bluuebunny/crossref_metadata_2025 huggingface dataset:
Numerical simulation of laser machining of carbon-fibre-reinforced composites
Authors: Negarestani R , Sundar M , Sheikh M A , Mativenga P , Li L , Li Z L , Chu P L , Khin C C , Zheng H Y , Lim G C
Published: January 2010

The growing use of carbon-fibre-reinforced polymer (CFRP) composites as high-performance lightweight materials in aerospace and automotive industries demands efficient and low-cost machining technologies. The use of laser machining for cutting and drilling composites is attractive owing to its high speed, flexibility, and ease of automation. However, the anisotropic material properties of composites, and issues related to the heat-affected zone (HAZ), charring, and potential delamination during laser processing, are major obstacles in its industrial applications. In order to improve the quality and dimensional accuracy of CFRP laser machining, it is important to understand the mechanism of the transient thermal behaviour and its effect on material removal. Based on the ‘element death’ technique of the finite element (FE) method, a three-dimensional model for simulating the transient temperature field and subsequent material removal has been developed, for the first time, on a heterogeneous fibre—matrix mesh. In addition to the transient temperature field, the model also predicts the dimensions of the HAZ during the laser machining process. Experimental results obtained with same process variables using a 355 nm DPSS Nd:YVO4 laser were used to validate the model. Based on the investigation, the mechanism of material removal in laser composite machining is proposed. The results suggest that the employed FE approach can be used to simulate pulsed laser cutting of fibre-reinforced polymer composites.
Optimal replacement policy for a two-component cold standby system with repair priority
Authors: Leung K N F , Zhang Y L , Lai K K
Published: January 2010

In this paper, a cold standby repairable system consisting of two dissimilar components and one repairman is examined. It was assumed that both Component 1 and Component 2, were not as good as new after repair, and Component 1 had repair priority. Under these assumptions, using the geometric process repair model, a discrete replacement policy N under which the system is replaced when the number of failures of Component 1 reaches N is considered. The problem was to determine an optimal policy N∗ so that the long-run average loss per unit time L( N) of the system was minimized. The expression L( N) was explicitly derived, and the corresponding optimal policy N∗ can be determined by minimizing L( N) with respect to N. A numerical example and the associated MATLAB computer program are given to illustrate the model—s applicability. Finally, conclusions are drawn for this study.
Scheduling and balancing assembly lines with the task deterioration effect
Authors: Shahanaghi K , Yolmeh A M , Bahalke U
Published: January 2010

Assembly lines are special flowline production systems that are of great importance in industrial mass production. This paper introduces task deterioration into the traditional simple assembly line balancing problem (SALBP). Task deterioration means that a task processed later consumes more time than the same task processed earlier. The aim is to find an optimal assignment and schedule of tasks at workstations so as to minimize the cycle time for a given number of stations, which in the literature is known as SALBP-2. For this purpose, a mathematical model is proposed. As SALBP-2 is classified as NP hard, and as the considered problem becomes more complicated with the additional deterioration parameter, a genetic algorithm is proposed. Finally, several well-known examples are solved to illustrate the approach proposed.
Green aero-engines: Technology to mitigate aviation impact on environment
Authors: Parker R , Lathoud M
Published: January 2010

Despite consistent, continued efforts by the aviation industry to reduce emissions, further technological advances are required to mitigate its impact on the global climate. This article first outlines aviation's importance in the global challenge and its specific constraints relative to other industries. It then investigates the current understanding of aviation's climate impact and the ongoing Rolls-Royce efforts to develop technologies to mitigate it. This includes improving the engine's propulsive efficiency, thermal efficiency, and combustion process. This article also discusses paradigm shifts that might redefine the way this industry operates in the global environment.
The use of ensemble empirical mode decomposition to improve bispectral analysis for fault detection in rotating machinery
Authors: Lei Y , Zuo M J , Hoseini M
Published: January 2010

Empirical mode decomposition (EMD) has been widely applied to analyse signals for the detection of faults in rotating machinery. However, sometimes, it cannot reveal signal characteristics accurately because of the mode mixing problem. Ensemble empirical mode decomposition (EEMD) was developed recently to alleviate the mode mixing problem of EMD. With EEMD, components that are physically meaningful can be extracted from the signals. Bispectrum, a third-order statistic, helps identify phase coupling effects, which are useful for detecting faults in rotating machinery. Utilizing the advantages of EEMD and bispectrum, this article proposes a joint method for detecting such faults. First, original vibration signals collected from rotating machinery are decomposed by EEMD and a set of intrinsic mode functions (IMFs) is produced. Then, the IMFs are reconstructed into new signals using the weighted reconstruction algorithm developed in this article. Finally, the reconstructed signals are analysed via bispectrum to detect faults. The simulation experiments and the physical experiments of two gears with a chipped tooth and a cracked tooth, respectively, demonstrate that the proposed method can detect faults more clearly than can directly performing bispectrum on the original vibration signals.
The effects of the shape of tooth profile modifications on the transmission error, bending, and contact stress of spur gears
Authors: Tesfahunegn Y A , Rosa F , Gorla C
Published: January 2010

Nowadays, the basic requirements of gear transmissions are not limited to resistance and reliability, but often include good efficiency and low vibration and noise emissions. This article investigates the role of tooth flank micro-geometry in fulfilling these needs. A non-linear finite element approach has been conceived and exploited to investigate in detail the influence of the shape of profile modifications (PMs) on transmission error, root stress, and contact pressure. In this approach, the contact between teeth flanks is handled by ABAQUS general purpose contact algorithm without introducing any simplification based on gear geometry peculiarities. The boundary conditions are defined so that it is possible to automatically run a sequence of static analyses. The numerical results are first assessed by comparison with experimental measurements and then a comparison of contact and bending stresses of the same gear with long linear and long circular PMs is presented and discussed. The results of these comparisons show that the optimal amount of PMs is not independent of PM shape; hence, the procedures used to design linear PMs cannot be directly applied to the design of non-linear PMs.
Force sensing and its application in minimally invasive surgery and therapy: A survey
Authors: Trejos A L , Patel R V , Naish M D
Published: January 2010

The reduced access conditions of minimally invasive surgery and therapy (MIST) impair or completely eliminate the feel of tool—tissue interaction forces. Many researchers have been working actively on the development of force sensors and sensing techniques to address this problem. The goal of this survey article is to summarize the state of the art in force sensing techniques for medical interventions in order to identify existing limitations and future directions. A literature search was performed from January to July 2009 using a combination of keywords relevant to the area, including force, sensor, sensing, haptics, and minimally invasive surgery.

The literature search resulted in 126 articles with valuable content. This article presents a summary of the force sensing technologies, design specifications for force sensors in clinical applications, force sensors and sensing instruments that have been developed for MIST, and the experiments performed to determine the need for force information. Open areas of research include force sensor design, development of alternative methods of sensing, assessment of the impact of force information on performance, determination of the benefits of haptic information, and evaluation of the human factors involved in the processing and use of force information.
An analytical study of radiation effects on the premixed laminar flames of aluminium dust clouds
Authors: Bidabadi M , Shabani Shahrbabaki A , Jadidi M , Montazerinejad S
Published: January 2010

A new analytical model of a quasi one-dimensional non-adiabatic dust flame is developed with the assumption that the particle burning rate in the flame front is controlled by the process of oxygen diffusion. In this model, the flame propagation mechanism is considered to be radiation, conduction, and convection. Algebraic equations defining the laminar flame speed were obtained in two limiting cases: lean and rich mixtures. The flame structure is assumed to consist of a preheat zone, a reaction zone, and a postflame zone for lean mixtures and a preheat zone and a reaction zone for rich mixtures. Under the lean mixture approximation, values of the flame speed, lean limit, and flame temperature were calculated by adding the radiation term; flame temperature in the preheat zone increased, while it decreased in the postflame zone. This phenomenon may be attributed to the radiative heat transfer from the postflame zone to the preheat zone. Also, when the radiation term was considered, the flame speed increased but the lean limit decreased. In addition, radiation in the rich mixture resulted in the increase of the flame speed and the gas phase temperature in the preheat zone, whereas in the flame zone, the gas phase temperature decreased. Calculated values of the flame speed and flame temperature are in a good agreement with the experimental data in the literature.
Asymptotic analysis of the forced vibrations of a one-disc rotor on a non-linear flexible base
Authors: Avramov K V
Published: January 2010

Equations of motion for a four-degree-of-freedom dynamical system describing the vibrations of a one-disc elastic rotor taking into account gyroscopic moments on a non-linear flexural base are derived. A new version of the multiple scales method is developed and applied to analyse the non-linear dynamics of such a system for different resonances. The steady motions of the rotor are analysed. From the asymptotic analysis, it is shown that out-of-plane motions of the disc exist in the symmetric rotor.
A study of novel viscous dissipation measurement for polymer melts in microchannels
Authors: Xu B , Wang M , Yu T , Zhao D
Published: January 2010

Studies on the rheological behaviour of polymer melts, flowing through microchannels, are complicated because a large number of factors affect the melt viscosity. One such factor, viscous dissipation, is investigated in the current work through a novel experimental technique that is used in determining the viscous dissipation of a polymer melt flowing through microchannels. Relative tests are conducted using melts of high-density polyethylene (HDPE) extruded through several capillary dies at different temperatures. Experimental results indicate that the temperature rises due to viscous dissipation increase with increasing shear rate. In addition, simulations considering viscous dissipation are carried out. The comparison of the experimental results with those predicted from the simulations at different melt temperatures indicates that the maximum temperature rise deviation is about 15 per cent. Therefore, the measurement method of viscous dissipation is available, which is helpful to better understand the flow characteristics of microchannels.
Robotic surgery litigation
Authors: McLean T R , Waxman S
Published: January 2010

Like robotic surgery itself, the litigation that follows a robotic surgical misadventure is complex. This complexity is not only a reflection of a product's liability, but also because metadata are contained in surgical robots. Analogous to the ‘black box’ stored on airplanes, at the time of litigation, metadata may be a friend or a foe to the robot's manufacturer. This section provides an overview of the products liability law that can impact a robotic surgical manufacturer and concludes that for most surgical misadventures, a robotic surgical manufacturer will be better off if the surgical instrument stores large volumes of metadata.
Explicit formulation for the axial collapse of a pipe during drilling
Authors: Almasi A
Published: January 2010

New closed-form expressions are introduced for ax-symmetric progressive axial collapse of pipes that use a plastic folding mechanism based on variable length of an active plastic hinge zone. A procedure for determination of a load—displacement curve of axial pipe collapse is presented. Theoretical predictions give a good agreement with the experimental results owing to the influence of presented new refinements.
Mechanical characterization of materials for bulk forming using a drop weight testing machine
Authors: Silva C M A , Rosa P A R , Martins P A F
Published: January 2010

The main limitation of mechanical testing equipments is nowadays centred in the characterization of materials at medium loading rates. This is particularly important in bulk forming because strain rate can easily reach values within the aforesaid range.

The aim of this article is twofold: (a) to present the development of a low-cost, flexible drop weight testing equipment that can easily and effectively replicate the kinematic behaviour of presses and hammers and (b) to provide a new level of understanding about the mechanical characterization of materials for bulk forming at medium rates of loading. Special emphasis is placed on the adequacy of test operating conditions to the functional characteristics of the presses and hammers where bulk forming takes place and to its influence on the flow stress. This is needed because non-proportional loading paths during bulk forming are found to have significant influence on material response in terms of flow stress.

The quality of the flow curves that were experimentally determined is evaluated through its implementation in a finite-element computer program and assessment is performed by means of axisymmetric upset compression with friction. Results show that mechanical characterization of materials under test operating conditions that are similar to real bulk forming conditions is capable of meeting the increasing demand of accurate and reliable flow stress data for the benefit of those who apply numerical modelling of process design in daily practice.
The effect of temperature on the mechanical properties of adhesives for the automotive industry
Authors: Banea M D , da Silva L F M
Published: January 2010

The application of adhesively bonded joints in structural components made of composite materials for automotive industry applications has increased significantly in recent years and provides many benefits that will ultimately lead to lighter-weight vehicles, fuel savings, and reduced emissions. The principal benefits are design flexibility, opportunity for part consolidation, and joining of dissimilar materials. While much work has been conducted in adhesive bonding for the aerospace industry, the automotive industry does not currently have a full portfolio of processes and methods for evaluating candidate adhesives for use in bonding structural automotive components. Aerospace techniques and materials are not generally applicable, since the automotive industry must be more cognizant of cost and high volume production.

In this article, the performances of two different adhesive types, an epoxy and a polyurethane, have been studied through bulk specimen and adhesive joint tests. Results showed that the failure loads of both the bulk test and joint test specimens vary with temperature and this needs to be considered in any design procedure. Also, for the polyurethane adhesive, the single lap joint is sufficient to determine the adhesive shear strength.
Computational simulation of the relaxation of local stresses due to foreign object damage under cyclic loading
Authors: Davis T , Ding J , Sun W , Leen S B
Published: January 2010

In this study, the phenomenon of residual stress relaxation from foreign object damage (FOD) is numerically simulated using a hybrid explicit—implicit finite-element method. The effects of cycle fatigue loadings on stress relaxation were studied. FOD is first simulated by firing a 3mm cube impacting onto a plate made of titanium alloy Ti-6Al-4V at 200m/s. The FOD impact produces two distinct stress concentrations: one is compressive directly beneath the impact site; the other is tensile around the outer edge of the impact. The plate was then assumed to be subjected to a cyclic fatigue loading. The stress relaxation was investigated under a range of stress ratios and maximum applied stresses. Two different material models were considered for the simulations, namely an elastic—perfectly plastic model and a non-linear kinematic hardening model.
Generic approach for deriving reliability and maintenance requirements through consideration of in-context customer objectives
Authors: Jones J A , Warrington L
Published: January 2010

Not all implementations of reliability are equally effective at providing customer and user benefit. Random system failure with no prior warning or failure accommodation will have an immediate, usually adverse impact on operation. Nevertheless, this approach to reliability, implicit in measurements such as failure rate and mean time between failures, is widely assumed without consideration of potential benefits of proactive maintenance. Similarly, it is easy to assume that improved maintainability is always a good thing. However, maintainability is only one option available to reduce the cost of ownership and reduce the impact of failure. This paper discusses a process for deriving optimized reliability and maintenance requirements through consideration of in-context customer objectives rather than a product in isolation.
Population Health: Data, Trends and Indicators
Authors: Wright Kath , Harden Melissa , Misso Kate
Published: January 2010

Several websites provide information about the health of the population including health indicators at regional and district levels. These allow health services researchers to access comparable statistics for different countries. This edition of ‘What's on the web’ lists some of the websites that provide easy access to reliable population health data and statistics.

If you would like to alert readers to useful web pages or suggest topics for this column, please send details to:
The Impact of Misalignment of Organizational Structure and Product Architecture on Quality in Complex Product Development
Authors: Gokpinar Bilal , Hopp Wallace J. , Iravani Seyed M. R.
Published: January 2010

Product architecture and organizational communication play significant roles in complex product development efforts. By using networks to characterize both product structure and communication patterns, we examine the impact of mismatches between these on new product development (NPD) performance. Specifically, we study the vehicle development process of a major auto company and use vehicle quality (warranty repairs) as our NPD performance metric. Our empirical results indicate that centrality in a product architecture network is related to quality according to an inverted-U relationship, which suggests that vehicle subsystems of intermediate complexity exhibit abnormally high levels of quality problems. To identify specific subsystems in danger of excessive quality problems, we characterize mismatches between product architecture and organizational structure by defining a new metric, called coordination deficit, and show that it is positively associated with quality problems. These results deepen our understanding of the impact of organizational structure and product architecture on the NPD process and provide tools with which managers can diagnose and improve their NPD systems.
Package Size Decisions
Authors: Koenigsberg Oded , Kohli Rajeev , Montoya Ricardo
Published: January 2010

We describe a model examining how a firm might choose the package size and price for a product that deteriorates over time. Our model considers four factors: (1) the usable life of the product, (2) the rates at which consumers use the product, (3) the relation between package size and the variable cost of the product, and (4) the minimum quantities consumers seek to consume for each dollar they spend (we call these reservation quantities). We allow heterogeneity in the usage rates and reservation quantities for the consumers. We show that when the cost increases as a linear or convex function of the package size, the firm should make packages of the smallest possible size. Smaller packages reduce waste and allow consumers to more closely match their purchases with desired consumption. This in turn allows the firm to charge a higher unit price and also sell more unit volume. The results imply that in a market with multiple package sizes (produced by the same or competing firms), at least one of the packages must have the smallest possible size, provided the fixed cost of making the product is sufficiently low. For concave cost functions, the firm may find it optimal to make larger than smallest-size packages.
Differential Effects of Tau on the Integrity and Function of Neurons Essential for Learning in Drosophila
Authors: Kosmidis Stylianos , Grammenoudi Sofia , Papanikolopoulou Katerina , Skoulakis Efthimios M. C.
Published: January 2010

Tauopathies are a heterogeneous group of neurodegenerative dementias involving perturbations in the levels, phosphorylation, or mutations of the microtubule-binding protein Tau. The heterogeneous pathology in humans and model organisms suggests differential susceptibility of neuronal types to wild-type (WT) and mutant Tau. WT and mutant human Tau-encoding transgenes expressed pan-neuronally in theDrosophilaCNS yielded specific and differential toxicity in the embryonic neuroblasts that generate the mushroom body (MB) neurons, suggesting cell type-specific effects of Tau in the CNS. Frontotemporal dementia with parkinsonism-17-linked mutant isoforms were significantly less toxic in MB development. Tau hyperphosphorylation was essential for these MB aberrations, and we identified two novel putative phosphorylation sites, Ser238and Thr245, on WT hTau essential for its toxic effects on MB integrity. Significantly, blocking putative Ser238and Thr245phosphorylation yielded animals with apparently structurally normal but profoundly dysfunctional MBs, because animals accumulating this mutant protein exhibited strongly impaired associative learning.

Interestingly, the mutant protein was hyperphosphorylated at epitopes typically associated with toxicity and neurodegeneration, such as AT8, AT100, and the Par-1 targets Ser262and Ser356, suggesting that these sites in the context of adult intact MBs mediate dysfunction and occupation of these sites may precede the toxicity-associated Ser238and Thr245phosphorylation. The data support the notion that phosphorylation at particular sites rather than hyperphosphorylation per se mediates toxicity or dysfunction in a cell type-specific manner.
Serotonergic Neurons Migrate Radially through the Neuroepithelium by Dynamin-Mediated Somal Translocation
Authors: Hawthorne Alicia L. , Wylie Christi J. , Landmesser Lynn T. , Deneris Evan S. , Silver Jerry
Published: January 2010

Embryonic CNS neurons can migrate from the ventricular zone to their final destination by radial glial-guided locomotion. Another less appreciated mechanism is somal translocation, where the young neuron maintains its primitive ventricular and pial processes, through which the cell body moves. A major problem in studying translocation has been the identification of neuronal-specific markers that appear in primitive, radially shaped cells. We used enhanced yellow fluorescent protein under control of the Pet-1 enhancer/promoter region (ePet-EYFP), a specific marker of early differentiated serotonergic neurons, to study their migration via immunohistology and time-lapse imaging of living slice cultures. As early as E10.0, ePet-EYFP-expressing neurons were axonless, radially oriented, and spanned the entire neuroepithelium. The soma translocated within the pial process toward the pial surface and could also translocate through its neurites, which sprouted from the pial process. The dynamin inhibitor dynasore significantly reduced translocation velocity, while the nonmuscle myosin II inhibitor blebbistatin and the kinesin inhibitor AMP-PNP had no significant effect. Here we show for the first time that serotonergic neurons migrate by somal translocation mediated, in part, by dynamin.
GABABReceptor Activation Protects Neurons from Apoptosis via IGF-1 Receptor Transactivation
Authors: Tu Haijun , Xu Chanjuan , Zhang Wenhua , Liu Qiuyao , Rondard Philippe , Pin Jean-Philippe , Liu Jianfeng
Published: January 2010

The G-protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs) play key roles in cell–cell communication. Several studies revealed important synergisms between these two types of receptors, with some of the actions of either receptor being mediated through transactivation of the other. Among the large GPCR family, GABABreceptor is activated by the neurotransmitter GABA, and is expressed in most neurons where it mediates slow and prolonged inhibition of synaptic transmission. Here we show that this receptor is involved in the regulation of life and death decisions of cerebellar granule neurons (CGNs). We show that specific activation of GABABreceptor can protect neurons from apoptosis through a mechanism that involves transactivation of the IGF-1 receptor (IGF-1R). Further work demonstrated that this cross talk was dependent on Gi/o-protein, PLC, cytosolic Ca2+, and FAK1 but independent of PKC, while IGF-1R-induced signaling involved Src kinase, PI3 kinase, and Akt activation. These results reveal a new function for this important GPCR and further highlight the importance of functional cross-talk networks between GPCRs and RTKs. Our results reveal GABABreceptor as a potential drug target for the treatment of neurodegenerative disorders.
Attentional Gain Control of Ongoing Cortical Speech Representations in a “Cocktail Party”
Authors: Kerlin Jess R. , Shahin Antoine J. , Miller Lee M.
Published: January 2010

Normal listeners possess the remarkable perceptual ability to select a single speech stream among many competing talkers. However, few studies of selective attention have addressed the unique nature of speech as a temporally extended and complex auditory object. We hypothesized that sustained selective attention to speech in a multitalker environment would act as gain control on the early auditory cortical representations of speech. Using high-density electroencephalography and a template-matching analysis method, we found selective gain to the continuous speech content of an attended talker, greatest at a frequency of 4–8 Hz, in auditory cortex. In addition, the difference in alpha power (8–12 Hz) at parietal sites across hemispheres indicated the direction of auditory attention to speech, as has been previously found in visual tasks. The strength of this hemispheric alpha lateralization, in turn, predicted an individual's attentional gain of the cortical speech signal. These results support a model of spatial speech stream segregation, mediated by a supramodal attention mechanism, enabling selection of the attended representation in auditory cortex.
Dysregulation of mTOR Signaling in Fragile X Syndrome
Authors: Sharma Ali , Hoeffer Charles A. , Takayasu Yukihiro , Miyawaki Takahiro , McBride Sean M. , Klann Eric , Zukin R. Suzanne
Published: January 2010

Fragile X syndrome, the most common form of inherited mental retardation and leading genetic cause of autism, is caused by transcriptional silencing of theFmr1gene. The fragile X mental retardation protein (FMRP), the gene product ofFmr1, is an RNA binding protein that negatively regulates translation in neurons. TheFmr1knock-out mouse, a model of fragile X syndrome, exhibits cognitive deficits and exaggerated metabotropic glutamate receptor (mGluR)-dependent long-term depression at CA1 synapses. However, the molecular mechanisms that link loss of function of FMRP to aberrant synaptic plasticity remain unclear. The mammalian target of rapamycin (mTOR) signaling cascade controls initiation of cap-dependent translation and is under control of mGluRs. Here we show that mTOR phosphorylation and activity are elevated in hippocampus of juvenileFmr1knock-out mice by four functional readouts: (1) association of mTOR with regulatory associated protein of mTOR; (2) mTOR kinase activity; (3) phosphorylation of mTOR downstream targets S6 kinase and 4E-binding protein; and (4) formation of eukaryotic initiation factor complex 4F, a critical first step in cap-dependent translation. Consistent with this, mGluR long-term depression at CA1 synapses of FMRP-deficient mice is exaggerated and rapamycin insensitive. We further show that the p110 subunit of the upstream kinase phosphatidylinositol 3-kinase (PI3K) and its upstream activator PI3K enhancer PIKE, predicted targets of FMRP, are upregulated in knock-out mice. Elevated mTOR signaling may provide a functional link between overactivation of group I mGluRs and aberrant synaptic plasticity in the fragile X mouse, mechanisms relevant to impaired cognition in fragile X syndrome.
Value Computations in Ventral Medial Prefrontal Cortex during Charitable Decision Making Incorporate Input from Regions Involved in Social Cognition
Authors: Hare Todd A. , Camerer Colin F. , Knoepfle Daniel T. , O'Doherty John P. , Rangel Antonio
Published: January 2010

Little is known about the neural networks supporting value computation during complex social decisions. We investigated this question using functional magnetic resonance imaging while subjects made donations to different charities. We found that the blood oxygenation level-dependent signal in ventral medial prefrontal cortex (VMPFC) correlated with the subjective value of voluntary donations. Furthermore, the region of the VMPFC identified showed considerable overlap with regions that have been shown to encode for the value of basic rewards at the time of choice, suggesting that it might serve as a common valuation system during decision making. In addition, functional connectivity analyses indicated that the value signal in VMPFC might integrate inputs from networks, including the anterior insula and posterior superior temporal cortex, that are thought to be involved in social cognition.
Dynamic Expression of Axon Guidance Cues Required for Optic Tract Development Is Controlled by Fibroblast Growth Factor Signaling
Authors: Atkinson-Leadbeater Karen , Bertolesi Gabriel E. , Hehr Carrie L. , Webber Christine A. , Cechmanek Paula B. , McFarlane Sarah
Published: January 2010

Axons are guided to their targets by molecular cues expressed in their environment. How is the presence of these cues regulated? Although some evidence indicates that morphogens establish guidance cue expression as part of their role in patterning tissues, an important question is whether morphogens are then required to maintain guidance signals. We found that fibroblast growth factor (FGF) signaling sustains the expression of two guidance cues,semaphorin3A(xsema3A) andslit1(xslit1), throughout the period ofXenopusoptic tract development. With FGF receptor inhibition,xsema3Aandxslit1levels were rapidly diminished, and retinal ganglion cell axons arrested in the mid-diencephalon, before reaching their target. Importantly, direct downregulation of XSema3A and XSlit1 mostly phenocopied this axon guidance defect. Thus, FGFs promote continued presence of specific guidance cues critical for normal optic tract development, suggesting a second later role for morphogens, independent of tissue patterning, in maintaining select cues by acting to regulate their transcription.
Human Middle Temporal Cortex, Perceptual Bias, and Perceptual Memory for Ambiguous Three-Dimensional Motion
Authors: Brascamp Jan W. , Kanai Ryota , Walsh Vincent , van Ee Raymond
Published: January 2010

When faced with inconclusive or conflicting visual input human observers experience one of multiple possible perceptions. One factor that determines perception of such an ambiguous stimulus is how the same stimulus was perceived on previous occasions, a phenomenon called perceptual memory. We examined perceptual memory of an ambiguous motion stimulus while applying transcranial magnetic stimulation (TMS) to the motion-sensitive areas of the middle temporal cortex (hMT+). TMS increased the predominance of whichever perceptual interpretation was most commonly reported by a given observer at baseline, with reduced perception of the less favored interpretation. This increased incidence of the preferred percept indicates impaired long-term buildup of perceptual memory traces that normally act against individual percept biases. We observed no effect on short-term memory traces acting from one presentation to the next. Our results indicate that hMT+ is important for the long-term buildup of perceptual memory for ambiguous motion stimuli.
Conduction Block in PMP22 Deficiency
Authors: Bai Yunhong , Zhang Xuebao , Katona Istvan , Saporta Mario Andre , Shy Michael E. , O'Malley Heather A. , Isom Lori L. , Suter Ueli , Li Jun
Published: January 2010

Patients with PMP22 deficiency present with focal sensory and motor deficits when peripheral nerves are stressed by mechanical force. It has been hypothesized that these focal deficits are due to mechanically induced conduction block (CB). To test this hypothesis, we induced 60–70% CB (defined by electrophysiological criteria) by nerve compression in an authentic mouse model of hereditary neuropathy with liability to pressure palsies (HNPP) with an inactivation of one of the twopmp22alleles (pmp22+/−). Induction time for the CB was significantly shorter inpmp22+/−mice than that inpmp22+/+mice. This shortened induction was also found inmyelin-associated glycoproteinknock-out mice, but not in the mice with deficiency of myelin protein zero, a major structural protein of compact myelin.Pmp22+/−nerves showed intact tomacula with no segmental demyelination in both noncompressed and compressed conditions, normal molecular architecture, and normal concentration of voltage-gated sodium channels by [3H]-saxitoxin binding assay. However, focal constrictions were observed in the axonal segments enclosed by tomacula, a pathological hallmark of HNPP. The constricted axons increase axial resistance to action potential propagation, which may hasten the induction of CB in Pmp22 deficiency. Together, these results demonstrate that a function of Pmp22 is to protect the nerve from mechanical injury.
Constitutive Genetic Deletion of the Growth Regulator Nogo-A Induces Schizophrenia-Related Endophenotypes
Authors: Willi Roman , Weinmann Oliver , Winter Christine , Klein Julia , Sohr Reinhard , Schnell Lisa , Yee Benjamin K. , Feldon Joram , Schwab Martin E.
Published: January 2010

The membrane protein Nogo-A, which is predominantly expressed by oligodendrocytes in the adult CNS and by neurons mainly during development, is well known for limiting neurite outgrowth and regeneration in the injured mammalian CNS. In addition, it has recently been proposed that abnormal Nogo-A expression or Nogo receptor (NgR) mutations may confer genetic risks for neuropsychiatric disorders of presumed neurodevelopmental origin, such as schizophrenia. We therefore evaluated whether Nogo-A deletion may lead to schizophrenia-like abnormalities in a mouse model of genetic Nogo-A deficiency. Here, we show that systemic, lifelong knock-out of the Nogo-A gene can lead to specific behavioral abnormalities resembling schizophrenia-related endophenotypes: deficient sensorimotor gating, disrupted latent inhibition, perseverative behavior, and increased sensitivity to the locomotor stimulating effects of amphetamine. These behavioral phenotypes were accompanied by altered monoaminergic transmitter levels in specific striatal and limbic structures, as well as changes in dopamine D2 receptor expression in the same brain regions. Nogo-A deletion was further associated with elevated expression of growth-related markers. In contrast, acute antibody-mediated Nogo-A neutralization in adult wild-type mice failed to produce such phenotypes, suggesting that the phenotypes observed in the knock-out mice might be of developmental origin, and that Nogo-A normally subserves critical functions in neurodevelopment. This study provides the first experimental demonstration that Nogo-A bears neuropsychiatric relevance, and alterations in its expression may be one etiological factor in schizophrenia and related disorders.
A Distraction Can Impair or Enhance Motor Performance
Authors: Hemond Christopher , Brown Rachel M. , Robertson Edwin M.
Published: January 2010

Humans have a prodigious capacity to perform multiple tasks simultaneously. Being distracted while, for example, performing a complex motor skill adds complexity to a task and thus leads to a performance impairment. Yet, it may not be just the presence or absence of a distraction that affects motor performance. Instead, the characteristics of the distraction may play a critical role in affecting human motor performance. Here, we show that performance of a motor sequence can be substantially enhanced by simultaneously learning an independent color sequence. In contrast, performance of the same motor sequence was impaired by concurrently counting the number of red cues that were in the color sequence. The color and motor sequences had different lengths (10 vs 12 items), different numbers of elements (five vs four elements), and different temporal patterns (randomly intermittent vs continuous) and thus were independent of one another. These observations show that distracting information does not always impair motor performance, and so is not a sufficient explanation for the impaired performance. Instead, the influence that a distraction exerts upon performance is mediated by the type of processes engaged: when similar core processes are engaged, motor performance is enhanced, whereas when very different processes are engaged (i.e., counting and sequence performance), performance is impaired. Thus, these observations deepen our understanding of how a distraction, depending on its characteristics, can either impair or enhance performance and may offer novel approaches to optimizing human cognition.
Dynamics of the Rapsyn Scaffolding Protein at the Neuromuscular Junction of Live Mice
Authors: Bruneau Emile G. , Akaaboune Mohammed
Published: January 2010

The efficacy of synaptic transmission depends on the maintenance of a high density of neurotransmitter receptors and their associated scaffold proteins in the postsynaptic membrane. While the dynamics of receptors has been extensively studied, the dynamics of the intracellular scaffold proteins that make up the postsynaptic density are largely unknownin vivo. Here, we focused on the dynamics of rapsyn, a protein required for the clustering and maintenance of acetylcholine receptor (AChR) density at postsynaptic sites. Using time-lapse imaging, we demonstrated that rapsyn is remarkably dynamic compared to AChRs at functional synapses, turning over 4–6 times more rapidly than AChRs. In addition we found that the rapid turnover of rapsyn is insensitive to alterations in synaptic activity, whereas AChR turnover is profoundly affected, illustrating that rapsyn and receptor dynamics are controlled by distinct mechanisms. These data indicate that individual postsynaptic components are in permanent exchange despite the overall stability of synaptic structure, which may play a role in synaptic plasticity.
The Hsp90 Cochaperone, FKBP51, Increases Tau Stability and Polymerizes Microtubules
Authors: Jinwal Umesh K. , Koren John , Borysov Sergiy I. , Schmid Andreas B. , Abisambra Jose F. , Blair Laura J. , Johnson Amelia G. , Jones Jeffrey R. , Shults Cody L. , O'Leary John C. , Jin Ying , Buchner Johannes , Cox Marc B. , Dickey Chad A.
Published: January 2010

Imbalanced protein load within cells is a critical aspect for most diseases of aging. In particular, the accumulation of proteins into neurotoxic aggregates is a common thread for a host of neurodegenerative diseases. Our previous work demonstrated that age-related changes to the cellular chaperone repertoire contributes to abnormal buildup of the microtubule-associated protein tau that accumulates in a group of diseases termed tauopathies, the most common being Alzheimer's disease. Here, we show that the Hsp90 cochaperone, FK506-binding protein 51 (FKBP51), which possesses both an Hsp90-interacting tetratricopeptide domain and a peptidyl-prolylcis-transisomerase (PPIase) domain, prevents tau clearance and regulates its phosphorylation status. Regulation of the latter is dependent on the PPIase activity of FKBP51. FKB51 enhances the association of tau with Hsp90, but the FKBP51/tau interaction is not dependent on Hsp90.In vitroFKBP51 stabilizes microtubules with tau in a reaction depending on the PPIase activity of FKBP51. Based on these new findings, we propose that FKBP51 can use the Hsp90 complex to isomerize tau, altering its phosphorylation pattern and stabilizing microtubules.
Control of Cannabinoid CB1Receptor Function on Glutamate Axon Terminals by Endogenous Adenosine Acting at A1Receptors
Authors: Hoffman Alexander F. , Laaris Nora , Kawamura Masahito , Masino Susan A. , Lupica Carl R.
Published: January 2010

Marijuana is a widely used drug that impairs memory through interaction between its psychoactive constituent, Δ-9-tetrahydrocannabinol (Δ9-THC), and CB1receptors (CB1Rs) in the hippocampus. CB1Rs are located on Schaffer collateral (Sc) axon terminals in the hippocampus, where they inhibit glutamate release onto CA1 pyramidal neurons. This action is shared by adenosine A1receptors (A1Rs), which are also located on Sc terminals. Furthermore, A1Rs are tonically activated by endogenous adenosine (eADO), leading to suppressed glutamate release under basal conditions. Colocalization of A1Rs and CB1Rs, and their coupling to shared components of signal transduction, suggest that these receptors may interact. We examined the roles of A1Rs and eADO in regulating CB1R inhibition of glutamatergic synaptic transmission in the rodent hippocampus. We found that A1R activation by basal or experimentally increased levels of eADO reduced or eliminated CB1R inhibition of glutamate release, and that blockade of A1Rs with caffeine or other antagonists reversed this effect. The CB1R–A1R interaction was observed with the agonists WIN55,212-2 and Δ9-THC and during endocannabinoid-mediated depolarization-induced suppression of excitation. A1R control of CB1Rs was stronger in the C57BL/6J mouse hippocampus, in which eADO levels were higher than in Sprague Dawley rats, and the eADO modulation of CB1R effects was absent in A1R knock-out mice. Since eADO levels and A1R activation are regulated by homeostatic, metabolic, and pathological factors, these data identify a mechanism in which CB1R function can be controlled by the brain adenosine system. Additionally, our data imply that caffeine may potentiate the effects of marijuana on hippocampal function.
Cytoplasmic Mislocalization of TDP-43 Is Toxic to Neurons and Enhanced by a Mutation Associated with Familial Amyotrophic Lateral Sclerosis
Authors: Barmada Sami J. , Skibinski Gaia , Korb Erica , Rao Elizabeth J. , Wu Jane Y. , Finkbeiner Steven
Published: January 2010

Mutations in the gene encoding TDP-43—the major protein component of neuronal aggregates characteristic of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) with ubiquitin-positive inclusion bodies—have been linked to familial forms of both disorders. Aggregates of TDP-43 in cortical and spinal motorneurons in ALS, or in neurons of the frontal and temporal cortices in FTLD, are closely linked to neuron loss and atrophy in these areas. However, the mechanism by which TDP-43 mutations lead to neurodegeneration is unclear. To investigate the pathogenic role of TDP-43 mutations, we established a model of TDP-43 proteinopathies by expressing fluorescently tagged wild-type and mutant TDP-43 in primary rat cortical neurons. Expression of mutant TDP-43 was toxic to neurons, and mutant-specific toxicity was associated with increased cytoplasmic mislocalization of TDP-43. Inclusion bodies were not necessary for the toxicity and did not affect the risk of cell death. Cellular survival was unaffected by the total amount of exogenous TDP-43 in the nucleus, but the amount of cytoplasmic TDP-43 was a strong and independent predictor of neuronal death. These results suggest that mutant TDP-43 is mislocalized to the cytoplasm, where it exhibits a toxic gain-of-function and induces cell death.
Postsynaptic Clustering and Activation of Pyk2 by PSD-95
Authors: Bartos Jason A. , Ulrich Jason D. , Li Hongbin , Beazely Michael A. , Chen Yucui , MacDonald John F. , Hell Johannes W.
Published: January 2010

The tyrosine kinase Pyk2 plays a unique role in intracellular signal transduction by linking Ca2+influx to tyrosine phosphorylation, but the molecular mechanism of Pyk2 activation is unknown. We report that Pyk2 oligomerization by antibodiesin vitroor overexpression of PSD-95 in PC6-3 cells inducestrans-autophosphorylation of Tyr402, the first step in Pyk2 activation. In neurons, Ca2+influx through NMDA-type glutamate receptors causes postsynaptic clustering and autophosphorylation of endogenous Pyk2 via Ca2+- and calmodulin-stimulated binding to PSD-95. Accordingly, Ca2+influx promotes oligomerization and thereby autoactivation of Pyk2 by stimulating its interaction with PSD-95. We show that this mechanism of Pyk2 activation is critical for long-term potentiation in the hippocampus CA1 region, which is thought to underlie learning and memory.