bluuebunny/crossref_metadata_2025 huggingface dataset:
GluR‐ and TrkB‐mediated maturation of GABAA receptor function during the period of eye opening
Authors: Henneberger Christian , Jüttner René , Schmidt Sonja A. , Walter Jan , Meier Jochen C. , Rothe Thomas , Grantyn Rosemarie
Published: January 2005

Synapse maturation includes the shortening of postsynaptic currents, due to changes in the subunit composition of respective transmitter receptors. Patch clamp experiments revealed that GABAergic inhibitory postsynaptic currents (ISPCs) of superior colliculus neurons significantly shorten from postnatal day (P)1 to P21. The change started after P6 and was steepest between P12 and P15, i.e. around eye opening. It was accompanied by enhanced sensitivity to zolpidem and increased expression of GABAAR α1 mRNA, whereas the level of α3 mRNA decreased. This result is consistent with the hypothesis that the IPSC kinetics of developing collicular neurons is determined by the level of α1/α3. As α1/α3 peaked when N‐methyl‐D‐aspartate receptor (NMDAR)‐mediated synaptic currents reached their maximum (P12) it was asked whether NMDAR activity can shape the kinetics of GABAergic IPSCs. Cultured collicular neurons were treated with NMDA or NMDAR block, and it was found that the former resulted in faster and the latter in slower IPSC decay. Group I mGluR blockade had no effect. Experiments with bdnf–/– mice revealed that, with some delay, the increase of α1/α3 mRNA also occurred in the chronic absence of brain‐derived neurotrophic factor (BDNF) and, again, this was accompanied by the shortening of IPSCs. In addition, there was an age‐dependent depression of IPSC amplitudes by endogenous BDNF, which might reflect the developmental increase in the expression of GABAAR γ2L, as opposed to γ2S. Together, these experiments suggest that the GABAAR α subunit switch and the associated change in the IPSC kinetics were specifically controlled by NMDAR activity and independent on the signalling through group I mGluRs or TrkB.
Sexual dimorphism in the effect of nonhabituating stress on neurogenic plasma extravasation
Authors: Green Paul G. , Levine Jon D.
Published: January 2005

The sympathoadrenal axis contributes to the sexual dimorphism of the inflammatory response. As stress both activates the sympathoadrenal axis and profoundly affects inflammation and inflammatory disease, we evaluated whether stress exerts a sexually dimorphic effect on a major component of the inflammatory response, plasma extravasation. We evaluated the effect of a nonhabituating stress, repeated intermittent sound (30 min/day for 4 days), on neurogenic synovial plasma extravasation, induced by bradykinin in the rat knee joint. Sound stress profoundly inhibited bradykinin‐induced plasma extravasation in male rats, but profoundly enhanced it in female rats. These effects took 24 h to fully develop after the last exposure to stress. In gonadectomized males, bradykinin‐induced plasma extravasation was lower than intact males, and sound stress now enhanced it, i.e. gonadectomized males were phenotypically like intact females. In gonadectomized females, bradykinin‐induced plasma extravasation was greater than in intact adult females, and sound stress still enhanced it. Adrenal enucleation significantly attenuated the effect of sound stress on bradykinin‐induced plasma extravasation in both male and female rats. We tested the hypothesis that these effects of sound stress were due to sustained enhanced plasma levels of stress hormones. Corticosterone and epinephrine, only when administered in combination, over five days, produced a qualitatively similar effect as sound stress, i.e. bradykinin‐induced plasma extravasation was significantly decreased in males and increased in females. These findings suggest that a combined effect of the hypothalamic‐pituitary adrenal and sympathoadrenal stress axes are responsible for the marked sexual dimorphism in the effect of stress on the inflammatory response.
New neurons in the dentate gyrus are involved in the expression of enhanced long‐term memory following environmental enrichment
Authors: Bruel‐Jungerman Elodie , Laroche Serge , Rampon Claire
Published: January 2005

Although thousands of new neurons are continuously produced in the dentate gyrus of rodents each day, the function of these newborn cells remains unclear. An increasing number of reports have provided correlational evidence that adult hippocampal neurogenesis is involved in learning and memory. Exposure of animals to an enriched environment leads to improvement of performance in several learning tasks and enhances neurogenesis specifically in the hippocampus. These data raise the question of whether new neurons participate in memory improvement induced by enrichment. To address this issue, we have examined whether the increase in the number of surviving adult‐generated cells following environmental enrichment contributes to improved memory function. To this end, neurogenesis was substantially reduced throughout the environmental enrichment period using the antimitotic agent methylazoxymethanol acetate (MAM). Recognition memory performance of MAM‐treated enriched rats was evaluated in a novel object recognition task and compared with that of naïve and nontreated enriched rats. Injections of 5‐bromo‐2′‐deoxyuridine were used to label dividing cells, together with double immunofluorescent labelling using glial or neuronal cell‐specific markers. We found that enrichment led to improved long‐term recognition memory and increased hippocampal neurogenesis, and that MAM treatment during environmental enrichment completely prevented both the increase in neurogenesis and enrichment‐induced long‐term memory improvement. These results establish that newborn cells in the dentate gyrus contribute to the expression of the promnesic effects of behavioural enrichment, and they provide further support for the idea that adult‐generated neurons participate in modulating memory function.
Chondroitin 6‐sulphate synthesis is up‐regulated in injured CNS, induced by injury‐related cytokines and enhanced in axon‐growth inhibitory glia
Authors: Properzi Francesca , Carulli Daniela , Asher Richard A. , Muir Elizabeth , Camargo Luiz M. , Van Kuppevelt Toin H. , Ten Dam Gerdy B. , Furukawa Yoko , Mikami Tadishima , Sugahara Kazuyuki , Toida Toshihiko , Geller Herbert M. , Fawcett James W.
Published: January 2005

Chondroitin sulphate proteoglycans (CSPGs) are up‐regulated in the CNS after injury and inhibit axon regeneration mainly through their glycosaminoglycan (CS‐GAG) chains. We have analysed the mRNA levels of the CS‐GAG synthesizing enzymes and measured the CS‐GAG disaccharide composition by chromatography and immunocytochemistry. Chondroitin 6‐sulfotransferase 1 (C6ST1) is up‐regulated in most glial types around cortical injuries, and its sulphated product CS‐C is also selectively up‐regulated. Treatment with TGFα and TGFβ, which are released after brain injury, promotes the expression of C6ST1 and the synthesis of 6‐sulphated CS‐GAGs in primary astrocytes. Oligodendrocytes, oligodendrocyte precursors and meningeal cells are all inhibitory to axon regeneration, and all express high levels of CS‐GAG, including high levels of 6‐sulphated GAG. In axon growth‐inhibitory Neu7 astrocytes C6ST1 and 6‐sulphated GAGs are expressed at high levels, whereas in permissive A7 astrocytes they are not detectable. These results suggest that the up‐regulation of CSPG after CNS injury is associated with a specific sulphation pattern on CS‐GAGs, mediating the inhibitory properties of proteoglycans on axonal regeneration.
Factors limiting motor recovery after facial nerve transection in the rat: combined structural and functional analyses
Authors: Guntinas‐Lichius Orlando , Irintchev Andrey , Streppel Michael , Lenzen Mithra , Grosheva Maria , Wewetzer Konstantin , Neiss Wolfram F. , Angelov Doychin N.
Published: January 2005

It is believed that a major reason for the poor functional recovery after peripheral nerve lesion is collateral branching and regrowth of axons to incorrect muscles. Using a facial nerve injury protocol in rats, we previously identified a novel and clinically feasible approach to combat axonal misguidance – the application of neutralizing antibodies against neurotrophic factors to the injured nerve. Here, we investigated whether reduced collateral branching at the lesion site leads to better functional recovery. Treatment of rats with antibodies against nerve growth factor, brain‐derived neurotrophic factor, fibroblast growth factor, insulin‐like neurotrophic factor I, ciliary neurotrophic factor or glial cell line‐derived neurotrophic factor increased the precision of reinnervation, as evaluated by multiple retrograde labelling of motoneurons, more than two‐fold as compared with control animals. However, biometric analysis of vibrissae movements did not show positive effects on functional recovery, suggesting that polyneuronal reinnervation – rather than collateral branching – may be the critical limiting factor. In support of this hypothesis, we found that motor end‐plates with morphological signs of multiple innervation were much more frequent in reinnervated muscles of rats that did not recover after injury (51% of all end‐plates) than in animals with good functional performance (10%). Because polyneuronal innervation of muscle fibres is activity‐dependent and can be manipulated, the present findings raise hopes that clinically feasible and effective therapies could be soon designed and tested.
Sound‐guided shaping of the receptive field in the mouse auditory cortex by basal forebrain activation
Authors: Yan Jun , Zhang Yunfeng
Published: January 2005

The mammalian auditory cortex undergoes continuous plasticity following auditory experience. This study demonstrates the instructive roles of sound frequency and amplitude in representational plasticity in the primary auditory cortex of the mouse. Electrical stimulation of the basal forebrain paired with a tone led to a pronounced shift in the receptive field of the cortical neurons in both frequency and amplitude domains, the shift being towards the frequency and amplitude of the tone. Importantly, the plasticity in the frequency tuning of cortical neurons appeared to be largely dependent upon frequency‐specific decreases in the response threshold. The minimum threshold of cortical neurons could be reduced only if the amplitude of the presented tone was lower than the minimum threshold. This finding suggests that training with low‐intensity sound can increase the sensitivity of cortical neurons. Furthermore, all of these effects evoked by basal forebrain activation could be eliminated by cortical application of atropine, the acetylcholine muscarinic receptor antagonist. The data suggest that cortical plasticity is guided by both sound frequency and amplitude. The basal forebrain promotes sound‐guided cortical plasticity by facilitating neural mechanisms intrinsic to the auditory system.
Partial unilateral lesions of the mushroom bodies affect olfactory learning in honeybees Apis mellifera L.
Authors: Komischke Bernhard , Sandoz Jean‐Christophe , Malun Dagmar , Giurfa Martin
Published: January 2005

The mushroom bodies (MBs) are central structures in the insect brain that have been associated with olfactory learning and memory. Here we used hydroxyurea (HU) to treat honeybee larvae and induce partial MB ablations at the adult stage. We studied olfactory learning in honeybees with unilateral loss of the median calyces of their MBs and compared their ability to solve different forms of olfactory discrimination. When odorants were delivered in a side‐specific manner, ablated bees could not solve either discrimination of the unambiguous problem (Paradigm 1: A+, B– on one antenna, C+, D– on the other; A+B–/C+D–) whereas they could solve at least one of both discriminations of the ambiguous problem (Paradigm 2: A+B–/A–B+), namely that proposed to their intact brain side. Non‐ablated bees could learn side‐specific discriminations on both brain sides. When odorants were delivered simultaneously to both antennae (Paradigm 3: A+B–C+D–), HU‐ablated bees learned slower than HU‐normal bees. Thus, in all three paradigms, the unilateral loss of a median calyx affected olfactory learning. We propose that the MBs are required for solving elemental olfactory tasks whose complexity is increased by the number of stimuli involved and that MB ablations could have an effect on the inhibition of information exchange between brain hemispheres.
Activity‐dependent maturation of excitatory synaptic connections in solitary neuron cultures of mouse neocortex
Authors: Takada Naoki , Yanagawa Yuchio , Komatsu Yukio
Published: January 2005

Activity plays important roles in the formation and maturation of synaptic connections. We examined these roles using solitary neocortical excitatory neurons, receiving only self‐generated synaptic inputs, cultured in a microisland with and without spontaneous spike activity. The amplitude of excitatory postsynaptic currents (EPSCs), evoked by applying brief depolarizing voltage pulses to the cell soma, continued to increase from 7 to 14 days in culture. Short‐term depression of EPSCs in response to paired‐pulse or 10‐train‐pulse stimulation decreased with time in culture. These developmental changes were prevented when neurons were cultured in a solution containing tetrodotoxin (TTX). The number of functional synapses estimated by recycled synaptic vesicles with FM4‐64 was significantly smaller in TTX‐treated than control neurons. However, the miniature EPSC amplitude remained unchanged during development, irrespective of activity. Transmitter release probability, assessed by use‐dependent blockade of N‐methyl‐d‐aspartate receptor‐mediated EPSCs with MK‐801, was higher in TTX‐treated than control neurons. Therefore, the activity‐dependent increase in EPSC amplitude was mainly ascribed to the increase in synapse number, while activity‐dependent alleviation of short‐term depression was mostly ascribed to the decrease in release probability. The effect of activity blockade on short‐term depression, but not EPSC amplitude, was reversed after 4 days of TTX removal, indicating that synapse number and release probability are controlled by activity in very different ways. These results demonstrate that activity regulates the conversion of immature synapses transmitting low‐frequency input signals preferentially to mature synapses transmitting both low‐ and high‐frequency signals effectively, which may be necessary for information processing in mature cortex.
Repeated morphine treatment alters polysialylated neural cell adhesion molecule, glutamate decarboxylase‐67 expression and cell proliferation in the adult rat hippocampus
Authors: Kahn Laëtitia , Alonso Gérard , Normand Elisabeth , Manzoni Olivier J.
Published: January 2005

Altered synaptic transmission and plasticity in brain areas involved in reward and learning are thought to underlie the long‐lasting effects of addictive drugs. In support of this idea, opiates reduce neurogenesis [A.J. Eisch et al. (2000) Proceedings of the National Academy of Sciences USA, 97, 7579–7584] and enhance long‐term potentiation in adult rodent hippocampus [J.M. Harrison et al. (2002) Journal of Neurophysiology, 87, 2464–2470], a key structure of learning and memory processes. Here we studied how repeated morphine treatment and withdrawal affect cell proliferation and neuronal phenotypes in the dentate gyrus‐CA3 region of the adult rat hippocampus. Our data showed a strong reduction of cellular proliferation in morphine‐dependent animals (54% of control) that was followed by a rebound increase after 1 week withdrawal and a return to normal after 2 weeks withdrawal. Morphine dependence was also associated with a drastic reduction in the expression levels of the polysialylated form of neural cell adhesion molecule (68% of control), an adhesion molecule expressed by newly generated neurons and involved in cell migration and structural plasticity. Polysialylated neural cell adhesion molecule levels quickly returned to normal following withdrawal. In morphine‐dependent rats, we found a significant increase of glutamate decarboxylase‐67 mRNA transcription (170% of control) in dentate gyrus granular cells which was followed by a marked rebound decrease after 1 week withdrawal and a return to normal after 4 weeks withdrawal. Together, the results show, for the first time, that, in addition to reducing cell proliferation and neurogenesis, chronic exposure to morphine dramatically alters neuronal phenotypes in the dentate gyrus‐CA3 region of the adult rat hippocampus.
Internalized GABAA‐receptor subunits are transferred to an intracellular pool associated with the postsynaptic density
Authors: Van Rijnsoever Carolien , Sidler Corinne , Fritschy Jean‐Marc
Published: January 2005

Endocytosis represents an important mechanism regulating cell‐surface expression of neurotransmitter receptors, including GABAAreceptors, in neurons. Little is known, however, about trafficking of internalized receptors. Here, we used antibody tagging in living rat hippocampal neurons in culture to monitor GABAAreceptor internalization. We show that cell‐surface receptors have a homogeneous distribution reflecting their mobility in the membrane. Unexpectedly, internalized GABAAreceptors were detected mainly in a subsynaptic pool associated with gephyrin at postsynaptic sites, whereas AMPA‐type glutamate receptors were accumulated in the soma. This process was time‐dependent and could be prevented by blocking clathrin‐coated vesicle endocytosis. In control experiments, the existence of an intracellular pool of GABAAreceptors associated with gephyrin was confirmed independently of internalization of surface receptors, and constitutive endocytosis, unrelated to antibody‐tagging, could be demonstrated for both AMPA and GABAAreceptors using a biotinylation assay. These results suggest that cycling of GABAAreceptors between the cell surface and the subsynaptic pool provides a mechanism for the short‐term regulation of GABAergic neurotransmission. Furthermore, the close association of gephyrin with internalized GABAAreceptors suggests a role in intracellular receptor trafficking.
Morphine withdrawal increases intrinsic excitability of oxytocin neurons in morphine‐dependent rats
Authors: Brown Colin H. , Stern Javier E. , Jackson Keshia L. M. , Bull Philip M. , Leng Gareth , Russell John A.
Published: January 2005

To determine whether intrinsic mechanisms drive supraoptic nucleus oxytocin neuron excitation during morphine withdrawal, we calculated the probability of action potential (spike) firing with time after each spike for oxytocin neurons in morphine‐naïve and morphine‐dependent rats in vivo and measured changes in intrinsic membrane properties in vitro. The opioid receptor antagonist, naloxone, increased oxytocin neuron post‐spike excitability in morphine‐dependent rats; this increase was greater for short interspike intervals (< 0.1 s). Naloxone had similar, but smaller (P = 0.04), effects in oxytocin neurons in morphine‐naïve rats. The increased post‐spike excitability for short interspike intervals was specific to naloxone, because osmotic stimulation increased excitability without potentiating excitability at short interspike intervals. By contrast to oxytocin neurons, neither morphine dependence nor morphine withdrawal increased post‐spike excitability in neighbouring vasopressin neurons. To determine whether increased post‐spike excitability in oxytocin neurons during morphine withdrawal reflected altered intrinsic membrane properties, we measured the in vitro effects of naloxone on transient outward rectification (TOR) and after‐hyperpolarization (AHP), properties mediated by K+ channels and that affect supraoptic nucleus neuron post‐spike excitability. Naloxone reduced the TOR and AHP (by 20% and 60%, respectively) in supraoptic nucleus neurons from morphine‐dependent, but not morphine‐naïve, rats. In vivo, spike frequency adaptation (caused by activity‐dependent AHP activation) was reduced by naloxone (from 27% to 3%) in vasopressin neurons in morphine‐dependent, but not morphine‐naïve, rats. Thus, multiple K+ channel inhibition increases post‐spike excitability for short interspike intervals, contributing to the increased firing of oxytocin neurons during morphine withdrawal.
Gastric Juice: A Barrier Against Infectious Diseases
Authors: Martinsen Tom C. , Bergh Kåre , Waldum Helge L.
Published: January 2005

Abstract: All vertebrates produce gastric acid. Its main function is inactivation of ingested microorganisms. The majority of microbiological pathogens ingested never reaches the intestine because of the gastric barrier. Although gastric hypochlorhydria is fairly common due to atrophic gastritis, gastric surgery or use of inhibitors of gastric acid secretion, the resulting susceptibility to infection has not been studied extensively. Drug‐induced blockade of acid secretion leads to gastrointestinal bacterial overgrowth; the clinical significance of this is still controversial. Gastric acidity is known to protect against non‐typhoid salmonellosis and cholera and it is suspected that it protects against several parasitic diseases as giardiasis and strongyloides. There is a lack of studies focusing on the impact of the gastric acidic barrier on viral infections. Concerning prion infections only a single study has been performed, demonstrating a possible role of gastric acidity in the protection against foodborne prion disease in mice. The combination of malnutrition and hypochlorhydria may contribute to the high prevalence of gastrointestinal infections in developing countries. Further studies are needed to evaluate the clinical consequences of impaired gastric acidity with respect to susceptibility to infections.
Existence of a Clinically Relevant Interaction between Clopidogrel and HMG‐CoA Reductase Inhibitors? Re‐evaluating the Evidence
Authors: Poulsen Tina Svenstrup , Vinholt Pernille , Mickley Hans , Korsholm Lars , Kristensen Søren Risom , Damkier Per
Published: January 2005

Abstract: Clopidogrel is an inactive prodrug, which requires activation by the cytochrome P450 3A4 system in order to exert its antiplatelet action. Some statins (atorvastatin, lovastatin and simvastatin) also requires metabolism by the cytochrome P450 3A4 system. From a theoretical point of view, a clinical relevant interaction may exist between clopidogrel and cytochrome P450 3A4 metabolized statins. Nine studies have investigated the existence of this potential interaction. Seven studies have used results based on platelet function as surrogate endpoints and two studies have dealt with objective clinical events including mortality, acute myocardial infarction and stroke. However the studies have yielded conflicting results. This controversy is primarily caused by substantial differences in study design and methods used for assessment of the antiaggregatory effect of clopidogrel. Most studies have included too few patients, and there appears to be no consensus regarding the definition of and optimal way of measuring the platelet inhibitory effect of clopidogrel. Therefore an adequately powered prospective study, ensuring elimination of identified possible confounders and with the use of a well‐defined surrogate ex vivo parameter should be performed.
Disruption of Neuronal Calcium Homeostasis after Chronic Aluminium Toxicity in Rats
Authors: Kaur Amarpreet , Gill Kiran Dip
Published: January 2005

Abstract: The present study was designed to investigate the possible effects of chronic aluminium exposure on the various aspects of calcium homeostasis in rat brain. Chronic aluminium administration caused significant rise in the intrasynaptosomal calcium levels. The activity of major calcium‐expelling enzyme, i.e. Ca2+ ATPase was found to be lowered. Also, the calcium uptake via voltage‐operated calcium channels increased significantly. Similar to the increase in intrasynaptosomal calcium, calpain activity was found to be increased. The results presented here, indicate that the toxic effects of aluminium could be mediated through modifications in the intracellular calcium homeostasis, which may lead to impaired neuronal function.
Effect of β‐Adrenoceptor Blockers on HumanEther‐a‐go‐go‐Related Gene (HERG) Potassium Channels
Authors: Dupuis Delphine S. , Klaerke Dan A. , Olesen Søren‐Peter
Published: January 2005

Abstract: Patients with congenital long QT syndrome may develop arrhythmias under conditions of increased sympathetic tone. We have addressed whether some of the β‐adrenoceptor blockers commonly used to prevent the development of these arrhythmias could per se block the cardiac HERG (Human Ether‐a‐go‐go‐Related Gene) potassium channels, which would be a most unwanted side effect. HERG potassium channels were heterologously expressed in Xenopus oocytes and the currents measured by two‐electrode‐voltage‐clamp technique. Propranolol caused a concentration‐dependent inhibition of HERG current with an IC50 value of 81 μM at −10 mV. When HERG was co‐expressed with the accessory subunit KCNE2, an IC50 value of 52 μM was determined. The block by propranolol was voltage‐dependent, but it did not change the HERG channel deactivation kinetics. The propranolol analogue ICI118551 ((±)‐1‐[2,3‐(dihydro‐7‐methyl‐1H‐inden‐4‐yl)oxy]‐3‐[(1‐methylethyl)amino]‐2‐butanol hydrochloride) blocked the HERG channel with similar affinity, whereas the β1‐receptor antagonists metoprolol and atenolol showed weak effects. Further, the four compounds blocked HERG channels expressed in a mammalian HEK293 cell line. These data showed that HERG blockade by β‐adrenoceptor blockers occurred only at high micromolar concentrations, which are significantly above the recently established safe margin of 100 (Redfern et al., 2003).
Comparison of Carcinogenic and in vivo Genotoxic Potency Estimates
Authors: Sanner Tore , Dybing Erik
Published: January 2005

Abstract: Mutagenic substances classified as carcinogens are primarily regulated on the basis of their carcinogenic effect. Regulation of mutagens that have not been tested for carcinogenicity represents a problem. In cases where a threshold cannot be identified, the substances may be banned or if their uses are deemed to be unavoidable, the exposure may be reduced to as low as technically and economically feasible. In an attempt to develop a procedure that may be helpful in regulation of mutagenic substances when studies on carcinogenicity are lacking, we have compared the lowest effective dose (LED) giving a response in an in vivo genotoxic test after oral or inhalation exposure with the carcinogenic dose descriptor T25 (the chronic daily dose which will give 25% of the animals tumours above background at a specific tissue site). The 34 carcinogens in the present analysis for which genotoxic mechanisms are likely or possible, represent different classes of carcinogens and different genotoxic endpoints, exhibiting carcinogenic and mutagenic potencies both covering a range of 10,000 between the most and least potent substances. A linear correlation was found between the lowest effective dose for in vivo genotoxicity after oral administration or inhalation exposure and the lowest dose descriptor T25 for tumour formation. The finding that the median of the ratio LED/T25 was 1.05 and that the ratio for 90% of the substances studied fell in the range 0.21 to 9.2 shows that the numerical value of LED is similar to the numerical value of T25 within a factor of 5–10. The results suggest that LED may be used as a basis for regulation of mutagens in cases where a threshold cannot be demonstrated or inferred, and where the substance has not been studied in long‐term carcinogenicity studies. In such cases LED divided by a specified assessment factor may represent a virtually safe level or a tolerable risk level for a possible carcinogenic effect.
FLAVOR SYMMETRIES IN EXTRA DIMENSIONS
Authors: ARANDA ALFREDO , LORENZO DIAZ-CRUZ J.
Published: January 2005

We present a class of models of flavor that rely on the use of flavor symmetries and the Froggart–Nielsen mechanism in extra dimensions. The particle content is that of the standard model plus an additional flavon field; all the fields propagate in universal extra dimensions and the flavor scale is associated with the cutoff of the theory, which in 5D is ~ 10 TeV. The Yukawa matrices are generated by higher dimension operators involving flavon fields, whose vacuum expectation values break the flavor symmetry. We apply this framework and present a specific 5D model based on a discrete local symmetry that reproduces all fermion masses and mixing angles both in the quark and charged lepton sectors.
DISCRETE GRAVITY AND ITS CONTINUUM LIMIT
Authors: LING YI
Published: January 2005

Recently Gambini and Pullin proposed a new consistent discrete approach to quantum gravity and applied it to cosmological models. One remarkable result of this approach is that the cosmological singularity can be avoided in a general fashion. However, whether the continuum limit of such discretized theories exists is model dependent. In the case of massless scalar field coupled to gravity with Λ=0, the continuum limit can only be achieved by fine tuning the recurrence constant. We regard this failure as the implication that cosmological constant should vary with time. For this reason we replace the massless scalar field by Chaplygin gas which may contribute an effective cosmological constant term with the evolution of the universe. It turns out that the continuum limit can indeed be reached in this case.
SHAPE OF GAUGE FIELD TADPOLES IN HETEROTIC STRING THEORY
Authors: GROOT NIBBELINK STEFAN
Published: January 2005

Orbifolds in field theory are potentially singular objects for at their fixed points the curvature becomes infinite, therefore one may wonder whether field theory calculations near orbifold singularities can be trusted. String theory is perfectly well defined on orbifolds and can therefore be taken as a UV completion of field theory on orbifolds. We investigate the properties of field and string theory near orbifold singularities by reviewing the computation of a one-loop gauge field tadpole. We find that in string theory the twisted states give contributions that have a spread of a couple of string lengths around the singularity, but otherwise the field theory picture is confirmed. One additional surprise is that in some orbifold models one can identify local tachyons that give contributions near the orbifold fixed point.
THE p-WAVE THRESHOLD EFFECT AND QUASIRESONANT SCATTERING
Authors: HATEGAN CORNEL , GRAW GERHARD , COMISEL HORIA
Published: January 2005

The p-wave threshold effect is described in terms of the reduced scattering matrix. The relationship of this approach to previous theoretical threshold models is established. We prove that this phenomenon is related to the reaction-mechanism of quasiresonant scattering: a single particle neutron threshold state and direct interaction coupling to open observed channels. Spectroscopic aspects of the threshold effect, both with respect to the magnitude and microstructure, are discussed in terms of the neutron strength function.
CYLINDRICAL SOLUTIONS IN DILATON–AXION GRAVITY AND COSMIC STRINGS INTERACTING WITH GRAVITATIONAL AND DILATON–AXION WAVES
Authors: YAZADJIEV STOYTCHO S.
Published: January 2005

In the present paper we present and analyze exact cylindrically symmetric diagonal and nondiagonal solutions in the so-called dilaton–axion gravity. It is shown that they are free of curvature singularities, (quasi)regular on the axis of symmetry, asymptotically flat and describe rotating or nonrotating cosmic strings interacting with gravitational and dilaton–axion waves.
CONCEPTUALIZATION, PROTOTYPING AND PROCESS OF HYPERMEDIA APPLICATIONS
Authors: NAVARRO ANTONIO , FERNÁNDEZ-VALMAYOR ALFREDO , FERNÁNDEZ-MANJÓN BALTASAR , SIERRA JOSÉ LUIS
Published: January 2005

Latest-generation hypermedia applications represent a new challenge in traditional design and development software engineering techniques. Although there is an impressive array of models to design hypertext applications, these models may not be specially suited for conceptualization-prototyping stages. In this paper, we provide a comprehensive software engineering approach for dealing with the conceptualization, prototyping, and process of hypermedia applications. This approach uses the Pipe Model to characterize hypermedia applications during the conceptualization stage, while prototyping is accomplished using XML and Java technologies. An XML-based representation of the Pipe structures is the input for a Java application that automatically builds the prototypes of the hypermedia application. This XML representation may reference to Subordinate Processes, i.e. compiled Java classes that implement a predefined interface and can be executed in the hypermedia application without interacting with the navigation. We also present the Plumbing and PlumbingXJ process models, two specializations of a well-known hypermedia process model, which integrate and manage the use of the Pipe model and its associated XML and Java technologies.
HSGS: AN INTERACTIVE SYSTEM FOR HIGH-LEVEL SPECIFICATION AND GENERATION OF HYPERMEDIA PRESENTATIONS
Authors: BERTINO E. , MAZZOLENI P. , SANTI D.
Published: January 2005

In this paper we present a constraint-based approach for the fast prototyping of flexible hypermedia presentations. The key features of the proposed approach include: an extensive set of object types; a large variety of spatial and temporal relation types for combining objects into presentations; and relaxation techniques to automatically correct inconsistent specifications. Furthermore, our approach organizes presentations according to a multi-page model to increase reusability of presentation fragments and to support flexible content delivery to final users. The proposed approach has been implemented in the HSGS system that provides a tool for automatically generating presentations, coded in SMIL, according to the constraints specification given by presentation authors.
FROM KNOWLEDGE MODELING TO ONTOLOGY CONSTRUCTION
Authors: CHAN CHRISTINE W.
Published: January 2005

This paper presents the Knowledge Modeling System (KMS) and its application. The KMS supports users in formalizing and documenting knowledge elements acquired for development of knowledge-based systems. The system was developed based on a knowledge modeling technique called the Inferential Modeling Technique. It facilitates building an application ontology of a domain by explicitly structuring and formalizing both domain and task knowledge of any industrial problem domain. The system also supports knowledge sharing by converting the ontology into the Extensible Mark-Up Language (XML). The tool is compared against some other existing efforts at ontology construction support. Application of the KMS for constructing an application ontology in the domain of monitoring and control of a petroleum separation process is also presented.
LANGUAGE-DRIVEN SYSTEM DESIGN
Authors: MAUW S. , WIERSMA W. T. , WILLEMSE T. A. C.
Published: January 2005

Studies have shown significant benefits of the use of Domain-Specific Languages (DSL) in software engineering. We discuss a software engineering methodology that fully exploits these benefits. The methodology, called the Language-Driven Approach (LDA), is centred around the design of a DSL. It prescribes a staged development of a DSL, which is tailored to the system-under-construction. On the basis of a domain analysis, a formal definition of the problem is obtained. This formal problem definition contains all the relevant ingredients for designing the syntax, the semantics and the pragmatics, which together comprise the DSL. The methodology is illustrated by an elaborate example dealing with the problem of regulating traffic lights at a traffic junction.
DATA MINING FOR THE MANAGEMENT OF SOFTWARE DEVELOPMENT PROCESS
Authors: ÁLVAREZ-MACÍAS J. L. , MATA-VÁZQUEZ J. , RIQUELME-SANTOS J. C.
Published: January 2005

In this paper we present a new method for the application of data mining tools on the management phase of software development process. Specifically, we describe two tools, the first one based on supervised learning, and the second one on unsupervised learning. The goal of this method is to induce a set of management rules that make easy the development process to the managers. Depending on how and to what is this method applied, it will permit an a priori analysis, a monitoring of the project or a post-mortem analysis.
EPDAODMRP: AN EXTENDED PDAODMRP PROTOCOL
Authors: CAI SHAOBIN , WANG LING , YANG XIAOZONG
Published: January 2005

An ad hoc network is a multi-hop wireless network of mobile nodes without fixed infrastructure. Its limited bandwidth and frequently changing topology require that its protocol should be robust, simple and energy conserving. We have proposed PDAODMRP (Passive Data Acknowledgement ODMRP) based on the passive acknowledgement function of data packets. PDAODMRP defines the adjacent un-forwarding nodes of forwarding nodes as pool nodes. With the help of pool nodes, PDAODMRP reduces its local route maintenance scope to at least one-hop. Although PDAODMRP has reduced its control overhead and data delivery delay greatly, it still selects multiple paths between a source and a member. And, its data overhead is still high. Hence, in this paper, we propose EPDAODMRP (Extended PDAODMRP) to extend PDAODMRP. Compared PDAODMRP, EPDAODMRP only selects the shortest path between a source and a member instead of all disjoint paths between a source and a member; its local route maintenance is as strong as that of PDAODMRP, which can amend all link failures. The simulation results show that EPDAODMRP has lower data overhead and lower data delivery delay.
TRAVERSAL OF A QUASI-PLANAR SUBDIVISION WITHOUT USING MARK BITS
Authors: CHÁVEZ EDGAR , DOBREV ŠTEFAN , KRANAKIS EVANGELOS , OPATRNY JAROSLAV , STACHO LADISLAV , URRUTIA JORGE
Published: January 2005

The problem of traversal of planar subdivisions or other graph-like structures without using mark bits is central to many real-world applications [7, 8, 11, 12, 13, 17, 18]. The first such algorithms developed were able to traverse triangulated subdivisions [10]. Later these algorithms were extended to traverse vertices of an arrangement or a convex polytope [3]. The research progress culminated to an algorithm that can traverse any planar subdivision [6, 9]. In this paper, we extend the notion of planar subdivision to quasi-planar subdivision in which we allow many edges to cross each other. We generalize the algorithm from [9] to traverse any quasi-planar subdivision that satisfies a simple geometric requirement. If we use techniques from [6] the worst case running time of our algorithm is O(|E| log |E|); matching the running time of the traversal algorithm for planar subdivisions [6].
AN EFFICIENT MULTI-PURPOSE OPTIMIZATION METHOD FOR QOS ROUTING USING GENETIC ALGORITHM
Authors: KOYAMA AKIO , BAROLLI LEONARD , CAPI GENCI , APDUHAN BERNADY O. , ARAI JUNPEI , DURRESI ARJAN
Published: January 2005

In order to support multimedia communication, it is necessary to develop routing algorithms that make decisions based on multiple Quality of Service (QoS) parameters. This is because new services such as video on demand and remote meeting systems have multiple QoS requirements. However, the problem of QoS routing is difficult because finding a feasible route with two independent path constraints is NP-complete problem. Also, QoS routing algorithms for broadband networks must be adaptive, flexible, and intelligent for efficient network management. In this paper, we propose a multi-purpose optimization method for QoS routing based on Genetic Algorithm (GA). The simulation results show that the proposed method has a good performance and therefore is a promising method for QoS routing.
APPROXIMATING HYPERCUBES BY INDEX-SHUFFLE GRAPHS VIA DIRECT-PRODUCT EMULATIONS
Authors: OBRENIĆ BOJANA
Published: January 2005

Index-shuffle graphs are a family of bounded-degree hypercube-like interconnection networks for parallel computers, introduced by [Baumslag and Obrenić (1997): Index-Shuffle Graphs, …], as an efficient substitute for two standard families of hypercube derivatives: butterflies and shuffle-exchange graphs. In the theoretical framework of graph embedding and network emulations, this paper shows that the index-shuffle graph efficiently approximates the direct-product structure of the hypercube, and thereby has a unique potential to approximate efficiently all of its derivatives.

One of the consequences of our results is that any member of the following group of standard bounded-degree hypercube derivatives: butterflies, shuffles, tori, meshes of trees, is emulated by the index-shuffle graph with a slowdown in the order of the logarithm of the slowdown of the most efficient emulation achieved by any other member of this group.

Emulation algorithms are presented where the emulation host is the n-dimensional index-shuffle graph Ψn, having N=2n nodes. The emulated graph G is a direct product of the form: G=F0×F1×⋯×Fk-1 where k is a power of 2, and each factor Fi is an instance of any of the following three graph families: cycle, complete binary tree, X-tree. Let the size of each factor be |Fi|≤2nf, where k·nf≤n. The index-shuffle graph Ψn, emulates any factor Fi in the product G with slowdown: O( log k) + O( log nf), which is O( log n) = O( log log N). Any collection of 2ℓ copies of the product G, such that: ℓ+k·nf≤n is emulated by the index-shuffle graph Ψn simultaneously, without any additional slowdown. Relaxing the assumption that k is a power of 2 introduces an additional factor of O( lg *N) into the slowdown.
Diet-induced obesity impairs mammary development and lactogenesis in murine mammary gland
Authors: Flint David J. , Travers Maureen T. , Barber Michael C. , Binart Nadine , Kelly Paul A.
Published: January 2005

We have developed a mouse model of diet-induced obesity that shows numerous abnormalities relating to mammary gland function. Animals ate ∼40% more calories when offered a high-fat diet and gained weight at three times the rate of controls. They exhibited reduced conception rates, increased peripartum pup mortality, and impaired lactogenesis. The impairment of lactogenesis involved lipid accumulation in the secretory epithelial cells indicative of an absence of copius milk secretion. Expression of mRNAs for β-casein, whey acid protein, and α-lactalbumin were all decreased immediately postpartum but recovered as lactation was established over 2–3 days. Expression of acetyl-CoA carboxylase (ACC)-α mRNA was also decreased at parturition as was the total enzyme activity, although there was a compensatory increase in the proportion in the active state. By day 10 of lactation, the proportion of ACC in the active state was also decreased in obese animals, indicative of suppression of de novo fatty acid synthesis resulting from the supply of preformed fatty acids in the diet. Although obese animals consumed more calories in the nonpregnant and early pregnant states, they showed a marked depression in fat intake around day 9 of pregnancy before food intake recovered in later pregnancy. Food intake increased dramatically in both lean and obese animals during lactation although total calories consumed were identical in both groups. Thus, despite access to high-energy diets, the obese animals mobilized even more adipose tissue during lactation than their lean counterparts. Obese animals also exhibited marked abnormalities in alveolar development of the mammary gland, which may partially explain the delay in differentiation evident during lactogenesis.
Endothelin-1 induces lipolysis in 3T3-L1 adipocytes
Authors: Juan Chi-Chang , Chang Chih-Ling , Lai Ying-Hsiu , Ho Low-Tone
Published: January 2005

Endothelin-1 (ET-1) affects glucose uptake in adipocytes and may play an important role in adipose physiology. One of the principal functions of adipose tissue is the provision of energy substrate through lipolysis. In the present study, we investigated the effects of ET-1 on lipolysis in 3T3-L1 adipocytes. When glycerol release in the culture medium was measured as an index of lipolysis, the results showed that ET-1 caused a significant increase that was time and dose dependent. With a concentration of 10 nM ET-1, stimulation of glycerol release plateaued after 4 h of exposure. This effect was inhibited by the ETAreceptor antagonist BQ-610 (10 μM) but not by the ETBreceptor antagonist BQ-788 (10 μM). To further explore the underlying mechanisms of ET-1 action, we examined the involvement of the cAMP-dependent protein kinase A-mediated, phospholipase A2(PLA2)-mediated, protein kinase C (PKC)-mediated, phosphatidylinositol 3 (PI 3)-kinase-mediated, and the mitogen-activated protein kinase (MAPK)-mediated pathways. Inhibition of adenylyl cyclase activation by SQ-22536 (100 μM) did not block ET-1-induced lipolysis. Pretreatment of adipocytes with the PLA2inhibitor dexamethasone (100 nM), the PKC inhibitor H-7 (6 μM), or the PI 3-kinase inhibitor wortmannin (100 nM) also had no effect. ET-1-induced lipolysis was blocked by inhibition of extracellular signal-regulated kinase (ERK) activation using PD-98059 (75 μM), whereas a p38 MAPK inhibitor (SB-203580; 20 μM) had no effect. Results of Western blot further demonstrated that ET-1 induced ERK phosphorylation. These data show that ET-1 induces lipolysis in 3T3-L1 adipocytes via a pathway that is different from the conventional cAMP-dependent pathway used by isoproterenol and that involves ERK activation.
Vitamin D and phosphate regulate fibroblast growth factor-23 in K-562 cells
Authors: Ito Mikiko , Sakai Yuko , Furumoto Mari , Segawa Hiroko , Haito Sakiko , Yamanaka Setsuko , Nakamura Rie , Kuwahata Masashi , Miyamoto Ken-ichi
Published: January 2005

Fibroblast growth factor-23 (FGF-23) has been recently identified as playing an important pathophysiological role in phosphate homeostasis and vitamin D metabolism. To elucidate the precise physiological regulation of FGF-23, we characterized the mouse FGF-23 5′-flanking region and analyzed its promoter activity. The 5′-flanking region of the mouse FGF-23 gene contained a TFIID site (TATA box) and several putative transcription factor binding sites, including MZF1, GATA-1 and c-Ets-1 motifs, but it did not contain the typical sequences of the vitamin D response element. Plasmids encoding 554-bp (pGL/−0.6), 364-bp (pGL/−0.4) and 200-bp (pGL/−0.13) promoter regions containing the TFIID element and +1-bp fragments drove the downstream expression of a luciferase reporter gene in transfection assays. We also found that FGF-23 mRNA was expressed in K-562 erythroleukemia cell lines but not in MC3T3-E1, Raji, or Hep G2 human carcinoma cells. Treatment with 1,25-dihydroxyvitamin D3in the presence of high phosphate markedly stimulated pGL/−0.6 activity, but calcium had no effect. In addition, the plasma FGF-23 levels were affected by the dietary and plasma inorganic phosphate concentrations. Finally, the levels of plasma FGF-23 in vitamin D receptor-null mice were significantly lower than in wild-type mice. The presents study demonstrated that vitamin D and the plasma phosphate level are important regulators of the transcription of the mouse FGF-23 gene.