bluuebunny/crossref_metadata_2025 huggingface dataset:
Stress fields by the symmetric Galerkin boundary element method
Authors: Panzeca T , Cucco F , Milana V , Terravecchia S
Published: November 2004

The paper examines the stress state of a body with the discretized boundary embedded in the infinite domain subjected to layered or double-layered actions, such as forces and displacement discontinuities on the boundary, and to internal actions, such as body forces and thermic variations, in the ambit of the symmetric Galerkin boundary element method (SGBEM). The stress distributions due to internal actions (body forces and thermic variations) were computed by transforming the volume integrals into boundary integrals.

The aim of the paper is to show the tension state in Ω∞ as a response to all the actions acting in Ω when this analysis concerns the crossing of the discretized boundary, thus demonstrating the possible presence of singularities. Finally, the displacement method by SGBEM is mentioned and some examples are presented using the KARNAK program codified by some of the present authors.
Identification of the parameters of a non-linear continuum damage mechanics model for ductile failure in metals
Authors: Bonora N , Gentile D , Pirondi A
Published: November 2004

Damage modelling in ductile metal has received a lot of attention in the last thirty years. Since 1969, many models have been proposed in the literature even though, in most of the cases, the experimental aspects related to the damage parameter evaluation have often been neglected. In this work the procedure to evaluate the damage parameters, for the continuum damage mechanics based model proposed by Bonora, is presented. Here, the ductile damage is experimentally measured in terms of progressive elastic modulus reduction as a function of strain measured in an hourglass-shaped specimen loaded in tension. The proposed technique, which is based on performing multiple, partial unloading, is reliable and relatively simple to implement. Additional tensile testing, performed with a round notch tensile bar, provides critical data that can be used to identify unequivocally the full damage parameter set and to assure their geometry transferability. The procedure presented here has been applied to identify the damage parameters for 20MnMoNi55 steel.
Prop imperfection effects on the one-way buckling of plates
Authors: Hobbs R. E
Published: November 2004

A plate carrying a significant transverse pressure or self-weight and subjected to biaxial in-plane compression while lying on a rigid supporting plane may buckle by lifting away from the rigid constraint, an example of ‘one-way’ buckling. The isolated circular buckles or ‘blisters’ that form are a two-dimensional analogue of the more familiar one-dimensional upheaval buckling of railway tracks and pipelines. These buckles can be initiated from simple imperfections in the form of point supports or props.

The development of upheaval buckling from prop imperfections in plates is examined. As a means of increasing buckling loads, the control of prop sizes in fabrication processes is recommended. The work has applications including the behaviour of thermally loaded linings to pressure vessels, including (as a limiting case) lined pipelines where the liner radius is large compared with the liner thickness.
A two-phase K-means algorithm for large datasets
Authors: Pham D T , Dimov S S , Nguyen C D
Published: November 2004

One of the drawbacks of the K-means algorithm is the need for several iterations over datasets before it converges on a solution. Therefore, its application is limited to relatively small datasets. This paper presents a scalable version of the K-means algorithm that employs a buffering technique. The new algorithm, Two-Phase K-means, can robustly find a good solution in only one iteration.
A rule merging technique for handling noise in inductive learning
Authors: Pham D T , Bigot S , Dimov S S
Published: November 2004

Inductive learning algorithms are used for extracting IF-THEN rules from examples. The main weakness of most existing algorithms is their poor ability to handle data containing noise. This problem is even more severe when inductive learning techniques are applied to real engineering data. The paper presents a new pruning technique that improves significantly the performance of the RULES family of inductive learning algorithms. The technique is designed for RULES-5, the latest algorithm in the family, but could readily be applied to rule sets created by other algorithms.
The measurement of the rocking behaviour of graphite bricks using ultrasound
Authors: Holmes C , Drinkwater B W
Published: November 2004

Assemblies of graphite bricks are found in graphite cored nuclear reactors throughout the world. In such reactors the graphite bricks, which are used to moderate the nuclear fission reaction, are assembled in arrays of the order of 10 m in height and 10m in width. The bricks themselves come in a range of shapes and sizes. The static and dynamic response of such structures is dependent on both the properties of the bulk material and the nature of the interface between individual bricks. Typical real surfaces exhibit some form of macroscopic waviness in addition to the microscopic roughness and therefore only a small fraction of the surfaces are in contact. This interfacial behaviour has been found to be one of the most significant factors affecting the rocking behaviour of dry-jointed structures, such as graphite cored reactors, and has proved one of the most difficult to explore experimentally.

This paper describes a novel application of the ultrasonic measurement technique for the investigation of the effect of microscopic and macroscopic surface features on the rocking behaviour of graphite bricks. An ultrasonic scanning system has been combined with a loading rig to enable factors such as the size of the contact area and its position relative to the edge of a brick to be measured in situ as the brick is loaded. The ultrasound is used to measure the contact pressure distribution between a brick and a rigid foundation. This information has been used in a model to predict the rocking stiffness of the brick-foundation system and good comparisons with rocking experiments achieved. This measurement system could also be used to study the rocking behaviour of other systems of dry contacting blocks such as those found in costal defences and ancient buildings.
Vibration control of a servomotor-driven coupled elastic shaft-elastic beam system
Authors: Diken H , Ankarali A
Published: November 2004

In this study an elastodynamic control system consisting of servomotor, elastic shaft, disc and elastic beam, which is attached to the disc, is considered. Non-dimensional parametric equations of motions are obtained. The control system damping ratio, the frequency ratio of the torsional natural frequency to the beam natural frequency and also the frequency ratio of the beam natural frequency to the control system frequency are used as parameters. Simulation results are obtained for the step response of the disc rotation and for the beam tip vibration for different frequency ratios. Results show that even for highly flexible systems the effect of flexibility on the control system behaviour can be substantially reduced by proper selection of the control system frequency.
Solid state refrigeration: Cooling and refrigeration using crystalline phase changes in metal alloys
Authors: Quarini J , Prince A
Published: November 2004

The well-known fact that a phase change is normally accompanied by a relatively large change in internal energy is explored and is used to develop an innovative method of achieving refrigerative effects in solid state metal alloys. Applying a cyclic mechanical stress in certain materials can induce crystalline structural changes, with accompanying absorption or release of heat. Simple experiments are reported with a particular nickel-titanium alloy where temperature drops well below 10 °C of ambient were achieved. The experimental work was undertaken at ambient temperature and temperature excursions of + 16 and -14 °C of ambient temperatures were measured. These temperature excursions occurred in a material with a density of over 6000 kg/m3. Ways in which the concept of ‘solid state refrigeration’ using mechanical actuation are suggested and partially examined.
Modelling of tennis ball impacts on a rigid surface
Authors: Goodwill S R , Haake S J
Published: November 2004

A viscoelastic model of a tennis ball impact at normal incidence on a rigid surface is presented in this study. The ball model has three discrete elements that account for the structural stiffness, material damping and momentum flux loading. Experiments using a force platform are performed to determine the force that acts on the ball during impact, for a range of ball inbound velocities. The inbound and rebound velocities of the ball are measured using speed gates. The contact time and coefficient of restitution for the impact are also determined in these experiments. The model parameters are determined such that the values of the coefficient of restitution and contact time that are calculated by the model are consistent with those values determined experimentally. The model can be used to calculate the force that acts on the ball during impact. Generally, the force-time plots calculated by the model were consistent with those determined experimentally. Furthermore, the model can be used to calculate the three components of the force that acts on the ball during impact. It is shown that the main component of the force during the first 0.6 ms of impact is that due to momentum flux loading. This is approximately equal in magnitude for each ball type and explains why the total force acting on each ball is very similar during this period.
Characteristic equations of longitudinally vibrating rods carrying a tip mass and several viscously damped spring-mass systems in-span
Authors: Erol H
Published: November 2004

This paper deals with the determination of two alternative approximate formulations for the frequency equation of a longitudinally vibrating fixed-free elastic rod carrying a tip mass (primary system) to which several spring-mass-damper systems (secondary systems) are attached in-span. The first approximate formulation presented in this study is based upon the assumed-mode method in conjunction with the Lagrange multiplier method. The result is a simple analytical formula for the characteristic equation of the system. Hence, the eigenfrequency parameters of the system are determined by solving this non-linear equation. In this method, the beam is treated as one component and the spring-mass-damper systems that are attached to the beam are treated as separate components. The dynamics of the beam and spring-mass-damper systems are initially expressed in terms of component modes; then the total system dynamics are evaluated by invoking the constraint equations that described the attachments of the spring-mass-damper system to the beam. Lagrange multipliers are used to include the constraint equations in the Lagrange equations of motion for the total system. The second form of the characteristic equation presented in this study follows directly from the formalism of the Lagrange equations where the displacements of the attachment points of the spring-mass-damper systems to the rod are expressed in terms of the generalized coordinates. This method is essentially based upon the classical Rayleigh-Ritz modal method. The formulation leads to a standard eigenvalue problem, the solution of which gives the eigenfrequency parameters of the system. Afterwards, for comparison purposes, ‘exact’ characteristic equations for one secondary system and two secondary systems are established separately via a boundary value problem formulation. All characteristic equations are then numerically solved for various combinations of physical parameters and the results are collected in tables. The comparison of the numerical results obtained via boundary value problem formulations justifies the approximate approaches used here.
Probable Ischemic Colitis Caused by Pseudoephedrine with Tramadol as a Possible Contributing Factor
Authors: Traino Amelia A , Buckley Nick A , Bassett Mark L
Published: November 2004

OBJECTIVE

To report a case of acute self-limiting ischemic colitis in a patient who was self-medicating with a proprietary over-the counter oral decongestant containing pseudoephedrine.

CASE SUMMARY

A 46-year-old white man developed clinical, endoscopic, and histologic features of acute ischemic colitis after taking a proprietary oral decongestant containing pseudoephedrine 240 mg/day for one week. The total daily dose was at the upper limit of recommended doses for pseudoephedrine (as a single drug or in combination products). The patient was also taking tramadol 150 mg/day for chronic back pain. He made a complete recovery. There were no other explanations for the episode of ischemic colitis.

DISCUSSION

An objective causality assessment based on the Naranjo probability scale revealed pseudoephedrine to be a probable cause of ischemic colitis in our patient. Pseudoephedrine occasionally causes vascular insufficiency due to intense vasoconstriction, even at standard doses. Although our patient was not taking an excessive dose of pseudoephedrine, it is possible that the concurrent use of pseudoephedrine and tramadol may have increased adrenergic vasoconstriction, predisposing to ischemic colitis.

CONCLUSIONS

Prolonged or intensive use of medications containing pseudoephedrine should be avoided, and the package information should contain advice that the medication should be ceased if abdominal pain or other ischemic symptoms occur.
Initiating Warfarin Therapy: 5 mg versus 10 mg
Authors: Eckhoff Courtney D , DiDomenico Robert J , Shapiro Nancy L
Published: November 2004

OBJECTIVE

To review the literature investigating initial dosing of warfarin at 5 or 10 mg for treatment of acute venous thromboembolism.

DATA SOURCES

Articles were identified through searches of MEDLINE (1966–December 2003) using the key words warfarin, oral anticoagulation, warfarin dose, warfarin initiation, venous thromboembolism, and anticoagulation. Additional references were located through review of the bibliographies of the articles cited.

STUDY SELECTION AND DATA EXTRACTION

Studies of the initial dosing of warfarin at 5 or 10 mg were evaluated and relevant information was included, as were those that identified known factors that influence the maintenance dose of warfarin.

DATA SYNTHESIS

For the treatment of acute venous thromboembolism, warfarin dosing is often provider dependent. Until recently, studies suggested that 5 mg initiation was as effective as 10 mg, without increasing the risk of bleeding. However, the most recent study comparing a 5- versus 10-mg initial dosing nomogram supports an initial dose of 10 mg. These results should be interpreted with caution, however, since patients at high risk for bleeding were excluded from the study. Several patient-specific factors will affect the maintenance dose, guiding clinicians to start with lower (<5 mg) or higher (>5 mg) doses.

CONCLUSIONS

Although recent evidence supports a 10-mg initiation nomogram, clinicians should consider patient-specific factors prior to deciding an initial warfarin dose. If a 10-mg loading dose is utilized, strict compliance with the protocol is necessary.
Duloxetine: A Dual Reuptake Inhibitor
Authors: Dugan Sara E , Fuller Matthew A
Published: November 2004

OBJECTIVE

To review the pharmacology, pharmacokinetics, clinical efficacy, and safety profile of duloxetine for the treatment of major depressive disorder (MDD).

DATA SOURCES

Searches using MEDLINE and PsycINFO were conducted (1966 to November 2003).

STUDY SELECTION AND DATA EXTRACTION

All duloxetine MDD information gathered was considered. Articles containing comprehensive information regarding duloxetine use for MDD were evaluated.

DATA SYNTHESIS

Duloxetine is a serotonin–norepinephrine reuptake inhibitor being considered for treatment of MDD and stress urinary incontinence. While approved dosing ranges have not yet been determined, studies support the efficacy and safety of 40–60 mg twice daily for the treatment of acute MDD. Adverse effects have been of mild to moderate severity and are considered to be transient. Cardiovascular effects (increased heart rate or blood pressure), while present, do not appear to be clinically significant. Overall, duloxetine appears to be well tolerated.

CONCLUSIONS

Duloxetine is a safe and effective antidepressant. Approval of this agent provides another treatment option for the management of MDD. THIS ARTICLE IS APPROVED FOR CONTINUING EDUCATION CREDIT ACPE UNIVERSAL PROGRAM NUMBER: 407-000-04-036-H01
Poisoning in Older Adults: A 5-Year Experience of US Poison Control Centers
Authors: Crouch Barbara Insley , Caravati E Martin , Mitchell Alice , Martin Andrew C
Published: November 2004

BACKGROUND

Poisoning in older adults has received relatively little attention.

OBJECTIVE

To describe poison exposures in older adults reported to US poison centers and identify substances that pose a unique risk to this population. METHODS: A retrospective review of human exposures for patients aged 60 years reported to the American Association of Poison Control Center's Toxic Exposure Surveillance System from 1993 to 1997 was performed. Frequencies and cross-tabulations were used to describe the data. Hazard factor analysis was conducted to identify medications that pose risk in this population. Statistical analysis included χ2 and Fisher's exact test for hazard factors.

RESULTS

A total of 298 713 poison exposure cases were reported to US poison centers involving individuals aged 60 years between 1993 and 1997. The proportion of cases in this age group also steadily increased from 2.5% of all cases in 1993 to 3.4% of all cases in 1997. The mean age of the patients was 64.7 years, and 34.1% were males. Hazard factor analysis was conducted on unintentional exposures and adverse reactions to pharmaceutical agents to determine medications that posed increased risk to older adults. The substance categories that had the highest hazard factor were radiopharmaceuticals, asthma therapies, anticoagulants, anesthetics, and antidepressants.

CONCLUSIONS

Therapeutic errors and adverse reactions to medications are common reasons for major effects and fatal outcomes among older adults reported to poison centers. Understanding poisoning issues specific to this population may help direct future outreach education efforts.
From Little Big Man to little green men: the captivity scenario in American culture
Authors: Panay Andrew
Published: November 2004

This paper seeks to link the seemingly diverse genres of the Indian captivity narrative and the alien abduction scenario. Whilst the Indian captivity narrative is plainly derived from first-hand accounts and can demonstrate a historical development based on the actuality of the experiences it describes, the alien abduction scenario though protesting its objective basis cannot. Rather than rejecting the validity of the alien abduction scenario on this account, the following attempts to account for the claims to reality of the alien abduction narrative by arguing that it exists in a historical continuum with the Indian captivity narrative. The narrative functions as part of a greater historical myth system in which national values of community safety and security, national progress and vitality and the preservation of core values against hostile enemies are central components. I argue that in the twentieth century the alien abduction narrative re-imagines these core concerns and in the context of exploration of the new frontier of space, provides for a re-energizing of the traditional captivity narrative, one in which abductees are positioned as colonists in perilous existence on the ‘final frontier’.
Book Reviews
Authors: Antonucci Clara , Briand R.J. , Munro Stephanie , Roynon Tessa , Geraghty Lincoln , Goode Alex , De Loth John
Published: November 2004

Literature and the Visual Arts in Twentieth-Century America, Michele Bottalico (ed.) (2002), Bari, Italy: Palomar, 210 pp., ISBN 88-87467-97-8 (pbk), £58.

Lies and the Lying Liars who Tell Them: A Fair and Balanced Look at The Right, Al Franken (2003),
London: Allen Lane, 372 pp., ISBN 0 713 99790 7 (pbk), £12.

A Students’ Guide to African American Literature, 1760 to the Present, Lovalerie King (2003), New York: Peter Lang Publishing, xvi + 219 pp., ISBN 0-8204-5521-0 (pbk), £21.

Love, Toni
Morrison (2003), London: Chatto and Windus, 216 pp., ISBN 0701175109 (hbk), £16.99.

The American Horror Film: An Introduction, Reynold Humphries (2002), Edinburgh: Edinburgh University Press, vi + 216 pp., ISBN 0748614168 (pbk), £16.99.

American Exceptionalism
and the Legacy of Vietnam: US Foreign Policy Since 1974, Trevor McCrisken (2003), Basingstoke: Palgrave, 248 pp., ISBN 8240108X (hbk), £50.

Performing Menken: Adah Isaacs Menken and the Birth of American Celebrity, R.M. Sentilles (2003), Cambridge: Cambridge
University Press, 326 pp., ISBN 0521820707 (hbk), £45.
The Kinetic Profile of Intracellular Calcium Predicts Long-Term Potentiation and Long-Term Depression
Authors: Ismailov Iskander , Kalikulov Djanenkhodja , Inoue Takafumi , Friedlander Michael J.
Published: November 2004

Efficiency of synaptic transmission within the neocortex is regulated throughout life by experience and activity. Periods of correlated or uncorrelated presynaptic and postsynaptic activity lead to enduring changes in synaptic efficiency [long-term potentiation (LTP) and long-term depression (LTD), respectively]. The initial plasticity triggering event is thought to be a precipitous rise in postsynaptic intracellular calcium, with higher levels inducing LTP and more moderate levels inducing LTD. We used a pairing protocol in visual cortical brain slices from young guinea pigs with whole-cell recording and calcium imaging to compare the kinetic profiles of calcium signals generated in response to individual pairings along with the cumulative calcium wave and plasticity outcome. The identical pairing protocol applied to layer 2/3 pyramidal neurons results in different plasticity outcomes between cells. These differences are not attributable to variations in the conditioning protocol, cellular properties, inter-animal variability, animal age, differences in spike timing between the synaptic response and spikes, washout of plasticity factors, recruitment of inhibition, or activation of different afferents. The different plasticity outcomes are reliably predicted by individual intracellular calcium transients in the dendrites after the first few pairings. In addition to the differences in the individual calcium transients, the cumulative calcium wave that spreads to the soma also has a different profile for cells that undergo LTP versus LTD. We conclude that there are biological differences between like-type cells in the dendritic calcium signals generated by coincident synaptic input and spiking that determine the sign of the plasticity response after brief associations.
A Novel Epilepsy Mutation in the Sodium ChannelSCN1AIdentifies a Cytoplasmic Domain for β Subunit Interaction
Authors: Spampanato J. , Kearney J. A. , de Haan G. , McEwen D. P. , Escayg A. , Aradi I. , MacDonald B. T. , Levin S. I. , Soltesz I. , Benna P. , Montalenti E. , Isom L. L. , Goldin A. L. , Meisler M. H.
Published: November 2004

A mutation in the sodium channel SCN1A was identified in a small Italian family with dominantly inherited generalized epilepsy with febrile seizures plus (GEFS+). The mutation, D1866Y, alters an evolutionarily conserved aspartate residue in the C-terminal cytoplasmic domain of the sodium channel α subunit. The mutation decreased modulation of the α subunit by β1, which normally causes a negative shift in the voltage dependence of inactivation in oocytes. There was less of a shift with the mutant channel, resulting in a 10 mV difference between the wild-type and mutant channels in the presence of β1. This shift increased the magnitude of the window current, which resulted in more persistent current during a voltage ramp. Computational analysis suggests that neurons expressing the mutant channels will fire an action potential with a shorter onset delay in response to a threshold current injection, and that they will fire multiple action potentials with a shorter interspike interval at a higher input stimulus. These results suggest a causal relationship between a positive shift in the voltage dependence of sodium channel inactivation and spontaneous seizure activity. Direct interaction between the cytoplasmic C-terminal domain of the wild-typeα subunit with the β1or β3 subunit was first demonstrated by yeast two-hybrid analysis. The SCN1A peptide K1846-R1886 is sufficient for β subunit interaction. Coimmunoprecipitation from transfected mammalian cells confirmed the interaction between the C-terminal domains of the α and β1 subunits. The D1866Y mutation weakens this interaction, demonstrating a novel molecular mechanism leading to seizure susceptibility.
Glycogen Synthase Kinase-3β Phosphorylates Bax and Promotes Its Mitochondrial Localization during Neuronal Apoptosis
Authors: Linseman Daniel A. , Butts Brent D. , Precht Thomas A. , Phelps Reid A. , Le Shoshona S. , Laessig Tracey A. , Bouchard Ron J. , Florez-McClure Maria L. , Heidenreich Kim A.
Published: November 2004

Glycogen synthase kinase-3β (GSK-3β) is a critical activator of neuronal apoptosis induced by a diverse array of neurotoxic insults. However, the downstream substrates of GSK-3β that ultimately induce neuronal death are unknown. Here, we show that GSK-3β phosphorylates and regulates the activity of Bax, a pro-apoptotic Bcl-2 family member that stimulates the intrinsic (mitochondrial) death pathway by eliciting cytochromecrelease from mitochondria. In cerebellar granule neurons undergoing apoptosis, inhibition of GSK-3β suppressed both the mitochondrial translocation of an expressed green fluorescent protein (GFP)-Baxαfusion protein and the conformational activation of endogenous Bax. GSK-3β directly phosphorylated Baxαon Ser163, a residue found within a species-conserved, putative GSK-3β phosphorylation motif. Coexpression of GFP-Baxαwith a constitutively active mutant of GSK-3β, GSK-3β(Ser9Ala), enhanced thein vivophosphorylation of wild-type Baxα, but not a Ser163Ala mutant of Baxα, in transfected human embryonic kidney 293 (HEK293) cells. Moreover, cotransfection with constitutively active GSK-3β promoted the localization of Baxαto mitochondria and induced apoptosis in both transfected HEK293 cells and cerebellar granule neurons. In contrast, neither a Ser163Ala point mutant of Baxαnor a naturally occurring splice variant that lacks 13 amino acids encompassing Ser163 (Baxσ) were driven to mitochondria in HEK293 cells coexpressing constitutively active GSK-3β. In a similar manner, either mutation or deletion of the identified GSK-3β phosphorylation motif prevented the localization of Bax to mitochondria in cerebellar granule neurons undergoing apoptosis. Our results indicate that GSK-3β exerts some of its pro-apoptotic effects in neurons by regulating the mitochondrial localization of Bax, a key component of the intrinsic apoptotic cascade.
HCN2 and HCN1 Channels Govern the Regularity of Autonomous Pacemaking and Synaptic Resetting in Globus Pallidus Neurons
Authors: Chan C. Savio , Shigemoto Ryuichi , Mercer Jeff N. , Surmeier D. James
Published: November 2004

The globus pallidus (GP) is a critical component of the basal ganglia circuitry controlling motor behavior. Dysregulation of GP activity has been implicated in a number of psychomotor disorders, including Parkinson's disease (PD), in which a cardinal feature of the pathophysiology is an alteration in the pattern and synchrony of discharge in GP neurons. Yet the determinants of this activity in GP neurons are poorly understood. To help fill this gap, electrophysiological, molecular, and computational approaches were used to identify and characterize GABAergic GP neurons in tissue slices from rodents.In vitro, GABAergic GP neurons generate a regular, autonomous, single-spike pacemaker activity. Hyperpolarization-activated, cyclic nucleotide-gated cation (HCN) channels make an important contribution to this process: their blockade with ZD7288 significantly slowed discharge rate and decreased its regularity. HCN currents evoked by somatic voltage clamp had fast and slow components. Single-cell RT-PCR and immunohistochemical approaches revealed robust expression of HCN2 subunits as well as significant levels of HCN1 subunits in GABAergic GP neurons. Transient activation of striatal GABAergic input to GP neurons led to a resetting of rhythmic discharge that was dependent on HCN currents. Simulations suggested that the ability of transient striatal GABAergic input to reset pacemaking was dependent on dendritic HCN2/HCN1 channels. Together, these studies show that HCN channels in GABAergic GP neurons are key determinants of the regularity and rate of pacemaking as well as striatal resetting of this activity, implicating HCN channels in the emergence of synchrony in PD.
Molecular Organization of the Ferret Visual Thalamus
Authors: Kawasaki Hiroshi , Crowley Justin C. , Livesey Frederick J. , Katz Lawrence C.
Published: November 2004

The visual system encodes and deciphers information using parallel, anatomically segregated, processing streams. To reveal patterns of gene expression in the visual thalamus correlated with physiological processing streams, we designed a custom ferret cDNA microarray. By isolating specific subregions and layers of the thalamus, we identified a set of transcription factors, includingZic2, Islet1, andSix3, the unique distribution profiles of which differentiated the lateral geniculate nucleus (LGN) from the associated perigeniculate nucleus. Within the LGN,odd homeobox1differentiated the A layers, which contain X cells and Y cells, from the C layers. One neuron-specific protein,Purkinje cell protein 4(PCP4), was strongly expressed in Y cells in the ferret LGN and in the magnocellular layers of the primate LGN. In the ferret LGN,PCP4expression began as early as postnatal day 7 (P7), suggesting that Y cells are already specified by P7. These results reveal a rich molecular repertoire that correlates with functional divisions of the LGN.
Phasic Activation of Monkey Locus Ceruleus Neurons by Simple Decisions in a Forced-Choice Task
Authors: Clayton Edwin C. , Rajkowski Janusz , Cohen Jonathan D. , Aston-Jones Gary
Published: November 2004

The noradrenergic locus ceruleus (LC) system has been implicated in several behavioral functions, most notably, response to salient sensory events. Here, we provide new evidence indicating a role in the execution of responses associated with simple decisions. We examined impulse activity of monkey LC neurons during performance of a forced-choice discrimination task. The timing of LC activity more closely tracked behavioral responses than stimulus presentation. LC neurons were phasically activated preceding behavioral responses for both correct and incorrect identifications but were not activated by stimuli that failed to elicit lever responses nor by nontask-related lever movements. We hypothesize that the LC responds to the outcome of task-related decision processes, facilitating their influence on overt behavior. This role of the LC in regulating the behavioral outcome of decisional processes contrasts with more traditional views of LC responses as primarily related to sensory processes.
Glial Nitric Oxide-Mediated Long-Term Presynaptic Facilitation Revealed by Optical Imaging in Rat Spinal Dorsal Horn
Authors: Ikeda Hiroshi , Murase Kazuyuki
Published: November 2004

We investigated a presynaptic form of long-term potentiation (LTP) in horizontal slices of the rat spinal cord by visualizing presynaptic and postsynaptic excitation with a voltage-sensitive dye. To record presynaptic excitation, we stained primary afferent fibers anterogradely from the dorsal root. A single-pulse test stimulation of C fiber-activating strength to the dorsal root elicited action potential (AP)-like or compound AP-like optical signals throughout the superficial dorsal horn. After conditioning (240 pulses at 2 Hz for 2 min), the presynaptic excitation was augmented. Furthermore, new excitation was elicited in the areas that were silent before conditioning. For postsynaptic recording, projection neurons in spinal lamina I were stained retrogradely from the periaqueductal gray in the brain stem. The test stimulation elicited AP-like or EPSP-like optical signals in the stained neurons. After conditioning, the EPSP-like responses were augmented, and previously silent neurons were converted to active ones. Results obtained with a nitric oxide (NO) donor, NO synthase inhibitors, metabotropic glutamate receptor (mGluR) agonist and mGluR1 antagonist, and a glial metabolism inhibitor suggest that after conditioning, presynaptic excitation is facilitated by NO released from glial cells via the activation of mGluR1. The results also indicate the possible presence of additional presynaptic and postsynaptic mechanism(s) for the LTP induction. Activity-dependent LTP of nociceptive afferent synaptic transmission in the spinal cord is believed to underlie central sensitization after inflammation or nerve injury. This glial NO-mediated control of presynaptic excitation may contribute to the induction at least in part.
Transcranial Direct Current Stimulation during Sleep Improves Declarative Memory
Authors: Marshall Lisa , Mölle Matthias , Hallschmid Manfred , Born Jan
Published: November 2004

In humans, weak transcranial direct current stimulation (tDCS) modulates excitability in the motor, visual, and prefrontal cortex. Periods rich in slow-wave sleep (SWS) not only facilitate the consolidation of declarative memories, but in humans, SWS is also accompanied by a pronounced endogenous transcortical DC potential shift of negative polarity over frontocortical areas. To experimentally induce widespread extracellular negative DC potentials, we applied anodal tDCS (0.26 mA/cm2) repeatedly (over 30 min) bilaterally at frontocortical electrode sites during a retention period rich in SWS. Retention of declarative memories (word pairs) and also nondeclarative memories (mirror tracing skills) learned previously was tested after this period and compared with retention performance after placebo stimulation as well as after retention intervals of wakefulness. Compared with placebo stimulation, anodal tDCS during SWS-rich sleep distinctly increased the retention of word pairs (p< 0.005). When applied during the wake retention interval, tDCS did not affect declarative memory. Procedural memory was also not affected by tDCS. Mood was improved both after tDCS during sleep and during wake intervals. tDCS increased sleep depth toward the end of the stimulation period, whereas the average power in the faster frequency bands (θ,α, andβ) was reduced. Acutely, anodal tDCS increased slow oscillatory activity <3 Hz. We conclude that effects of tDCS involve enhanced generation of slow oscillatory EEG activity considered to facilitate processes of neuronal plasticity. Shifts in extracellular ionic concentration in frontocortical tissue (expressed as negative DC potentials during SWS) may facilitate sleep-dependent consolidation of declarative memories.
Visualizing Synaptic Ribbons in the Living Cell
Authors: Zenisek David , Horst Nicole K. , Merrifield Christien , Sterling Peter , Matthews Gary
Published: November 2004

Visual and auditory information is encoded by sensory neurons that tonically release neurotransmitter at high rates. The synaptic ribbon is an essential organelle in nerve terminals of these neurons. Its precise function is unknown, but if the ribbon could be visualized in a living terminal, both its own dynamics and its relation to calcium and vesicle dynamics could be studied. We designed a short fluorescent peptide with affinity for a known binding domain of RIBEYE, a protein unique to the ribbon. When introduced via a whole-cell patch pipette, the peptide labeled structures at the presynaptic plasma membrane of ribbon-type terminals. The fluorescent spots match in size, location, number, and distribution the known features of synaptic ribbons. Furthermore, fluorescent spots mapped by confocal microscopy directly match the ribbons identified by electron microscopy in the same cell. Clearly the peptide binds to the synaptic ribbon, but even at saturating concentrations it affects neither the morphology of the ribbon nor its tethering of synaptic vesicles. It also does not inhibit exocytosis. Using the peptide label, we observed that the ribbon is immobile over minutes and that calcium influx is concentrated at the ribbon. Finally, we find that each ribbon in a retinal bipolar cell contains ∼4000 molecules of RIBEYE, indicating that it is the major component of the synaptic ribbon.
Activity Affects Dendritic Shape and Synapse Elimination during Steroid Controlled Dendritic Retraction inManduca sexta
Authors: Duch Carsten , Mentel Tim
Published: November 2004

Insect metamorphosis is a compelling example for dendritic and synaptic remodeling as larval and adult behaviors place distinct demands on the CNS. During the metamorphosis of the moth,Manduca sexta, many larval motoneurons are remodeled to serve a new function in the adult. During late larval life, steroid hormones trigger axonal and dendritic regression as well as larval synapse elimination. These regressive events are accompanied by stereotypical changes in motor behavior during the so-called wandering stages. Both normally occurring changes in dendritic shape and in motor output have previously been analyzed quantitatively for the individually identified motoneuron MN5. This study tested whether activity affected steroid-induced dendritic regression and synapse disassembly in MN5 by means of chronically implanted extracellular electrodes. Stimulating MN5in vivoin intact, normally developing animals during a developmental period when it usually shows no activity significantly slowed the regression of high-order dendrites. Both physiological and anatomical analysis demonstrated that reduced dendritic regression was accompanied by a significant reduction in larval synapse disassembly. Therefore, steroid-induced alterations of dendritic shape and synaptic connectivity are modified by activity-dependent mechanisms. This interaction might be a common mechanism for rapid adjustments of rigid, inflexible, hormonal programs.
TheS6KII(rsk) Gene ofDrosophila melanogasterDifferentially Affects an Operant and a Classical Learning Task
Authors: Putz Gabriele , Bertolucci Franco , Raabe Thomas , Zars Troy , Heisenberg Martin
Published: November 2004

In an attempt to dissect classical and operant conditioning inDrosophila melanogaster, we have isolated the gene for ribosomal S6 kinase II (S6KII). This enzyme is part of a family of serine-threonine kinases that in mammals have been implicated in the MAPK (mitogen-activated protein kinase) signaling cascade controlling (among other processes) synaptic plasticity (long-term potentiation/long-term depression) and memory formation. The human homologrsk2has been linked to mental retardation (Coffin-Lowry syndrome). Mutant analysis inDrosophilashows thatS6KIIserves different functions in operant place learning and classical (pavlovian) olfactory conditioning. Whereas in the null mutant only pavlovian olfactory learning is affected, a P-element insertion mutant reducing the amount of S6KII only affects operant place learning. A mutant lacking part of the N-terminal kinase domain and performing poorly in both learning tasks is dominant in the operant paradigm and recessive in the pavlovian paradigm. The behavioral defects in the pavlovian task can be rescued by the genomicS6KIItransgene. Overexpression of S6KII in wild type has a dominant-negative effect on the operant task that is rescued by the null mutant, whereas in the pavlovian task overexpression may even enhance learning performance.
Endocannabinoids Link Feeding State and Auditory Perception-Related Gene Expression
Authors: Soderstrom Ken , Tian Qiyu , Valenti Marta , Di Marzo Vincenzo
Published: November 2004

Singing by adult male zebra finches is a learned behavior important for courtship, kin recognition, and nest defense (Zann, 1996) and is inhibited by both brief periods of limited food availability and systemic injection of cannabinoids. These similar effects on singing, combined with increasing evidence for endocannabinoid involvement in feeding behavior, led us to evaluate a possible shared mechanism. We found that limited food availability both reduces singing in a cannabinoid antagonist-reversible manner and increases levels of the endocannabinoid 2-arachidonyl glycerol in various brain regions including the caudal telencephalon, an area that contains auditory telencephalon including the L2 subfield of L (L2) and caudal medial nidopallium (NCM). Development and use of an anti-zebra finch cannabinoid receptor type 1 (CB1) antibody demonstrates distinct, dense cannabinoid receptor expression within song regions including Area X, lMAN (lateral magnocellular nucleus of anterior nidopallium), HVC, RA (robust nucleus of arcopallium), and L2. NCM receives L2 projections and is implicated in integration of auditory information. Activity in this area, determined through expression of the transcription factor ZENK, is increased after exposure to unfamiliar song. Because previous work has shown that these novel song-stimulated increases in NCM activity are mitigated by cannabinoid exposure, we tested and found that similar effects on ZENK expression are produced by limiting food. Limited food-related reductions in the activity of NCM neurons were reversed by the cannabinoid antagonist SR141716A (N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide), implicating CB1cannabinoid receptor involvement. Taken together, these experiments indicate a link between feeding state and gene expression related to auditory perception that is mediated by endocannabinoid signaling.
Target-Dependent Release of a Presynaptic Neuropeptide Regulates the Formation and Maturation of Specific Synapses inAplysia
Authors: Hu Jiang-Yuan , Goldman Jonathan , Wu Fang , Schacher Samuel
Published: November 2004

The correct wiring of neurons is critical for the normal functioning of the nervous system. Sensory neurons ofAplysiaform synapses with specific postsynaptic targets. Interaction with appropriate target cells in culture induces a significant increase in axon growth, the number of sensory neuron varicosities with release sites contacting the target, and regulates the expression and distribution of mRNAs encoding presynaptic proteins such as syntaxin and the sensory neuron-specific neuropeptide sensorin. Synapse stabilization is accompanied by the maintenance of presynaptic varicosities and target-dependent regulation of mRNA distributions. We report here that specific targets induce the release of sensorin from sensory neurons, which then regulates synaptic efficacy, axonal growth associated with synapse formation, the maintenance of synaptic contacts, and the specific distribution of mRNAs. Bath application of an antisensorin antibody during the early phase of synapse formation blocked the expected increase in synaptic strength, the growth and formation of new presynaptic varicosities, and the target-dependent regulation of mRNA distribution. In contrast, bath application of sensorin accelerated the increase in synaptic strength and enhanced the formation of new varicosities and target-dependent regulation of mRNA distribution in sensory neurons. As synapses stabilize, sensorin secretion declines but is required for the maintenance of synaptic efficacy, presynaptic varicosities, and mRNA distributions. These results suggest that a retrograde target signal regulates the secretion and actions of a presynaptic neuropeptide critical for the formation and maintenance of specific synapses.
How Old Is the Most Recent Ancestor of Two Copies of an Allele?
Authors: Patterson Nick J
Published: November 2004

An important clue to the evolutionary history of an allele is the structure of the neighboring region of the genome, which we term the genomic background of the allele. Consider two copies of the allele. How similar we expect their genomic background to be is strongly influenced by the age of their most recent common ancestor (MRCA). We apply diffusion theory, first used by Motoo Kimura as a tool for predicting the changes in allele frequencies over time and developed by him in many articles in this journal, to prove a variety of new results on the age of the MRCA under the simplest demographic assumptions. In particular, we show that the expected age of the MRCA of two copies of an allele with population frequency f is just 2Nf generations, where N is the effective population size. Our results are a first step in running exact coalescent simulations, where we also simulate the history of the population frequency of an allele.
Trans-splicing of the mod(mdg4) Complex Locus Is Conserved Between the Distantly Related Species Drosophila melanogaster and D. virilis
Authors: Gabler Manuela , Volkmar Michael , Weinlich Susan , Herbst Andreas , Dobberthien Philine , Sklarss Stefanie , Fanti Laura , Pimpinelli Sergio , Kress Horst , Reuter Gunter , Dorn Rainer
Published: November 2004

The modifier of mdg4, mod(mdg4), locus in Drosophila melanogaster represents a new type of complex gene in which functional diversity is resolved by mRNA trans-splicing. A protein family of >30 transcriptional regulators, which are supposed to be involved in higher-order chromatin structure, is encoded by both DNA strands of this locus. Mutations in mod(mdg4) have been identified independently in a number of genetic screens involving position-effect variegation, modulation of chromatin insulators, apoptosis, pathfinding of nerve cells, and chromosome pairing, indicating pleiotropic effects. The unusual gene structure and mRNA trans-splicing are evolutionary conserved in the distantly related species Drosophila virilis. Chimeric mod(mdg4) transcripts encoded from nonhomologous chromosomes containing the splice donor from D. virilis and the acceptor from D. melanogaster are produced in transgenic flies. We demonstrate that a significant amount of protein can be produced from these chimeric mRNAs. The evolutionary and functional conservation of mod(mdg4) and mRNA trans-splicing in both Drosophila species is furthermore demonstrated by the ability of D. virilis mod(mdg4) transgenes to rescue recessive lethality of mod(mdg4) mutant alleles in D. melanogaster.
The Structured Ancestral Selection Graph and the Many-Demes Limit
Authors: Slade Paul F , Wakeley John
Published: November 2004

We show that the unstructured ancestral selection graph applies to part of the history of a sample from a population structured by restricted migration among subpopulations, or demes. The result holds in the limit as the number of demes tends to infinity with proportionately weak selection, and we have also made the assumptions of island-type migration and that demes are equivalent in size. After an instantaneous sample-size adjustment, this structured ancestral selection graph converges to an unstructured ancestral selection graph with a mutation parameter that depends inversely on the migration rate. In contrast, the selection parameter for the population is independent of the migration rate and is identical to the selection parameter in an unstructured population. We show analytically that estimators of the migration rate, based on pairwise sequence differences, derived under the assumption of neutrality should perform equally well in the presence of weak selection. We also modify an algorithm for simulating genealogies conditional on the frequencies of two selected alleles in a sample. This permits efficient simulation of stronger selection than was previously possible. Using this new algorithm, we simulate gene genealogies under the many-demes ancestral selection graph and identify some situations in which migration has a strong effect on the time to the most recent common ancestor of the sample. We find that a similar effect also increases the sensitivity of the genealogy to selection.