bluuebunny/crossref_metadata_2025 huggingface dataset:
Allis shad (Alosa alosa) exhibit an intensity-graded behavioral response when exposed to ultrasound
Authors: Wilson Maria , Acolas Marie-Laure , Bégout Marie-Laure , Madsen Peter T. , Wahlberg Magnus
Published: October 2008

Most fish cannot hear frequencies above 3kHz, but a few species belonging to the subfamily Alosinae (family Clupeidae) can detect intense ultrasound. The response of adult specimens of the European allis shad (Alosa alosa) to sinusoidal ultrasonic pulses at 70 and 120kHz is tested. The fish showed an intensity-graded response to the ultrasonic pulses with a response threshold between 161 and 167dB re 1μPa (pp) for both frequencies. These response thresholds are similar to thresholds derived from juvenile American shad (Alosa sapidissima) in previous studies, supporting the suggestion that these members of Alosinae have evolved a dedicated ultrasound detector adapted to detect and respond to approaching echolocating toothed whales.
Detection in reverberation using space time adaptive prewhiteners
Authors: Li Wei , Ma Xiaochuan , Zhu Yun , Yang Jun , Hou Chaohuan
Published: October 2008

A major problem in moving platform active sonar systems is the detection of targets in spatially distributed and Doppler-spread reverberation. This paper presents a novel space time adaptive prewhitener for reverberation based on a two-dimensional autoregressive model. The space time adaptive prewhitener jointly processes received data in angle and Doppler to improve the separation of a target from reverberation. The detector using the space time adaptive prewhitener is shown to yield better detection performance than previously known schemes when operating in a reverberation background containing target echoes.
The influence of noise exposure on the parameters of a convolution model of the compound action potential
Authors: Chertoff M. E. , Lichtenhan J. T. , Tourtillott B. M. , Esau K. S.
Published: October 2008

The influence of noise exposure on the parameters of a convolution model of the compound action potential (CAP) was examined. CAPs were recorded in normal-hearing gerbils and in gerbils exposed to a 117dBSPL 8kHz band of noise for various durations. The CAPs were fitted with an analytic CAP to obtain the parameters representing the number of nerve fibers (N), the probability density function [P(t)] from a population of nerve fibers, and the single-unit waveform [U(t)]. The results showed that the analytic CAP fitted the physiologic CAPs well with correlations of approximately 0.90. A subsequent analysis using hierarchical linear modeling quantified the change in the parameters as a function of both signal level and hearing threshold. The results showed that noise exposure caused some of the parameter-level functions to simply shift along the signal level axis in proportion to the amount of hearing loss, whereas others shifted along the signal level axis and steepened. Significant changes occurred in the U(t) parameters, but they were not related to hearing threshold. These results suggest that noise exposure alters the physiology underlying the CAP, some of which can be explained by a simple lack of gain, whereas others may not.
Ultrasonic measurement of condensate film thickness
Authors: Kimball Jeramy T. , Bailey Michael R. , Hermanson James C.
Published: October 2008

The current work describes a modified time-of-flight ultrasound signal processing technique applied to the study of a distal liquid layer with a free surface. The technique simulates multiple reflections analytically and determines the film thickness by comparison to the measured pulse echo signal. The technique is applied with 20MHz transducers to an n-pentane film condensing on a copper plate. The technique proved capable of measuring liquid thickness from approximately 8μm, 1∕6 the acoustic wavelength in pentane, to greater than 5mm. Near the lower thickness limit, echoes from the liquid/vapor interface overlap each other and the significantly larger echoes from the metal/liquid interface.
Use of psychometric-function slopes for forward-masked tones to investigate cochlear nonlinearity
Authors: Schairer Kim S. , Messersmith Jessica , Jesteadt Walt
Published: October 2008

Schairer et al. [(2003). “Effects of peripheral nonlinearity on psychometric functions for forward-masked tones,” J. Acoust. Soc. Am. 133, 1560–1573] demonstrated that cochlear nonlinearity is reflected in psychometric-function (PF) slopes for 4 kHz forward-masked tones. The goals of the current study were to use PF slopes to compare the degree of compression between signal frequencies of 0.25 and 4 kHz in listeners with normal hearing (LNH), and between LNH and listeners with cochlear hearing loss (LHL). Forward-masked thresholds were estimated in LNH and LHL using on- and off-frequency maskers and 0.25 and 4 kHz signals in three experiments. PFs were reconstructed from adaptive-procedure data for each subject in each condition. Trends in PF slopes across conditions suggest comparable compression at 0.25 and 4 kHz, and potentially a wider bandwidth of compression in relative frequency at 0.25 kHz. This is consistent with other recent behavioral studies that revise earlier estimates of less compression at lower frequencies. The preliminary results in LHL demonstrate that PF slopes are abnormally steep at frequencies with HL, but are similar to those for LNH at frequencies with NH. Overall, the results are consistent with the notion that PF slopes reflect degree of cochlear nonlinearity and can be used as an additional measure of compression across frequency.
Neuronal periodicity detection as a basis for the perception of consonance: A mathematical model of tonal fusion
Authors: Ebeling Martin
Published: October 2008

A mathematical model is presented here to explain the sensation of consonance and dissonance on the basis of neuronal coding and the properties of a neuronal periodicity detection mechanism. This mathematical model makes use of physiological data from a neuronal model of periodicity analysis in the midbrain, whose operation can be described mathematically by autocorrelation functions with regard to time windows. Musical intervals produce regular firing patterns in the auditory nerve that depend on the vibration ratio of the two tones. The mathematical model makes it possible to define a measure for the degree of these regularities for each vibration ratio. It turns out that this measure value is in line with the degree of tonal fusion as described by Stumpf [Tonpsychologie (Psychology of Tones) (Knuf, Hilversum), reprinted 1965]. This finding makes it probable that tonal fusion is a consequence of certain properties of the neuronal periodicity detection mechanism. Together with strong roughness resulting from interval tones with fundamentals close together or close to the octave, this neuronal mechanism may be regarded as the basis of consonance and dissonance.
Analysis of facial motion patterns during speech using a matrix factorization algorithm
Authors: Lucero Jorge C. , Munhall Kevin G.
Published: October 2008

This paper presents an analysis of facial motion during speech to identify linearly independent kinematic regions. The data consists of three-dimensional displacement records of a set of markers located on a subject’s face while producing speech. A QR factorization with column pivoting algorithm selects a subset of markers with independent motion patterns. The subset is used as a basis to fit the motion of the other facial markers, which determines facial regions of influence of each of the linearly independent markers. Those regions constitute kinematic “eigenregions” whose combined motion produces the total motion of the face. Facial animations may be generated by driving the independent markers with collected displacement records.
Surface wave conversion analysis on a lengthwise soldered circular cylindrical shell
Authors: Baillard André , Chiumia Jeremiah , Décultot Dominique , Maze Gérard , Klauson Aleksander , Metsaveer Jaan
Published: October 2008

This paper deals with wave conversion phenomena through a study of the acoustic scattering from a stiffened cylindrical shell at normal incidence. The analysis presented follows the experimental study which explored the acoustic wave propagation and scattering processes in the case of air-filled submerged cylindrical shells having internal axial solder [J. Chiumia, N. Touraine, D. Décultot, G. Maze, A. Klauson, and J. Metsaveer, J. Acoust. Soc. Am. 105, 183–193 (1999)]. The significant observed phenomena were generation, reflection, and conversion of circumnavigating waves at the solder. The present work confirms the presence of the three phenomena through a theoretical approach based on the elasticity theory. In particular, resonances with new feature whose frequencies are very close to those of the S0 wave are highlighted here. The origin of this new resonance feature is identified and can be associated to wave type conversions between A0 and S0 Lamb waves, occurring when these propagating waves encounter the solder. The air-filled stainless steel studied tube submerged in water has an internal lengthwise solder, which is, in theoretical computations, considered as an internal axial mass layer. The reduced frequency range (k1a) of the study is between 25 and 90, (k1: wave number in water; a: external radius of the shell).
Influence of growth history on the accumulation of energy reserves and winter mortality in young fish
Authors: Huss Magnus , Byström Pär , Strand Åsa , Eriksson Lars-Ove , Persson Lennart
Published: October 2008

In seasonal environments, accumulated energy reserves are important to avoid starvation mortality during periods of low resource levels. Here we investigated patterns of energy accumulation and the importance of growth history for winter survival in young-of-the-year Eurasian perch ( Perca fluviatilis ). Under simulated winter conditions in aquaria, we showed that high winter mortality most likely relates to the depletion of energy reserves in small perch. Correspondingly, in a field study, using four lakes covering 3–6 lake-years each, overwinter survival within cohorts was positively related to individual size. However, average size in autumn did not explain the variation in overwinter survival between cohorts. Instead, we showed that seasonal growth history is an important factor. High growth rates late in season may increase cohort survival over winter, irrespective of average size, related to a positive growth-dependent increase in allocation to energy reserves when approaching winter. Mechanisms regulating within-season temporal dynamics of growth rates are therefore suggested to be important for overall cohort performance.
Coupling stable isotopes with bioenergetics to evaluate sources of variation in organochlorine concentrations in Baltic salmon (Salmo salar)
Authors: Kiljunen Mikko , Peltonen Heikki , Jones Roger I. , Kiviranta Hannu , Vuorinen Pekka J. , Verta Matti , Karjalainen Juha
Published: October 2008

Atlantic salmon ( Salmo salar ) collected from three locations around the northern Baltic Sea in 2003–2004 showed large spatial and individual variation in their organochlorines (OCs) (polychlorinated dibenzo-p-dioxins and furans and polychlorinated biphenyls). This variation could be explained only partly by their size or sea age. The variability arose from the differences in salmon diet, trophic position, and prey OC concentrations and lipid content. A salmon bioenergetics accumulation model was used to evaluate the contribution of salmon growth and their diet to the observed individual variation in OC content. Our model revealed that the contribution of three main prey species in the OC accumulation of salmon varied markedly between the study areas. Amount of lipids in salmon explained a large proportion of their OC concentration. However, trophic position of salmon calculated from the δ15N values explained almost 80% of the variation in lipid-normalized OC concentrations. In the Gulf of Finland, where OC concentrations of salmon were highest, their prey species had the highest OC concentrations and trophic positions. Higher OC concentrations in the Gulf of Finland might be related to elevated trophic positions caused by invasion of the predatory cladoceran Cercopagis pengoi in 1990.
Long-term variation in isotopic baselines and implications for estimating consumer trophic niches
Authors: Solomon Christopher T. , Carpenter Stephen R. , Rusak James A. , Vander Zanden M. Jake
Published: October 2008

Carbon and nitrogen stable isotope ratios are increasingly used to study long-term food web change. Temporal variation at the base of the food web may impact the accuracy of trophic niche estimates, but data describing interannual baseline variation are limited. We quantified baseline variation over a 23-year period in a north-temperate lake and used a simulation model to examine how this variation might affect consumer trophic niche estimates. Interannual variation in C and N stable isotope ratios was significant for both benthic and pelagic primary consumer baselines. Long-term linear trends and shorter-term autoregressive patterns were apparent in the data. There were no correlations among benthic and pelagic C and N baselines. Simulations demonstrated that error in estimated fish trophic niches, but not bias, increased substantially when sampling of baselines was incomplete. Accurate trophic niche estimates depended more on accurate estimation of baseline time series than on accurate estimation of growth and turnover rates. These results highlight the importance of previous and continued efforts to constrain bias and error in long-term stable isotope food web studies.
Observations of avoidance reactions of migrating salmon to a mobile survey vessel in a riverine environment
Authors: Xie Yunbo , Michielsens Catherine G.J. , Gray Andrew P. , Martens Fiona J. , Boffey Jacqueline L.
Published: October 2008

Detailed avoidance reactions of adult migrating salmon to a mobile survey vessel were successfully observed with side-looking dual-frequency identification sonar (DIDSON) in the lower Fraser River (British Columbia, Canada). Both adult sockeye ( Oncorhynchus nerka ) and pink salmon ( Oncorhynchus gorbuscha ) returning to the river were found to avoid the approaching vessel by initiating lateral movements away from the vessel, making the fish unlikely to be insonified by the downward-looking transducers towed by the vessel. The vessel was found to have an estimated mean interference range of 4 m from its propeller. Analyses of the data concluded that once the vessel and fish were separated by more than 7 m, the vessel no longer affected the normal migration behaviour of the fish.
Validation of annual growth rings in freshwater mussel shells using cross dating
Authors: Rypel Andrew L. , Haag Wendell R. , Findlay Robert H.
Published: October 2008

We examined the usefulness of dendrochronological cross-dating methods for studying long-term, interannual growth patterns in freshwater mussels, including validation of annual shell ring formation. Using 13 species from three rivers, we measured increment widths between putative annual rings on shell thin sections and then removed age-related variation by standardizing measurement time series using cubic splines. Initially, cross dating was a valuable quality control technique allowing us to correct interpretive and measurement errors in 16% of specimens. For all species, growth varied among years but was highly synchronous among individuals. Standardized measurement time series of 94% of individuals were significantly correlated with species master chronologies, and mean interseries correlations ranged from 0.37 to 0.96. Growth was also synchronous among species, even from different rivers, and growth was negatively correlated with mean annual streamflow for most species except Quadrula pustulosa from a regulated dam tailrace. Highly synchronous growth and the strong relationship to streamflow showed that large-scale environmental signals generated non-age-related variation in mussel growth giving strong support for annual formation of the growth increments we measured. Cross dating can be a valuable technique for studying freshwater mussel growth providing quality control, validation of annual rings, and reconstruction of long-term growth histories.
Comparison of three microquantity techniques for measuring total lipids in fish
Authors: Lu Yuehan , Ludsin Stuart A. , Fanslow David L. , Pothoven Steven A.
Published: October 2008

To measure lipids in juvenile and adult fishes, we refined three microquantity approaches (microgravimetric, microcolorimetric sulfophosphovanillan (SPV), and Iatroscan thin layer chromatography – flame ionization detection (TLC–FID)) that were originally developed to measure lipids in small aquatic invertebrates. We also evaluated their precision and comparability by quantifying the total lipid content of age-1+ walleye ( Sander vitreus ), yellow perch ( Perca flavescens ), and lake whitefish ( Coregonus clupeaformis ) collected in Lake Erie (US–Canada), Lake Michigan (USA), and Muskegon Lake (Michigan, USA). Our findings demonstrate that (i) microquantity approaches provide estimates of total lipids in juvenile and adult fishes similar to those of more traditional macroquantity approaches, (ii) the microcolorimetric SPV and microgravimetric approaches produce near identical estimates of total lipid content, and (iii) the Iatroscan TLC–FID approach underestimates total lipids relative to the other approaches for individuals with high lipid levels. Ultimately, our research makes available additional techniques for measuring total lipid content of fishes that are less expensive than traditional techniques, owing to a reduced need for large quantities of samples and solvents.
It’s time to sharpen our definition of sustainable fisheries management
Authors: Shelton Peter A. , Sinclair Alan F.
Published: October 2008

We review and evaluate the sustainability paradigm as it applies to wild capture fisheries in the context of a recently developed harvest strategy framework that, if implemented, will meet Canada’s national and international obligations with regard to sustainable fisheries. This framework is based on an operationally explicit definition of sustainability that includes a commitment to managing for maximum sustainable yield. Although Canadian policy strongly supports sustainable fisheries management in principle, usage of the term has been vague and implementation of sustainable fisheries management strategies has lagged. Fisheries managed under the recently developed framework would be better able to meet new ecocertification and ecolabelling standards. An emerging governance structure discussed herein with respect to fisheries management is conducive to implementing sustainable management practices that meet long-term public good objectives.
Étude de la loi conjointe débit-niveau par les copules : Cas de la rivière Châteauguay
Authors: El Adlouni Salaheddine , Ouarda Taha B.M.J.
Published: October 2008

Plusieurs catastrophes naturelles sont le résultat de l’occurrence simultanée de deux ou plusieurs événements extrêmes. L’évaluation du risque d’apparition de ces catastrophes repose sur une bonne estimation de la probabilité conjointe de ces événements. Le présent travail étudie l’effet combiné des débits extrêmes à l’embouchure de la rivière Châteauguay avec le niveau au Lac Saint-Louis. La modélisation de la loi conjointe de ces deux variables est basée sur la notion de copule qui permet de séparer le choix des lois marginales de la structure de dépendance. Les résultats montrent que le fait d’ignorer l’effet combiné du débit de la rivière ou du niveau du lac, conduit à une sous-estimation des événements extrêmes.
THE GRAND VIEW OF PHYSICS
Authors: 't HOOFT GERARD
Published: October 2008

Abdus Salam was known for his "grand views", grand views of science as well as grand views of society. In this talk the grand view of theoretical physics is put in perspective.
SLIDING DISKS IN THE PLANE
Authors: BEREG SERGEY , DUMITRESCU ADRIAN , PACH JÁNOS
Published: October 2008

Given a pair of start and target configurations, each consisting of n pairwise disjoint disks in the plane, what is the minimum number of moves that suffice for transforming the start configuration into the target configuration? In one move a disk slides in the plane without intersecting any other disk, so that its center moves along an arbitrary (open) continuous curve. We discuss efficient algorithms for this task and estimate their number of moves under different assumptions on disk radii. For example, with n congruent disks, [Formula: see text] moves always suffice for transforming the start configuration into the target configuration; on the other hand, [Formula: see text] moves are sometimes necessary.
MULTI-DIRECTIONAL WIDTH-BOUNDED GEOMETRIC SEPARATOR AND PROTEIN FOLDING
Authors: FU BIN , OPRISAN SORINEL A. , XU LIZHE
Published: October 2008

We introduce the concept of multi-directional width-bounded geometric separators and obtain an improved separator for grid graphs. This yields an improved exact algorithm for the protein folding problem in the HP-model. For a grid graph G with n grid points P, there exists a separator A ⊆ P such that A has at most [Formula: see text] points, and G − A has two disconnected subgraphs each with at most [Formula: see text] nodes. This improves the previous upper bound of [Formula: see text]. We also derive a [Formula: see text] lower bound for such a separator in grid graphs.
PROVABLE DIMENSION DETECTION USING PRINCIPAL COMPONENT ANALYSIS
Authors: CHENG SIU-WING , WANG YAJUN , WU ZHUANGZHI
Published: October 2008

We analyze an algorithm based on principal component analysis (PCA) for detecting the dimension k of a smooth manifold [Formula: see text] from a set P of point samples. The best running time so far is O(d 2O(k7 log k)) by Giesen and Wagner after the adaptive neighborhood graph is constructed. Given the adaptive neighborhood graph, the PCA-based algorithm outputs the true dimension in O(d2O(k)) time, provided that P satisfies a standard sampling condition as in previous results. Our experimental results validate the effectiveness of the approach. A further advantage is that both the algorithm and its analysis can be generalized to the noisy case, in which small perturbations of the samples and a small portion of outliers are allowed.
ON THE MATABILITY OF POLYGONS
Authors: BAREQUET GILL , STEINER AYA
Published: October 2008

Interpolating a piecewise-linear triangulated surface between two polygons lying in parallel planes has attracted a lot of attention in the literature over the past three decades. This problem is the simplest variant of interpolation between parallel slices, which may contain multiple polygons with unrestricted geometries and/or topologies. Its solution has important applications to medical imaging, digitization of objects, geographical information systems, and more. Practically all currently-known methods for surface reconstruction from parallel slices assume a priori the existence of a non-self-intersecting triangulated surface defined over the vertices of the two polygons, which connects them. Gitlin et al. were the first to specify a nonmatable pair of polygons. In this paper we provide proof of the nonmatability of a “simpler” pair of polygons, which is less complex than the example given by Gitlin et al. Furthermore, we provide a family of polygon pairs with unbounded complexity, which we believe to be nonmatable. We also give a few sufficient conditions for polygon matability.
Electron Linacs for High Energy Physics
Authors: Wilson Perry B.
Published: October 2008

The purpose of this article is to introduce some of the basic physical principles underlying the operation of electron linear accelerators (electron linacs). Electron linacs have applications ranging from linacs with an energy of a few MeV, such that the electrons are approximately relativistic, to future electron–positron linear colliders having a collision energy in the several-TeV energy range. For the most part, only the main accelerating linac is treated in this article.
The Development of High Power Hadron Accelerators
Authors: Rees G. H.
Published: October 2008

A brief review is given of the development of linacs, cyclotrons, synchrotrons (also accumulators) and FFAG accelerators for a variety of high power hadron beam applications.
Accelerators and the Accelerator Community
Authors: Sessler Andrew , Malamud Ernest
Published: October 2008

In this paper, standing back — looking from afar — and adopting a historical perspective, the field of accelerator science is examined. The subjects explored are: how it grew, what were the forces that made it what it is, where it is now, and what it is likely to be in the future. Clearly, many personal opinions, are offered in this process.
Epac is involved in cAMP-stimulated proglucagon expression and hormone production but not hormone secretion in pancreatic α- and intestinal L-cell lines
Authors: Islam Diana , Zhang Nina , Wang Peixiang , Li Hang , Brubaker Patricia L. , Gaisano Herbert Y. , Wang Qinghua , Jin Tianru
Published: October 2008

Both Epac and PKA are effectors of the second messenger cAMP. Utilizing an exchange protein directly activated by cAMP (Epac) pathway-specific cAMP analog (ESCA), we previously reported that Epac signaling regulates proglucagon gene (gcg) expression in the glucagon-like peptide-1 (GLP-1)-producing intestinal endocrine L-cell lines GLUTag and STC-1. We now show that Epac-2 is also expressed in glucagon-producing pancreatic α-cell lines, including PKA-deficient InR1-G9 cells, and that ESCA stimulates gcg promoter and mRNA expression in the InR1-G9 cells. Using a dominant-negative Epac-2 expression plasmid (Epac-2DN), we found that Epac inhibition attenuated forskolin-stimulated gcg promoter expression in the PKA-active STC-1 cell line and blocked forskolin-stimulated gcg promoter expression in the InR1-G9 cells. Consistently, ESCA was shown to stimulate glucagon and GLP-1 production in the InR1-G9 and GLUTag cell lines, respectively. Surprisingly, ESCA treatment did not show a notable stimulation of glucagon or GLP-1 secretion from these two cell lines. This is in contrast to its ability to stimulate insulin secretion from the pancreatic INS-1 β-cell line. Our findings suggest that Epac is selectively involved in peptide hormone secretion in pancreatic and intestinal endocrine cells and that distinct signaling cascades are involved in stimulating production vs. secretion of glucagon and GLP-1 in response to cAMP elevation.
APPL1: role in adiponectin signaling and beyond
Authors: Deepa Sathyaseelan S. , Dong Lily Q.
Published: October 2008

Adiponectin, an adipokine secreted by the white adipose tissue, plays an important role in regulating glucose and lipid metabolism and controlling energy homeostasis in insulin-sensitive tissues. A decrease in the circulating level of adiponectin has been linked to insulin resistance, type 2 diabetes, atherosclerosis, and metabolic syndrome. Adiponectin exerts its effects through two membrane receptors, AdipoR1 and AdipoR2. APPL1 is the first identified protein that interacts directly with adiponectin receptors. APPL1 is an adaptor protein with multiple functional domains, the Bin1/amphiphysin/rvs167, pleckstrin homology, and phosphotyrosine binding domains. The PTB domain of APPL1 interacts directly with the intracellular region of adiponectin receptors. Through this interaction, APPL1 mediates adiponectin signaling and its effects on metabolism. APPL1 also functions in insulin-signaling pathway and is an important mediator of adiponectin-dependent insulin sensitization in skeletal muscle. Adiponectin signaling through APPL1 is necessary to exert its anti-inflammatory and cytoprotective effects on endothelial cells. APPL1 also acts as a mediator of other signaling pathways by interacting directly with membrane receptors or signaling proteins, thereby playing critical roles in cell proliferation, apoptosis, cell survival, endosomal trafficking, and chromatin remodeling. This review focuses mainly on our current understanding of adiponectin signaling in various tissues, the role of APPL1 in mediating adiponectin signaling, and also its role in the cross-talk between adiponectin/insulin-signaling pathways.
A key role for the peroxisomalABCD2transporter in fatty acid homeostasis
Authors: Fourcade Stéphane , Ruiz Montserrat , Camps Carme , Schlüter Agatha , Houten Sander M. , Mooyer Petra A. W. , Pàmpols Teresa , Dacremont Georges , Wanders Ronald J. A. , Giròs Marisa , Pujol Aurora
Published: October 2008

Peroxisomes are essential organelles exerting key functions in fatty acid metabolism such as the degradation of very long-chain fatty acids (VLCFAs). VLCFAs accumulate in X-adrenoleukodystrophy (X-ALD), a disease caused by deficiency of the Abcd1 peroxisomal transporter. Its closest homologue, Abcd2, exhibits a high degree of functional redundancy on the catabolism of VLCFA, being able to prevent X-ALD-related neurodegeneration in the mouse. In the search for specific roles of Abcd2, we screened fatty acid profiles in organs and primary neurons of mutant knockout mice lacking Abcd2 in basal conditions and under dietary challenges. Our results indicate that ABCD2 plays a role in the degradation of long-chain saturated and ω9-monounsaturated fatty acids and in the synthesis of docosahexanoic acid (DHA). Also, we demonstrated a defective VLCFA β-oxidation ex vivo in brain slices of Abcd1 and Abcd2 knockouts, using radiolabeled hexacosanoic acid and the precursor of DHA as substrates. As DHA levels are inversely correlated with the incidence of Alzheimer's and several degenerative conditions, we suggest that ABCD2 may act as modulator/modifier gene and therapeutic target in rare and common human disorders.
Intracortical Augmenting Responses in Networks of Reduced Compartmental Models of Tufted Layer 5 Cells
Authors: Karameh Fadi N. , Massaquoi Steve G.
Published: October 2008

Augmenting responses (ARs) are characteristic recruitment phenomena that can be generated in target neural populations by repetitive intracortical or thalamic stimulation and that may facilitate activity transmission from thalamic nuclei to the cortex or between cortical areas. Experimental evidence suggests a role for cortical layer 5 in initiating at least one form of augmentation. We present a three-compartment model of tufted layer 5 (TL5) cells that faithfully reproduces a wide range of dynamics in these neurons that previously has been achieved only partially and in much more complex models. Using this model, the simplest network exhibiting AR was a single pair of TL5 and inhibitory (IN5) neurons. Intracellularly, AR initiation was controlled by low-threshold Ca2+ current ( IT), which promoted TL5 rebound firing, whereas AR strength was dictated by inward-rectifying current ( Ih), which regulated TL5 multiple-spike firing and also prevented excessive firing under high-amplitude stimuli. Synaptically, AR was significantly more salient under concurrent stimulus delivery to superficial and deep dendritic zones of TL5 cells than under conventional single-zone stimuli. Moreover, slow GABA-B–mediated inhibition in TL5 cells controlled AR strength and frequency range. Finally, a network model of two cortical populations interacting across functional hierarchy showed that intracortical AR occurred prominently upon exciting superficial cortical layers either directly or via intrinsic connections, with AR frequency dictated by connection strength and background activity. Overall, the investigation supports a central role for a TL5–IN5 skeleton network in low-frequency cortical dynamics in vivo, particularly across functional hierarchies, and presents neuronal models that facilitate accurate large-scale simulations.
Responses of Areas 3b and 1 in Anesthetized Squirrel Monkeys to Single- and Dual-Site Stimulation of the Digits
Authors: Friedman Robert M. , Chen Li Min , Roe Anna W.
Published: October 2008

Stimulation of the skin evokes topographically organized activation in somatosensory cortex. This representation is context dependent, however, since a different cortical topography is observed in area 3b when stimulated with complex tactile stimuli that evoke the von Békésy funneling illusion. Here we report on the population responses, as observed with intrinsic optical imaging, of area 1 and area 3b in the anesthetized squirrel monkey to pressure indentation of distal finger pads. Individual finger pad stimulation revealed that area 1 exhibited a smaller magnification factor than 3b, as evidenced by a smaller area of activation elicited by distal finger pad stimulation. Effects of paired finger pad stimulation produced largely similar effects in area 1 and area 3b. Paired finger pad stimulation produced reductions in the area of digit activation in area 1, suggesting the presence of lateral inhibition and funneling of information in area 1. Suppressive effects were stronger for paired stimulations at adjacent than at nonadjacent sites. Single-unit recordings revealed a mixture of either a summation or a suppression of the response to paired finger stimulation, compared with single finger pad stimulation of the primary digit. However, the average population response showed that paired finger pad stimulation resulted in response suppression. Based on this study and previous studies, we suggest the presence of at least three distinct ranges of lateral inhibition in areas 3b and 1.
Distribution of the Olfactory Fiber Input Into the Olfactory Tubercle of the In Vitro Isolated Guinea Pig Brain
Authors: Carriero Giovanni , Uva Laura , Gnatkovsky Vadym , de Curtis Marco
Published: October 2008

The olfactory tubercle (OT) is a cortical component of the olfactory system involved in reward mechanisms of drug abuse. This region covers an extensive part of the rostral ventral cerebrum and is relatively poorly studied. The intrinsic network interactions evoked by olfactory input are analyzed in the OT of the in vitro isolated guinea pig brain by means of field potential analysis and optical imaging of voltage-sensitive signals. Stimulation of the lateral olfactory tract induces a monosynaptic response that progressively decreases in amplitude from lateral to medial. The monosynaptic input induces a disynaptic response that is proportionally larger in the medial portion of the OT. Direct stimulation of the piriform cortex and subsequent lesion of this pathway showed the existence of an associative disynaptic projection from the anterior part of the piriform cortex to the lateral part of the OT that integrates with the component mediated by the local intra-OT collaterals. Optical and electrophysiological recordings of the signals evoked by stimulation of the olfactory tract during arterial perfusion with the voltage-sensitive dye di-2-ANEPEQ confirmed the pattern of distribution of the mono and disynaptic responses in the OT. Finally, current source density analysis of laminar profiles recorded with 16-channel silicon probes confirmed that the monosynaptic and disynaptic potentials localize in the most superficial and the deep portions of the plexiform layer I, as suggested by previous reports. This study sets the standard for further analysis of the modulation of network properties in this largely unexplored brain region.
Designing Heart Performance by Gene Transfer
Authors: Davis Jennifer , Westfall Margaret V. , Townsend Dewayne , Blankinship Michael , Herron Todd J. , Guerrero-Serna Guadalupe , Wang Wang , Devaney Eric , Metzger Joseph M.
Published: October 2008

The birth of molecular cardiology can be traced to the development and implementation of high-fidelity genetic approaches for manipulating the heart. Recombinant viral vector-based technology offers a highly effective approach to genetically engineer cardiac muscle in vitro and in vivo. This review highlights discoveries made in cardiac muscle physiology through the use of targeted viral-mediated genetic modification. Here the history of cardiac gene transfer technology and the strengths and limitations of viral and nonviral vectors for gene delivery are reviewed. A comprehensive account is given of the application of gene transfer technology for studying key cardiac muscle targets including Ca2+handling, the sarcomere, the cytoskeleton, and signaling molecules and their posttranslational modifications. The primary objective of this review is to provide a thorough analysis of gene transfer studies for understanding cardiac physiology in health and disease. By comparing results obtained from gene transfer with those obtained from transgenesis and biophysical and biochemical methodologies, this review provides a global view of cardiac structure-function with an eye towards future areas of research. The data presented here serve as a basis for discovery of new therapeutic targets for remediation of acquired and inherited cardiac diseases.
An Overview of the Pressurized Thermal Shock Issue in the Context of the NURESIM Project
Authors: Lucas D. , Bestion D. , Bodèle E. , Coste P. , Scheuerer M. , D′Auria F. , Mazzini D. , Smith B. , Tiselj I. , Martin A. , Lakehal D. , Seynhaeve J.-M. , Kyrki-Rajamäki R. , Ilvonen M. , Macek J.
Published: October 2008

Within the European Integrated Project NURESIM, the simulation of PTS is investigated. Some accident scenarios for Pressurized Water Reactors may cause Emergency Core Coolant injection into the cold leg leading to PTS situations. They imply the formation of temperature gradients in the thick vessel walls with consequent localized stresses and the potential for propagation of possible flaws present in the material. This paper focuses on two‐phase conditions that are potentially at the origin of PTS. It summarizes recent advances in the understanding of the two‐phase phenomena occurring within the geometric region of the nuclear reactor,that is, the cold leg and the downcomer, where the “PTS fluid‐dynamics" is relevant. Available experimental data for validation of two‐phase CFD simulation tools are reviewed and the capabilities of such tools to capture each basic phenomenon are discussed. Key conclusions show that several two‐phase flow subphenomena are involved and can individually be simulated at least at a qualitative level, but the capability to simulate their interaction and the overall system performance is still limited. In the near term, one may envisage a simplified treatment of two‐phase PTS transients by neglecting some effects which are not yet well controlled, leading to slightly conservative predictions.
Src and ADAM-17–Mediated Shedding of Transforming Growth Factor-α Is a Mechanism of Acute Resistance to TRAIL
Authors: Van Schaeybroeck Sandra , Kelly Donal M. , Kyula Joan , Stokesberry Susan , Fennell Dean A. , Johnston Patrick G. , Longley Daniel B.
Published: October 2008

Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL/Apo-2L) has emerged as a promising anticancer agent. However, resistance to TRAIL is likely to be a major problem, and sensitization of cancer cells to TRAIL may therefore be an important anticancer strategy. In this study, we examined the effect of the epidermal growth factor receptor (EGFR)–tyrosine kinase inhibitor (TKI) gefitinib and a human epidermal receptor 2 (HER2)–TKI (M578440) on the sensitivity of human colorectal cancer (CRC) cell lines to recombinant human TRAIL (rhTRAIL). A synergistic interaction between rhTRAIL and gefitinib and rhTRAIL and M578440 was observed in both rhTRAIL-sensitive and resistant CRC cells. This synergy correlated with an increase in EGFR and HER2 activation after rhTRAIL treatment. Furthermore, treatment of CRC cells with rhTRAIL resulted in activation of the Src family kinases (SFK). Importantly, we found that rhTRAIL treatment induced shedding of transforming growth factor-α (TGF-α) that was dependent on SFK activity and the protease ADAM-17. Moreover, this shedding of TGF-α was critical for rhTRAIL-induced activation of EGFR. In support of this, SFK inhibitors and small interfering RNAs targeting ADAM-17 and TGF-α also sensitized CRC cells to rhTRAIL-mediated apoptosis. Taken together, our findings indicate that both rhTRAIL-sensitive and resistant CRC cells respond to rhTRAIL treatment by activating an EGFR/HER2-mediated survival response and that these cells can be sensitized to rhTRAIL using EGFR/HER2-targeted therapies. Furthermore, this acute response to rhTRAIL is regulated by SFK-mediated and ADAM-17–mediated shedding of TGF-α, such that targeting SFKs or inhibiting ADAM-17, in combination with rhTRAIL, may enhance the response of CRC tumors to rhTRAIL. [Cancer Res 2008;68(20):8312–21]
Phosphorylated Caveolin-1 Regulates Rho/ROCK-Dependent Focal Adhesion Dynamics and Tumor Cell Migration and Invasion
Authors: Joshi Bharat , Strugnell Scott S. , Goetz Jacky G. , Kojic Liliana D. , Cox Michael E. , Griffith Obi L. , Chan Simon K. , Jones Steven J. , Leung Sher-Ping , Masoudi Hamid , Leung Samuel , Wiseman Sam M. , Nabi Ivan R.
Published: October 2008

Rho/ROCK signaling and caveolin-1 (Cav1) are implicated in tumor cell migration and metastasis; however, the underlying molecular mechanisms remain poorly defined. Cav1 was found here to be an independent predictor of decreased survival in breast and rectal cancer and significantly associated with the presence of distant metastasis for colon cancer patients. Rho/ROCK signaling promotes tumor cell migration by regulating focal adhesion (FA) dynamics through tyrosine (Y14) phosphorylation of Cav1. Phosphorylated Cav1 is localized to protrusive domains of tumor cells and Cav1 tyrosine phosphorylation is dependent on Src kinase and Rho/ROCK signaling. Increased levels of phosphorylated Cav1 were associated with elevated GTP-RhoA levels in metastatic tumor cells of various tissue origins. Stable expression and knockdown studies of Cav1 in tumor cells showed that phosphorylated Cav1 expression stimulates Rho activation, stabilizes FAK association with FAs, and promotes cell migration and invasion in a ROCK-dependent and Src-dependent manner. Tyrosine-phosphorylated Cav1, therefore, functions as an effector of Rho/ROCK signaling in the regulation of FA turnover and, thereby, tumor cell migration and invasion. These studies define a feedback loop between Rho/ROCK, Src, and phosphorylated Cav1 in tumor cell protrusions, identifying a novel function for Cav1 in tumor metastasis that may contribute to the poor prognosis of some Cav1-expressing tumors. [Cancer Res 2008;68(20):8210–20]
Spinal Glioma: Platelet-Derived Growth Factor B–Mediated Oncogenesis in the Spinal Cord
Authors: Hitoshi Yasuyuki , Harris Brent T. , Liu Huan , Popko Brian , Israel Mark A.
Published: October 2008

Human platelet-derived growth factor B (hPDGFB) has been characterized in vitro and shown to mediate numerous cellular responses including glial proliferation and differentiation. Expression of PDGFB is thought to be important in the pathogenesis of glioma and several animal models of cerebral glioma based on PDGF expression have been described. To examine whether PDGF could contribute to the pathogenesis of spinal cord glioma, we developed transgenic mice that express hPDGFB under the control of a tetracycline-responsive element (TRE/hPDGFB). These TRE/hPDGFB mice were mated with transgenic mice expressing the tetracycline transcriptional activator (tet-off), tTA, regulated by the human glial fibrillary acidic protein (GFAP) promoter and exhibiting uniquely strong promoter activity in the spinal cord. These transgenic mice (GFAP/tTA:TRE/hPDGFB) expressed hPDGFB in GFAP-expressing glia in a manner responsive to doxycycline administration. Without doxycycline, almost all GFAP/tTA:TRE/hPDGFB mice developed spinal cord neoplasms resembling human mixed oligoastrocytoma. Tumorigenesis in these animals was suppressed by doxycycline. To further examine the importance of PDGFB in mouse primary intramedullary spinal cord tumors, we also created transgenic mice expressing hPDGFB under the control of the human GFAP promoter (GFAP/hPDGFB). These GFAP/hPDGFB mice also developed spinal oligoastrocytoma. PDGFB can mediate the development of mouse spinal tumors that are histologically and pathologically indistinguishable from primary intramedullary spinal tumors of humans and may provide opportunities for both novel insights into the pathogenesis of these tumors and the development of new therapeutics. [Cancer Res 2008;68(20):8507–15]
Pleiotropic Biological Activities of Alternatively Spliced TMPRSS2/ERG Fusion Gene Transcripts
Authors: Wang Jianghua , Cai Yi , Yu Wendong , Ren Chengxi , Spencer David M. , Ittmann Michael
Published: October 2008

TMPRSS2/ERG gene fusions are found in the majority of prostate cancers; however, there is significant heterogeneity in the 5′ region of the alternatively spliced fusion gene transcripts. We have found that there is also significant heterogeneity within the coding exons as well. There is variable inclusion of a 72-bp exon and other novel alternatively spliced isoforms. To assess the biological significance of these alternatively spliced transcripts, we expressed various transcripts in primary prostatic epithelial cells (PrEC) and in an immortalized PrEC line, PNT1a. The fusion gene transcripts promoted proliferation, invasion, and motility with variable activities that depended on the structure of the 5′ region encoding the TMPRSS2/ERG fusion and the presence of the 72-bp exon. Cotransfection of different isoforms further enhanced biological activity, mimicking the situation in vivo, in which multiple isoforms are expressed. Finally, knockdown of the fusion gene in VCaP cells resulted in inhibition of proliferation in vitro and tumor progression in an in vivo orthotopic mice model. Our results indicate that TMPRSS2/ERG fusion isoforms have variable biological activities promoting tumor initiation and progression and are consistent with our previous clinical observations indicating that certain TMPRSS2/ERG fusion isoforms are significantly correlated with more aggressive disease. [Cancer Res 2008;68(20):8516–24]
ATP Citrate Lyase: Activation and Therapeutic Implications in Non–Small Cell Lung Cancer
Authors: Migita Toshiro , Narita Tadahito , Nomura Kimie , Miyagi Erika , Inazuka Fumika , Matsuura Masaaki , Ushijima Masaru , Mashima Tetsuo , Seimiya Hiroyuki , Satoh Yukitoshi , Okumura Sakae , Nakagawa Ken , Ishikawa Yuichi
Published: October 2008

Enhanced glucose and lipid metabolism is one of the most common properties of malignant cells. ATP citrate lyase (ACLY) is a key enzyme of de novo fatty acid synthesis responsible for generating cytosolic acetyl-CoA and oxaloacetate. To evaluate its role in lung cancer progression, we here analyzed ACLY expression in a subset of human lung adenocarcinoma cell lines and showed a relationship with the phosphatidyl-inositol-3 kinase–Akt pathway. The introduction of constitutively active Akt into cells enhanced the phosphorylation of ACLY, whereas dominant-negative Akt caused attenuation. In human lung adenocarcinoma samples, ACLY activity was found to be significantly higher than in normal lung tissue. Immunohistochemical analysis further showed phosphorylated ACLY overexpression in 162 tumors, well-correlating with stage, differentiation grade, and a poorer prognosis. Finally, to show the therapeutic potential and mechanism of ACLY inhibition for lung cancer treatment, we assessed the effect of RNA interference targeting ACLY on lipogenesis and cell proliferation in A549 cells. ACLY inhibition resulted in growth arrest in vitro and in vivo. Interestingly, increased intracellular lipids were found in ACLY knockdown cells, whereas de novo lipogenesis was inhibited. Supplementation of insulin could rescue the proliferative arrest elicited by ACLY inhibition; however, in contrast, fatty acid palmitate induced cell death. Taken together, these findings suggest that ACLY is involved in lung cancer pathogenesis associated with metabolic abnormality and might offer a novel therapeutic target. [Cancer Res 2008;68(20):8547–54]