bluuebunny/crossref_metadata_2025 huggingface dataset:
Sensitivity Analysis in Linear Semi-Infinite Programming via Partitions
Authors: Goberna M. A. , Terlaky T. , Todorov M. I.
Published: December 2009

This paper provides sufficient conditions for the optimal value function of a given linear semi-infinite programming (LSIP) problem to depend linearly on the size of the perturbations, when these perturbations involve either the cost coefficients or the right-hand side function or both, and they are sufficiently small. Two kinds of partitions are considered. The first concerns the effective domain of the optimal value as a function of the cost coefficients and consists of maximal regions on which this value function is linear. The second class of partitions considered in this paper concerns the index set of the constraints through a suitable extension of the concept of optimal partition from ordinary to LSIP. These partitions provide convex sets, in particular, segments, on which the optimal value is a linear function of the size of the perturbations, for the three types of perturbations considered in this paper.
Weak Differentiability of Product Measures
Authors: Heidergott Bernd , Leahu Haralambie
Published: December 2009

In this paper, we study cost functions over a finite collection of random variables. For these types of models, a calculus of differentiation is developed that allows us to obtain a closed-form expression for derivatives where “differentiation” has to be understood in the weak sense. The technique for proving the results is new and establishes an interesting link between functional analysis and gradient estimation. The key contribution of this paper is a product rule of weak differentiation. In addition, a product rule of weak analyticity is presented that allows for Taylor series approximations of finite products measures. In particular, from characteristics of the individual probability measures, a lower bound (i.e., domain of convergence) can be established for the set of parameter values for which the Taylor series converges to the true value. Applications of our theory to the ruin problem from insurance mathematics and to stochastic activity networks arising in project evaluation review techniques are provided.
On Sums of Conditionally Independent Subexponential Random Variables
Authors: Foss Serguei , Richards Andrew
Published: December 2009

The asymptotic tail behaviour of sums of independent subexponential random variables is well understood, one of the main characteristics being the principle of the single big jump. We study the case of dependent subexponential random variables, for both deterministic and random sums, using a fresh approach, by considering conditional independence structures on the random variables. We seek sufficient conditions for the results of the theory with independent random variables to still hold. For a subexponential distribution, we introduce the concept of a boundary class of functions, which we hope will be a useful tool in studying many aspects of subexponential random variables. The examples we give demonstrate a variety of effects owing to the dependence, and are also interesting in their own right.
Competitive Two-Agent Scheduling and Its Applications
Authors: Leung Joseph Y.-T. , Pinedo Michael , Wan Guohua
Published: December 2009

We consider a scheduling environment with m (m ≥ 1) identical machines in parallel and two agents. Agent A is responsible for n1 jobs and has a given objective function with regard to these jobs; agent B is responsible for n2 jobs and has an objective function that may be either the same or different from the one of agent A. The problem is to find a schedule for the n1 + n2 jobs that minimizes the objective of agent A (with regard to his n1 jobs) while keeping the objective of agent B (with regard to his n2 jobs) below or at a fixed level Q. The special case with a single machine has recently been considered in the literature, and a variety of results have been obtained for two-agent models with objectives such as fmax, ∑ wjCj, and ∑ Uj. In this paper, we generalize these results and solve one of the problems that had remained open. Furthermore, we enlarge the framework for the two-agent scheduling problem by including the total tardiness objective, allowing for preemptions, and considering jobs with different release dates; we consider also identical machines in parallel. We furthermore establish the relationships between two-agent scheduling problems and other areas within the scheduling field, namely rescheduling and scheduling subject to availability constraints.
Stochastic Kriging for Simulation Metamodeling
Authors: Ankenman Bruce , Nelson Barry L. , Staum Jeremy
Published: December 2009

We extend the basic theory of kriging, as applied to the design and analysis of deterministic computer experiments, to the stochastic simulation setting. Our goal is to provide flexible, interpolation-based metamodels of simulation output performance measures as functions of the controllable design or decision variables, or uncontrollable environmental variables. To accomplish this, we characterize both the intrinsic uncertainty inherent in a stochastic simulation and the extrinsic uncertainty about the unknown response surface. We use tractable examples to demonstrate why it is critical to characterize both types of uncertainty, derive general results for experiment design and analysis, and present a numerical example that illustrates the stochastic kriging method.
Limited Sampling Strategies for Predicting Area Under the Concentration-Time Curve of Mycophenolic Acid in Islet Transplant Recipients
Authors: Al-Khatib Mai , Shapiro R Jean , Partovi Nilufar , Ting Lillian SL , Levine Marc , Ensom Mary HH
Published: December 2009

BACKGROUND

Mycophenolate mofetil is widely used in islet transplant recipients and its active metabolite, mycophenolic acid (MPA), exhibits wide pharmacokinetic variability. However, to our knowledge, no limited sampling strategy (LSS) exists for monitoring MPA in this subpopulation.

OBJECTIVE

To define optimal LSSs for MPA monitoring and to test their predictive performance in islet transplant recipients.

METHODS

After written informed consent was obtained and upon administration of a steady-state morning mycophenolate mofetil dose, blood samples were collected at 0, 0.3, 0.6, 1, 1.5, 2, 3, 4, 6, 8, 10, and 12 hours from 16 stable islet transplant recipients. MPA concentrations were measured by a validated high-performance liquid chromatography method with ultraviolet detection and pharmacokinetic parameters analyzed by noncompartmental modeling. All 16 patients' profiles were used to develop the LSSs via multiple regression analysis. Potential LSSs were restricted to ones having R2 0.90 or greater and 3 or fewer time points within the first 4 hours postdose. Resulting equations were validated for their predictive performance using the jackknife method, with acceptable criteria for bias and precision preset to within ±15%. In addition, 14 published LSSs (in the renal transplant population) were tested in our islet transplant patients.

RESULTS

Five LSSs met preset criteria and had conventional sampling times: [Formula: see text] where AUC = area under the concentration-time curve. None of the other published LSSs in the renal transplant population met the preset criteria for bias and precision.

CONCLUSIONS

To our knowledge, these are the first precise and accurate LSSs for predicting MPA AUC developed specifically for islet transplant recipients. The LSS that we recommend is the one utilizing 2 concentrations: AUC = 1.547 + 1.417C1 + 9.448C4. This equation is convenient and clinically feasible. Other islet transplant centers may wish to validate our equation in their population or use our template as a guide to develop accurate and precise LSSs specific to their patient population.
Brain-Derived Neurotrophic Factor Signaling in the HVC Is Required for Testosterone-Induced Song of Female Canaries
Authors: Hartog Tessa E. , Dittrich Falk , Pieneman Anton W. , Jansen René F. , Frankl-Vilches Carolina , Lessmann Volkmar , Lilliehook Christina , Goldman Steven A. , Gahr Manfred
Published: December 2009

Testosterone-induced singing in songbirds is thought to involve testosterone-dependent morphological changes that include angiogenesis and neuronal recruitment into the HVC, a central part of the song control circuit. Previous work showed that testosterone induces the production of vascular endothelial growth factor (VEGF) and its receptor (VEGFR2 tyrosine kinase), which in turn leads to an upregulation of brain-derived neurotrophic factor (BDNF) production in HVC endothelial cells. Here we report for the first time that systemic inhibition of the VEGFR2 tyrosine kinase is sufficient to block testosterone-induced song in adult female canaries, despite sustained androgen exposure and the persistence of the effects of testosterone on HVC morphology. Expression of exogenous BDNF in HVC, induced locally byin situtransfection, reversed the VEGFR2 inhibition-mediated blockade of song development, thereby restoring the behavioral phenotype associated with androgen-induced song. The VEGFR2-inhibited, BDNF-treated females developed elaborate male-like song that included large syllable repertoires and high syllable repetition rates, features known to attract females. Importantly, although functionally competent new neurons were recruited to HVC after testosterone treatment, the time course of neuronal addition appeared to follow BDNF-induced song development. These findings indicate that testosterone-associated VEGFR2 activity is required for androgen-induced song in adult songbirds and that the behavioral effects of VEGFR2 inhibition can be rescued by BDNF within the adult HVC.
Atypical Functional Properties of GluK3-Containing Kainate Receptors
Authors: Perrais David , Coussen Françoise , Mulle Christophe
Published: December 2009

The properties of synaptic receptors determine their mode of action at presynaptic and postsynaptic loci. Here, we investigated the atypical biophysical properties of GluK3-containing kainate receptors, which contribute to presynaptic facilitation at hippocampal mossy fiber synapses. We show, using fast glutamate applications on outside-out patches and kinetic modeling, that the low sensitivity of GluK3 receptors for glutamate is attributable to fast desensitization of partially bound receptors. Consequently, these receptors can only be activated by fast transients of high glutamate concentration. In addition, GluK3 receptors are very sensitive to voltage-dependent block by intracellular spermine that precludes activation of substantial currents at potentials positive to −50 mV. Two specific residues within the channel pore define this high-affinity site. Finally, GluK3 are calcium permeable in the same way as unedited GluK2 receptors. These receptors present unique properties among AMPA/kainate receptors that could reflect a specialized presynaptic function.
Cellular Mechanisms Underlying Burst Firing in Substantia Nigra Dopamine Neurons
Authors: Blythe Sarah N. , Wokosin David , Atherton Jeremy F. , Bevan Mark D.
Published: December 2009

Burst firing of substantia nigra dopamine (SN DA) neurons is believed to represent an important teaching signal that instructs synaptic plasticity and associative learning. However, the mechanisms through which synaptic excitation overcomes the limiting effects of somatic Ca2+-dependent K+current to generate burst firing are controversial. Modeling studies suggest that synaptic excitation sufficiently amplifies oscillatory dendritic Ca2+and Na+channel currents to lead to the initiation of high-frequency firing in SN DA neuron dendrites. To test this model, visually guided compartment-specific patch-clamp recording and ion channel manipulation were applied to rodent SN DA neuronsin vitro.

As suggested previously, the axon of SN DA neurons was typically found to originate from a large-diameter dendrite that was proximal to the soma. However, in contrast to the predictions of the model, (1) somatic current injection generated firing that was similar in frequency and form to burst firingin vivo, (2) the efficacy of glutamatergic excitation was inversely related to the distance of excitation from the axon, (3) pharmacological blockade or genetic deletion of Ca2+channels did not prevent high-frequency firing, (4) action potential bursts were invariably detected first at sites that were proximal to the axon, and (5) pharmacological blockade of Na+channels in the vicinity of the axon/soma but not dendritic excitation impaired burst firing. Together, these data suggest that SN DA neurons integrate their synaptic input in a more conventional manner than was hypothesized previously.
The Lysosomal Sialic Acid Transporter Sialin Is Required for Normal CNS Myelination
Authors: Prolo Laura M. , Vogel Hannes , Reimer Richard J.
Published: December 2009

Salla disease and infantile sialic acid storage disease are autosomal recessive lysosomal storage disorders caused by mutations in the gene encoding sialin, a membrane protein that transports free sialic acid out of the lysosome after it is cleaved from sialoglycoconjugates undergoing degradation. Accumulation of sialic acid in lysosomes defines these disorders, and the clinical phenotype is characterized by neurodevelopmental defects, including severe CNS hypomyelination. In this study, we used a sialin-deficient mouse to address how loss of sialin leads to the defect in myelination. Behavioral analysis of thesialin−/−mouse demonstrates poor coordination, seizures, and premature death. Analysis by histology, electron microscopy, and Western blotting reveals a decrease in myelination of the CNS but normal neuronal cytoarchitecture and normal myelination of the PNS. To investigate potential mechanisms underlying CNS hypomyelination, we studied myelination and oligodendrocyte development in optic nerves. We found reduced numbers of myelinated axons in optic nerves fromsialin−/−mice, but the myelin that was present appeared grossly normal. Migration and density of oligodendrocyte precursor cells were normal; however, a marked decrease in the number of postmitotic oligodendrocytes and an associated increase in the number of apoptotic cells during the later stages of myelinogenesis were observed. These findings suggest that a defect in maturation of cells in the oligodendrocyte lineage leads to increased apoptosis and underlies the myelination defect associated with sialin loss.
Millisecond Timescale Disinhibition Mediates Fast Information Transmission through an Avian Basal Ganglia Loop
Authors: Leblois Arthur , Bodor Ágnes L. , Person Abigail L. , Perkel David J.
Published: December 2009

Avian song learning shares striking similarities with human speech acquisition and requires a basal ganglia (BG)–thalamo-cortical circuit. Information processing and transmission speed in the BG is thought to be limited by synaptic architecture of two serial inhibitory connections. Propagation speed may be critical in the avian BG circuit given the temporally precise control of musculature during vocalization. We used electrical stimulation of the cortical inputs to the BG to study, with fine time resolution, the functional connectivity within this network. We found that neurons in thalamic and cortical nuclei that are not directly connected with the stimulated area can respond to the stimulation with extremely short latencies. Through pharmacological manipulations, we trace this property back to the BG and show that the cortical stimulation triggers fast disinhibition of the thalamic neurons. Surprisingly, feedforward inhibition mediated by striatal inhibitory neurons onto BG output neurons sometimes precedes the monosynaptic excitatory drive from cortical afferents. The fast feedforward inhibition lengthens a single interspike interval in BG output neurons by just a few milliseconds. This short delay is sufficient to drive a strong, brief increase in firing probability in the target thalamic neurons, evoking short-latency responses. By blocking glutamate receptorsin vivo, we show that thalamic responses do not appear to rely on excitatory drive, and we show in a theoretical model that they could be mediated by postinhibitory rebound properties. Such fast signaling through disinhibition and rebound may be a crucial specialization for learning of rapid and temporally precise motor acts such as vocal communication.
Phospholipase C β4 in the Medial Septum Controls Cholinergic Theta Oscillations and Anxiety Behaviors
Authors: Shin Jonghan , Gireesh Gangadharan , Kim Seong-Wook , Kim Duk-Soo , Lee Sukyung , Kim Yeon-Soo , Watanabe Masahiko , Shin Hee-Sup
Published: December 2009

Anxiety is among the most prevalent and costly diseases of the CNS, but its underlying mechanisms are not fully understood. Although attenuated theta rhythms have been observed in human subjects with increased anxiety, no study has been done on the possible physiological link between these two manifestations. We found that the mutant mouse for phospholipase C β4 (PLC-β4−/−) showed attenuated theta rhythm and increased anxiety, presenting the first animal model for the human condition. PLC-β4 is abundantly expressed in the medial septum, a region implicated in anxiety behavior. RNA interference-mediated PLC-β4 knockdown in the medial septum produced a phenotype similar to that of PLC-β4−/−mice. Furthermore, increasing cholinergic signaling by administering an acetylcholinesterase inhibitor cured the anomalies in both cholinergic theta rhythm and anxiety behavior observed in PLC-β4−/−mice. These findings suggest that (1) PLC-β4 in the medial septum is involved in controlling cholinergic theta oscillation and (2) cholinergic theta rhythm plays a critical role in suppressing anxiety. We propose that defining the cholinergic theta rhythm profile may provide guidance in subtyping anxiety disorders in humans for more effective diagnosis and treatments.
Activation of Glycogen Synthase Kinase-3β Is Required for Hyperdopamine and D2Receptor-Mediated Inhibition of Synaptic NMDA Receptor Function in the Rat Prefrontal Cortex
Authors: Li Yan-Chun , Xi Dong , Roman Joy , Huang Yue-Qiao , Gao Wen-Jun
Published: December 2009

The interactions between dopamine and glutamate systems play an essential role in normal brain functions and neuropsychiatric disorders. The mechanism of NMDA receptor regulation through high concentrations of dopamine, however, remains unclear. Here, we show the signaling pathways involved in hyperdopaminergic regulation of NMDA receptor functions in the prefrontal cortex by incubating cortical slices with high concentration of dopamine or administering dopamine reuptake inhibitor 1-(2-[bis-(4-fluorophenyl)methoxy]ethyl)- 4-(3-phenylpropyl)piperazine (GBR12909)in vivo. We found that, under both conditions, the synaptic NMDA receptor-mediated currents were significantly attenuated by excessive dopamine stimulation through activation of D2receptors. Furthermore, high dose of dopamine failed to affect NMDA receptor-mediated currents after blockade of NR2B subunits but triggered a dynamin-dependent endocytosis of NMDA receptors. The high-dose dopamine/D2receptor-mediated suppression of NMDA receptors was involved in the increase of glycogen synthase kinase-3β (GSK-3β) activity, which in turn phosphorylates β-catenin and disrupts β-catenin–NR2B interaction, but was dependent on neither Gq11 nor PLC (phospholipase C). Moreover, the hyperdopamine induced by GBR12909 significantly decreased the expression of both surface and intracellular NR2B proteins, as well as NR2B mRNA levels, suggesting an inhibition of protein synthesis. These effects were, however, completely reversed by administration of either GSK-3β inhibitor or D2receptor antagonist. These results therefore suggest that GSK-3β is required for the hyperdopamine/D2receptor-mediated inhibition of NMDA receptors in the prefrontal neurons and these actions may underlie D2receptor-mediated psychostimulant effects and hyperdopamine-dependent behaviors in the brain.
Neuromodulation at Single Presynaptic Boutons of Cerebellar Parallel Fibers Is Determined by Bouton Size and Basal Action Potential-Evoked Ca Transient Amplitude
Authors: Zhang Wei , Linden David J.
Published: December 2009

Most presynaptic terminals in the brain contain G-protein-coupled receptors that function to reduce action potential-evoked neurotransmitter release. These neuromodulatory receptors, including those for glutamate, GABA, endocannabinoids, and adenosine, exert a substantial portion of their effect by reducing evoked presynaptic Ca2+transients. Many axons form synapses with multiple postsynaptic neurons, but it is unclear whether presynaptic attenuation in these synapses is homogeneous, as suggested by population-level Ca2+imaging. We loaded Ca2+-sensitive dyes into cerebellar parallel fiber axons and imaged action potential-evoked Ca2+transients in individual presynaptic boutons with application of three different neuromodulators and found that adjacent boutons on the same axon showed striking heterogeneity in their strength of attenuation. Moreover, attenuation was predicted by bouton size or basal Ca2+response: smaller boutons were more sensitive to adenosine A1 agonist but less sensitive to CB1 agonist, while boutons with high basal action potential-evoked Ca2+transient amplitude were more sensitive to mGluR4 agonist. These results suggest that boutons within brief segment of a single parallel fiber axon can have different sensitivities toward neuromodulators and may have different capacities for both short-term and long-term plasticities.
Neuronal Avalanches Imply Maximum Dynamic Range in Cortical Networks at Criticality
Authors: Shew Woodrow L. , Yang Hongdian , Petermann Thomas , Roy Rajarshi , Plenz Dietmar
Published: December 2009

Spontaneous neuronal activity is a ubiquitous feature of cortex. Its spatiotemporal organization reflects past input and modulates future network output. Here we study whether a particular type of spontaneous activity is generated by a network that is optimized for input processing. Neuronal avalanches are a type of spontaneous activity observed in superficial cortical layersin vitroandin vivowith statistical properties expected from a network operating at “criticality.” Theory predicts that criticality and, therefore, neuronal avalanches are optimal for input processing, but until now, this has not been tested in experiments. Here, we use cortex slice cultures grown on planar microelectrode arrays to demonstrate that cortical networks that generate neuronal avalanches benefit from a maximized dynamic range, i.e., the ability to respond to the greatest range of stimuli. By changing the ratio of excitation and inhibition in the cultures, we derive a network tuning curve for stimulus processing as a function of distance from criticality in agreement with predictions from our simulations. Our findings suggest that in the cortex, (1) balanced excitation and inhibition establishes criticality, which maximizes the range of inputs that can be processed, and (2) spontaneous activity and input processing are unified in the context of critical phenomena.
Brain-Derived Neurotrophic Factor Reduces Amyloidogenic Processing through Control of SORLA Gene Expression
Authors: Rohe Michael , Synowitz Michael , Glass Rainer , Paul Steven M. , Nykjaer Anders , Willnow Thomas E.
Published: December 2009

Sorting protein-related receptor with A-type repeats (SORLA) is a major risk factor in cellular processes leading to Alzheimer's disease (AD). It acts as sorting receptor for the amyloid precursor protein (APP) that regulates intracellular trafficking and processing into amyloidogenic-β peptides (Aβ). Overexpression of SORLA in neurons reduces while inactivation of gene expression (as in knock-out mouse models) accelerates amyloidogenic processing and senile plaque formation. The current study aimed at identifying molecular pathways that control SORLA gene transcriptionin vivoand that may contribute to low levels of receptor expression in the brain of patients with AD. Using screening approaches in primary neurons, we identified brain-derived neurotrophic factor (BDNF) as a major inducer ofSorlathat activates receptor gene transcription through the ERK (extracellular regulated kinase) pathway. In line with a physiological role as regulator ofSorla, expression of the receptor is significantly impaired in mouse models with genetic (Bdnf−/−) or disease-related loss of BDNF activity in the brain (Huntington's disease). Intriguingly, exogenous application of BDNF reduced Aβ production in primary neurons and in the brain of wild-type micein vivo, but not in animals genetically deficient forSorla. These findings demonstrate that the beneficial effects ascribed to BDNF in APP metabolism act through induction ofSorlathat encodes a negative regulator of neuronal APP processing.
Cytotoxic CD8+T Cell–Neuron Interactions: Perforin-Dependent Electrical Silencing Precedes But Is Not Causally Linked to Neuronal Cell Death
Authors: Meuth Sven G. , Herrmann Alexander M. , Simon Ole J. , Siffrin Volker , Melzer Nico , Bittner Stefan , Meuth Patrick , Langer Harald F. , Hallermann Stefan , Boldakowa Nadia , Herz Josephine , Munsch Thomas , Landgraf Peter , Aktas Orhan , Heckmann Manfred , Lessmann Volkmar , Budde Thomas , Kieseier Bernd C. , Zipp Frauke , Wiendl Heinz
Published: December 2009

Cytotoxic CD8+T cells are considered important effector cells contributing to neuronal damage in inflammatory and degenerative CNS disorders. Using time-lapse video microscopy and two-photon imaging in combination with whole-cell patch-clamp recordings, we here show that major histocompatibility class I (MHC I)-restricted neuronal antigen presentation and T cell receptor specificity determine CD8+T-cell locomotion and neuronal damage in culture and hippocampal brain slices. Two separate functional consequences result from a direct cell–cell contact between antigen-presenting neurons and antigen-specific CD8+T cells. (1) An immediate impairment of electrical signaling in single neurons and neuronal networks occurs as a result of massive shunting of the membrane capacitance after insertion of channel-forming perforin (and probably activation of other transmembrane conductances), which is paralleled by an increase of intracellular Ca2+levels (within <10 min). (2) Antigen-dependent neuronal apoptosis may occur independently of perforin and members of the granzyme B cluster (within ∼1 h), suggesting that extracellular effects can substitute for intracellular delivery of granzymes by perforin. Thus, electrical silencing is an immediate consequence of MHC I-restricted interaction of CD8+T cells with neurons. This mechanism is clearly perforin-dependent and precedes, but is not causally linked, to neuronal cell death.
Cav1.3 Channel Voltage Dependence, Not Ca2+Selectivity, Drives Pacemaker Activity and Amplifies Bursts in Nigral Dopamine Neurons
Authors: Putzier Ilva , Kullmann Paul H. M. , Horn John P. , Levitan Edwin S.
Published: December 2009

Cav1.3 (α1D) L-type Ca2+channels have been implicated in substantia nigra (SN) dopamine (DA) neuron pacemaking and vulnerability to Parkinson's disease. These effects may arise from the depolarizing current and cytoplasmic Ca2+elevation produced by Cav1.3 channels at subthreshold membrane potentials. However, the assumption that the Ca2+selectivity of Cav1.3 channels is essential has not been tested. In this study the properties of SN DA neuron L-type Ca2+channels responsible for driving pacemaker activity in juvenile rat brain slices were probed by replacing native channels blocked with the dihydropyridine nimodipine with virtual channels generated by dynamic clamp. Surprisingly, virtual L-type channels that mimic native and recombinant Cav1.3 channels supported pacemaker activity even though dynamic clamp currents are not carried by Ca2+. This effect is specific because pacemaker activity could not be restored by tonic current injection, virtual nonselective leak channels or virtual NMDA receptors, which share with L-type channels a negative slope conductance region in their current–voltage (I–V) curve. Altering virtual channels showed that the production of pacemaker activity depended on the characteristic voltage dependence of DA neuron L-type channels, while activation kinetics and reversal potential were not critical parameters. Virtual L-type channels also supported slow oscillatory potentials and enhanced firing rate during evoked bursts. Thus, Cav1.3 channel voltage dependence, rather than Ca2+selectivity, drives pacemaker activity and amplifies bursts in SN DA neurons.
AF4 Is a Critical Regulator of the IGF-1 Signaling Pathway during Purkinje Cell Development
Authors: Bitoun Emmanuelle , Finelli Mattéa J. , Oliver Peter L. , Lee Sheena , Davies Kay E.
Published: December 2009

Deregulation of the insulin-like growth factor 1 (IGF-1) signaling pathway is a recurrent finding in mouse models and human patients with cerebellar ataxia and thus represents a common pathological cascade in neuronal cell death that may be targeted for therapy. We have previously identified a point mutation in AF4, a transcription cofactor of RNA polymerase II elongation and chromatin remodeling, that causes progressive and highly specific Purkinje cell (PC) death in the ataxic mouse mutantrobotic, leading to the accumulation of AF4 in PCs. Here we confirm that the spatiotemporal pattern of PC degeneration in the robotic cerebellum correlates with the specific profile of AF4 upregulation. To identify the underlying molecular pathways, we performed microarray gene expression analysis of PCs obtained by laser capture microdissection (LCM) at the onset of degeneration.Igf-1was significantly downregulated in robotic PCs compared with wild-type controls before and throughout the degenerative process. Consistently, we observed a decrease in the activation of downstream signaling molecules including type 1 IGF receptor (IGF-1R) and the extracellular signal-regulated kinase (ERK) 1 and ERK2. Chromatin immunoprecipitation confirmed thatIgf-1is a direct and the first validated target of the AF4 transcriptional regulatory complex, and treatment of presymptomatic robotic mice with IGF-1 indeed markedly delayed the progression of PC death. This study demonstrates that small changes in the levels of a single transcriptional cofactor can deleteriously affect normal cerebellum function and opens new avenues of research for the manipulation of the IGF-1 pathway in the treatment of cerebellar ataxia in humans.
Radio Physical and Structural Parameters of Forests as an Object of Remote Sensing
Authors: Gaykovich K. P. , Gorobets V. N.
Published: December 2009

The object of investigation is the permittivity of a leaf of deciduous trees, the dependence between the forest’s outgoing eigen signal and its projective covering, the temperature inhomogeneities of the forest elements, radio wave diffraction and their repeated re-reflections in the tree crowns.
The Economics of Carbon Capture
Authors: Islegen Ozge , Reichelstein Stefan J
Published: December 2009

As carbon capture technologies are likely to allow power plants to reduce emissions by up to 90 percent, Ozge Islegen and Stefan Reichelstein of Stanford Business School feel that plants will choose to implement such technologies to avoid paying even modest emissions permit prices.
“I was also absent at my dairy-house”: The Representation and Symbolic Function of the Dairy House in Samuel Richardson's Clarissa
Authors: Lipsedge Karen
Published: December 2009

Exploring the symbolic function of the dairy house in Samuel Richardson's Clarissa helps to unearth the novel's commentary on the relation between garden buildings and concepts of self. An examination of recent work on the role of space in the novel and eighteenth-century architectural manuals and images reveals how Richardson's representation of the dairy house intersects with contemporary ideas of self and interiority. Richardson employs the dairy house's removed location at her grandfather's estate and the reason for its construction (her grandfather constructed it for Clarissa in honour of her skills in dairy house management) to emphasize Clarissa's independence, self-sufficiency, and command of space. He draws on the dairy house's association with Arcadian rural simplicity and wholesome purity to underline Clarissa's exemplary piety and pastoral innocence. As a symbol, her dairy house also reinforces the distance between Clarissa and the Harlowes’ economic ambitions.
Science and the information society
Authors: Dixon Bernard
Published: December 2009

The paperless society may be just around the corner, but it may take us some time to reach that turning point because papyrophilic practices persist peroasively.
Problems of the paperless book
Authors: Eisenberg Daniel
Published: December 2009

The foundations of electronic publishing have been established, but questions and limitations still restrict its use in scholarly publishing.
Scholarly publishing on the national networks
Authors: Arms William Y.
Published: December 2009

Electronic networks provide fast, accurate, and economical scholarly communication; they hold great promise though gaps must be filled before fundamental change will be realized.
Author problems in a collaborative research project
Authors: Piternick Anne B.
Published: December 2009

Multidisciplinary collaborative projects can be rewarding, but they poseproblems in ensuring that authors receive fair creditfor their work
Subscriber Interest in Electronic Copy
Authors: Woolfrey Sandra
Published: December 2009

Journals publishing is frequently touted as the field most likely to be overtaken by electronic forms of dissemination. What sectors of scholarly journals' readers are most interested in receiving the publications in electronic formats? For what reasons? Are subscribers willing to pay the additional cost of formatting and distribution? One joumal's subscribers are surveyed on their attitudes towards receiving the publication in an electronic form.
The Cost of Implementing an Electronic Journal
Authors: Meadows Jack , Pullinger David , Such Peter
Published: December 2009

The ELVYN project was established in the United Kingdom to examine how a publisher might best interact with research libraries in the delivery of an electronic version of a printed journal. As part of the study, data were collected at both the publisher and the libraries on the costs (in terms primarily of materials and manpower) that were incurred in setting up, and subsequently running, such an electronic version. The costs incurred by the publishers are examined here in terms of the activities involved. For the type of scientific journal considered in this project, it is clear that the costs and the computer skills involved in setting up an electronic version are considerable.
On the Future of the Book, or Does It Have a Future?
Authors: Meadow Charles T.
Published: December 2009

Many readers identify themselves as 'book lovers' and are dismayed by the technological changes affecting the format of books. Electronic publication leads us to ask, 'What is a book?' In transforming the media by which 'books' are delivered, the 'authority' of the author is undermined, but the value of the work may remain intact and even enhanced. In fact, books have been undergoing transformations in form since their invention. It will likely take a generation, however, before we can cherish the electronic book as 'object.'
The University Press in the 21st Century
Authors: Walker Nick
Published: December 2009

The information revolution has the potential to revitalize the form and culture of scholarship in all fields of study. In the midst of the enormous growth in computerized information and electronic publication, scholarly presses must continue to assert their role as disseminators of knowledge by maintaining high standards of quality in editing and production. Presses can capitalize on their expertise in marketing and product development to pursue new initiatives in electronic publication. However, sponsoring institutions need to recognize the benefits of this potent capability to the scholarly community and invest the necessary resources.
The Present and Future of Historical Journals
Authors: Fairbairn Brett
Published: December 2009

Journals play a critical scholarly role as regulators of both knowledgeand professional advancement. The fairness of the journal system, however, is notguaranteed by its structure, which is subject to arbitrariness inpeer review. To ensure the fairness of peer review and to serve scholarly goals in general, there needs to be a diverse range of publications available to academic authors and readers. Joumals are intrinsic to scholarship, yet they are increasingly required to meet commercial goals. The advent of electronic technologies will increase the financial pressures on journals by making levels of income less predictable and more reliant on large database vendors.
Book History at Penn State
Authors: West III James L.W.
Published: December 2009

Scholars who study the history of the book examine scribal and print culture, and theirinfluence on the development and transmission of culture. Academics worldwide have established organizations dedicated to defining thefield and to developing curriculums, research centres, and lecture forums in this nascent field. Onesuchorganization is the Penn State Center for the History of the Book, established by the author in 1992. The centre aims to teach the discipline, to establish a publication program, and tofurther promote thefield in theuniversity andgeneral communities through lectures, exhibits, and conferences. The centre's activities in studying book history also serve to illuminate the current debate over whether the book as we know it is an endangered species in an increasingly electronic environment.
Re-engineering Scholarly Communication: Thoughts Addressed to Authors
Authors: Bennett Scott
Published: December 2009

Much scholarly communication is crippled by economically irrational behaviours, including the disassociation of supply and demand, the dysfunctional management of intellectual property, an unsustainable spiral of capital cost, and the emerging failure of publishing decisions to guide economic rationing elsewhere in academic life. Remedies should besought not solely among established publishers but also among collaborations of researchers, librarians, and computing centre staff using new capabilities for electronic publishing. These collaborations should be founded in the creative impulse of teaching and research, but they must also be designed to survive in the marketplace for information and knowledge.
Publishing Economics: The Site Licence Effect
Authors: Olivieri Rene
Published: December 2009

Purchasers of journals are continuing each year to pay more for less, as prices rise far in excess of inflation and the body of knowledge available rapidly expands. The current economic model for journals publishing revolves around a monopolistic pricing structure, which, when applied to electronic products, is difficult to justify, given the lower marginal cost of each copy. An alternative economic model, based on site licensing, could be applied to both hard copy and electronic versions of works, and offer new benefits to both consumers and publishers in terms of wider access, increased usage, predictable prices, andflexible contrac ts. A site licence model also raises questions about cheating, about the effect on the role of academic societies, and about how to regulate a changing environment over a fixed term. However, some site licensing initiatives are already underway, most notably a nationwide pilot for the higher education sector in the United Kingdom.
Perceptions of Electronic Journals in British Universities
Authors: Gomes Suely , Meadows Jack
Published: December 2009

A survey of staff in British universities (including academic and administrative staff) has explored the ways in which they perceive electronic journals and the factors that affect their perceptions. Academics as readers are concerned with rather different factors from academics as authors. A profile can be constructed of those academics who are more likely to read electronic journals. It appears that the currently increasing parallel publication of print and electronic versions best satisfies authors' needs. All categories of respondents see the ultimate dominance of electronic journals as inevitable, and are therefore preparing for it.
The Merbecke Revival in Victorian Anglicanism: A Re-appraisal
Authors: Kim Hyun-Ah
Published: December 2009

Abstract:

John Merbecke's The Booke of Common Praier Noted (BCPN) is a musical manifestation of the English Reformation—the vernacular liturgical chants extensively utilized by the Victorian Anglicans as a key source for re-establishing the musical foundation of the Church. Since then, Merbecke's chants have spread throughout the Anglican churches and were adopted by many denominations of English-speaking countries and, furthermore, used for the English liturgy of the Roman Catholic Church after the Second Council. While the historical importance of BCPN is evident, however, the music and its remarkable popularization in later centuries have been misunderstood, especially because of the musical hybridity of Merbecke's chants that reflect the liturgical transition of the late 1540s. In light of more recent studies of Merbecke that elucidate the essential characteristics of his chants as musica rhetorica, this essay seeks to re-evaluate the Victorian motivation for and contribution to the rediscovery of Merbecke's chants. It examines how and why BCPN came to be viewed as a paradigm for the post-Tractarian revival of choral service, whose theological aesthetics of music is best manifested in The Ecclesiologist and Parish Choir and recapitulates the core of Christian music polemics articulated by the Church Fathers and the key Reformers. The essay thus argues for the historical and theological continuity between the Tudor Anglican ideal of “sacred music” underlying BCPN and its Victorian counterpart that views BCPN as a musical means for the realization of a via media in Christian antiquity—an icon of Anglican plainchant.
Development of Dynamic Transit Signal Priority Strategy
Authors: Ekeila Wael , Sayed Tarek , Esawey Mohamed El
Published: December 2009

Transit signal priority (TSP) is a popular strategy used to enhance the performance of transit systems by modifying the signal control logic to give transit vehicles priority at signalized intersections. Conventional TSP strategies used in most cities have been shown to offer significant benefits by reducing delay of transit vehicles. However, concerns about shortcomings of conventional TSP strategies have limited their application. The main concern is a potential negative impact on cross street traffic. Another concern is the static nature of conventional TSP strategies and the lack of responsiveness to real-time traffic and transit conditions. A dynamic TSP control system has been developed that can provide signal priority in response to real-time traffic and transit conditions. The dynamic TSP system consists of three main components: a virtual detection system, a dynamic arrival prediction model, and a dynamic TSP algorithm. Two case studies are presented to test and compare the dynamic and the conventional TSP systems. A hypothetical intersection is simulated in the first case study, and a proposed light rail transit line is simulated in the second. For both case studies, a virtual detection system was developed in VISSIM, along with a linear travel time arrival prediction model. Finally, a dynamic TSP algorithm was developed to determine what TSP strategy to use and when to apply it. The results show that the dynamic TSP system reduced the total delay of transit vehicles and outperformed the conventional TSP system for reducing transit trip travel time.
Development of Real-Time Optimal Bus Scheduling and Headway Control Models
Authors: Kim Wongil , Son Bongsoo , Chung Jin-Hyuk , Kim Eungcheol
Published: December 2009

Infrequent bus service because of a sudden rise in international gas prices has created a significant social problem in South Korea. Bus service frequency is determined by considering bus operation costs to the service supplier, passenger demand, and so forth. Optimal bus frequency was determined and a timetable for each bus stop was created by applying the DTR (demand- and travel time–responsive) model or the DTRC (demand- and travel time–responsive model for critical scheduling areas); both use data for each bus stop and route segment. A bus headway control model that can monitor and assess punctuality of an operation was also developed. This model was based on real-time event data, such as bus stop departures and arrivals for buses operating on a line-based timetable, constructed for each bus stop. It was also based on the bus stop traffic cost, which was applied in the bus scheduling model. The model's ability to evaluate the punctuality of operation made it possible to transmit headway control instructions (when to decelerate or accelerate) to a bus driver via an onboard unit. A model verification process was implemented by using data collected from a bus management system and integrated transit fare card system for the bus route in Seoul. To evaluate the reliability and uncertainty of the optimal solution, a sensitivity analysis was implemented for the various parameters and assumptions used in the models.
Efficient Bus Operational Parking Model
Authors: Ceder Avishai , Israel Gali
Published: December 2009

One of the operational problems for urban transit, especially with buses, occurs when vehicles need to park at route departure, controlled, or holding stops located on street; however, because of a lack of parking spaces, buses block the traffic lane adjacent to the parking bay or lane. A scheduling-based solution to this problem consists of two parts. First, a scheduling-based design tool describes the changes in operational parking spaces available at route departure points; this is called the surplus function and is based on the known deficit function. Second, with the developed model, efficient procedures are built for eliminating or reducing the impact of lane-blocked situations, by shifting departure times or by inserting deadheading trips in the timetables.
Planning for Bus Rapid Transit in Single Dedicated Bus Lane
Authors: Li Jing-Quan , Song Myoung Kyun , Li Meng , Zhang Wei-Bin
Published: December 2009

Bus rapid transit (BRT) systems with dedicated lanes have shown advantages over traditional bus systems and have attracted more transit riders. However, it is not always possible to build BRT systems with double dedicated lanes because of physical and cost constraints. A BRT system with a single dedicated lane is more practical in such situations. In a single-lane configuration, buses approaching from opposite directions have to share the same road section and can overtake or pass each other only at the bus stops. An optimization model is proposed to describe the synchronization requirements of the BRT buses with the objective of minimizing the total travel and dwell time. The computational results show that a BRT system with a single dedicated lane yields total travel time that is similar to that of a BRT system with double dedicated lanes when the headway is not short (e.g., more than 20 min). In addition, to address possible delay at intersections, a simple speed control algorithm is implemented to adjust the bus speed in real time if the bus is delayed considerably. A microscopic simulation based on VISSIM is conducted to examine the impacts of the BRT bus on other traffic and the performance of the speed control. The simulation result shows that the speed control effectively handles the delay in the intersection and the other traffic is rarely affected by the speed control.