bluuebunny/crossref_metadata_2025 huggingface dataset:
Argatroban and Renal Replacement Therapy in Patients with Heparin-Induced Thrombocytopenia
Authors: Tang Ignatius Y , Cox Donna S , Patel Kruti , Reddy Bharathi V , Nahlik Linda , Trevino Sharon , Murray Patrick T
Published: January 2005

BACKGROUND:

Argatroban, a direct thrombin inhibitor, is an effective anticoagulant for patients who have heparin-induced thrombocytopenia (HIT). Anticoagulation is usually required for renal replacement therapy (RRT).

OBJECTIVE:

To prospectively evaluate the pharmacokinetics, pharmacodynamics, and safety of argatroban during RRT in hospitalized patients with or at risk for HIT.

METHODS:

Five patients with known or suspected HIT underwent hemodialysis (n = 4) or continuous venovenous hemofiltration (CVVH, n = 1), while receiving a continuous infusion of argatroban 0.5–2 μg/kg/min. Activated partial thromboplastin times (aPTTs), activated clotting times (ACTs), argatroban concentrations (plasma, dialysate, CVVH effluent), and safety were assessed before, during, and after a 4-hour session of RRT. Systemic and dialytic argatroban clearances were calculated.

RESULTS:

Among the 4 hemodialysis patients, aPTT, ACT, and plasma argatroban concentrations remained stable during RRT, with respective mean ± SD values of 74.3 ± 34.2 seconds, 198 ± 23 seconds, and 499 ± 353 ng/mL before RRT, and 70.6 ± 21.4 seconds, 181 ± 12 seconds, and 453 ± 295 ng/mL 2 hours after starting RRT (p values NS). Systemic clearance was 17.7 ± 12.8 L/h before hemodialysis and 17.0 ± 9.5 L/h during hemodialysis (n = 2). The dialyzer clearance (dialysate recovery method) was 1.5 ± 0.4 L/h (n = 4). Generally similar responses occurred in the CVVH patient: systemic argatroban clearance was 4.8 L/h before CVVH and 4 L/h during CVVH. The hemofilter argatroban clearance was 0.9 L/h. No bleeding or thrombosis occurred.

CONCLUSIONS:

Argatroban provides effective alternative anticoagulation in patients with or at risk for HIT during RRT. Argatroban clearance by high-flux membranes during hemodialysis and CVVH is clinically insignificant, necessitating no dose adjustment.
The Influence of Pioneer Neurons on a Growing Motor Nerve inDrosophilaRequires the Neural Cell Adhesion Molecule Homolog FasciclinII
Authors: Sánchez-Soriano Natalia , Prokop Andreas
Published: January 2005

The phenomenon of pioneer neurons has been known for almost a century, but so far we have little insights into mechanisms and molecules involved. Here, we study the formation of theDrosophilaintersegmental motor nerve (ISN). We show that aCC/RP2 and U motor neurons grow together at the leading front of the ISN. Nevertheless, aCC/RP2 neurons are the pioneers, and U neurons are the followers, because only aCC/RP2 neurons effectively influence growth of the ISN. We also show that this influence depends on the neural cell adhesion molecule homolog FasciclinII. First, ablation of aCC/RP2 has a stronger impact on ISN growth than U ablation. Second, strong growth-influencing capabilities of aCC/RP2 are revealed with a stalling approach we used: when aCC/RP2 motor axons are stalled specifically, the entire ISN (including the U neurons) coarrests, demonstrating that aCC/RP2 neurons influence the behavior of U growth cones. In contrast, stalled U neurons do not have the same influence on other ISN motor neurons. The influence on ISN growth requires FasciclinII: targeted expression of FasciclinII in U neurons increases their influence on the ISN, whereas a FasciclinII loss-of-function background reduces ISN coarrest with stalled aCC/RP2 axons. The qualitative differences of both neuron groups are confirmed through our findings that aCC/RP2 growth cones are wider and more complex than those of U neurons. However, U growth cones adopt aCC/RP2-like wider shapes in a FasciclinII loss-of-function background. Therefore, FasciclinII is to a degree required and sufficient for pioneer-follower interactions, but its mode of action cannot be explained merely through an equally bidirectional adhesive interaction.
Temporal Dependence in Uncoupling of Blood Volume and Oxygenation during Interictal Epileptiform Events in Rat Neocortex
Authors: Suh Minah , Bahar Sonya , Mehta Ashesh D. , Schwartz Theodore H.
Published: January 2005

We investigated the dynamic spatiotemporal relationships of cerebral blood volume (CBV), deoxygenated hemoglobin (Hbr), and light scatter (LS) associated with interictal epileptiform events with multiwavelength optical recording of intrinsic signals and simultaneous field potential recording. Interictal spikes (IISs) were induced with iontophoresis of bicuculline methiodide in rat neocortex. Intrinsic signal changes appeared as early as 100 msec after the IIS at all wavelengths and could be appreciated after only a single IIS. Initially, the largest signal arose from a focal increase in deoxygenation, which lasted for ∼2 sec, consistent with an “initial dip.” An equally early focal increase in CBV had a smaller amplitude than the Hbr signal until >2 sec after the IIS, when its amplitude surpassed that of the Hbr signal but also spread to a larger, less focal area. The most spatially restricted and smallest amplitude signal was produced by LS. A later hyperoxygenation, or increase in blood oxygenation level-dependent signal, was often seen in the draining veins but inconsistently seen in the IIS focus. An inverted optical signal was recorded at all wavelengths from multiple regions in the surrounding cortex within 100 msec of the IIS. We therefore conclude that the IIS induces a rapid increase in metabolic demand, which cannot be met by a rapid, initially focal but small increase in CBV that results in a prolonged increase in Hbr (epileptic dip in oxygenated hemoglobin). The inverted optical signal in the surround arises from a decrease in CBV and a decrease in Hbr, likely resulting from a combination of shunting of CBV to the focus and decreased metabolic demand resulting from decreased neuronal activity, consistent with “surround inhibition.”
Congenital Stationary Night Blindness Type 2 Mutations S229P, G369D, L1068P, and W1440X Alter Channel Gating or Functional Expression of Cav1.4 L-type Ca2+Channels
Authors: Hoda Jean-Charles , Zaghetto Francesca , Koschak Alexandra , Striessnig Jörg
Published: January 2005

Mutations in theCACNA1Fgene (voltage-dependent L-type calcium channel α1F subunit) encoding retinal Cav1.4 L-type Ca2+channels cause X-linked recessive congenital stationary night blindness type 2 (CSNB2). Many of them are predicted to yield nonfunctional channels. Complete loss of Cav1.4 function is therefore regarded as a pathogenetic mechanism for the impaired signaling from photoreceptors to second-order retinal neurons. We investigated the functional consequences of CSNB2 missense mutations S229P, G369D, and L1068P and the C-terminal truncation mutant W1440X.

After expression inXenopus laevisoocytes or human embryonic kidney tsA-201 cells, inward Ca2+current (ICa) and inward Ba2+current (IBa) could be recorded from mutations G369D and L1068P. G369D shifted the half-maximal voltage for channel activation (V0.5,act) significantly to more negative potentials (>11 mV), slowed inactivation, and removed Ca2+-dependent inactivation. The L1068P mutant yielded currents only in the presence of the channel activator BayK8644. Currents (IBa) inactivated faster than wild type (WT) and recovered more slowly from inactivation (IBaandICa). No channel activity could be measured for mutants S229P and W1440X after oocyte expression. No W1440X α1 protein was detected after expression in tsA-201 cells, whereas S229P (as well as G369D and L1068P) α1 subunits were expressed at levels indistinguishable from WT (n= 3).

Our data provide unequivocal evidence that CSNB2 missense mutations can induce severe changes in Cav1.4 function, which may decrease (L1068P and S229P) or even increase (G369D) channel activity. The lower activation range of G369D can explain the reduced dynamic range of photoreceptor signaling. Moreover, we demonstrate that loss of channel function of one (L1068P) CSNB2 mutation can be rescued by a Ca2+channel activator.
A Circadian Clock and Light/Dark Adaptation Differentially Regulate Adenosine in the Mammalian Retina
Authors: Ribelayga Christophe , Mangel Stuart C.
Published: January 2005

Although the purine adenosine acts as an extracellular neuromodulator in the mammalian CNS in both normal and pathological conditions and regulates sleep, the regulation of extracellular adenosine in the day and night is incompletely understood. To determine how extracellular adenosine is regulated, rabbit neural retinas were maintained by superfusion at different times of the regular light/dark and circadian cycles. The adenosine level in the superfusate, representing adenosine overflow from the retinas, and the adenosine level in retinal homogenates, representing adenosine content, were measured using HPLC with fluorescence detection in the absence or presence of blockers of adenosine transport and/or extracellular adenosine synthesis. We report that darkness, compared with illumination, increases the level of extracellular adenosine, and that a circadian clock also increases extracellular adenosine at night. In addition, we show that the darkness-evoked increase in the level of extracellular adenosine results primarily from an increase in the conversion of extracellular ATP into adenosine, but that the clock-induced increase at night results primarily from an increase in the accumulation of intracellular adenosine. We also show that a slightly hypoxic state increases adenosine content and overflow to an extent similar to that of the clock. Our findings demonstrate that the extracellular level of adenosine in the mammalian retina is differentially regulated by a circadian clock and the lighting conditions and is maximal at night under dark-adapted conditions. We conclude that adenosine is a neuromodulator involved in both circadian clock and dark-adaptive processes in the vertebrate retina.
Protons Trap NR1/NR2B NMDA Receptors in a Nonconducting State
Authors: Banke Tue G. , Dravid Shashank M. , Traynelis Stephen F.
Published: January 2005

NMDA receptors are highly expressed in the CNS and are involved in excitatory synaptic transmission, as well as synaptic plasticity. Given that overstimulation of NMDA receptors can cause cell death, it is not surprising that these channels are under tight control by a series of inhibitory extracellular ions, including zinc, magnesium, and H+. We studied the inhibition by extracellular protons of recombinant NMDA receptor NR1/NR2B single-channel and macroscopic responses in transiently transfected human embryonic kidney HEK 293 cells using patch-clamp techniques. We report that proton inhibition proceeds identically in the absence or presence of agonist, which rules out the possibility that protonation inhibits receptors by altering coagonist binding. The response of macroscopic currents in excised patches to rapid jumps in pH was used to estimate the microscopic association and dissociation rates for protons, which were 1.4 × 109m-1sec-1and 110-196 sec-1, respectively (Kdcorresponds to pH 7.2). Protons reduce the open probability without altering the time course of desensitization or deactivation. Protons appear to slow at least one time constant describing the intra-activation shut-time histogram and modestly reduce channel open time, which we interpret to reflect a reduction in the overall channel activation rate and possible proton-induced termination of openings. This is consistent with a modest proton-dependent slowing of the macroscopic response rise time. From these data, we propose a physical model of proton inhibition that can describe macroscopic and single-channel properties of NMDA receptor function over a range of pH values.
Pharmacological Properties of GABAAReceptors in Rat Hypothalamic Neurons Expressing the ϵ-Subunit
Authors: Sergeeva Olga A. , Andreeva Nadja , Garret Maurice , Scherer Annette , Haas Helmut L.
Published: January 2005

The pharmacological properties and functional role of native GABAAreceptors (GABAARs) were investigated in rat hypothalamic neurons expressing the ϵ-subunit with the help of whole-cell patch-clamp recording and single-cell reverse transcription-PCR. Two cell groups were identified: histaminergic tuberomamillary and orexinergic/hypocretinergic neurons. Approximately 25% of histaminergic and 70% of orexinergic neurons contained mRNA encoding for the ϵ-subunit. Double-immunofluorescence staining revealed a somatic localization of this protein in these two neuronal groups. Constitutive activity, diazepam modulation, fast desensitization of maximal currents, and activation by propofol (6-98 μm) of GABAARs did not correlate withϵ-subunit expression. Propofol at 3-12 μmpotentiated GABA-mediated currents similarly in all neurons. However, noise variance analysis of GABA-mediated currents enhanced by propofol revealed a significant difference between ϵ-positive and ϵ-negative neurons. The former displayed no difference between control and potentiated responses, and, in the latter, noise was decreased in the presence of propofol. Spontaneous IPSCs recorded in cultured hypothalamic neurons were prolonged in the presence of propofol in all ϵ-negative neurons, whereas propofol-resistant IPSCs were recorded in ϵ-positive cells. The infrequent expression of the ϵ-subunit may be a key factor in the recently discovered central role of the tuberomamillary nucleus in anesthesia.
Posterior Parietal Cortex Automatically Encodes the Location of Salient Stimuli
Authors: Constantinidis Christos , Steinmetz Michael A.
Published: January 2005

We examined the responses of neurons in posterior parietal area 7a to salient stimuli appearing alone or within multiple-stimulus displays in monkeys trained only to maintain fixation. Discharges in a population of parietal neurons encoded the location of the salient stimulus, although the latter had no task significance for the monkey. Neuronal selectivity for the location of the salient stimulus depended solely on its intrinsic difference from the background elements in the array and not on the color of the stimulus per se. These results were similar to those reported in monkeys trained to actively locate a salient stimulus in a multiple-stimulus display. A lower percentage of neurons with significant selectivity for the salient stimulus was observed in the fixation-only animals. These neurons took longer for the selective responses to emerge and showed a lower power of discrimination. The findings suggest that the posterior parietal cortex automatically detects and encodes the location of salient stimuli even when they are unrelated to the behavioral task.
NMDA Receptor Activation Mediates Copper Homeostasis in Hippocampal Neurons
Authors: Schlief Michelle L. , Craig Ann Marie , Gitlin Jonathan D.
Published: January 2005

Copper is an essential transition metal with a critical role in the CNS. This requirement is underscored by Menkes disease, a fatal neurodegenerative disorder of childhood resulting from the absence or dysfunction of a copper-transporting P-type ATPase. To elucidate the cell biological mechanisms of copper homeostasis in the CNS, a polyclonal antisera against Menkes ATPase was used in immunoblot and immunohistochemical studies, demonstrating abundant expression of this copper transporter in hippocampal neurons. Consistent with this observation, immunofluorescent analysis revealed Menkes ATPase in the late Golgi of hippocampal neurons in primary culture. Glutamate receptor activation was found to result in the rapid and reversible trafficking of Menkes ATPase to neuronal processes, independent of the intracellular copper concentration and specific for activation of the NMDA- but not AMPA/kainate-type glutamate receptors. Metabolic studies revealed that trafficking of Menkes ATPase after NMDA receptor activation is associated with rapid release of copper from hippocampal neurons. Menkes ATPase is directly required for this copper efflux, because similar studies in hippocampal neurons derived from mice lacking a functional Menkes ATPase demonstrated no copper release. Together, these data reveal a critical role for Menkes ATPase in the availability of an NMDA receptor-dependent, releasable pool of copper in hippocampal neurons and demonstrate a unique mechanism linking copper homeostasis and neuronal activation within the CNS.
Developmental Changes in Parvalbumin Regulate Presynaptic Ca2+Signaling
Authors: Collin Thibault , Chat Mireille , Lucas Marie Gabrielle , Moreno Herman , Racay Peter , Schwaller Beat , Marty Alain , Llano Isabel
Published: January 2005

Certain interneurons contain large concentrations of specific Ca2+-binding proteins (CBPs), but consequences on presynaptic Ca2+signaling are poorly understood. Here we show that expression of the slow CBP parvalbumin (PV) in cerebellar interneurons is cell specific and developmentally regulated, leading to characteristic changes in presynaptic Ca2+dynamics (Cai). Using whole-cell recording and fluorescence imaging, we studied action potential-evoked Caitransients in axons of GABA-releasing interneurons from mouse cerebellum. At early developmental stages [postnatal days 10-12 (P10-P12)], decay kinetics were significantly faster for basket cells than for stellate cells, whereas at P19-P21 both interneurons displayed fast decay kinetics. Biochemical and immunocytochemical analysis showed parallel changes in the expression levels and cellular distribution of PV. By comparing wild-type and PV(-/-) mice, PV was shown to accelerate the initial decay of action potential-evoked Caisignals in single varicosities and to introduce an additional slow phase that summates during bursts of action potentials. The fast initial Caidecay accounts for a previous report that PV elimination favors synaptic facilitation. The slow decay component is responsible for a pronounced, PV-dependent, delayed transmitter release that we describe here at interneuron-interneuron synapses after presynaptic bursts of action potentials. Numerical simulations account for the effect of PV on Caikinetics, allow estimates for the axonal PV concentration (∼150 μm), and predict the time course of volume-averaged Caiin the absence of exogenous buffer. Overall, PV arises as a major contributor to presynaptic Caisignals and synaptic integration in the cerebellar cortex.
A Role for p38 Mitogen-Activated Protein Kinase in the Regulation of the Serotonin Transporter: Evidence for Distinct Cellular Mechanisms Involved in Transporter Surface Expression
Authors: Samuvel Devadoss J. , Jayanthi Lankupalle D. , Bhat Narayan R. , Ramamoorthy Sammanda
Published: January 2005

The serotonin transporter (SERT) is regulated by various signaling mechanisms that may operate to maintain appropriate levels of synaptic serotonin (5-HT). We demonstrate that one of the mitogen-activated protein kinases (MAPKs), p38 MAPK, regulates SERT. Treatment of rat midbrain synaptosomes with p38 MAPK-specific inhibitors, PD169316 [4-(4-fluorophenyl)-2-(4-nitrophenyl)-5-(4-pyridyl)-1H-imidazole] or SB203580 [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole], reduced 5-HT uptake. An additive SERT inhibition by PD169316 and β-phorbol 12-myristate 13-acetate (β-PMA) indicated the involvement of a protein kinase C (PKC)-independent MAPK pathway. Kinetic studies indicated a significant decrease in the transport capacity (Vmax) after PD169316 treatment of synaptosomes. Biotinylation studies showed reduced SERT proteins in the plasma membrane of synaptosomes after p38 MAPK inhibition and PKC activation. Phosphorylation studies using synaptosomes revealed decreased SERT phosphorylation by PD169316 but increased phosphorylation by β-PMA.d-Amphetamine enhanced SERT basal phosphorylation and PD169316 blocked this effect. SERT interaction with protein phosphatase 2A catalytic subunit and syntaxin 1A decreased after PD169316 or β-PMA treatment of synaptosomes. In synaptosomes, PKC activation but not p38 MAPK inhibition resulted in SERT redistribution from cholesterolrich lipid raft fractions to nonlipid raft fractions. The presence of phospho-p38 MAPK in synaptosomes and human embryonic kidney 293 (HEK-293) cells suggested the presence of constitutively active p38 MAPK in these preparations. Cotransfection of HEK-293 cells with SERT and a constitutively active form of MAP kinase kinase 3b(E) [MKK3b(E)] increased 5-HT transport, and RNA interference targeted to p38 MAPK inhibited 5-HT uptake, confirming the involvement of active p38 MAPK in SERT expression. Although PD169316 inhibited SERT insertion to the plasma membrane, β-PMA increased SERT internalization in HEK-293 cells. Together, these results indicate a distinct role of p38 MAPK in SERT regulation.
A Functional Interaction of Sodium and Calcium in the Regulation of NMDA Receptor Activity by Remote NMDA Receptors
Authors: Xin Wen-Kuan , Kwan Chun L. , Zhao Xiao-Han , Xu Jindong , Ellen Richard P. , McCulloch Christopher A. G. , Yu Xian-Min
Published: January 2005

The NMDA receptor is an important subtype glutamate receptor that acts as a nonselective cation channel highly permeable to both calcium (Ca2+) and sodium (Na+). The activation of NMDA receptors produces prolonged increases of intracellular Ca2+concentration ([Ca2+]i) and thereby triggers downstream signaling pathways involved in the regulation of many physiological and pathophysiological processes. Previous studies have focused on how Ca2+or Na+affects NMDA receptor activity in isolation. Specifically, [Ca2+]iincrease may downregulate NMDA channels and thus is considered an important negative feedback mechanism controlling NMDA receptor activity, whereas an increase in intracellular Na+concentration ([Na+]i) may upregulate NMDA channel activity. Thus so that the activity-dependent regulation of NMDA receptors and neuroplasticity may be further understood, a critical question that has to be answered is how an individual NMDA receptor may be regulated when both of these ionic species flow into neurons during the same time period via neighboring activated NMDA receptors. Here we report that the gating of a NMDA channel is regulated by the activation of remote NMDA receptors via a functional Na+-Ca2+interaction and that during the activation of NMDA receptors Na+influx potentiates Ca2+influx on one hand and overcomes Ca2+-induced inhibition of NMDA channel gating on the other hand. Furthermore, we have identified that a critical increase (5 ± 1 mm) in [Na+]iis required to mask the effects of Ca2+on NMDA channel gating in cultured hippocampal neurons. Thus cross talk between NMDA receptors mediated by a functional Na+-Ca2+interaction is a novel mechanism regulating NMDA receptor activity.
APH-1a Is the Principal Mammalian APH-1 Isoform Present in γ-Secretase Complexes during Embryonic Development
Authors: Ma Guojun , Li Tong , Price Donald L. , Wong Philip C.
Published: January 2005

APH-1 (anterior pharynx defective) along with nicastrin and PEN-2 (presenilin enhancer) are essential components of the presenilin (PS)-dependent γ-secretase complex. There exist three murineAph-1alleles termedAph-1a,Aph-1b, andAph-1cthat encode four distinct APH-1 isoforms: APH-1aL and APH-1aS derived from differential splicing ofAph-1a, APH-1b, and APH-1c. To determine the contributions of mammalian APH-1 homologs in formation of functional γ-secretase complexes, we generatedAph-1a-/-mice and derived immortalized fibroblasts from these embryos. Compared with littermate controls, the development ofAph-1a-/-embryos was dramatically retarded by embryonic day 9.5 and exhibited patterning defects that resemble, but are not identical to, those ofNotch1,nicastrin, orPSnull embryos. Moreover, in immortalizedAph-1a-/-fibroblasts, the levels of nicastrin, PS fragments, and PEN-2 were dramatically decreased. Consequently, deletion ofAph-1aresulted in significant reduction in levels of high-molecular-weight γ-secretase complex and secretion of β-amyloid (Aβ). Importantly, complementation analysis revealed that all mammalian APH-1 isoforms were capable of restoring the levels of nicastrin, PS, and PEN-2, as well as Aβ secretion inAph-1a-/-cells. Together, our findings establish that APH-1a is the major mammalian APH-1 homolog present in PS-dependent γ-secretase complexes during embryogenesis and support the view that mammalian APH-1 isoforms define a set of distinct functional γ-secretase complexes.
Transient Inactivation of Perirhinal Cortex Disrupts Encoding, Retrieval, and Consolidation of Object Recognition Memory
Authors: Winters Boyer D. , Bussey Timothy J.
Published: January 2005

Damage to perirhinal cortex (PRh) impairs object recognition memory in humans, monkeys, and rats when tested in tasks such as delayed nonmatching to sample, visual paired comparison, and its rodent analog, the spontaneous object recognition task. In the present study, we have capitalized on the discrete one-trial nature of the spontaneous object recognition task to investigate the role of PRh in several distinct stages of object recognition memory. In a series of experiments, transient inactivation of PRh was accomplished with bilateral infusions of lidocaine directly into PRh immediately before the sample phase (encoding), immediately before the choice phase (retrieval), or within the retention delay after the sample phase (storage-consolidation). Compared with performance on trials in which they received saline infusions, rats were significantly impaired when lidocaine was infused before the sample phase, regardless of the length of the retention delay. Similarly, delay-independent deficits were observed after immediate pre-choice infusions of lidocaine. Finally, PRh inactivation immediately and 20 min after the sample phase, but not 40, 60, or 80 min after, also disrupted subsequent object recognition when the retention delay was sufficiently long to ensure the dissipation of the actions of lidocaine during the choice phase. The effects of pre-sample and pre-choice inactivation indicate involvement of PRh in encoding and retrieval stages of object recognition, and the time course of post-sample inactivation effects suggests a role for PRh in the maintenance of the object trace during memory consolidation.
CytochromecAssociation with the Inner Mitochondrial Membrane Is Impaired in the CNS of G93A-SOD1 Mice
Authors: Kirkinezos Ilias G. , Bacman Sandra R. , Hernandez Dayami , Oca-Cossio Jose , Arias Laura J. , Perez-Pinzon Miguel A. , Bradley Walter G. , Moraes Carlos T.
Published: January 2005

A “gain-of-function” toxic property of mutant Cu-Zn superoxide dismutase 1 (SOD1) is involved in the pathogenesis of some familial cases of amyotrophic lateral sclerosis (ALS). Expression of a mutant form of the human SOD1 gene in mice causes a degeneration of motor neurons, leading to progressive muscle weakness and hindlimb paralysis. Transgenic mice overexpressing a mutant human SOD1 gene (G93A-SOD1) were used to examine the mitochondrial involvement in familial ALS. We observed a decrease in mitochondrial respiration in brain and spinal cord of the G93A-SOD1 mice. This decrease was significant only at the last step of the respiratory chain (complex IV), and it was not observed in transgenic wild-type SOD1 and nontransgenic mice. Interestingly, this decrease was evident even at a very early age in mice, long before any clinical symptoms arose. The effect seemed to be CNS specific, because no decrease was observed in liver mitochondria. Differences in complex IV respiration between brain mitochondria of G93A-SOD1 and control mice were abolished when reduced cytochromecwas used as an electron donor, pinpointing the defect to cytochromec. Submitochondrial studies showed that cytochromecin the brain of G93A-SOD1 mice had a reduced association with the inner mitochondrial membrane (IMM). Brain mitochondrial lipids, including cardiolipin, had increased peroxidation in G93A-SOD1 mice. These results suggest a mechanism by which mutant SOD1 can disrupt the association of cytochromecwith the IMM, thereby priming an apoptotic program.
Activity Dependence of Cortical Axon Branch Formation: A Morphological and Electrophysiological Study Using Organotypic Slice Cultures
Authors: Uesaka Naofumi , Hirai Satoshi , Maruyama Takuro , Ruthazer Edward S. , Yamamoto Nobuhiko
Published: January 2005

The influence of neuronal activity on cortical axon branching was studied by imaging axons of layer 2/3 neurons in organotypic slice cultures of rat visual cortex. Upper layer neurons labeled by electroporation of plasmid encoding yellow fluorescent protein were observed by confocal microscopy. Time-lapse observation of single-labeled axons showed that axons started to branch after 8-10 din vitro. Over the succeeding 7-10 d, branch complexity gradually increased by both growth and retraction of branches, resulting in axon arbors that morphologically resembled those observed in 2- to 3-week-old animals. Electrophysiological recordings of neuronal activity in the upper layers, made using multielectrode dishes, showed that the frequency of spontaneous firing increased dramatically ∼10 din vitroand remained elevated at later stages. To examine the involvement of spontaneous firing and synaptic activity in branch formation, various blockers were applied to the culture medium. Cultures were silenced by TTX or by a combination of APV and DNQX but exhibited a homeostatic recovery of spontaneous activity over several days in the presence of blockers of either NMDA-type or non-NMDA-type glutamate receptors alone. Axonal branching was suppressed by TTX and AMPA receptor blockade but not by NMDA receptor blockade. We conclude that cortical axon branching is highly dynamic and that neural activity regulates the early developmental branching of upper layer cortical neurons through the activation of AMPA-type glutamate receptors.
Mechanisms Underlying Developmental Speeding in AMPA-EPSC Decay Time at the Calyx of Held
Authors: Koike-Tani Maki , Saitoh Naoto , Takahashi Tomoyuki
Published: January 2005

The time course of synaptic conductance is important in temporal precision of information processing in the neuronal network. The AMPA receptor (AMPAR)-mediated EPSCs at the calyx of Held become faster in decay time as animals mature. To clarify how desensitization and deactivation of AMPARs contribute to developmental speeding of EPSCs, we compared the decay time of quantal EPSCs (qEPSCs) with the deactivation and desensitization times of AMPAR currents induced in excised patches by fast glutamate application (AMPA patch currents). Both the deactivation and desensitization times of AMPA patch currents became markedly faster from postnatal day 7 (P7) to P14 and changed little thereafter. In individual neurons, throughout development (P7-P21), the time constants of deactivation and fast desensitization in AMPA patch currents were similar to each other and close to the qEPSC decay time constant. Cyclothiazide (CTZ) abolished the fast desensitization, prolonged deactivation of AMPA patch currents, and slowed the decay time of EPSCs. The effects of CTZ on AMPA patch currents were unchanged throughout development, whereas its effect on EPSCs became weaker as animals matured. In single-cell reverse transcription-PCR analysis, glutamate receptor subunit 4 (GluR4) flop increased from P7 to P14 and changed little thereafter. At P7, the GluR4 flop abundance had an inverse correlation with the qEPSC decay time. These results together suggest that both desensitization and deactivation of AMPARs are involved in the EPSC decay time, but the contribution of desensitization decreases during postnatal development at the calyx of Held.
Orientation Selectivity without Orientation Maps in Visual Cortex of a Highly Visual Mammal
Authors: Van Hooser Stephen D. , Heimel J. Alexander F. , Chung Sooyoung , Nelson Sacha B. , Toth Louis J.
Published: January 2005

In mammalian neocortex, the orderly arrangement of columns of neurons is thought to be a fundamental organizing principle. In primary visual cortex (V1), neurons respond preferentially to bars of a particular orientation, and, in many mammals, these orientation-selective cells are arranged in a semiregular, smoothly varying map across the cortical surface. Curiously, orientation maps have not been found in rodents or lagomorphs. To explore whether this lack of organization in previously studied rodents could be attributable to low visual acuity, poorly differentiated visual brain areas, or small absolute V1 size, we examined V1 organization of a larger, highly visual rodent, the gray squirrel. Using intrinsic signal optical imaging and single-cell recordings, we found no evidence of an orientation map, suggesting that formation of orientation maps depends on mechanisms not found in rodents. We did find robust orientation tuning of single cells, and this tuning was invariant to stimulus contrast. Therefore, it seems unlikely that orientation maps are important for orientation tuning or its contrast invariance in V1. In vertical electrode penetrations, we found little evidence for columnar organization of orientation-selective neurons and little evidence for local anisotropy of orientation preferences. We conclude that an orderly and columnar arrangement of functional response properties is not a universal characteristic of cortical architecture.
Uncoupling Protein-2 Is Critical for Nigral Dopamine Cell Survival in a Mouse Model of Parkinson's Disease
Authors: Andrews Zane B. , Horvath Balazs , Barnstable Colin J. , Elseworth John , Yang Lichuan , Beal M. Flynt , Roth Robert H. , Matthews Russell T. , Horvath Tamas L.
Published: January 2005

Mitochondrial uncoupling proteins dissociate ATP synthesis from oxygen consumption in mitochondria and suppress free-radical production. We show that genetic manipulation of uncoupling protein-2 (UCP2) directly affects substantia nigra dopamine cell function. Overexpression of UCP2 increases mitochondrial uncoupling, whereas deletion of UCP2 reduces uncoupling in the substantia nigra-ventral tegmental area. Overexpression of UCP2 decreased reactive oxygen species (ROS) production, which was measured using dihydroethidium because it is specifically oxidized to fluorescent ethidium by the superoxide anion, whereas mice lacking UCP2 exhibited increased ROS relative to wild-type controls. Unbiased electron microscopic analysis revealed that the elevation ofin situmitochondrial ROS production in UCP2 knock-out mice was inversely correlated with mitochondria number in dopamine neurons. Lack of UCP2 increased the sensitivity of dopamine neurons to 1-methyl-4-phenyl-1,2,5,6 tetrahydropyridine (MPTP), whereas UCP2 overexpression decreased MPTP-induced nigral dopamine cell loss. The present results expose the critical importance of UCP2 in normal nigral dopamine cell metabolism and offer a novel therapeutic target, UCP2, for the prevention/treatment of Parkinson's disease.
Two‐parameter optimization procedure for a TN display
Authors: Olifierczuk Marek , Zieliński Jerzy
Published: January 2005

Abstract— In our work, a two‐parameter optimization procedure for a TN display has been performed. The procedure consists of the numerical calculation of the optical parameters of a TN display, such as contrast ratio and luminance as a function of both the LC‐layer dichroic properties and the polarization coefficient of the polarizers used. The calculations have been done for: human eye sensitivity; real spectral characteristics of light sources (both internal and external ones); both the positive and negative modes of operating of the display; real director profile of the LC layer. Additionally, our procedure takes into account the interference phenomena of the display and the quasi‐real properties of the polarizing films. As a result of our work, a close relationship between the TN display optical parameters and the dichroic LC layer and polarizing films used have been obtained. This makes it possible to choose the initial display elements for different display application and user requirements.
Electron emission from polymer films under electric‐field influence
Authors: Lachinov A. N. , Kornilov V. M. , Yumaguzin Yu. M. , Tchurlina E. E.
Published: January 2005

Abstract— This paper presents the field‐emission characteristics of a polymer‐covered tungsten‐spike cathode. The emission images obtained from a field‐emission microscope together with the electron energy distribution and Fowler‐Nordheim curves compared with those of a typical tungsten cathode are presented.
3D television: Developing a multi‐modal multi‐viewer TV system of the future
Authors: Surman Phil , Sexton Ian , Bates Richard , Lee Wing Kai , Yow Kam Chaun
Published: January 2005

Abstract— Under the European Union funded Advanced Three‐dimensional Television System Technologies (ATTEST) project, De Montfort University (DMU) is developing a 3D display system targeted specifically at domestic television applications. This system uses a modified transmissive LCD panel together with novel backlighting and optics to project multiple viewing regions, or exit pupils, into the viewing space. These exit pupils are located in space using a head tracker. The display accommodates multiple viewers simultaneously and imposes no physical constraints, such as special eyewear. Viewers may move freely over a “typical” room‐sized area. The design of the backlighting facilitates many other display regimes beyond the “standard” 3DTV mode in which each viewer sees the same image pair.
High‐frequency drive of high‐Xe‐content PDPs for high efficiency and low‐voltage performance
Authors: Minami Tetsuo , Shiga Tomokazu , Mikoshiba Shigeo , Oversluizen Gerrit
Published: January 2005

Abstract— It has been well known that the luminous efficiency of PDPs can be improved by increasing the Xe content in the panel. For instance, the efficiency is improved by a factor 1.7 when the Xe content is increased from 3.5% to 30%. The sustain pulse voltage, however, increases from 180 to 230 V by a factor 1.3. It was found that the increase in the sustain pulse voltage can be suppressed by increasing the sustain pulse frequency. The high‐frequency operation further increases the luminous efficiency. If the Xe content is increased from 3.5% to 30% and the drive pulse frequency is increased from 147 to 313 kHz, the luminous efficiency becomes 2.7 times higher and the luminance 4.5 times higher. Furthermore, the increase in the sustain pulse voltage is suppressed 1.1 times, from 180 to 200 V. A mechanism of attaining high efficiency and low‐voltage performance can be considered as follows. A train of pulses is applied during a sustain period. As the sustain pulse frequency is increased, the pulse repetition rate becomes faster and a percentage of the space charge created by the previous pulse remains until the following pulse is applied. Due to the priming effect of these space charge, the discharge current build‐up becomes faster, the width of the discharge current becomes narrower, ion‐heating loss is reduced, and the effective electron temperature is optimized so that Xe atoms are excited more efficiently. The intensity of Xe 147‐nm radiation, dominant in low‐pressure Xe dis‐charges, saturates with respect to electron density due to plasma saturation. This determines the high end of the sustain pulse frequency.
3.2: Integrated a‐Si Gate Driver Circuit for TFT‐LCD Panel
Authors: Jeon Jin , Choo Kyo‐Seop , Lee Won‐Kyu , Song Jun‐Ho , Kim Hyung‐Guel
Published: January 2005

We developed an a‐Si TFT‐LCD panel with integrated gate driver circuit using a standard 5‐MASK process. To minimize the effect of the a‐Si TFT current and LC's capacitance variation with temperature, we developed a new a‐Si TFT circuit structure and minimized coupling capacitance by changing vertical architecture above gate driver circuit. Integration of gate driver circuit on glass substrate enables single chip and 3‐side free panel structure in a‐Si TFT‐LCD of QVGA(240*320) resolution.
3.3: Display Driver Circuits Fabricated on Flexible Stainless Steel Foils
Authors: Afentakis Themistokles , Hatalis Miltiadis , Voutsas Apostolos , Hartzell John
Published: January 2005

This paper discusses the design and fabrication of digital circuits (primarily shift registers) for display and other active‐matrix driving applications on flexible substrates. The unique advantages of the substrate material and their relation to circuit performance are indicated. A high temperature fabrication process for laser annealed polycrystalline silicon MOS transistors on stainless steel foils is outlined, resulting in effective mobility values up to 267cm2/Vs for n‐channel and 88cm2/Vs for p‐channel devices. Transistor CMOS inverters with a minimum propagation delay of 1.02ns per inverter stage are reported. Both static and dynamic register designs with a high degree of integration are reported, having maximum operating frequencies up to 1.5MHz and 2.5MHz respectively, at supply voltages of 10V or less. These results constitute the first realization of this level of performance and complexity on flexible substrates, and demonstrate the feasibility of high‐speed digital circuitry on thin foils suited for ‐ but not limited to‐ active matrix array driving.
3.4: Invited Paper: Developments of Transmissive a‐Si TFT‐LCD using Low Temperature Processes on Plastic Substrate
Authors: Kim B. S. , Hong M. , Lee Y. U. , Ryu M. S. , Choi T. Y. , Huh J. M. , Seo J. H. , Lee W. J. , Park A. N. , Rho S. G. , Kim S. I. , Lim J. S. , Chung K. , Won S. H. , Chung J. K. , Ahn J. H. , Jang J. , Kwon S.‐B. , Kim W. S. , Min K. S. , Choi M. S. , Kim H. S.
Published: January 2005

In this paper, we describe the formatting guidelines for the SID: International Symposium Digest of Technical Papers. By downloading this template from the website, you will have the formats for your article, so that it can be electronically submitted.
4.2: Development of a Novel Transflective Color LTPS‐LCD with Cap‐Divided VA‐Mode
Authors: Kang Seung‐Gon , Kim Seong‐Ho , Song Seock‐Cheon , Park Won‐Sang , Yi Chung , Kim Chi‐Woo , Chung Kyu‐Ha
Published: January 2005

A novel transflective VA‐mode to realize the good display performance was developed. In order to drive both transmissive and reflective modes simultaneously without any modulation of gamma in a single‐gap structure, we have introduced a new design concept into the reflective region of each pixel, where the capacitance is separated into liquid crystal(CLC) and organic layer(COL), playing a key role as a voltage divider in our cap‐divided VA‐mode. With this single‐gamma driving method, quite suitable for practical application to the mobile multimedia system due to its merits of simplifying processes and good legibility, we have achieved good optical characteristics such as high contrast ratio and wide viewing angle in a single‐gap homeotropic panel design.
5.2: A High Efficiency Phosphorescent White OLED for LCD Backlight and Display Applications
Authors: Tung Yeh‐Jiun , Ngo Tan , Hack Michael , Brown Julie , Koide Naotaka , Nagara Yoshiaki , Kato Yoshifumi , Ito Hironori
Published: January 2005

We demonstrate a three‐component RGB phosphorescent white OLED with efficiencies of 38 cd/A, 18.4 lm/W, and 16% EQE at 1000 cd/m2 and CIE coordinates of (0.39, 0.39). The CRI is 79, indicating good suitability for use in full‐color LCD backlights and OLED displays based on RGB color filters. High performance is attributed to use of all phosphorescent dopants (red, green and blue). To the best of the authors' knowledge, this device is the highest efficiency white OLED reported to date in the literature.
3.1: MVA LCD for Notebook or Mobile PCs with High Transmittance, High Contrast Ratio, and Wide Angle Viewing
Authors: Yoshida Hidefumi , Tasaka Yasutoshi , Tanaka Yoshinori , Sukenori Hidetoshi , Koike Yoshio , Okamoto Kenji
Published: January 2005

We have developed a new MVA‐LCD with high transmittance comparable to a TN‐LCD. We stacked a pair of quarter wave plates and stabilized the molecular alignment by dividing each pixel and arranging fine slits and nipple‐shaped protrusions. The quality affordable for desk‐top monitor is realized for mobile display.
7.1: Invited Paper: Plotting the Course of the Next VESA Flat Panel Display Measurements Standard
Authors: Kelley Edward F.
Published: January 2005

The Display Metrology Committee of the Video Electronics Standards Association is developing the next Flat Panel Display Measurements Standard. The document's philosophy and the standard's acceptance are reviewed. New directions will be reviewed, including more diagnostics, robust reflection measurements and their scaling, motion artifacts, and robustness of the measurement.
8.1: Improvement of the Discharge Time lag and Luminous Efficiency in an AC ‐ PDP with 200μm Sustain Gap
Authors: Lee Seung Hun , Lee Jae Hyun , Lee Kyo Sung , Shin Bhum Jae , Choi Kyung Cheol
Published: January 2005

The characteristics of 200 μm sustain‐gap discharge in an AC PDP with auxiliary electrode and high Xe content were investigated. When the voltage of the pulse applied to auxiliary electrode during sustain period was the range of 20–50 volt, the luminance and luminous efficiency of Ne+13% gas mixture discharges in an AC PDP with 200 μm sustain‐gap had their maximum value. The luminous efficiency was improved by 166% in comparison with that of the conventional structure with Ne+4% Xe gas‐mixture. Using the pulse applied to the auxiliary electrode during address period, the discharge time lag of address pulse was improved by 55%.
8.2: New Electrode Structure to Improve Discharge Characteristics in AC PDPs
Authors: Son Seung‐Hyun , Kim Young‐Mo , Hatanaka Hidekazu , Jang Sang‐Hun , Kim Gi‐Young , Park Hyoung‐Bin , Lee Seong‐Eui , Kang Kyoung‐Doo , Heo Eun‐Gi
Published: January 2005

A new structure including igniter electrode is proposed to achieve a low sustaining voltage and high luminous efficacy. By measuring minimum sustaining voltage(Vsm), discharge current(Ion), displacement current(Ioff) and brightness of the light from a 6‐inch AC PDP, performances of the conventional structure and the igniter structure are compared. When compared with the conventional structure, the igniter structure showed 10% Vsm improvement at the Ne‐Xe(10%) gas mixture of 600 mbar. Therefore, we could apply the higher partial pressure of Ne‐Xe(12%) to the igniter structure, which results in 42% luminous efficacy improvement at the similar sustaining voltage range.
Electro‐optic properties of an intrinsic half‐V‐mode FLCD and its application to field‐sequential full‐color LCDs using a poly‐Si TFT matrix array
Authors: Furuta Hirokazu , Xu Jun , Kobayashi Shunsuke
Published: January 2005

Abstract— An intrinsic half‐V‐mode ferroelectric liquid‐crystal display (FLCD) exhibiting a high contrast ratio (300:1), owing to defect‐free gray‐scale capability, with a high response speed (τ ≅ 400 μsec) and good switchability with TFTs, has been developed. Furthermore, this FLCD features high‐temperature reliability owing to the use of a special hybrid alignment technique. We successfully fabricated an active‐matrix poly‐Si TFT field‐sequential full‐color (FS FC) LCD with XGA specifications and a 0.9‐in. diagonal using a half‐V‐mode FLCD and an RGB light‐emitting‐diode (LED) array microdisplay. It is shown that the fabricated active‐matrix FS FCLCD exhibits good moving‐image performance with high full‐color display capability.
An integrated poly‐Si TFT current data driver with a data‐line pre‐charge function
Authors: Shimoda M. , Abe K. , Haga H. , Asada H. , Hayama H. , Iguchi K. , Iga D. , Imura H. , Miyano S.
Published: January 2005

Abstract— We have developed an integrated poly‐Si TFT current data driver with a data‐line pre‐charge function for active‐matrix organic light‐emitting diode (AMOLED) displays. The current data driver is capable of outputting highly accurate (±0.8%) current determined by 6‐bit digital input data. A novel current‐programming approach employing a data‐line pre‐charge function helps achieve accurate current programming at low brightness. A 1.9‐in. 120 × 136‐pixel AMOLED display using these circuits was demonstrated.
Tracking system of the Fast‐Intelligent‐Tracking (F!T) tube
Authors: van den Brink H. B. , Willemsen O. H.
Published: January 2005

Abstract— In this paper, we describe the principles of the tracking system of the Fast Intelligent Tracking (F!T) tube. We will show how the tracking system is divided in a fast‐responding system and a slowly responding system, according to the observed deviations of the beam positions from their intended positions.