bluuebunny/crossref_metadata_2025 huggingface dataset:
Pretreatment Plasma Folate Modulates the Pharmacodynamic Effect of High-Dose Methotrexate in Children with Acute Lymphoblastic Leukemia and Non-Hodgkin Lymphoma: “Folate Overrescue” Concept Revisited
Authors: Sterba Jaroslav , Dusek Ladislav , Demlova Regina , Valik Dalibor
Published: February 2006

Background: To evaluate the influence of pretreatment plasma folate concentrations on methotrexate exposure in children with acute lymphoblastic leukemia/non-Hodgkin lymphoma treated with high-dose methotrexate, we assessed time profiles of plasma homocysteine, folate, and vitamin B12 concentrations in children treated with high-dose methotrexate with leucovorin rescue.

Methods: We analyzed 98 treatment courses. The study endpoints were to determine how methotrexate exposure is related to homocysteine accumulation and whether it is influenced by pretreatment plasma folate.

Results: Peak concentrations of homocysteine increased from the start of the intravenous infusion through cessation of methotrexate therapy up to time point t42, when this trend was reversed by administration of folinic acid. The area under the curve (AUC) for plasma homocysteine showed decreasing course-to-course tendencies with a statistically significant decrease only between courses 1 and 2 (P ≤0.05), indicating decreased whole-body homocysteine accumulation in response to administration of consecutive methotrexate courses. Therapeutic courses with low initial folate concentrations (≤10 nmol/L) gave significantly higher responses in homocysteine accumulation expressed both as hcysAUC0–66 h and the peak t42 homocysteine concentrations than did courses with initial folate >10 nmol/L. Correspondingly, in the courses with low initial folate, peak plasma concentrations of methotrexate were significantly higher than in courses with high precourse concentrations of plasma folate.

Conclusion: Endogenous pretreatment plasma folate modulates the magnitude of the methotrexate effect, providing support for a “folate overrescue” concept.
The Chloride Transporter Na+-K+-Cl−Cotransporter Isoform-1 Contributes to Intracellular Chloride Increases afterIn VitroIschemia
Authors: Pond Brooks B. , Berglund Ken , Kuner Thomas , Feng Guoping , Augustine George J. , Schwartz-Bloom Rochelle D.
Published: February 2006

Ischemic episodes in the CNS cause significant disturbances in neuronal ionic homeostasis. To directly measure changes in intracellular Cl−concentration ([Cl−]i) during and after ischemia, we used Clomeleon, a novel ratiometric optical indicator for Cl−. Hippocampal slices from adult transgenic mice expressing Clomeleon in hippocampal neurons were subjected to 8 min of oxygen-glucose deprivation (OGD) (anin vitromodel for ischemia) and reoxygenated in the presence of glucose. This produced mild neuronal damage 3 h later that was prevented when the extracellular [Cl−] was maintained at 10 mmduring reoxygenation. OGD induced a transient decrease in fluorescence resonance energy transfer within Clomeleon, indicating an increase in [Cl−]i. During reoxygenation, there was a partial recovery in [Cl−]i, but [Cl−]irose again 45 min later. To investigate sources of Cl−accumulation, we examined the effects of Cl−transport inhibitors on the rises in [Cl−]iduring and after OGD. Bumetanide and furosemide, which inhibit Cl−influx through the Na+-K+-Cl−cotransporter isoform-1 (NKCC-1) and efflux through the K+-Cl−cotransporter isoform-2, were unable to inhibit the first rise in [Cl−]i, yet entirely prevented the secondary rise in [Cl−]iduring reoxygenation. In contrast, picrotoxin, which blocks the GABA-gated Cl−channel, did not inhibit the secondary rise in [Cl−]iafter OGD. [Cl−]iincreases during reoxygenation were accompanied by an increase in phosphorylation of NKCC-1, an indication of increased NKCC-1 activity after OGD. We conclude that NKCC-1 plays an important role in OGD-induced Cl−accumulation and subsequent neuronal damage.
Intracranial Delivery of CLN2 Reduces Brain Pathology in a Mouse Model of Classical Late Infantile Neuronal Ceroid Lipofuscinosis
Authors: Passini Marco A. , Dodge James C. , Bu Jie , Yang Wendy , Zhao Qi , Sondhi Dolan , Hackett Neil R. , Kaminsky Stephen M. , Mao Qinwen , Shihabuddin Lamya S. , Cheng Seng H. , Sleat David E. , Stewart Gregory R. , Davidson Beverly L. , Lobel Peter , Crystal Ronald G.
Published: February 2006

Classical late infantile neuronal ceroid lipofuscinosis (cLINCL) is a lysosomal storage disorder caused by mutations inCLN2, which encodes lysosomal tripeptidyl peptidase I (TPP1). Lack of TPP1 results in accumulation of autofluorescent storage material and curvilinear bodies in cells throughout the CNS, leading to progressive neurodegeneration and death typically in childhood. In this study, we injected adeno-associated virus (AAV) vectors containing the human CLN2 cDNA into the brains ofCLN2−/−mice to determine therapeutic efficacy. AAV2CUhCLN2 or AAV5CUhCLN2 were stereotaxically injected into the motor cortex, thalamus, and cerebellum of both hemispheres at 6 weeks of age, and mice were then killed at 13 weeks after injection. Mice treated with AAV2CUhCLN2 and AAV5CUhCLN2 contained TPP1 activity at each injection tract that was equivalent to 0.5- and 2-fold that ofCLN2+/+control mice, respectively. Lysosome-associated membrane protein 1 immunostaining and confocal microscopy showed intracellular targeting of TPP1 to the lysosomal compartment. Compared with control animals, there was a marked reduction of autofluorescent storage in the AAV2CUhCLN2 and AAV5CUhCLN2 injected brain regions, as well as adjacent regions, including the striatum and hippocampus. Analysis by electron microscopy confirmed a significant decrease in pathological curvilinear bodies in cells. This study demonstrates that AAV-mediated TPP1 enzyme replacement corrects the hallmark cellular pathologies of cLINCL in the mouse model and raises the possibility of using AAV gene therapy to treat cLINCL patients.
Synaptic Ras GTPase Activating Protein Regulates Pattern Formation in the Trigeminal System of Mice
Authors: Barnett Mark W. , Watson Ruth F. , Vitalis Tania , Porter Karen , Komiyama Noboru H. , Stoney Patrick N. , Gillingwater Thomas H. , Grant Seth G. N. , Kind Peter C.
Published: February 2006

The development of ordered connections or “maps” within the nervous system is a common feature of sensory systems and is crucial for their normal function. NMDA receptors are known to play a key role in the formation of these maps; however, the intracellular signaling pathways that mediate the effects of glutamate are poorly understood. Here, we demonstrate that SynGAP, a synaptic Ras GTPase activating protein, is essential for the anatomical development of whisker-related patterns in the developing somatosensory pathways in rodent forebrain. Mice lacking SynGAP show only partial segregation of barreloids in the thalamus, and thalamocortical axons segregate into rows but do not form whisker-related patches. In cortex, layer 4 cells do not aggregate to form barrels. InSyngap+/−animals, barreloids develop normally, and thalamocortical afferents segregate in layer 4, but cell segregation is retarded. SynGAP is not necessary for the development of whisker-related patterns in the brainstem. Immunoelectron microscopy for SynGAP from layer 4 revealed a postsynaptic localization with labeling in developing postsynaptic densities (PSDs). Biochemically, SynGAP associates with the PSD in a PSD-95-independent manner, andPsd-95−/−animals develop normal barrels. These data demonstrate an essential role for SynGAP signaling in the activity-dependent development of whisker-related maps selectively in forebrain structures indicating that the intracellular pathways by which NMDA receptor activation mediates map formation differ between brain regions and developmental stage.
Layer Positioning of Late-Born Cortical Interneurons Is Dependent on Reelin But Not p35 Signaling
Authors: Hammond Vicki , So Eva , Gunnersen Jenny , Valcanis Helen , Kalloniatis Michael , Tan Seong-Seng
Published: February 2006

We tested the response of interneurons to the absence of Reelin signaling or p35 in the mouse neocortex. We provide three independent strands of evidence to demonstrate that layering of late-born (but not early-born) interneurons is regulated by Reelin signaling. First, early-born and late-born interneurons behaved differently in mice lacking Reelin or disabled 1 (Dab1). Early-born interneurons showed layer inversion, whereas late-born interneurons did not demonstrate layer inversion but were randomly distributed across the cortex. Second, inp35mutant brains (in which Reelin signaling is intact), late-born interneurons are appropriately positioned in the upper layers despite the malpositioning of all other cortical neurons in these mice. Third, transplanted late-born interneuron precursors (wild type) intoDab1−/−cortices showed appropriate upper layer segregation. Together, these results indicate that, in the absence of Reelin signaling, late-born interneurons fail to laminate properly, and this is restored in an environment in which Reelin signaling is intact. These studies suggest different mechanisms for the stratification of cortical interneurons. Whereas the early-born interneurons appear to be associated with projection neuron layering, late-born interneurons rely on Reelin signaling for their correct lamination.
Neuromechanics of Coordination during Swallowing inAplysia californica
Authors: Ye Hui , Morton Douglas W. , Chiel Hillel J.
Published: February 2006

Bernstein (1967) hypothesized that preparation of the periphery was crucial for correct responses to motor output. To test this hypothesis in a behaving animal, we examined the roles of two identified motor neurons, B7 and B8, which contribute to feeding behavior in the marine molluskAplysia californica. Neuron B7 innervates a hinge muscle and has no overt behavioral effect during smaller-amplitude (type A) swallows, because the hinge muscle is too short to exert force. Neuron B8 activates a muscle (I4) that acts solely to grasp material during type A swallows. During larger-amplitude (type B) swallows, the behavioral actions of both motor neurons change, because the larger-amplitude anterior movement of the grasper sets up the periphery to respond differently to motor outputs. The larger anterior movement stretches the hinge muscle, so that activating neuron B7 mediates the initial retraction phase of swallowing. The changed position of the I4 muscle allows neuron B8 not only to induce grasping but also to pull material into the buccal cavity, contributing to retraction. Thus, larger-amplitude swallows are associated with the expression of two new degrees of freedom (use of the hinge to retract and use of the grasper to retract) that are essential for mediating type B swallows. These results provide a direct demonstration of Bernstein's hypothesis that properly positioning the periphery can be crucial for its ability to correctly respond to motor output and also demonstrate that biomechanical context can alter the functions of identified motor neurons.
The Level and Integrity of Synaptic Input Regulates Dendrite Structure
Authors: Sorensen Staci A. , Rubel Edwin W.
Published: February 2006

How localized synaptic input regulates dendritic branch structure is not well understood. For these experiments, we used single-cell electroporation, live cell imaging,in vitrodeafferentation, pharmacology, and electrophysiological stimulation to study how local alterations in synaptic input affect dendritic branch structure in nucleus laminaris (NL). We found that interrupting or modulating synaptic input to distinct sets of NL dendrites can regulate their structure on a very short timescale. Specifically, eliminating synaptic input by deafferenting only one set of the bitufted NL dendrites caused a selective reduction in the total dendritic branch length of the deafferented dendrites but relatively few changes in the normally innervated dendrites on the same cell. An analysis of individual dendritic branch changes demonstrated that both control and deafferented NL dendrites exhibit branch extension and retraction. However, the presence of intact synaptic inputs balanced these changes, maintaining the total dendritic branch length of control dendrites. When glutamate receptor signaling was blocked (DNQX and AP-5), NL neurons exhibited significant dendrite retraction, demonstrating that NL dendrite maintenance depends in part on presynaptic glutamatergic input. Electrophysiological experiments further confirmed that modulating the level of synaptic input regulates NL dendrite structure. Differential stimulation of the two sets of dendrites resulted in a selective reduction in the total dendritic branch length of the unstimulated dendrites and a selective increase in the total dendritic branch length of the stimulated dorsal dendrites. These results suggest that balanced activation of the two sets of NL dendrites is required to maintain the relative amount of dendritic surface area allotted to each input.
Simultaneous Release of Glutamate and Acetylcholine from Single Magnocellular “Cholinergic” Basal Forebrain Neurons
Authors: Allen Timothy G.J. , Abogadie Fe C. , Brown David A.
Published: February 2006

Basal forebrain (BF) neurons provide the principal cholinergic drive to the hippocampus and cortex. Their degeneration is associated with the cognitive defects of Alzheimer’s disease. Immunohistochemical studies suggest that some of these neurons contain glutamate, so might also release it. To test this, we made microisland cultures of single BF neurons from 12- to 14-d-old rats. Over 1–8 weeks in culture, neuronal processes made autaptic connections onto the neuron. In 34 of 36 cells tested, a somatically generated action potential was followed by a short-latency EPSC that was blocked by 1 mmkynurenic acid, showing that they released glutamate. To test whether the same neuron also released acetylcholine, we placed a voltage-clamped rat myoball expressing nicotinic receptors in contact with a neurite. In six of six neurons tested, the glutamatergic EPSC was accompanied by a nicotinic (hexamethonium-sensitive) myoball current. Stimulation of the M2-muscarinic presynaptic receptors (characterized using tripitramine and pirenzepine) produced a parallel inhibition of autaptic glutamatergic and myoball nicotinic responses; metabotropic glutamate receptor stimulation produced similar but less consistent and weaker effects. Atropine enhanced the glutamatergic EPSCs during repetitive stimulation by 25 ± 6%; the anti-cholinesterase neostigmine reduced the train EPSCs by 37 ± 6%. Hence, synaptically released acetylcholine exerted a negative-feedback inhibition of coreleased glutamate. We conclude that most cholinergic basal forebrain neurons are capable of releasing glutamate as a cotransmitter and that the release of both transmitters is subject to simultaneous feedback inhibition by synaptically released acetylcholine. This has implications for BF neuron function and for the use of cholinesterase inhibitors in Alzheimer’s disease.
Hippocampal CA3 NMDA Receptors Are Crucial for Adaptive Timing of Trace Eyeblink Conditioned Response
Authors: Kishimoto Yasushi , Nakazawa Kazu , Tonegawa Susumu , Kirino Yutaka , Kano Masanobu
Published: February 2006

Classical conditioning of the eyeblink reflex is a simple form of associative learning for motor responses. To examine the involvement of hippocampal CA3 NMDA receptors (NRs) in nonspatial associative memory, mice lacking an NR1 subunit selectively in adult CA3 pyramidal cells [CA3-NR1 knock-out (KO) mice] were subjected to eyeblink conditioning paradigms. Mice received paired presentations of an auditory conditioned stimulus (CS) and a periorbital shock unconditioned stimulus (US). With repeated presentation of the CS followed by the US, wild-type mice learned to blink in anticipation of the US before its onset. We first confirmed that wild-type mice require an intact hippocampus in the trace version of eyeblink conditioning in which the CS and US do not overlap, creating a stimulus-free time gap of 500 ms. Under the same condition, CA3-NR1 KO mice successfully acquired conditioned responses (CRs) during the 10 d acquisition sessions, whereas the extinction of CRs was impaired on the first day of extinction sessions. Importantly, CA3-NR1 KO mice were impaired in the formation of an adaptively timed CR during the first five trials in the daily acquisition sessions. The aberrantly timed CR was also observed in the extinction sessions in accordance with the impaired extinction of CRs. These results indicate that CA3-NR1 KO mice are unable to rapidly retrieve adaptive CR timing, suggesting that CA3 NRs play a crucial role in the memory of adaptive CR timing in trace conditioning.
Presynaptic, Activity-Dependent Modulation of Cannabinoid Type 1 Receptor-Mediated Inhibition of GABA Release
Authors: Földy Csaba , Neu Axel , Jones Mathew V. , Soltesz Ivan
Published: February 2006

Endocannabinoid signaling couples activity-dependent rises in postsynaptic Ca2+levels to decreased presynaptic GABA release. Here, we present evidence from paired recording experiments that cannabinoid-mediated inhibition of GABA release depends on the firing rates of the presynaptic interneurons. Low-frequency action potentials inpost hocidentified cholecystokinin-positive CA1 basket cells elicited IPSCs in the postsynaptic pyramidal cells that, as expected, were fully abolished by the exogenous application of the cannabinoid receptor agonist WIN55,212-2 [R-(+)-(2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrol[1,2,3-de]-1,4-benzoxazin-6-yl)(1-naphthalenyl) methanone monomethanesulfonate] at 5 μm. However, the presynaptic basket cells recovered from the cannabinoid agonist-induced inhibition of GABA release when the presynaptic firing rate was increased to ≥20 Hz. Pharmacological experiments showed that the recovered transmission was exclusively dependent on presynaptic N-type Ca2+channels. Furthermore, the increased presynaptic firing could also overcome even complete depolarization-induced suppression of inhibition, indicating that the magnitude of DSI markedly depends on the activity levels of basket cells. These results reveal a new locus of activity-dependent modulation for endocannabinoid signaling and suggest that endocannabinoid-mediated inhibition of GABA release may differ in distinct behavioral states.
Retinoid-Related Orphan Receptor α Controls the Early Steps of Purkinje Cell Dendritic Differentiation
Authors: Boukhtouche Fatiha , Janmaat Sonja , Vodjdani Guilan , Gautheron Vanessa , Mallet Jacques , Dusart Isabelle , Mariani Jean
Published: February 2006

Dendritic differentiation involves both regressive and growth events. The mechanisms controlling the regressive events are poorly understood. This study is aimed at determining the role of the nuclear receptor retinoid-related orphan receptor α (RORα) in Purkinje cell (PC) dendritic differentiation in organotypic cultures. As observedin vivo, in these cultures, fusiform PCs with embryonic bipolar shape undergo regression before the outgrowth of the ultimate dendritic tree. We show that lentiviral-mediated hRORα1 overexpression in fusiform PCs leads to a cell-autonomous accelerated progression of dendritic differentiation. In addition, RORα is necessary for the PC regressive events: whereasstaggererRORα-deficient PCs remain in the embryonic fusiform stage, replacement of hRORα1 restores normal dendritogenesis. These results demonstrate that RORα expression in fusiform PCs is crucial for the dendritic regression and progression of the following step of extension of dendritic processes. However, it does not seem to participate to the last stage of dendritic growth. This study identifies RORα as a nuclear receptor crucial for the control of dendritic remodeling during development.
A Specific Role for NR2A-Containing NMDA Receptors in the Maintenance of Parvalbumin and GAD67 Immunoreactivity in Cultured Interneurons
Authors: Kinney Jefferson W. , Davis Christopher N. , Tabarean Iustin , Conti Bruno , Bartfai Tamas , Behrens M. Margarita
Published: February 2006

Several lines of evidence suggest that a hypoglutamatergic condition may induce a phenotypic loss of cortical parvalbumin (PV)-positive GABAergic interneurons, such as that observed in brain tissue of schizophrenic subjects. However, it is not known whether the loss of PV interneurons is a consequence of the hypoglutamatergic condition or a secondary aspect of the disease. We characterized the signaling and subunit expression of NMDA receptors in cultured cortical PV interneurons and determined whether a hypoglutamatergic condition, created by direct application of sublethal concentrations of ketamine or subunit-selective NMDA receptor antagonists, can affect the expression of the GABAergic markers as observedin vivo. Real-time PCR performed on mRNA isolated from single neurons showed that PV interneurons present a fivefold higher NR2A/NR2B ratio than pyramidal neurons. Brief, nontoxic, exposure to NMDA led to an increase in ERK1/2 (extracellular signal-regulated kinase 1/2) and cAMP response element-binding protein phosphorylation in PV interneurons, and this increase was blocked by the NR2A-selective antagonist NVP-AAM077. Application of the nonselective NMDA receptor antagonist ketamine, at sublethal concentrations, induced a time and dose-dependent decrease in parvalbumin and GAD67 immunoreactivity specifically in PV interneurons. These effects were reversible and were also observed with the NR2A-selective antagonist, whereas the NR2B-selective antagonist Ro-25-6981 only partially reduced GAD67 immunoreactivity. Coexposure to the calcium channel opener BayK, or the group I metabotropic glutamate receptor agonist DHPG [(RS)-3,5-dihydroxyphenylglycine] attenuated the decrease in GAD67 and parvalbumin induced by the NMDA receptor antagonists. These results suggest that the activity of NR2A-containing NMDA receptors play a pivotal role in the maintenance of the GABAergic function of PV interneurons.
Coordination and Modulation of Locomotion Pattern Generators inDrosophilaLarvae: Effects of Altered Biogenic Amine Levels by the Tyramine β Hydroxlyase Mutation
Authors: Fox Lyle E. , Soll David R. , Wu Chun-Fang
Published: February 2006

Forward locomotion ofDrosophila melanogasterlarvae is composed of rhythmic waves of contractions that are thought to be produced by segmentally organized central pattern generators. We present a systematic description of spike activity patterns during locomotive contraction waves in semi-intact wild-type and mutant larval preparations. We have shown previously thatTβhnM18mutants, with altered levels of octopamine and tyramine, have a locomotion deficit. By recordingen passantfrom the segmental nerves, we investigated the coordination of the neuronal activity driving contraction waves of the abdominal body-wall muscles. Rhythmic bursts of activity that occurred concurrently with locomotive waves were frequently observed in wild-type larvae but were rarely seen inTβhnM18mutants. These centrally generated patterned activities were eliminated in the distal stumps of both wild-type andTβhnM18larvae after severing the segmental nerve from the CNS. Patterned activities persisted in the proximal stumps deprived of sensory feedback from the periphery. Simultaneous recordings demonstrated a delay in the bursting activity between different segments, with greater delay for segments that were farther apart. In contrast, bilateral recordings within a single segment revealed a well synchronized activity pattern in nerves innervating each hemisegment in both wild-type andTβhnM18larvae. Significantly, rhythmic patterns of bursts and waves could be evoked inTβhnM18mutants by head or tail stimulation despite their highly irregular spontaneous activities. These observations suggest a role of the biogenic amines in the initiation and modulation of motor pattern generation. The technique presented here can be readily extended to examine the locomotion motor program of other mutants.
Systematischer Entwurf eines signalbasierten Fehlerdiagnosesystems, Teil 2 (A Systematic Designing Approach for Signal-based Fault Diagnosis System, Part 2)
Authors: Feid Michael , Pandit Madhukar
Published: February 2006

In Teil 1 des vorliegenden Aufsatzes wurden die Grundlagen des Entwurfs eines erweiterten signalbasierten Fehlerdiagnosesystems beschrieben. In Teil 2 werden die beschriebenen Verfahren für den Entwurf eines Diagnosesystems eines pneumatischen Stellventils als praktisches Beispiel angewendet.
Flachheitsbasierte Steuerstrategien für Batch-Reaktoren (Flatness based Feedforward Control Strategies for Batch Reactors)
Authors: Pfeiffer Bernd-Markus , Schneider Matthias
Published: February 2006

Mit Hilfe der Flachheitsanalyse nichtlinearer dynamischer Systeme wird es erstmals möglich, eine geschlossene analytische Formel zur Berechnung von Steuertrajektorien für Batch-Reaktoren direkt aus den verfahrenstechnischen Spezifikationen des Reaktors herzuleiten. Bisher wurde diese Theorie nur dazu genutzt, spezielle Lösungen für eine einzelne Anwendung zu finden. Jetzt ist es erstmals gelungen, eine im Rahmen von Prozessleitsystemen breit einsetzbare Lösung für eine große Klasse von Chemie-Reaktoren zu finden. Die in der Praxis geforderte Robustheit wird durch Kombination mit einem Trajektorien-Folgeregler erreicht.
Regelkreisüberwachung in der Metallindustrie. Teil 2: Anwendungskonzept und Fallstudie (Control Performance Monitoring in the Metal Industry. Part 2: Application Concept and Case Study)
Authors: Jelali Mohieddine
Published: February 2006

Die Automatisierungssysteme in der Metallindustrie sind in der Regel hierarchisch, d. h. aus mehreren Ebenen aufgebaut, wobei jede Ebene eine große Anzahl von Regelkreisen beinhaltet. Dieser Teil 2 der Arbeit stellt ein neues systematisches Konzept zur kontinuierlichen Regelkreisüberwachung in solchen Automatisierungssystemen vor. Die dabei gewählte Vorgehensweise besteht aus zwei Phasen. In der ersten erfolgt die Festlegung, in welcher Reihenfolge (Top-down oder Bottom-up) die hierarchisch angeordneten Regelkreise zu bewerten sind. Dann wird in der zweiten Phase die Performanceanalyse nach einer Prozedur durchgeführt, die verschiedene Verfahren und Indices des CPM kombiniert. Das Konzept wird an der Performancebewertung einer industriellen Banddickenregelung in einem Kaltwalzwerk demonstriert. Damit gelingt es erstmalig, CPM-Methoden auf einen hochdynamischen Prozess anzuwenden. Bestandteil der Fallstudie ist auch der Vergleich unterschiedlicher Parametrierungsansätze zur Totzeitschätzung und Modellidentifikation.
Toons and Tenants: Settlement and Society in Shetland, 1299–1899
Authors: Church Jonathan , Taaffe Thomas
Published: February 2006

Toons and Tenants: Settlement and Society in Shetland, 1299–1899. Brian Smith. Lerwick, Shetland Islands: The Shetland Times, Ltd. 2000. xviii. 108pp. index. ISBN 1‐898852‐68‐5.
Chemical manipulation of glucose metabolism in porcine oocytes: effects on nuclear and cytoplasmic maturation in vitro
Authors: Herrick Jason R , Brad Amber M , Krisher Rebecca L
Published: February 2006

The objectives of this study were to manipulate metabolism of glucose through glycolysis and the pentose phosphate pathway (PPP) in porcine oocytes during in vitro maturation, and determine the effects of this manipulation on meiotic progression, intracellular glutathione (GSX) concentrations and embryonic development. Cumulus-oocyte complexes isolated from abattoir ovaries were matured (40–44 h) in Purdue Porcine Medium for maturation alone (control) or supplemented with pyrroline-5 carboxylate (PC, 0.1 μM; PPP stimulator), diphenyleneiodonium (DPI, 0.1 μM; PPP inhibitor), dinitrophenol (DNP, 10 μM; glycolytic stimulator), hexametaphosphate (HMP, 100 μM; glycolytic inhibitor), PC + HMP or DNP + DPI. At the conclusion of in vitro maturation, cumulus cells were removed and oocytes were randomly allocated for analysis of GSX, metabolism and nuclear maturation, or in vitro fertilization and embryo culture. Both DPI and DNP + DPI decreased (P ≤ 0.05) the activity of glycolysis and the PPP, increased (P ≤ 0.05) the percentage of immature oocytes, and decreased (P ≤ 0.05) the proportion of mature oocytes compared with control oocytes and oocytes from the other treatments. Embryonic development (cleavage and blastocyst stage) and the intracellular content of GSX were also decreased (P ≤ 0.05) following exposure to DPI or DNP + DPI compared with control oocytes and oocytes from the other treatments. Oocyte metabolism, nuclear maturation, GSX content and embryonic development were unaffected (P > 0.05) following exposure to PC, DNP, HMP or PC + HMP. Our results suggest that metabolism of glucose through the PPP and/or glycolysis plays a key role in the control of nuclear and cytoplasmic maturation of porcine oocytes in vitro.
Parents’ concerns regarding their ART children
Authors: Fisher-Jeffes L J , Banerjee I , Sutcliffe A G
Published: February 2006

A cohort of children conceived by assisted reproductive therapy (ART) – in vitro fertilisation (IVF) and intra-cytoplasmic sperm injection (ICSI) has been followed up in a National Child Development Study (Sutcliffe et al. 1999, 2001 and Bonduelle et al. 2005). Their parents were contacted and asked questions designed to elicit any concerns on their part about their child. 329 replies were received (90% response rate), and 86 of the families posed additional questions. We found that a small number of parents (26% of respondents) raised questions about a variety of issues regarding their ART-conceived child. The most commonly expressed theme (8% of all respondents, or 27/86 (31%) of the respondents with questions) pertained to their child’s future fertility. This question was asked more frequently by ICSI than IVF parents.
Regulation of dynamic events by microfilaments during oocyte maturation and fertilization
Authors: Sun Qing-Yuan , Schatten Heide
Published: February 2006

Actin filaments (microfilaments) regulate various dynamic events during oocyte meiotic maturation and fertilization. In most species, microfilaments are not required for germinal vesicle breakdown and meiotic spindle formation, but they mediate peripheral nucleus (chromosome) migration, cortical spindle anchorage, homologous chromosome separation, cortex development/maintenance, polarity establishment, and first polar body emission during oocyte maturation. Peripheral cortical granule migration is controlled by microfilaments, while mitochondria movement is mediated by microtubules. During fertilization, microfilaments are involved in sperm incorporation, spindle rotation (mouse), cortical granule exocytosis, second polar body emission and cleavage ring formation, but are not required for pronuclear apposition (except for the mouse). Many of the events are driven by the dynamic interactions between myosin and actin filaments whose polymerization is regulated by RhoA, Cdc42, Arp2/3 and other signaling molecules. Studies have also shown that oocyte cortex organization and polarity formation mediated by actin filaments are regulated by mitogen-activated protein kinase, myosin light-chain kinase, protein kinase C and its substrate p-MARKS as well as PAR proteins. The completion of several dynamic events, including homologous chromosome separation, spindle anchorage, spindle rotation, vesicle organelle transport and pronuclear apposition (mouse), requires interactions between microfilaments and microtubules, but determination of how the two systems of the cytoskeleton precisely cross-link, and which proteins link microfilaments to microtubules to perform functions in eggs, requires further studies. Finally, the meaning of microfilament-mediated oocyte polarity versus embryo polarity and embryo development in different species (Drosophila, Xenopus and mouse) is discussed.
Body composition, dietary carbohydrates and fatty acids determine post-fertilisation development of bovine oocytes in vitro
Authors: Adamiak S J , Powell K , Rooke J A , Webb R , Sinclair K D
Published: February 2006

This study assessed the interactive effects of carbohydrate type (fibre vs starch) and fatty acid (FA) supplementation (0% vs 6% calcium soaps of palm oil FA) on the post-fertilisation development of oocytes recovered from low and moderate body condition score (BCS) heifers. A secondary objective was to compare the FA composition of plasma to that of granulosa cells (GCs) and cumulus–oocyte complexes (COCs) from these animals, and to relate these findings to the developmental potential of oocytes. Plasma, GCs and COCs were recovered from 32 heifers on day 5 of a synchronised oestrous cycle for FA analyses. Oocytes were also recovered on days 10 and 15 of the same cycle after short-term ovarian stimulation (FSH + GnRH), and matured, fertilised and cultured to the blastocyst stage in vitro. High levels of dietary starch increased (P < 0.01) plasma insulin but, together with dietary FA, reduced (P < 0.05) blastocyst yields in low, but not in moderate, BCS heifers. Diet-induced alterations to the FA content of plasma were less apparent in GCs and COCs. In summary, although dietary lipids increased the FA content of COCs, the selective uptake of saturated FAs at the expense of mainly polyunsaturated FAs within the follicular compartment ensured that the FA composition of COCs was largely unaffected by diet. However, the concentration of saturated FAs within COCs was inherently high, and so further increases in FA content may have impaired post-fertilisation development. The data establish a robust nutritional framework for more detailed studies into the mechanistic effects of dietary composition on the post-fertilisation developmental potential of oocytes.
Evidence for heterodimeric association of leukemia inhibitory factor (LIF) receptor and gp130 in the mouse uterus for LIF signaling during blastocyst implantation
Authors: Song Haengseok , Lim Hyunjung
Published: February 2006

Implantation failure in mice lacking leukemia inhibitory factor (LIF) establishes that this cytokine is crucial to this process. LIF transcripts are expressed in the uterus in a biphasic manner: LIF is expressed in the gland on the morning of day 4 and again in stromal cells surrounding the blastocyst with the onset of implantation in the evening of day 4 of pregnancy. However, it is not yet clear whether both phases of LIF expression are required for implantation, since the receptor usage by uterine LIF still remains elusive. Here we have provided evidence that major cell types expressing theLIF receptor (LIFR) and its signal transducing partner gp130 are mostly disparate in the mouse uterus during the glandular LIF expression in the morning of day 4. In contrast, LIFR and gp130 expressions overlap in the luminal epithelium at the time of blastocyst attachment on the evening of day 4 when the second phase of LIF expression occurs in stromal cells surrounding the blastocyst, suggesting that LIF participates in implantation in a paracrine manner. Similar expression patterns for LIFR and gp130 were observed when a delayed implantation model was used. For example, a transient overlapping expression of LIFR and gp130 was evident at 12 h after estrogen-induced termination of delayed implantation. Coimmunoprecipitation experiments showed that LIFR and gp130 form heterodimers and are available for LIF signaling at the time of blastocyst attachment. We have also shown that an intra-peritoneal administration of recombinant LIF in LIF-deficient pregnant mice on the evening of day 4, close to the time when the second phase of LIF expression is normally observed, is sufficient to rescue implantation failure, and that there is no evidence of antagonistic action by soluble forms of the receptors. Collectively, our results have provided evidence that LIFR and gp130 form a functional heterodimer in the uterus during the attachment reaction to direct LIF signaling.
Unique Evolutionary Mechanism in R-Genes Under the Presence/Absence Polymorphism in Arabidopsis thaliana
Authors: Shen Jingdan , Araki Hitoshi , Chen Lingling , Chen Jian-Qun , Tian Dacheng
Published: February 2006

While the presence/absence polymorphism is commonly observed in disease resistance (R-) genes in Arabidopsis, only a few R-genes under the presence/absence polymorphism (R-P/A) have been investigated. To understand the mechanism of the molecular evolution of R-P/A, we investigated genetic variation of nine R-P/A in A. thaliana from worldwide populations. The number of possessed R-genes varied widely among accessions (two to nine, on average 4.3 ± 1.6/accession). No pair of accessions shared the same haplotype, and no clear geographic differentiation was observed with respect to the pattern of presence/absence of the R-genes investigated. Presence allele frequencies also varied among loci (25–70%), and no linkage disequilibrium was detected among them. Although the LRR region in regular R-genes is known to be highly polymorphic and has a high Ka/Ks ratio in A. thaliana, nucleotide sequences of this region in the R-P/A showed a relatively low level of genetic variation (π = 0.0002–0.016) and low Ka/Ks (0.03–0.70, <1). In contrast, the nucleotide diversities around the deletion junction of R-P/A were constantly high between presence and absence accessions for the R-genes (Dxy = 0.031–0.103). Our results suggest that R-P/A loci evolved differently from other R-gene loci and that balancing selection plays an important role in molecular evolution of R-P/A.
Efficient Gene Targeting in Drosophila With Zinc-Finger Nucleases
Authors: Beumer Kelly , Bhattacharyya Gargi , Bibikova Marina , Trautman Jonathan K , Carroll Dana
Published: February 2006

This report describes high-frequency germline gene targeting at two genomic loci in Drosophila melanogaster, y and ry. In the best case, nearly all induced parents produced mutant progeny; 25% of their offspring were new mutants and most of these were targeted gene replacements resulting from homologous recombination (HR) with a marked donor DNA. The procedure that generates these high frequencies relies on cleavage of the target by designed zinc-finger nucleases (ZFNs) and production of a linear donor in situ. Increased induction of ZFN expression led to higher frequencies of gene targeting, demonstrating the beneficial effect of activating the target. In the absence of a homologous donor DNA, ZFN cleavage led to the recovery of new mutants at three loci—y, ry and bw—through nonhomologous end joining (NHEJ) after cleavage. Because zinc fingers can be directed to a broad range of DNA sequences and targeting is very efficient, this approach promises to allow genetic manipulation of many different genes, even in cases where the mutant phenotype cannot be predicted.
Prenatal Diagnosis of Familial Type I Choledochal Cyst
Authors: Clifton Matthew S. , Goldstein Ruth B. , Slavotinek Anne , Norton Mary E. , Lee Hanmin , Farrell Jody , Nobuhara Kerilyn K.
Published: February 2006

Familial choledochal cysts are extremely rare. High-resolution ultrasound now allows for the antenatal diagnosis of these anomalies. After delivery, elective surgical resection should be planned; however, increases in size, deterioration of liver function, and ascending cholangitis frequently force early intervention. We report an unusual occurrence of siblings with type I choledochal cysts and review the existing literature on cause, genetics, classification, diagnosis, and management of this disease.
On the asymptotic independent representations for sums of some weakly dependent random variables
Authors: Aguech Rafik , Louhichi Sana , Louhichi Sofyen
Published: February 2006

Let, for each n?N, (Xi,n)0?i?nbe a triangular array of stationary, centered, square integrable and associated real valued random variables satisfying the weakly dependence condition lim N?N0limsup n?+8nSr=NnCov (X0,n, Xr,n)=0;where N0is either infinite or the first positive integer Nfor which the limit of the sum nSr=NnCov (X0,n, Xr,n) vanishes as n goes to infinity. The purpose of this paper is to build, from (Xi,n)0?i?n, a sequence of independent random variables (X˜i,n)0?i?nsuch that the two sumsSi=1nXi,nandSi=1nX˜i,nhave the same asymptotic limiting behavior (in distribution).
A general Orlicz--Pettis theorem
Authors: Ronglu Li , Yunyan Yang , Swartz Charles
Published: February 2006

The key point of subseries convergence is discovered and the strongest Orlicz-Pettis-type result is established.
On cyclic codes in incidence rings
Authors: Alfaro Ricardo , Kelarev Andrei V.
Published: February 2006

Cyclic codes are defined as ideals in polynomial quotient rings. We are using a matrix ring construction in a similar way to define classes of codes. It is shown that all cyclic and all linear codes can be embedded as ideals in this construction. A formula for the largest Hamming weight of one-sided ideals in incidence rings is given. It is shown that every incidence ring defined by a directed graph always possesses a principal one-sided ideal that achieves the optimum Hamming weight.
On the Milnor fiber of non-isolated singularities
Authors: Horváth András , Némethi András
Published: February 2006

We prove that the homotopy type of the Milnor fiber Fof a hypersurface singularity f : (Cn+1,0)?(C,0) (n?3) with 1-dimensional singular locus is completely determined by its homology H*(F,Z), and, in fact, it has a canonical bouquet decomposition.
Phase field theory of crystal nucleation and polycrystalline growth: A review
Authors: Gránásy L. , Pusztai T. , Börzsönyi T. , Tóth G. , Tegze G. , Warren J.A. , Douglas J.F.
Published: February 2006

We briefly review our recent modeling of crystal nucleation and polycrystalline growth using a phase field theory. First, we consider the applicability of phase field theory for describing crystal nucleation in a model hard sphere fluid. It is shown that the phase field theory accurately predicts the nucleation barrier height for this liquid when the model parameters are fixed by independent molecular dynamics calculations. We then address various aspects of polycrystalline solidification and associated crystal pattern formation at relatively long timescales. This late stage growth regime, which is not accessible by molecular dynamics, involves nucleation at the growth front to create new crystal grains in addition to the effects of primary nucleation. Finally, we consider the limit of extreme polycrystalline growth, where the disordering effect due to prolific grain formation leads to isotropic growth patterns at long times, i.e., spherulite formation. Our model of spherulite growth exhibits branching at fixed grain misorientations, induced by the inclusion of a metastable minimum in the orientational free energy. It is demonstrated that a broad variety of spherulitic patterns can be recovered by changing only a few model parameters.
Mechanical properties of porous and fully dense low-κ dielectric thin films measured by means of nanoindentation and the plane-strain bulge test technique
Authors: Xiang Y. , Chen X. , Tsui T.Y. , Jang J-I. , Vlassak J.J.
Published: February 2006

We report on the results of a comparative study in which the mechanical response of both fully dense and porous low-κ dielectric thin films was evaluated using two different techniques: nanoindentation and the plane-strain bulge test. Stiffness values measured by nanoindentation are systematically higher than those obtained using the bulge test technique. The difference between the measurements is caused by the Si substrate, which adds significantly to the contact stiffness in the indentation measurements. Depending on the properties of the coatings, the effect can be as large as 20%, even if the indentation depth is less than 5% of the film thickness. After correction of the nanoindentation results for the substrate effect using existing models, good agreement is achieved between both techniques. The results further show that densification of porous material under the indenter does not affect stiffness measurements significantly. By contrast, nanoindentation hardness values of porous thin films are affected by both substrate and densification effects. It is possible to eliminate the effect of densification and to extract the yield stress of the film using a model for the indentation of porous materials proposed by the authors. After correcting for substrate and densification effects, the nanoindentation results are in close agreement with the bulge test measurements. The results of this comparative study validate the numerical models proposed by Chen and Vlassak for the substrate effect and by Chen et al. for the densification effect.
Experimental, analytical, and finite element analyses of nanoindentation of multilayer PZT/Pt/SiO2thin film systems on silicon wafers
Authors: Chima-Okereke C. , Bushby A.J. , Reece M.J. , Whatmore R.W. , Zhang Q.
Published: February 2006

The mechanical properties of lead zirconate titanate (PZT) multilayer systems are needed to model and design micro-electromechanical systems (MEMS) devices. Nanoindentation is a promising tool for obtaining the elastic properties of thin films. However, no means exist to obtain the elastic modulus of the lead zirconate titanate (PZT) in the multilayer system. The indentation modulus versusa/tbehavior of the multilayered PZT/Pt/SiO2film system on a silicon substrate was investigated and compared with finite element models and a new analytical solution. Six different PZT film thicknesses were indented (100, 140, 400, 700, 1500, and 2000 nm), using 5-, 10-, and 20-μm radius indenters. Good agreement was shown between the finite element analysis (FEA) and analytical solutions, and the experimental data. However the behavior of multilayer systems is complex, making deconvolution of properties difficult for films of less than a micron thick.
Thermal instability of Co-substituted barium hexaferrites with U-type structure
Authors: Lisjak Darja , McGuiness Paul , Drofenik Miha
Published: February 2006

Thermal stability studies of Co-substituted barium hexaferrites with the U-type structure are reported. Samples were prepared using solid-state reaction and high-energy milling at 1300 and 1250 °C, respectively. The influence of different annealing conditions on their compositions and magnetic properties was studied. Thermal instability of the studied compounds was observed at as low as 600 °C. Through x-ray powder diffraction, chemical analysis, and thermomagnetic measurements it was confirmed that a degradation of the U-hexaferrites occurred during the annealing at 600–800 °C. The observed changes in the samples’ phase compositions and structures did not have a significant influence on their magnetization and microwave properties.
Competing fracture modes in brittle materials subject to concentrated cyclic loading in liquid environments: Trilayer structures
Authors: Hermann Ilja , Bhowmick Sanjit , Zhang Yu , Lawn Brian R.
Published: February 2006

A study is made of top-surface cracks induced in brittle trilayers by cyclic indentation with a hard sphere in water. The trilayers consist of an external brittle layer (veneer) fused to an inner stiff and hard ceramic support layer (core), in turn adhesively bonded to a thick compliant base (substrate). These structures are meant to simulate essential aspects of dental crowns, but their applicability extends to a range of engineering coating systems. The study follows on from like studies of brittle monoliths and brittle-plate/soft-substrate bilayers. Competing fracture modes in the outer brittle layer remain the same as before: outer and inner cone cracks and radial cracks, all of which form in the near-contact zone and propagate downward toward the veneer/core interface. Inner cone cracks and radial cracks are especially dangerous because of their relatively steep descent through the outer layer as well as enhanced susceptibility to mechanical fatigue. Experiments are conducted on model glass/alumina/polycarbonate systems, using video cameras to record the fracture evolution in the transparent glass layer in situ during testing. Each fracture mode can lead to failure, depending on the maximum contact load and other variables (plate thickness, sphere radius). The potentially beneficial role of a stiff intervening core is discussed, along with potentially deleterious side effects of residual thermal-expansion-mismatch stresses.