bluuebunny/crossref_metadata_2025 huggingface dataset:
A wide-angle three-dimensional parabolic wave equation
Authors: Lee Ding , Siegmann William L. , Kriegsmann Oregory A.
Published: January 2006

One straightforward extension of the standard two-dimensional PE to the three-dimensional case can be accomplished by retaining the angular derivative term. However, a number of basic questions arise concerning the derivation of this equation and its domain of validity. We discuss answers to these basic questions. Our answers lead to formulation of a new wide angle, three-dimensional partial differential equation which models sound propagation in the three-dimensional ocean. This formulation is achieved by operator theory. Instead of straightforward, small-angle three-dimensional PE, the new wide-angle equation is (in principle) a third-order partial differential equation. This third-order PDE is in an implicit form, making its solution by some numerical methods difficult. However, we choose to solve our three-dimensional PE by the same Crank-Nicolson scheme as used to solve the two-dimensional PE. Using this implicit finite-difference scheme in conjunction with an efficient high-performance preconditioning technique, developed at Yale, can produce an accurate numerical solution. [Work supported jointly by ONR and NUSC.]
Application of the Yale sparse matrix technique to the three-dimensional parabolic wave equation
Authors: Lee Ding , Schultz Martin H. , Jackson Kenneth R.
Published: January 2006

The Yale University sparse matrix technique is an efficient method for solving large sparse systems of linear equations such as those that arise at each step in the numerical integration of the stiff system of ordinary differential equations resulting from the application of the method of lines to the three-dimensional parabolic wave equation. The theory behind the Yale sparse technique and the advantage of using it for this problem are discussed. The solution of a three-dimensional ocean eddy propagation problem is presented as an example. [Work supported jointly by ONR and NUSC.]
Time inversion of acoustic signals with weak dispersion
Authors: Felsen L. B. , Heyman E.
Published: January 2006

Wave propagation in a vertically inhomogeneous ocean exhibits effective dispersion although the medium itself is nondispersive. Wave dispersion is weak at sufficiently high frequencies. The resulting local plane wave spectral representation of a source-excited sound field may then be inverted exactly to yield the impulsive response. Alternative inversion techniques are the Cagniard-DeHoop and the more general Chapman procedures. Both have limitations which are overcome by an analytic function approach, from which either a generalized Cagniard-DeHoop or the Chapman formulations are derived systematically by manipulations in the complex spectral plane. The three methods are compared and illustrated on caustic-forming multiple reflected ray fields and on refraction arrivals.
Intrinsic modes in a wedge-shaped ocean
Authors: Arnold J. M. , Felsen L. B.
Published: January 2006

By a recently developed theory applied to propagation in a wedge-shaped ocean with penetrable bottom [J. M. Arnold and L. B. Felsen, J. Acoust. Sec. Am. 73 1105 (1983)], spectral integrals have been derived that yield, by asymptotic evaluation to lowest order in the small bottom slope, the adiabatic modes, where these are valid, but which also describe the previously inaccessible transition through cutoff in upslope propagation. These spectral integrals have now been reexamined by performing the evaluation to the next asymptotic order. It is found that the result generated in this manner agrees, to the same order of accuracy, with a direct coupled mode solution of the boundary value problem wherein the adiabatic modes appear as the basic elements. Thus, the mode forms generated by the spectral integral include lowest order coupling between adiabatic modes. We refer to these uncoupled “more adaptable” modes, which likewise apply in the transition through cutoff, as intrinsic modes in order to distinguish them from the “less adaptable” adiabatic modes. Some consideration is given to still further generalization of the intrinsic modes to furnish uncoupled modes in a more strongly range dependent environment. [Work supported by ONR Acoustics Branch.]
Acoustic normal modes propagation through ocean eddies
Authors: Desaubies Y. , Chiu C. S. , Miller J.
Published: January 2006

Uniformly valid asymptotic solutions are derived for normal mode propagation in a slowly varying ocean waveguide. The limits of validity of various approximations as a function of mode number, acoustic frequency, and range are discussed for realistic ocean environments. In particular, the first correction to the adiabatic equations is calculated, which provides an approximate solution to the coupled mode equations. The implications for numerical calculation of normal modes are discussed.
Effect of amplitude modulation upon fusion of spectral components
Authors: Bregman Albert S. , Abramson Jack , Darwin Christopher
Published: January 2006

We studied the perceptual integration of two complex tones, each sent to both ears and formed by amplitude modulation (AM) of a carrier frequency CF by a sinusoid with modulation frequency MF. One tone always had CF = 1500 Hz and MF = 100 Hz. The other had CFs around 500 Hz and MFs around 100 Hz. Both harmonic and inharmonic partials, produced by AM, were employed. The method involved studying the competition between two organizations: (a) the fusion of the two tones, and (b) the tendency of the higher to be stripped out of the mixture by a competing sequential organization. Fusion was best when the both tones had the same MF, even when the resulting partials did not form part of the same harmonic series. Fusion was enhanced when AM applied to the two tones was in phase. Results relate to the perceptual separation of simultaneous voices and favor a theory in which basilar membrane outputs that are amplitude modulated by the same glottal pulse will be allocated to the same voice.
Ocean acoustic hurricane classification
Authors: Wilson Joshua D. , Makris Nicholas C.
Published: January 2006

Theoretical and empirical evidence are combined to show that underwater acoustic sensing techniques may be valuable for measuring the wind speed and determining the destructive power of a hurricane. This is done by first developing a model for the acoustic intensity and mutual intensity in an ocean waveguide due to a hurricane and then determining the relationship between local wind speed and underwater acoustic intensity. From this it is shown that it should be feasible to accurately measure the local wind speed and classify the destructive power of a hurricane if its eye wall passes directly over a single underwater acoustic sensor. The potential advantages and disadvantages of the proposed acoustic method are weighed against those of currently employed techniques.
Validity of the Markov approximation in ocean acoustics
Authors: Henyey Frank S. , Ewart Terry E.
Published: January 2006

Moment equations and path integrals for wave propagation in random media have been applied to many ocean acoustics problems. Both these techniques make use of the Markov approximation. The expansion parameter, which must be less than one for the Markov approximation to be valid, is the subject of this paper. There is a standard parameter (the Kubo number) which various authors have shown to be sufficient. Fourth moment equations have been successfully used to predict the experimentally measured frequency spectrum of intensity in the mid-ocean acoustic transmission experiment (MATE). Yet, in spite of this success, the Kubo number is greater than 1 for the measured index of refraction variability for MATE, arriving at a contradiction. Here, that contradiction is resolved by showing that the Kubo parameter is far too pessimistic for the ocean case. Using the methodology of van Kampen, another parameter is found which appears to be both necessary and sufficient, and is much smaller than the Kubo number when phase fluctuations are dominated by large scales in the medium. This parameter is shown to be small for the experimental regime of MATE, justifying the applications of the moment equations to that experiment.
Inverse potential scattering in duct acoustics
Authors: Forbes Barbara J. , Pike E. Roy , Sharp David B. , Aktosun Tuncay
Published: January 2006

The inverse problem of the noninvasive measurement of the shape of an acoustical duct in which one-dimensional wave propagation can be assumed is examined within the theoretical framework of the governing Klein–Gordon equation. Previous deterministic methods developed over the last 40years have all required direct measurement of the reflectance or input impedance but now, by application of the methods of inverse quantum scattering to the acoustical system, it is shown that the reflectance can be algorithmically derived from the radiated wave. The potential and area functions of the duct can subsequently be reconstructed. The results are discussed with particular reference to acoustic pulse reflectometry.
Sound source localization in real sound fields based on empirical statistics of interaural parameters
Authors: Nix Johannes , Hohmann Volker
Published: January 2006

The role of temporal fluctuations and systematic variations of interaural parameters in localization of sound sources in spatially distributed, nonstationary noise conditions was investigated. For this, Bayesian estimation was applied to interaural parameters calculated with physiologically plausible time and frequency resolution. Probability density functions (PDFs) of the interaural level differences (ILDs) and phase differences (IPDs) were estimated by measuring histograms for a directional sound source perturbed by several types of interfering noise at signal-to-noise ratios (SNRs) between −5 and +30dB. A moment analysis of the PDFs reveals that the expected values shift and the standard deviations increase considerably with decreasing SNR, and that the PDFs have non-Gaussian shape at medium SNRs. A d′ analysis of the PDFs indicates that elevation discrimination is possible even at low SNRs in the median plane by integrating information across frequency. Absolute sound localization was simulated by a Bayesian maximum a posteriori (MAP) procedure. The simulation is based on frequency integration of broadly tuned “detectors.” Confusion patterns of real and estimated sound source directions are similar to those of human listeners. The results indicate that robust processing strategies are needed to exploit interaural parameters successfully in noise conditions due to their strong temporal fluctuations.
Subjective assessment of listening environments in university classrooms: Perceptions of students
Authors: Kennedy Susan M. , Hodgson Murray , Edgett Lisa Dillon , Lamb Noelle , Rempel Rod
Published: January 2006

A questionnaire is developed to evaluate perception of the listening environment by university students. The objectives were to develop a questionnaire-based measurement tool, derive a measure of perceived classroom-listening quality, use the questionnaire to investigate factors that enhance, impair, or do not affect perceived listening quality, and consider the implications for classroom design. The questionnaire was administered to over 5700 students in 30 classrooms at one university. Physical and acoustical measurements were also performed in each classroom. The questionnaire included items that recorded aspects of student perception, as well as individual, course-, and instructor-specific factors. Responses to 19 perception items generated a perception of listening ease (PLE) score for each student and a classroom-average score. Decreased PLE was associated with women, English-second-language students, those with hearing impairment, students not interested in the course material, and those who found the material difficult. Increased PLE was associated with higher speech transmission index, acceptable lighting, temperature and seating, better instructor voice, increased visual-aid use, and easier course material. Results indicate that PLE is a useful measure of student perception of the classroom-listening environment, and that optimal classroom acoustical design must take into consideration “in-use” conditions, as well as classroom physical characteristics.
First-language phonotactics in second-language listening
Authors: Weber Andrea , Cutler Anne
Published: January 2006

Highly proficient German users of English as a second language, and native speakers of American English, listened to nonsense sequences and responded whenever they detected an embedded English word. The responses of both groups were equivalently facilitated by preceding context that both by English and by German phonotactic constraints forced a boundary at word onset (e.g., lecture was easier to detect in moinlecture than in gorklecture, and wish in yarlwish than in plookwish). The American L1 speakers’ responses were strongly facilitated, and the German listeners’ responses almost as strongly facilitated, by contexts that forced a boundary in English but not in German (thrarshlecture, glarshwish). The German listeners’ responses were significantly facilitated also by contexts that forced a boundary in German but not in English (moycelecture, loitwish), while L1 listeners were sensitive to acoustic boundary cues in these materials but not to the phonotactic sequences. The pattern of results suggests that proficient L2 listeners can acquire the phonotactic probabilities of an L2 and use them to good effect in segmenting continuous speech, but at the same time they may not be able to prevent interference from L1 constraints in their L2 listening.
A specialized fast cross-correlation for acoustical measurements using coded sequences
Authors: Daigle John N. , Xiang Ning
Published: January 2006

In acoustics applications, binary maximal-length sequences and related sequences are increasingly used for acoustics system identification tasks. A number of coded sequences, such as binary maximal-length related sequences and ternary sequences possess two-valued or pulselike autocorrelation functions. It is this correlation property that is exploited in most of acoustical applications. However, the length of some of these sequences is not directly suitable for FFT-based cross-correlation algorithms. This paper explores using standard FFTs to calculate the cross-correlation between two periodic finite-length sequences of equal length, where the lengths of the sequences are not a power of 2. We apply our specialized correlation algorithm to analyze data collected in a room-acoustic environment to simultaneously obtain impulse responses between multiple sources and multiple receivers.
Broadband modeling of downslope propagation in a penetrable wedge
Authors: Yudichak T. W. , Royal G. S. , Knobles D. P. , Gray M. , Koch R. A. , Stotts S. A.
Published: January 2006

Sound propagation in a wedge-shaped environment with a penetrable bottom is simulated with broadband adiabatic mode, coupled mode, and parabolic equation model computations. Simulated results are compared to measured data taken in a tank experiment by Tindle et al. The coupled mode formalism is shown to predict, in agreement with that experiment, that modal wave fronts in penetrable wedges are approximately circular arcs centered at the apex of the wedge for a source near the apex. It is also shown that for wedge angles up to 6°, the received waveforms are well approximated by the adiabatic waveforms time-shifted by a depth-dependent interval to account for the curvature of the modal wave fronts. A small deviation from circularity in the modal wave fronts is possibly observed in the 6° case.
Distortion product otoacoustic emission (DPOAE) in tinnitus patients
Authors: Ozimek E. , Wicher A. , Szyfter W. , Szymiec E.
Published: January 2006

The aim of this study was to determine the effect of tinnitus (experiment I) and the combined effect of tinnitus and sensorineural hearing loss (experiment II) on the distortion product otoacoustic emission (DPOAE) for two age groups of tinnitus patients. Tinnitus patients with normal earing, along with normal-hearing control subjects, participated in experiment I. They were divided into two age groups, below 50 and above 50 years. Experiment I showed that the DPOAE levels in the tinnitus patients were lower than those in the normal-hearing (nontinnitus) subjects. The differences depended on the frequency and the age of the patients, suggesting the confounding influence of presbyacusis. The second group of tinnitus patients with increasing and notch-like hearing loss participated in experiment II. They were also divided into two age groups, below 50 and above 50 years. The data from experiment II showed that DPOAE activity well reflects the increasing and notch-like hearing loss functions up to about 40 dB HL. The effect of age on the DPOAE level was clearly noted only for the tinnitus patients with clinically normal-hearing thresholds and was ambiguous for the tinnitus patients with hearing loss.
Calibration of the pressure sensitivity of microphones by a free-field method at frequencies up to 80kHz
Authors: Zuckerwar Allan J. , Herring G. C. , Elbing Brian R.
Published: January 2006

A free-field (FF) substitution method for calibrating the pressure sensitivity of microphones at frequencies up to 80kHz is demonstrated with both grazing and normal-incidence geometries. The substitution-based method, as opposed to a simultaneous method, avoids problems associated with the nonuniformity of the sound field and, as applied here, uses a 14-in. air-condenser pressure microphone as a known reference. Best results were obtained with a centrifugal fan, which is used as a random, broadband sound source. A broadband source minimizes reflection-related interferences that can plague FF measurements. Calibrations were performed on 14-in. FF air-condenser, electret, and microelectromechanical systems (MEMS) microphones in an anechoic chamber. The uncertainty of this FF method is estimated by comparing the pressure sensitivity of an air-condenser FF microphone, as derived from the FF measurement, with that of an electrostatic actuator calibration. The root-mean-square difference is found to be ±0.3dB over the range 1–80kHz, and the combined standard uncertainty of the FF method, including other significant contributions, is ±0.41dB.
Comment on "A Hydrogen-Rich Early Earth Atmosphere"
Authors: Catling David C.
Published: January 2006

Tian et al. (Reports, 13 May 2005, p. 1014) proposed a hydrogen-rich early atmosphere with slow hydrogen escape from a cold thermosphere. However, their model neglects the ultraviolet absorption of all gases other than H
2
. The model also neglects Earth's magnetic field, which affects the temperature and density of ions and promotes nonthermal escape of neutral hydrogen.
Two-Way Laser Link over Interplanetary Distance
Authors: Smith David E. , Zuber Maria T. , Sun Xiaoli , Neumann Gregory A. , Cavanaugh John F. , McGarry Jan F. , Zagwodzki Thomas W.
Published: January 2006

Here we report timed observations with subnanosecond precision of short laser pulses at a distance of nearly 24 million kilometers between the Mercury Laser Altimeter (MLA) aboard the MESSENGER (MErcury Surface, Space ENvironment, GEochemistry, and Ranging) spacecraft and the NASA Goddard Geophysical and Astronomical Observatory (GGAO). Forty MLA downlink observations and 90 uplink observations were obtained during observing sessions on 27 and 31 May 2005. Precise standard ground timing allowed a solution for spacecraft range, range rate, and acceleration, as well as clock bias. This experiment established a new distance record for laser detection and accomplished a two-way laser link at an interplanetary distance.
Quantum Deconstruction of the Infrared Spectrum of CH
5
+
Authors: Huang Xinchuan , McCoy Anne B. , Bowman Joel M. , Johnson Lindsay M. , Savage Chandra , Dong Feng , Nesbitt David J.
Published: January 2006

We present two quantum calculations of the infrared spectrum of protonated methane (CH
5
+
) using full-dimensional, ab initio–based potential energy and dipole moment surfaces. The calculated spectra compare well with a low-resolution experimental spectrum except below 1000 cm
–1
, where the experimental spectrum shows no absorption. The present calculations find substantial absorption features below 1000 cm
–1
, in qualitative agreement with earlier classical calculations of the spectrum. The major spectral bands are analyzed in terms of the molecular motions. Of particular interest is an intense feature at 200 cm
–1
, which is due to an isomerization mode that connects two equivalent minima. Very recent high-resolution jet-cooled spectra in the CH stretch region (2825 to 3050 cm
–1
) are also reported, and assignments of the band origins are made, based on the present quantum calculations.
From presentation to publication: the natural history of orthopaedic abstracts in the United Kingdom
Authors: Guryel E , Durrant A W , Alakeson R , Ricketts D M
Published: January 2006

Background

Up to 63% of the chapters in major orthopaedic textbooks use the results from abstracts that have been presented at international orthopaedic meetings.

Methods

Orthopaedic abstracts were reviewed that were presented at the 1997 and 1998 meetings of the British Orthopaedic Association and other specialist orthopaedic meetings. The number of abstracts that had gone on to a full text publication was assessed and changes in study design or outcome were determined.

Results

Of the 415 abstracts 137 (33.0%) went on to full text publication. Abstracts presented at the British Orthopaedic Association were significantly more likely to go on to full text publication than abstracts from the other meetings studied. The mean time to publication was 15.6 months. Sample sizes in unpublished studies were smaller (mean 129.8 subjects compared with a mean of 191.4 subjects for published studies). Of full text papers, 19.0% differed regarding study design from the abstract presented at the initial meeting and 10.9% had published different results. Randomised controlled trials had the highest rate of later full text publication (53.6%) followed by observational studies (32.8%), basic science studies (31.4%), and case reports (6.7%).

Conclusions

In comparison with a study from North America, similar numbers of abstracts presented at meetings finally became published as full text articles, the abstracts had fewer authors, more often included randomised controlled trials and follow up data, and had fewer changes to the results. It is questionable whether the inclusion of such results from abstracts presented at international meetings by major orthopaedic textbooks should be undertaken before full text publication.
Vesicoureteric reflux and urinary tract infection in children
Authors: Blumenthal I
Published: January 2006

An association between vesicoureteric reflux (VUR) and renal damage was found in 1960. In 1973, the term reflux nephropathy (RN) was first used to describe the renal damage caused by VUR. Follow up studies show that about 10%–20% of children with RN develop hypertension or end stage renal disease. It is now evident that there is a sex difference in the development of RN. In most males with RN, the kidneys are congenitally abnormal. In females it is an acquired condition, the most severe damage being sustained by recurrent urinary tract infections (UTIs). The purpose of current UTI guidelines is to identify VUR or any other abnormality of the urinary tract. Since the advent of routine antenatal ultrasonography, there is no longer a need to identify an abnormality of the urinary tract after the first reported UTI. Routine investigations are not required. Recurrent UTIs and a family history of VUR need further evaluation. There is also an urgent need to establish the long term value of prophylactic antibiotics in children with VUR.
Malnutrition and ageing
Authors: Hickson M
Published: January 2006

This article aims to provide an overview of the problems that exist in relation to malnutrition and the elderly population. The changes that occur in body composition during ageing are described and how this may affect disease risk. The possible metabolic processes behind weight loss are discussed and the numerous factors that affect nutritional status in the older age group are described. Prevention of malnutrition in this group is important and so the roles of nutrition screening and assessment are examined.
"MÜNCHHAUSEN TRICK" AND AMENABILITY OF SELF-SIMILAR GROUPS
Authors: KAIMANOVICH VADIM A.
Published: January 2006

The structure of a self-similar group G naturally gives rise to a transformation which assigns to any probability measure μ on G and any vertex w in the action tree of the group a new probability measure μw. If the measure μ is self-similar in the sense that μw is a convex combination of μ and the δ-measure at the group identity, then the asymptotic entropy of the random walk (G, μ) vanishes; therefore, the random walk is Liouville and the group G is amenable. We construct self-similar measures on several classes of self-similar groups, including the Grigorchuk group of intermediate growth.
EXPONENT MATRICES AND TILED ORDERS OVER DISCRETE VALUATION RINGS
Authors: KIRICHENKO V. V. , ZELENSKY A. V. , ZHURAVLEV V. N.
Published: January 2006

Exponent matrices appear in the theory of tiled orders over a discrete valuation ring. Many properties of such an order and its quiver are fully determined by its exponent matrix. We prove that an arbitrary strongly connected simply laced quiver with a loop in every vertex is realized as the quiver of a reduced exponent matrix. The relations between exponent matrices and finite posets, Markov chains, and doubly stochastic matrices are discussed.
L2-BETTI NUMBERS OF DISCRETE MEASURED GROUPOIDS
Authors: SAUER ROMAN
Published: January 2006

There are notions of L2-Betti numbers for discrete groups (Cheeger–Gromov, Lück), for type II1-factors (recent work of Connes-Shlyakhtenko) and for countable standard equivalence relations (Gaboriau). Whereas the first two are algebraically defined using Lück's dimension theory, Gaboriau's definition of the latter is inspired by the work of Cheeger and Gromov. In this work we give a definition of L2-Betti numbers of discrete measured groupoids that is based on Lück's dimension theory, thereby encompassing the cases of groups, equivalence relations and holonomy groupoids with an invariant measure for a complete transversal. We show that with our definition, like with Gaboriau's, the L2-Betti numbers [Formula: see text] of a countable group G coincide with the L2-Betti numbers [Formula: see text] of the orbit equivalence relation [Formula: see text] of a free action of G on a probability space. This yields a new proof of the fact the L2-Betti numbers of groups with orbit equivalent actions coincide.
A TRANSFINITE FILTRATION OF SCHUR MULTIPLICATOR
Authors: MIKHAILOV ROMAN , PASSI INDER BIR S.
Published: January 2006

We study certain subgroups of the Schur multiplicator of a group G. These subgroups are related to the identification of subgroups of G determind by ideals in its integral group ring ℤ[G]. Suitably defined transfinite powers of the augmentation ideal of ℤ[G] provide an increasing transfinite filtration of the Schur multiplicator of G. We investigate the relationship of this filtration with the transfinite lower central series of groups which are HZ-local in the sense of Bousfield.
SHELLS OF SELFDUAL LATTICES VIEWED AS SPHERICAL DESIGNS
Authors: PACHE CLAUDE
Published: January 2006

We find out for which t shells of selfdual lattices and of their shadows are spherical t-designs. The method uses theta series of lattices, which are modular forms. We analyze fully cubic and Witt lattices, as well as all selfdual lattices of rank at most 24.
DYNAMIC BEHAVIOR OF A NONLINEAR SINGLE SPECIES DIFFUSIVE SYSTEM
Authors: CHEN FENGDE , CHEN XIAOXING , SHI JINLIN
Published: January 2006

In this paper, we consider the following nonlinear single species diffusive system [Formula: see text] where bi(t), aik(t), Dij(t), i, j = 1, 2,…, n; k = 1, 2,…, li are all continuous ω-periodic functions, and βik, i = 1, 2,…, n; k = 1, 2,…, li are positive constants. Sufficient conditions which guarantee the permanence, extinction and existence of a unique globally attractive positive ω-periodic solution are obtained. Examples together with their numeric simulations show the feasibility of the main results.
Light Stimulus Frequency Dependence of Activity in the Rat Visual System as Studied With High-Resolution BOLD fMRI
Authors: Van Camp Nadja , Verhoye Marleen , De Zeeuw Chris I. , Van der Linden Annemie
Published: January 2006

The neurophysiology of the rodent visual system has mainly been investigated by invasive and ex-vivo techniques providing fragmented data. This area of research has been deprived of functional MRI studies based on blood oxygenation level dependent (BOLD) contrast, which allows a whole brain approach with a high spatial and temporal resolution. In the present study, we looked at the neurovascular response properties of the visual system of the pigmented rat, focusing on the visual cortex (VC), the superior colliculus (SC) and the flocculus-paraflocculus of the cerebellum (FL-PFL), using BOLD fMRI under domitor anesthesia. Visual stimulation was performed monocularly or binocularly while flashing light from a strobe unit was presented. For each structure, we assessed the flashing frequency that evoked the optimal BOLD response: Neither the VC nor the FL-PFL displayed frequency dependence during monocular visual stimulation, but were most sensitive to low frequencies (1–5 Hz) when flashing light was provided binocularly. The SC responded optimally to high flashing rates (8–12 Hz) during both monocular and binocular stimulation. The signal intensity changes in the VC and FL-PFL were locked to the stimulation period, whereas the BOLD response in the SC showed a similar onset but a very slow recovery at offset. The VC and FL-PFL, but not the SC, showed signs of binocular competition. The observed correlation between frequency-dependent responses of different visual areas during binocular visual presentation suggests a functional relationship between the VC and FL-PFL rather than between the SC and FL-PFL.
Postsynaptic Mechanisms Are Essential for Forskolin-Induced Potentiation of Synaptic Transmission
Authors: Sokolova Irina V. , Lester Henry A. , Davidson Norman
Published: January 2006

It has been demonstrated that stimulation of protein kinase A (PKA) results in enhanced synaptic transmission in the hippocampus and other brain areas. To investigate mechanisms of the PKA-mediated potentiation of synaptic transmission, we used rat hippocampal embryonic cultures. In low-density cultures, paired recordings under the perforated patch demonstrated that 15-min forskolin treatment produced long-lasting potentiation of evoked excitatory postsynaptic currents (eEPSCs) mediated by the cAMP/PKA pathway. eEPSC amplitudes increased to 240 ± 10% of baseline after 15 min of forskolin treatment (early). After forskolin washout, eEPSCs declined to a potentiated level. Potentiation was sustained for ≥85 min after forskolin washout and, 60 min after forskolin washout, constituted 152 ± 7% of baseline (late potentiation). Disruption of presynaptic processes with the whole cell configuration and internal solution containing PKA inhibitor peptide did not affect forskolin-induced potentiation. Disruption of postsynaptic processes, in contrast, impaired early potentiation and abolished late potentiation. Study of mEPSCs confirmed the contribution of postsynaptic mechanisms. Forskolin-induced enhancement of mEPSC frequency observed under the perforated patch was attenuated by the whole cell configuration. Forskolin also induced an increase of mEPSC amplitudes in the perforated patch, but not in the whole cell, experiments. Potentiation of eEPSCs was not activity dependent, persisting in the absence of stimulation. NMDA receptor blockade did not abolish forskolin-induced potentiation. In summary, we demonstrate that forskolin-induced potentiation of eEPSCs was mediated by postsynaptic mechanisms, presumably by upregulation of AMPA receptors by phosphorylation.
Functional Analysis of c-Met/Hepatocyte Growth Factor Pathway in Malignant Pleural Mesothelioma
Authors: Jagadeeswaran Ramasamy , Ma Patrick C. , Seiwert Tanguy Y. , Jagadeeswaran Sujatha , Zumba Osvaldo , Nallasura Vidya , Ahmed Salman , Filiberti Rosangela , Paganuzzi Michela , Puntoni Riccardo , Kratzke Robert A. , Gordon Gavin J. , Sugarbaker David J. , Bueno Raphael , Janamanchi Varalakshmi , Bindokas Vytas P. , Kindler Hedy L. , Salgia Ravi
Published: January 2006

c-Met receptor tyrosine kinase (RTK) has not been extensively studied in malignant pleural mesothelioma (MPM). In this study, c-Met was overexpressed and activated in most of the mesothelioma cell lines tested. Expression in MPM tissues by immunohistochemistry was increased (82%) in MPM in general compared with normal. c-Met was internalized with its ligand hepatocyte growth factor (HGF) in H28 MPM cells, with robust expression of c-Met. Serum circulating HGF was twice as high in mesothelioma patients as in healthy controls. There was a differential growth response and activation of AKT and extracellular signal–regulated kinase 1/2 in response to HGF for the various cell lines. Dose-dependent inhibition (IC50 < 2.5 μmol/L) of cell growth in mesothelioma cell lines, but not in H2052, H2452, and nonmalignant MeT-5A (IC50 >10 μmol/L), was observed with the small-molecule c-Met inhibitor SU11274. Furthermore, migration of H28 cells was blocked with both SU11274 and c-Met small interfering RNA. Abrogation of HGF-induced c-Met and downstream signaling was seen in mesothelioma cells. Of the 43 MPM tissues and 7 cell lines, we have identified mutations within the semaphorin domain (N375S, M431V, and N454I), the juxtamembrane domain (T1010I and G1085X), and an alternative spliced product with deletion of the exon 10 of c-Met in some of the samples. Interestingly, we observed that the cell lines H513 and H2596 harboring the T1010I mutation exhibited the most dramatic reduction of cell growth with SU11274 when compared with wild-type H28 and nonmalignant MeT-5A cells. Ultimately, c-Met would be an important target for therapy against MPM. (Cancer Res 2006; 66(1): 352-61
The Kaposi's Sarcoma–Associated Herpesvirus G Protein–Coupled Receptor as a Therapeutic Target for the Treatment of Kaposi's Sarcoma
Authors: Montaner Silvia , Sodhi Akrit , Ramsdell Amanda K. , Martin Daniel , Hu Jiadi , Sawai Earl T. , Gutkind J. Silvio
Published: January 2006

The Kaposi's sarcoma–associated herpesvirus (KSHV) encodes a G protein–coupled receptor (vGPCR) that has been implicated in the initiation of Kaposi's sarcoma, identifying vGPCR as an attractive target for preventing Kaposi's sarcoma. However, as only a fraction of cells in advanced Kaposi's sarcoma lesions express vGPCR, it is unclear whether this unique viral oncogene contributes to Kaposi's sarcoma progression. We therefore set out to determine whether the few cells that express vGPCR in established tumors represent an appropriate therapeutic target for the treatment of patients with preexisting Kaposi's sarcoma. To this end, we generated endothelial cell lines stably expressing vGPCR or key KSHV latently expressed proteins (vCyclin, vFlip, and LANA1). The endothelial cell line expressing vGPCR was rendered sensitive to treatment with the nucleoside analogue ganciclovir by using a bicistronic construct coexpressing the herpes simplex virus 1 thymidine kinase. S.c. injection into nude mice with mixed-cell populations formed tumors that approximate the ratio of vGPCR-expressing and KSHV latent gene-expressing cells. These mice were then treated with ganciclovir to specifically target only the vGPCR-expressing cells. Surprisingly, despite the expression of KSHV latent genes in the vast majority of tumor cells, specifically targeting only the few vGPCR-expressing cells in established tumors resulted in tumor regression. Moreover, we observed an increase in apoptosis of latent gene-expressing cells after the pharmacologic deletion of the vGPCR-expressing cells. These findings indicate that vGPCR may play a key role in Kaposi's sarcoma progression and provide experimental justification for developing molecular-based therapies specifically targeting vGPCR and its effectors for the treatment of Kaposi's sarcoma patients. (Cancer Res 2006; 66(1): 168-74)
Epidermal Growth Factor Receptor Overexpression Results in Increased Tumor Cell Motility In vivo Coordinately with Enhanced Intravasation and Metastasis
Authors: Xue Chengsen , Wyckoff Jeffrey , Liang Fubo , Sidani Mazen , Violini Stefania , Tsai Kun-Lin , Zhang Zhong-Yin , Sahai Erik , Condeelis John , Segall Jeffrey E.
Published: January 2006

Although overexpression of the epidermal growth factor receptor (EGFR; ErbB1) has been correlated with poor prognosis in breast and other cancers, clinical trials of ErbB1 inhibitors have shown limited efficacy in inhibiting tumor proliferation. To evaluate other possible roles of ErbB1 in tumor malignancy besides proliferation, we have developed a series of tools for analysis of intravasation. Overexpression of ErbB1 in MTLn3 mammary adenocarcinoma cells results in increased intravasation and lung metastasis from tumors formed by injection of cells in the mammary fat pad. However, increased ErbB1 expression has no effect on primary tumor growth and lung seeding efficiency of cells injected i.v. Chemotactic responses to low concentrations of EGF in vitro and cell motility in vivo in the primary tumor measured using intravital imaging are significantly increased by ErbB1 overexpression. The increased cell motility is restricted to ErbB1-overexpressing cells in tumors containing mixtures of cells expressing different ErbB1 levels, arguing for a cell-autonomous effect of increased ErbB1 expression rather than alteration of the tumor microenvironment. In summary, we propose that ErbB1 overexpression makes more significant contributions to intravasation than growth in some tumors and present a novel model for studying ErbB1 contributions to tumor metastasis via chemotaxis and intravasation. (Cancer Res 2006; 66(1): 192-7)
Noninvasive Magnetic Resonance Spectroscopic Pharmacodynamic Markers of the Choline Kinase Inhibitor MN58b in Human Carcinoma Models
Authors: Al-Saffar Nada M.S. , Troy Helen , de Molina Ana Ramírez , Jackson Laura E. , Madhu Basetti , Griffiths John R. , Leach Martin O. , Workman Paul , Lacal Juan C. , Judson Ian R. , Chung Yuen-Li
Published: January 2006

MN58b is a novel anticancer drug that inhibits choline kinase, resulting in inhibition of phosphocholine synthesis. The aim of this work was to develop a noninvasive and robust pharmacodynamic biomarker for target inhibition and, potentially, tumor response following MN58b treatment. Human HT29 (colon) and MDA-MB-231 (breast) carcinoma cells were examined by proton (1H) and phosphorus (31P) magnetic resonance spectroscopy (MRS) before and after treatment with MN58b both in culture and in xenografts. An in vitro time course study of MN58b treatment was also carried out in MDA-MB-231 cells. In addition, enzymatic assays of choline kinase activity in cells were done. A decrease in phosphocholine and total choline levels (P < 0.05) was observed in vitro in both cell lines after MN58b treatment, whereas the inactive analogue ACG20b had no effect. In MDA-MB-231 cells, phosphocholine fell significantly as early as 4 hours following MN58b treatment, whereas a drop in cell number was observed at 48 hours. Significant correlation was also found between phosphocholine levels (measured by MRS) and choline kinase activities (r2 = 0.95, P = 0.0008) following MN58b treatment. Phosphomonoesters also decreased significantly (P < 0.05) in both HT29 and MDA-MB-231 xenografts with no significant changes in controls. 31P-MRS and 1H-MRS of tumor extracts showed a significant decrease in phosphocholine (P ≤ 0.05). Inhibition of choline kinase by MN58b resulted in altered phospholipid metabolism both in cultured tumor cells and in vivo. Phosphocholine levels were found to correlate with choline kinase activities. The decrease in phosphocholine, total choline, and phosphomonoesters may have potential as noninvasive pharmacodynamic biomarkers for determining tumor response following treatment with choline kinase inhibitors. (Cancer Res 2006; 66(1): 427-34)
Germ-Line Mutation of NKX3.1 Cosegregates with Hereditary Prostate Cancer and Alters the Homeodomain Structure and Function
Authors: Zheng S. Lilly , Ju Jeong-ho , Chang Bao-li , Ortner Elizabeth , Sun Jielin , Isaacs Sarah D. , Sun Jishang , Wiley Kathy E. , Liu Wennuan , Zemedkun Micheas , Walsh Patrick C. , Ferretti James , Gruschus James , Isaacs William B. , Gelmann Edward P. , Xu Jianfeng
Published: January 2006

NKX3.1, a gene mapped to 8p21, is a member of the NK class of homeodomain proteins and is expressed primarily in the prostate. NKX3.1 exerts a growth-suppressive and differentiating effect on prostate epithelial cells. Because of its known functions and its location within a chromosomal region where evidence for prostate cancer linkage and somatic loss of heterozygosity is found, we hypothesize that sequence variants in the NKX3.1 gene increase prostate cancer risk. To address this, we first resequenced the NKX3.1 gene in 159 probands of hereditary prostate cancer families recruited at Johns Hopkins Hospital; each family has at least three first-degree relatives affected with prostate cancer. Twenty-one germ-line variants were identified in this analysis, including one previously described common nonsynonymous change (R52C), two novel rare nonsynonymous changes (A17T and T164A), and a novel common 18-bp deletion in the promoter. Overall, the germ-line variants were significantly linked to prostate cancer, with a peak heterogeneity logarithm of odds of 2.04 (P = 0.002) at the NKX3.1 gene. The rare nonsynonymous change, T164A, located in the homeobox domain of the gene, segregated with prostate cancer in a family with three affected brothers and one unaffected brother. Importantly, nuclear magnetic resonance solution structure analysis and circular dichroism studies showed this specific mutation to affect the stability of the homeodomain of the NKX3.1 protein and decreased binding to its cognate DNA recognition sequence. These results suggest that germ-line sequence variants in NKX3.1 may play a role in susceptibility to hereditary prostate cancer and underscore a role for NKX3.1 as a prostate cancer gatekeeper. (Cancer Res 2006; 66(1): 69-77)
Molecular Fingerprinting and Autocrine Growth Regulation of Endothelial Cells in a Murine Model of Hepatocellular Carcinoma
Authors: Ryschich Eduard , Lizdenis Paulius , Ittrich Carina , Benner Axel , Stahl Simone , Hamann Alf , Schmidt Jan , Knolle Percy , Arnold Bernd , Hämmerling Günter J. , Ganss Ruth
Published: January 2006

In a mouse model of hepatocellular carcinogenesis, highly vascularized tumors develop through two distinct morphologic phases of neovascularization. We show that increased vascular caliber occurs first, followed by extensive vessel sprouting in late-stage carcinomas. To define molecular pathways in tumor neovascularization, endothelial cells were directly purified from normal liver and advanced tumors. Gene expression profiling experiments were then designed to identify genes enriched in the vascular compartment. We report that Cathepsin S is the major protease specifically overexpressed during vessel sprouting. We also show that the CC chemokines CCL2 and CCL3 are secreted by neovessels and stimulate proliferation through their cognate receptors in an autocrine fashion. This suggests that chemokine signaling represents the most prominent signaling pathway in tumor-associated endothelial cells and directly regulates vessel remodeling. Furthermore, high angiogenic activity is associated with attenuated lymphocyte extravasation and correlates with expression of the immunomodulatory cytokine interleukin 10. This is the first comprehensive study addressing liver-specific vascular changes in a murine autochthonous tumor model. These novel insights into liver angiogenesis infer an environmental control of neovascularization and have important implications for the design of antiangiogenic therapies. (Cancer Res 2006; 66(1): 198-211)
Increased Susceptibility to UV-Induced Skin Carcinogenesis in Polymerase η–deficient Mice
Authors: Lin Qingcong , Clark Alan B. , McCulloch Scott D. , Yuan Tao , Bronson Roderick T. , Kunkel Thomas A. , Kucherlapati Raju
Published: January 2006

Xeroderma pigmentosum variant (XPV) patients with mutations in the DNA polymerase η (pol η) gene are hypersensitive to sunlight and have greatly increased susceptibility to sunlight-induced skin cancer. Consistent with the ability of Pol η to efficiently bypass UV light–induced cyclobutane pyrimidine dimers, XPV cells lacking Pol η have diminished capacity to replicate UV-damaged DNA and are sensitive to UV light–induced killing and mutagenesis. To better understand these and other Pol η functions, we generated Pol η–deficient mice. Mice homozygous for a null mutation in pol η are viable, fertile, and do not show any obvious spontaneous defects during the first year of life. However, fibroblasts derived from these mutant mice are sensitive to killing by exposure to UV light, and all Pol η–deficient mice develop skin tumors after UV irradiation, in contrast to the wild-type littermate controls that did not develop such tumors. These results and biochemical studies of translesion synthesis by mouse Pol η indicate that Pol η–dependent bypass of cyclobutane pyrimidine dimers suppresses UV light–induced skin cancer in mice. Moreover, 37.5% of pol η heterozygous mice also developed skin cancer during 5 months after a 5-month exposure to UV light, suggesting that humans who are heterozygous for mutations in pol η may also have an increased risk of skin cancer. (Cancer Res 2006; 66(1): 87-94)
Potent Antiandrogen and Androgen Receptor Activities of anAngelica gigas–Containing Herbal Formulation: Identification of Decursin as a Novel and Active Compound with Implications for Prevention and Treatment of Prostate Cancer
Authors: Jiang Cheng , Lee Hyo-Jeong , Li Guang-xun , Guo Junming , Malewicz Barbara , Zhao Yan , Lee Eun-Ok , Lee Hyo-Jung , Lee Jae-Ho , Kim Min-Seok , Kim Sung-Hoon , Lu Junxuan
Published: January 2006

Androgen and androgen receptor (AR)–mediated signaling are crucial for the development of prostate cancer. Identification of novel and naturally occurring phytochemicals that target androgen and AR signaling from Oriental medicinal herbs holds exciting promises for the chemoprevention of this disease. In this article, we report the discovery of strong and long-lasting antiandrogen and AR activities of the ethanol extract of a herbal formula (termed KMKKT) containing Korean Angelica gigas Nakai (AGN) root and nine other Oriental herbs in the androgen-dependent LNCaP human prostate cancer cell model. The functional biomarkers evaluated included a suppression of the expression of prostate-specific antigen (PSA) mRNA and protein (IC50, ∼7 μg/mL, 48-hour exposure) and an inhibition of androgen-induced cell proliferation through G1 arrest and of the ability of androgen to suppress neuroendocrine differentiation at exposure concentrations that did not cause apoptosis. Through activity-guided fractionation, we identified decursin from AGN as a novel antiandrogen and AR compound with an IC50 of ∼0.4 μg/mL (1.3 μmol/L, 48-hour exposure) for suppressing PSA expression. Decursin also recapitulated the neuroendocrine differentiation induction and G1 arrest actions of the AGN and KMKKT extracts. Mechanistically, decursin in its neat form or as a component of AGN or KMKKT extracts inhibited androgen-stimulated AR translocation to the nucleus and down-regulated AR protein abundance without affecting the AR mRNA level. The novel antiandrogen and AR activities of decursin and decursin-containing herbal extracts have significant implications for the chemoprevention and treatment of prostate cancer and other androgen-dependent diseases. (Cancer Res 2006; 66(1): 453-63)