modulated transcription factor with an extensive literature pertaining to widespread actions across species, cell types and developmental stages. Analysis of NFκB in a complex environment such as neural tissue suffers from a difficulty in simultaneously establishing both activity and location. Much of the available data indicate a profound recalcitrance of NFκB activation in neurons, as compared with most other cell types. Few studies to date have sought to distinguish between the various combinatorial dimers of NFκB family members. Recent research has illuminated the importance of these problems, as well as opportunities to move past them to the nuances manifest through variable activation pathways, subunit complexity and target sequence preferences.
Graded response to GABA by native extrasynaptic GABAAreceptors
Authors: Lindquist Catarina E. L. , Birnir Bryndis 
Published: March 2006

AbstractGABA is the main inhibitory neurotransmitter in the mammalian CNS. GABA in the brain is commonly associated with a fast, point‐to‐point form of signalling called synaptic transmission (phasic inhibition), but there is growing evidence that GABA participates in another, slower and more diffuse form of signalling often referred to as tonic inhibition. Unresolved questions regarding tonic neuronal inhibition concern activation and functional properties of extrasynaptic GABAAreceptors (GABARex) present on neurones. Extrasynaptic receptors are exposed to submicromolar GABA concentrations and may modulate the overall excitability of neurones and neuronal networks. Here, we examined GABA‐activated single‐channel currents in dentate gyrus granule neurones in rat hippocampal slices. We activated three types (I, II, III) of GABARex channels by nanomolar GABA concentrations (EC50I: 27 ± 12; II: 4 ± 3; III: 43 ± 19 nm). The channels opened after a delay and the single‐channel conductance was graded (γmaxI: 61 ± 3; II: 85 ± 8, III: 40 ± 3 pS). The channels were differentially modulated by 1 µmdiazepam, 200 nmzolpidem, 1 µmflumazenil and 50 nmTHDOC (3α, 21‐dihydroxy‐5α‐pregnan‐20‐one), consistent with the following minimal subunit composition of GABARex I α1βγ2, GABARex II α4βγ2and GABARex III αβδ channels.