bluuebunny/crossref_metadata_2025 huggingface dataset:
Dispersion of passive tracers in the direct enstrophy cascade: Experimental observations
Authors: Jullien Marie-Caroline
Published: July 2003

The paper reports a statistical analysis of the separation of pairs in the enstrophy cascade, in a two-dimensional flow. The flow is produced experimentally, using electromagnetic forcing. Two regimes of separation are found. At early times (i.e., within two integral times) the separation process is exponential, following Lin’s law [J. T. Lin, J. Atmos. Sci. 29, 394 (1972)]. In this range of time, the probability density functions (PDFs) of separations are self-similar in time, developing stretched exponential tails, and one may define a Lagrangian correlation time. Above two integral times, an algebraic regime takes place, with exponential tails for the PDFs of the separations, and self-similar Lagrangian correlation functions. The present work thus confirms the existence of two regimes, by analyzing a number of statistical quantities including the Lagrangian PDF and the temporal Lagrangian correlation functions which so far, were left undetermined for the Batchelor regime.
Stability balloon for the double-lid-driven cavity flow
Authors: Albensoeder S. , Kuhlmann H. C.
Published: July 2003

The linear stability of the two-dimensional, steady, incompressible flow in a rectangular cavity is investigated numerically. The flow is driven by the parallel or antiparallel motion of two facing walls. When the cavity is infinitely extended in the spanwise direction a variety of different, three-dimensional flow instabilities can arise. We provide an overview on the global structure of the critical hypersurface in the three-dimensional parameter space spanned by the cross-sectional aspect ratio and the two side-wall Reynolds numbers. It turns out that the critical hypersurface is made up of six major segments belonging to different modes of instability. The interrelation and connectivity of these critical modes is elucidated.
Laminar-turbulent boundary-layer transition over a rough rotating disk
Authors: Zoueshtiagh F. , Ali R. , Colley A. J. , Thomas P. J. , Carpenter P. W.
Published: July 2003

Boundary-layer transition over a disk spinning under water is investigated. Transitional Reynolds numbers, Rec, and associated boundary-layer velocity profiles are determined from flow-visualizations and hot-film measurements, respectively. The value of Rec and the velocity profiles are studied as a function of the disk’s surface roughness. It is found that transition over rough disks occurs in a similar fashion to that over smooth disks, i.e., abruptly and axisymmetrically at well-defined radii. Wall roughness has little effect on Rec until a threshold relative roughness is reached. Above the threshold Rec decreases sharply. The decrease is consistent with the drop one expects for our flow for the absolute instability discovered by Lingwood [J. Fluid Mech. 299, 17 (1995); 314, 373 (1996); 331, 405 (1997)]. This indicates that the Lingwood absolute instability may continue to play a major role in the transition process even for large relative roughness.
Modeling shock unsteadiness in shock/turbulence interaction
Authors: Sinha Krishnendu , Mahesh Krishnan , Candler Graham V.
Published: July 2003

The RANS (Reynolds averaged Navier–Stokes) equations can yield significant error when applied to practical flows involving shock waves. We use the interaction of homogeneous isotropic turbulence with a normal shock to suggest improvements in the k–ε model applied to shock/turbulence interaction. Mahesh et al. [J. Fluid Mech. 334, 353 (1997)] and Lee et al. [J. Fluid Mech. 340, 22 (1997)] present direct numerical simulation (DNS) and linear analysis of the flow of isotropic turbulence through a normal shock, where it is found that mean compression, shock unsteadiness, pressure-velocity correlation, and up-stream entropy fluctuations play an important role in the interaction. Current RANS models based on the eddy viscosity assumption yield very high amplification of the turbulent kinetic energy, k, across the shock. Suppressing the eddy viscosity in a shock improves the model predictions, but is inadequate to match theoretical results at high Mach numbers. We modify the k equation to include a term due to shock unsteadiness, and model it using linear analysis. The dissipation rate equation is similarly altered based on linear analysis results. These modifications improve the model predictions considerably, and the new model is found to match the linear theory and DNS data well.
Closed-loop Lagrangian separation control in a bluff body shear flow model
Authors: Wang Yong , Haller George , Banaszuk Andrzej , Tadmor Gilead
Published: July 2003

We show how the location of Lagrangian coherent structures, such as unstable manifolds of Lagrangian separation points, can be controlled via feedback control in two-dimensional shear flows. Such control can be used, for instance, to guide fuel transport into designated regions of the flame in a combustor. Motivated by this example, we consider an unsteady vortex model for flow past a bluff body, and create unstable manifolds in this model at prescribed locations by applying control along the boundary. We find that oscillating the newly created unstable manifolds in 1:1 resonance with the von Kármán vortex shedding frequency enhances mixing in the wake significantly.
Streamwise turbulence intensity formulation for flat-plate boundary layers
Authors: Marusic Ivan , Kunkel Gary J.
Published: July 2003

A similarity formulation is proposed to describe the streamwise turbulence intensity across the entire smooth-wall zero-pressure-gradient turbulent boundary layer. The formulation is an extension of the Marusic, Uddin, and Perry [Phys. Fluids 9, 3718 (1997)] formulation that was restricted to the outer region of the boundary layer, including the logarithmic region. The new formulation is found to agree very well with experimental data over a large range of Reynolds numbers varying from laboratory to atmospheric flows. The formulation is founded on physical arguments based on the attached eddy hypothesis, and suggests that the boundary layer changes significantly with Reynolds number, with an outer flow influence felt all the way down to the viscous sublayer. The formulation may also be used to explain why the empirical mixed scaling of DeGraaff and Eaton [J. Fluid Mech. 422, 319 (2000)] appears to work.
Long-lasting photoluminescence in freestanding GaN templates
Authors: Reshchikov M. A. , Iqbal M. Zafar , Morkoç H. , Park S. S. , Lee K. Y.
Published: July 2003

We studied time-resolved photoluminescence (PL) over a temporal range 10−6–103 s in high-purity freestanding GaN templates. Red, yellow, green, blue, and shallow donor–acceptor emission bands can be resolved in the PL spectrum. Observation of luminescence long after the excitation is switched off is a striking feature of our study. The persistent PL observed for all above bands, except for the green band, is primarily attributed to the donor–acceptor-pair-type recombination. An unusually slow, nonexponential decay of radiative transitions from the conduction band to the shallow acceptor was also observed, pointing to some additional mechanism for the persistent PL. Possible role of the surface states in this effect is discussed.
Polymer-induced drag reduction: Effects of the variations in elasticity and inertia in turbulent viscoelastic channel flow
Authors: Housiadas Kostas D. , Beris Antony N.
Published: July 2003

In this work we systematically investigate the effects of the flow elasticity and inertia in polymer-induced drag reduction through (pseudo)spectral simulations of a turbulent channel flow of a dilute polymer solution. Viscoelastic effects are modeled by the finite-extensibility nonlinear elastic dumbbell model with the Peterlin approximation. The present work updates the low Weissenberg results (Weτ0⩽50) reported in earlier works by Sureshkumar et al. [Phys. Fluids 9, 743 (1997)] and Dimitropoulos et al. [J. Non-Newtonian Fluid Mech. 79, 433 (1998)] for a zero shear rate friction Reynolds number, Reτ0=125, by allowing for a lower value for the numerical diffusivity. In addition, we examine two effects on drag reduction: (A) high elasticity, by varying Weτ0 from 62.5 to 125 for a constant Reτ0=125, (B) friction Reynolds number, Reτ0=180, 395, and 590, for a constant Weτ0=50. In the high elasticity region, the mean Reynolds, Remean, continues to increase with increasing Weτ0, albeit at a smaller rate. Thus, the drag reduction achieved at the highest Weτ0 number, Weτ0=125, is about 37.5%, as compared to about 30% for Weτ0=50. On the other hand, the percent drag reduction remains virtually unchanged as Reτ0 is increased to 180, 395, and 590 for a constant Weτ0=50. Increasing the friction Reynolds number while keeping the friction Weissenberg number constant, does affect the detailed turbulent statistics. However, the boundary and the buffer layers approach an asymptote at a friction Reynolds number of 395 as it has also been observed in the Newtonian limit. The effect of variations in the computational domain, mesh resolution and the numerical diffusivity on the turbulent statistics is also reported.
Magneto-optical characteristics of magnetic nanowire arrays in anodic aluminum oxide templates
Authors: Peng Yong , Shen T.-H. , Ashworth Brian , Zhao Xue-Gen , Faunce Chester A. , Liu Yan-Wei
Published: July 2003

Nanocomposite films consisting of regularly ordered iron nanowires embedded in anodic aluminum oxide templates have been fabricated and their magneto-optical properties studied by determining the four Stokes parameters of the transmitted laser beam (λ=670 nm), originally linearly polarized and at normal incidence to the film surfaces. The results of the nanowire arrays are found to be considerably different from that of bulk iron. While an increase in diameter of the nanowire leads to a substantial increase in the values of the Faraday rotation angles per unit length at a fixed value of the magnetic fields, they are substantially less than that of bulk iron, indicating that the effective media theory may not be directly applicable.
Materials dependence of the spin-momentum transfer efficiency and critical current in ferromagnetic metal/Cu multilayers
Authors: Pufall M. R. , Rippard W. H. , Silva T. J.
Published: July 2003

We have quantitatively compared spin-momentum transfer effects in FM/Cu multilayers, with FM=Co, Co90Fe10, Ni80Fe20, Ni40Fe10Cu50, and Fe. All of the measured multilayers exhibited an abrupt step up in resistance at a critical current Ic, the value of which was a linear function of applied magnetic field Happ. The spin-transfer efficiencies determined from these data were in substantial agreement with their predicted values over the range of materials studied. Ic(Happ), when evaluated at zero net field, was found to increase with the exchange energy density of the ferromagnet, demonstrating the tunability of the critical current by materials selection.
Nanosecond time-resolved Raman spectroscopy on phase transition of polytetrafluoroethylene under laser-driven shock compression
Authors: Nagao H. , Matsuda A. , Nakamura K. G. , Kondo K.
Published: July 2003

Nanosecond time-resolved Raman spectroscopy is performed on polytetrafluoroethylene (PTFE) under laser shock compression at approximately 1 GPa. Blueshifts (8 cm−1) of a C–C stretching and redshifts (−8 cm−1) of a CF2 twisting in Raman spectrum due to a high-pressure phase (phase III) are observed. High-pressure phase transition to phase III of PTFE is suggested to occur within 10 ns.
A model for the evolution of turbulent bulges
Authors: Sun Meihong , Lichter Seth
Published: July 2003

It is shown that vortices rising through a high-Reynolds number boundary layer can interact with the mean shear so as to yield a localized structure similar to the bulges seen in turbulent boundary layers. These bulges evolve so as to entrain irrotational flow into the boundary layer. It is also shown that vortices can initiate the evolution of detrainment, in which rotational fluid is ejected into the outer flow. The results of this work support the idea that horseshoe vortices can lead to the evolution of large-scale structure in the boundary layer.
Fabrication of 1.4-kV mesa-type p+–n diodes with avalanche breakdown and without forward degradation on high-quality 6H-SiC substrate
Authors: Tanaka Yasunori , Nishizawa Shin-ichi , Fukuda Kenji , Arai Kazuo , Ohno Toshiyuki , Oyanagi Naoki , Suzuki Takaya , Yatsuo Tsutomu
Published: July 2003

Using our own substrate growth and epitaxial growth techniques, we fabricated a 1.4-kV mesa-type 6H-SiC p+–n diode with an ideal avalanche breakdown and without forward degradation. The 6H-SiC substrates were grown on Lely crystals with no micropipes and only minimal defects. A p+–n junction was fabricated by chemical vapor deposition with p+/n− epitaxial films. We obtained 1.4-kV breakdown voltage, consistent with the ideal breakdown voltage calculated from the thickness and doping concentration of the drift layer. The application of 200-A/cm2 current stress in the forward direction produced no degradation, which is often observed with p–n diodes on normal substrates.
Refraction as imaging signal for computerized (neutron) tomography
Authors: Treimer W. , Strobl M. , Hilger A. , Seifert C. , Feye-Treimer U.
Published: July 2003

Refraction of thermal neutrons was used as imaging signal for computerized neutron tomography. Using a special instrument, attenuation and refraction could be observed simultaneously, extracted and separated from each other, and two-dimensional (2D) images reconstructed from pure refraction data. Even in the case of no attenuation contrast, perfect 2D images of objects could be reconstructed using the refraction data only.
Photonic crystal waveguides with multiple 90° bends
Authors: Roh Young-Geun , Yoon Sungjoon , Kim Sunghwan , Jeon Heonsu , Han Seung-Ho , Park Q-Han , Park Inkyu
Published: July 2003

In order to emphasize and demonstrate the importance of light confinement in the vertical direction, an otherwise ordinary two-dimensional photonic crystal waveguide structure operating at microwave frequencies was sandwiched between two metal plates. Such waveguides exhibited excellent guiding properties despite the existence of multiple 90° bends. From the experimental data, we have estimated that the propagation velocity of the waveguide is about 0.47 c, regardless of the number of bends, and that the bending loss is only 0.1 dB per bend.
AlGaAs superlattice microcoolers
Authors: Zhang Jizhi , Anderson Neal G. , Lau Kei May
Published: July 2003

AlGaAs-based superlattice microcoolers are demonstrated. Maximum cooling temperatures of 0.8 °C and 2 °C were obtained at 25 °C and 100 °C, respectively, from 60 μm×60 μm devices with 100 period Al0.10Ga0.90As/Al0.20Ga0.80As n-type superlattice thermal barriers. These devices may be useful for in situ cooling of GaAs-based microelectronic and optoelectronic devices.
Resonant optical nonlinearities from intersubband transitions in GaN/AlN quantum wells
Authors: Rapaport R. , Chen Gang , Mitrofanov O. , Gmachl C. , Ng H. M. , Chu S. N. G.
Published: July 2003

We measured the resonant nonlinear optical response of the intersubband transitions in GaN/AlGaN multiple quantum well structures. The measured value for the nonlinear susceptibility is found to be much smaller than previous theoretical predictions. This is attributed to a large electron dephasing due to material imperfections. We show that at higher incident intensities, absorption saturation is possible, and measure the saturation intensity for various wavelengths around the transition resonance. We also discuss the prospects of using such structures as building blocks for all-optical nonlinear switches, in light of our experimental findings.
Radial distribution of attenuation in gamma-irradiated single-mode optical fibers
Authors: Girard S. , Trenteseaux I. , Ouerdane Y. , Meunier J.-P. , Boukenter A. , Derep J.-L. , Thonnérieux L.
Published: July 2003

In this letter, a method to determine the radial distribution of attenuation in single-mode optical fibers is proposed. This method is based on guided mode power and loss measurements for different fiber packaging. The most accurate radial attenuation distribution is calculated from experimental results. This approach allows localizing the absorbing or scattering defects along the radial cross section of fibers. As an example, a γ-irradiated germanosilicate fiber is studied at three different wavelengths. Through correlation with fiber chemical analysis, the contributions of each dopant to the permanent radiation-induced losses can be identified and quantified. At 980 nm, phosphorus-related color centers are the origin of induced losses, whereas for shorter wavelengths the influence of germanium-related color centers on fiber behavior becomes dominant.
Patterning damage in narrow trackwidth spin-valve sensors
Authors: Katine J. A. , Ho Michael K. , Ju Yongho Sungtaek , Rettner C. T.
Published: July 2003

Using a combination of electron-beam lithography and Ar ion milling, we have fabricated spin-valve sensors with widths ranging from 30 to 250 nm. Although the resistance of the sensors scales as expected with width, the giant magnetoresistance (GMR) ratio decreases with decreasing width, consistent with the presence of a region with negligible GMR at the edges of the sensors. Sensors patterned using a focused ion beam showed a similar but much greater effect. We attribute this behavior to edge damage associated with the patterning process.
Optimizing and quantifying dopant mapping using a scanning electron microscope with a through-the-lens detector
Authors: Schönjahn C. , Broom R. F. , Humphreys C. J. , Howie A. , Mentink S. A. M.
Published: July 2003

Although dopant contrast in the scanning electron microscope has been known for a long time, its quantification is still a matter of debate mainly due to the lack of understanding of the contrast mechanism. Here we show that dopant contrast can be usefully increased at low extraction voltages. The effect may be related to the different angular and energy distribution of secondary electrons emitted from the p and n regions and for quantitative work should be studied over the full range of extraction potential.
Atom mirror etched from a hard drive
Authors: Lev Benjamin , Lassailly Yves , Lee Chungsok , Scherer Axel , Mabuchi Hideo
Published: July 2003

We describe the fabrication of an atom mirror by etching of a common hard drive, and we report the observation of specular retroreflection of 11 μK cesium atoms using this mirror. The atoms were trapped and cooled above the hard drive using the mirror magneto-optical trap technique, and upon release, two full bounces were detected. The hard drive atom mirror will be a useful tool for both atom optics and quantum computation.
Effect of Zr concentration on the microstructure of Al and the magnetoresistance properties of the magnetic tunnel junction with a Zr-alloyed Al–oxide barrier
Authors: Lee Seong-Rae , Choi Chul-Min , Kim Young Keun
Published: July 2003

We studied the composition dependence of the microstructure of Al–Zr alloy films and the tunneling magnetoresistance (TMR) behavior of magnetic tunnel junctions (MTJ) with a Zr-alloyed Al–oxide barrier. A highly stable MTJ with a superior-quality 9.89 at. % Zr alloyed Al–oxide barrier was achieved with 39.5% TMR and a bias voltage of 711 mV at half (Vh) TMR. The microstructure of Al changed systematically from polycrystalline to single phase amorphous to duplex phases composed of an amorphous Al–Zr phase and a crystalline AlZr compound, probably Al3Zr, as the Zr concentration increased. The microstructure of the Al–Zr alloy before oxidation has a dominant effect on the TMR characteristics and MTJ stability. A single amorphous Al–Zr alloy (∼10 at. % Zr) film has superior surface uniformity; consequently, an ultrahigh-quality oxide barrier was formed after oxidation.
Ultraintense light filaments transmitted through clouds
Authors: Courvoisier François , Boutou Véronique , Kasparian Jérôme , Salmon Estelle , Méjean Guillaume , Yu Jin , Wolf Jean-Pierre
Published: July 2003

We demonstrate that ultrashort and ultraintense light filaments survive their interaction with water droplets as large as 95 μm and that they are transmitted through water clouds having an optical thickness as high as 3.2 (transmission 5%). In contrast with linear optics, this remarkable transmission through optically dense media results from a dynamic energy balance between the quasisolitonic structure and the surrounding laser photon bath, which acts as an energy reservoir. Implications for free-space laser communications, remote sensing, and telemetry are discussed.
Effect of polycrystalline-silicon gate types on the opposite flatband voltage shift in n-type and p-type metal–oxide–semiconductor field-effect transistors for high-k-HfO2 dielectric
Authors: Yang C. W. , Fang Y. K. , Chen C. H. , Chen S. F. , Lin C. Y. , Lin C. S. , Wang M. F. , Lin Y. M. , Hou T. H. , Chen C. H. , Yao L. G. , Chen S. C. , Liang M. S.
Published: July 2003

Hafnium dioxide (HfO2) gate dielectrics formed by the atomic layer deposition (ALD) process were fabricated to investigate the flatband voltage shift (ΔVFB) relative to SiO2. It is found that the direction of ΔVFB depends on the Fermi level position in the gate material, which shows respective positive and negative shifts in n-type and p-type metal–oxide–semiconductor field-effect transistors (MOSFETs), regardless of the substrate type. The opposite direction in the flatband voltage shift is attributed to both acceptor- and donor-like interface states existing at the interface between the polycrystalline-silicon (poly-Si) gate and HfO2 dielectric. A model is proposed to explain the effects of poly-Si gate type on the flatband voltage shift in MOSFETs.
Simultaneous cw red, yellow, and green light generation, “traffic signal lights,” by frequency doubling and sum-frequency mixing in an aperiodically poled LiTaO3
Authors: He Jing-Liang , Liao Jun , Liu Hui , Du Juan , Xu Fei , Wang Hui-Tian , Zhu S. N. , Zhu Y. Y. , Ming N. B.
Published: July 2003

We demonstrate simultaneously efficient generation of cw red, yellow, and green coherent radiations, “traffic signal lights,” by multifrequency conversions from a diode-pumped Nd:YVO4 dual-wavelength laser with a single-pass aperiodically poled LiTaO3. The 1.8 mW red at 671 nm and 0.64 mW green at 532 nm are, respectively, generated by frequency doubling of fundamental waves at 1342 and 1064 nm, and 0.79 mW yellow at 593 nm is produced by sum-frequency mixing of the two fundamental waves, under two fundamental waves of 970 mW at 1342 nm and 940 mW at 1064 nm.
Fabrication of oriented polymeric nanofibers on planar surfaces by electrospinning
Authors: Kameoka Jun , Craighead H. G.
Published: July 2003

We present a method for the formation of oriented polymeric nanofibers using electrospinning deposition from an integrated microfluidic device. The source includes a microfabricated triangular shaped tip, integrated at the exit of a microfluidic channel to form a source that can be brought close to a counter electrode and scanned over surface features. Using the ability to orient the nanofiber deposition, we formed a 140 nm diameter suspended nanofiber over etched trenches on a silicon wafer, a configuration that allows for electrical and mechanical measurements of deposited nanofibers.
The filtering analog of the variational multiscale method in large-eddy simulation
Authors: Vreman A. W.
Published: July 2003

The variational multiscale method introduced by Hughes et al. [Comput. Visual. Sci. 3, 47 (2000)] is extended to the classic filtering approach in large-eddy simulation. The role of the Germano identity in the formulation is precisely indicated. Multiscale methods based on standard eddy-viscosity models are related to (anisotropic) hyperviscosity models under certain conditions. Several models are tested and found to be as accurate as the standard dynamic model, while the implementations are more simple. Finally, the turbulent stress tensor is reformulated, such that filter and derivative in the filtered equations can be treated as a single operator.
𝑡–analogs of 𝑞–characters of Kirillov-Reshetikhin modules of quantum affine algebras
Authors: Nakajima Hiraku
Published: July 2003

We prove the Kirillov-Reshetikhin conjecture concerning certain finite dimensional representations of a quantum affine algebra

U

q

(

g

^

)

{\mathbf U}_q(\widehat {\mathfrak g})

when

g

^

\widehat {\mathfrak g}

is an untwisted affine Lie algebra of type

A
D
E

ADE

. We use

t
t

–analog of

q
q

–characters introduced by the author in an essential way.
Methods for optimizing antiviral combination therapies
Authors: Beerenwinkel Niko , Lengauer Thomas , Däumer Martin , Kaiser Rolf , Walter Hauke , Korn Klaus , Hoffmann Daniel , Selbig Joachim
Published: July 2003

Motivation: Despite some progress with antiretroviral combination therapies, therapeutic success in the management of HIV-infected patients is limited. The evolution of drug-resistant genetic variants in response to therapy plays a key role in treatment failure and finding a new potent drug combination after therapy failure is considered challenging.

Results: To estimate the activity of a drug combination against a particular viral strain, we develop a scoring function whose independent variables describe a set of antiviral agents and viral DNA sequences coding for the molecular targets of the respective drugs. The construction of this activity score involves (1) predicting phenotypic drug resistance from genotypes for each drug individually, (2) probabilistic modeling of predicted resistance values and integration into a score for drug combinations, and (3) searching through the mutational neighborhood of the considered strain in order to estimate activity on nearby mutants. For a clinical data set, we determine the optimal search depth and show that the scoring scheme is predictive of therapeutic outcome. Properties of the activity score and applications are discussed.

Contact: beerenwinkel@mpi-sb.mpg.de

*To whom correspondence should be addressed.

Keywords: HIV, antiretroviral therapy, drug resistance, SVM regression, therapy optimization, sequence space search.
Remote homology detection: a motif based approach
Authors: Ben-Hur Asa , Brutlag Douglas
Published: July 2003

Motivation: Remote homology detection is the problem of detecting homology in cases of low sequence similarity. It is a hard computational problem with no approach that works well in all cases.

Results: We present a method for detecting remote homology that is based on the presence of discrete sequence motifs. The motif content of a pair of sequences is used to define a similarity that is used as a kernel for a Support Vector Machine (SVM) classifier. We test the method on two remote homology detection tasks: prediction of a previously unseen SCOP family and prediction of an enzyme class given other enzymes that have a similar function on other substrates. We find that it performs significantly better than an SVM method that uses BLAST or Smith-Waterman similarity scores as features.

Availability: The software is available from the authors upon request.

Contact: asa.benhur@stanford.edu

Keywords: remote homology, discrete sequence motifs, sequence similarity, Support Vector Machines, kernel methods

*To whom correspondence should be addressed.
SNP and mutation discovery using base-specific
cleavage and MALDI-TOF mass spectrometry
Authors: Böcker Sebastian
Published: July 2003

Motivation: Single Nucleotide Polymorphisms (SNPs) are believed to contribute strongly to the genetic variability in living beings, in particular their disease or drug side effect predispositions. Mutation-induced sequence variations are playing an important role in the development of cancer, among others. From this, it is clear that SNP and mutation discovery is of great interest in today’s Life Sciences. Currently, such discovery is often performed utilizing electrophoresis-based Sanger Sequencing. Discovery of SNPs can also be performed by multiple sequence alignment of publicly available sequence data, but recent studies indicate that only a small percentage of SNPs can be discovered using this approach and, in particular, that SNPs with low frequency are often missed. Other SNP discovery methods only indicate the presence of a SNP in a sample region, but fail to resolve its characterization and localization.

Results: We present a method to discover mutations and SNPs using base-specific cleavage and mass spectrometry. An amplicon of known reference sequence with length usually between 100 and 1000 nt is amplified, transcribed, and cleaved using base-specific endonucleases such as RNAse A or T1. The resulting cleavage products (or fragments) are analyzed by MALDI-TOF mass spectrometry and, comparing the measured spectra with those predicted in-silico, the goal is to discover and pinpoint sequence variations of the sample sequence compared to the reference sequence. A time-efficient algorithm for discovering sequence variations is presented that enables fast analysis of such variations even if the sample sequence differs significantly from the reference sequence.

Contact: boecker@CeBiTec.uni-bielefeld.de

*Currently at AG Genome Informatics, Technische Fakultät, Universität Bielefeld, Germany.
Combining multiple microarray studies and modeling interstudy variation
Authors: Choi Jung Kyoon , Yu Ungsik , Kim Sangsoo , Yoo Ook Joon
Published: July 2003

We have established a method for systematic integration of multiple microarray datasets. The method was applied to two different sets of cancer profiling studies. The change of gene expression in cancer was expressed as ’ effect size’, a standardized index measuring the magnitude of a treatment or covariate effect. The effect sizes were combined to obtain the estimate of the overall mean. The statistical significance was determined by a permutation test extended to multiple datasets. It was shown that the data integration promotes the discovery of small but consistent expression changes with increased sensitivity and reliability. The effect size methods provided the efficient modeling framework for addressing interstudy variation as well. Based on the result of homogeneity tests, a fixed effects model was adopted for one set of datasets that had been created in controlled experimental conditions. By contrast, a random effects model was shown to be appropriate for the other set of datasets that had been published by independent groups. We also developed an alternative modeling procedure based on a Bayesian approach, which would offer flexibility and robustness compared to the classical procedure.

Contact: jkchoi@kaist.ac.kr

Keywords: microarray, meta-analysis, effect size, Bayesian meta-analysis

*To whom correspondence should be addressed.
Combining NLP and probabilistic categorisation for
document and term selection for Swiss-Prot medical annotation
Authors: Dobrokhotov Pavel B. , Goutte Cyril , Veuthey Anne-Lise , Gaussier Eric
Published: July 2003

Motivation: Searching relevant publications for manual database annotation is a tedious task. In this paper, we apply a combination of Natural Language Processing (NLP) and probabilistic classification to re-rank documents returned by PubMed according to their relevance to Swiss-Prot annotation, and to identify significant terms in the documents.

Results: With a Probabilistic Latent Categoriser (PLC) we obtained 69% recall and 59% precision for relevant documents in a representative query. As the PLC technique provides the relative contribution of each term to the final document score, we used the Kullback-Leibler symmetric divergence to determine the most discriminating words for Swiss-Prot medical annotation. This information should allow curators to understand classification results better. It also has great value for fine-tuning the linguistic pre-processing of documents, which in turn can improve the overall classifier performance.

Availability: The medical annotation dataset is available from the authors upon request

Contact: Pavel.Dobrokhotov@isb-sib.ch; Cyril.Goutte@xrce.xerox.com

*To whom correspondence should be addressed.
Protein structure prediction via combinatorial assembly of sub-structural units
Authors: Inbar Yuval , Benyamini Hadar , Nussinov Ruth , Wolfson Haim J.
Published: July 2003

Following the hierarchical nature of protein folding, we propose a three-stage scheme for the prediction of a protein structure from its sequence. First, the sequence is cut to fragments that are each assigned a structure. Second, the assigned structures are combinatorially assembled to form the overall 3D organization. Third, highly ranked predicted arrangements are completed and refined. This work focuses on the second stage of this scheme: the combinatorial assembly. We present CombDock, a combinatorial docking algorithm. CombDock gets an ordered set of protein sub-structures and predicts the inter-contacts that define their overall organization. We reduce the combinatorial assembly to a graph-theory problem, and give a heuristic polynomial solution to this computationally hard problem. We applied CombDock to various examples of structural units of two types: protein domains and building blocks, which are relatively stable sub-structures of domains. Moreover, we tested CombDock using increasingly distorted input, where the native structural units were replaced by similarly folded units extracted from homologous proteins and, in the more difficult cases, from globally unrelated proteins. The algorithm is robust, showing low sensitivity to input distortion. This suggests that CombDock is a useful tool in protein structure prediction that may be applied to large target proteins.

Supplementary information: More tables and figures are available at www.cs.tau.ac.il/~inbaryuv/combdock/

Contact: inbaryuv@tau.ac.il

Keywords: structure prediction, multiple docking, hierarchical model, combinatorial assembly.

*To whom correspondence should be addressed.
Talisman—rapid application development for the grid
Authors: Oinn Thomas M.
Published: July 2003

In order to make use of the emerging grid and network services offered by various institutes and mandated by many current research projects, some kind of user accessible client is required. In contrast with attempts to build generic workbenches, Talisman is designed to allow a bioinformatics expert to rapidly build custom applications, immediately visible using standard web technology, for users who wish to concentrate on the biology of their problem rather than the informatics aspects. As a component of the MyGrid project, it is intended to allow access to arbitrary resources, including but not limited to relational, object and flat file data sources, analysis programs and grid based storage, tracking and distributed annotation systems.

Contact: tmo@ebi.ac.uk
Using hidden Markov models to analyze gene expression time course data
Authors: Schliep Alexander , Schönhuth Alexander , Steinhoff Christine
Published: July 2003

Motivation: Cellular processes cause changes over time. Observing and measuring those changes over time allows insights into the how and why of regulation. The experimental platform for doing the appropriate large-scale experiments to obtain time-courses of expression levels is provided by microarray technology. However, the proper way of analyzing the resulting time course data is still very much an issue under investigation. The inherent time dependencies in the data suggest that clustering techniques which reflect those dependencies yield improved performance.

Results: We propose to use Hidden Markov Models (HMMs) to account for the horizontal dependencies along the time axis in time course data and to cope with the prevalent errors and missing values. The HMMs are used within a model-based clustering framework. We are given a number of clusters, each represented by one Hidden Markov Model from a finite collection encompassing typical qualitative behavior. Then, our method finds in an iterative procedure cluster models and an assignment of data points to these models that maximizes the joint likelihood of clustering and models.

Partially supervised learning—adding groups of labeled data to the initial collection of clusters—is supported. A graphical user interface allows quering an expression profile dataset for time course similar to a prototype graphically defined as a sequence of levels and durations. We also propose a heuristic approach to automate determination of the number of clusters.

We evaluate the method on published yeast cell cycle and fibroblasts serum response datasets, and compare them, with favorable results, to the autoregressive curves method.

Availability: The software is freely available at http://algorithmics.molgen.mpg.de/ghmm

Contact: schliep@molgen.mpg.de

Keywords: Gene Expression, time course, model-based clustering, Hidden Markov Models

*To whom correspondence should be addressed.
Gene structure-based splice variant deconvolution using a microarry platform
Authors: Wang Hui , Hubbell Earl , Hu Jing-shan , Mei Gangwu , Cline Melissa , Lu Gang , Clark Tyson , Siani-Rose Michael A. , Ares Manuel , Kulp David C. , Haussler David
Published: July 2003

Motivation: Alternative splicing allows a single gene to generate multiple mRNAs, which can be translated into functionally and structurally diverse proteins. One gene can have multiple variants coexisting at different concentrations. Estimating the relative abundance of each variant is important for the study of underlying biological function. Microarrays are standard tools that measure gene expression. But most design and analysis has not accounted for splice variants. Thus splice variant-specific chip designs and analysis algorithms are needed for accurate gene expression profiling.

Results: Inspired by Li and Wong (2001), we developed a gene structure-based algorithm to determine the relative abundance of known splice variants. Probe intensities are modeled across multiple experiments using gene structures as constraints. Model parameters are obtained through a maximum likelihood estimation (MLE) process/framework. The algorithm produces the relative concentration of each variant, as well as an affinity term associated with each probe. Validation of the algorithm is performed by a set of controlled spike experiments as well as endogenous tissue samples using a human splice variant array.

Contact: hui_wang@affymetrix.com

*To whom correspondence should be addressed.
rpoN, mmoR and mmoG, genes involved in regulating the expression of soluble methane monooxygenase in Methylosinus trichosporium OB3b
Authors: Stafford Graham P. , Scanlan Julie , McDonald Ian R. , Murrell J. Colin
Published: July 2003

The methanotrophic bacteriumMethylosinus trichosporiumOB3b converts methane to methanol using two distinct forms of methane monooxygenase (MMO) enzyme: a cytoplasmic soluble form (sMMO) and a membrane-bound form (pMMO). The transcription of these two operons is known to proceed in a reciprocal fashion with sMMO expressed at low copper-to-biomass ratios and pMMO at high copper-to-biomass ratios. Transcription of thesmmooperon is initiated from aσNpromoter 5′ ofmmoX. In this study the genes encodingσN(rpoN) and a typicalσN-dependent transcriptional activator (mmoR) were cloned and sequenced.mmoR, a regulatory gene, andmmoG, a gene encoding a GroEL homologue, lie 5′ of the structural genes for the sMMO enzyme. Subsequent mutation ofrpoNandmmoRby marker-exchange mutagenesis resulted in strains Gm1 and JS1, which were unable to express functional sMMO or initiate transcription ofmmoX. AnrpoNmutant was also unable to fix nitrogen or use nitrate as sole nitrogen source, indicating thatσNplays a role in both nitrogen and carbon metabolism inMs. trichosporiumOB3b. The data also indicate thatmmoGis transcribed in aσN- and MmoR-independent manner. Marker-exchange mutagenesis ofmmoGrevealed that MmoG is necessary forsmmogene transcription and activity and may be an MmoR-specific chaperone required for functional assembly of transcriptionally competent MmoRin vivo. The data presented allow the proposal of a more complete model for copper-mediated regulation ofsmmogene expression.
Genes involved in the copper-dependent regulation of soluble methane monooxygenase of Methylococcus capsulatus (Bath): cloning, sequencing and mutational analysis
Authors: Csáki Róbert , Bodrossy Levente , Klem József , Murrell J. Colin , Kovács Kornél L.
Published: July 2003

The key enzyme in methane metabolism is methane monooxygenase (MMO), which catalyses the oxidation of methane to methanol. Some methanotrophs, includingMethylococcus capsulatus(Bath), possess two distinct MMOs. The level of copper in the environment regulates the biosynthesis of the MMO enzymes in these methanotrophs. Under low-copper conditions, soluble MMO (sMMO) is expressed and regulation takes place at the level of transcription. The structural genes of sMMO were previously identified asmmoXYBZ,mmoDandmmoC. Putative transcriptional start sites, containing aσ70- and aσN-dependent motif, were identified in the 5′ region ofmmoX. The promoter region ofmmoXwas mapped using truncated 5′ end regions fused to a promoterless green fluorescent protein gene. A 9·5 kb region, adjacent to the sMMO structural gene cluster, was analysed. Downstream (3′) from the last gene of the operon,mmoC, four ORFs were found,mmoG,mmoQ,mmoSandmmoR.mmoGshows significant identity to the large subunit of the bacterial chaperonin gene,groEL. In the opposite orientation, two genes,mmoQandmmoS, showed significant identity to two-component sensor–regulator system genes. Next tommoS, a gene encoding a putativeσN-dependent transcriptional activator,mmoRwas identified. ThemmoGandmmoRgenes were mutated by marker-exchange mutagenesis and the effects of these mutations on the expression of sMMO was investigated. sMMO transcription was impaired in both mutants. These results indicate thatmmoGandmmoRare essential for the expression of sMMO inMc. capsulatus(Bath).
The paradoxical cyanide-stimulated respiration of Zymomonas mobilis: cyanide sensitivity of alcohol dehydrogenase (ADH II)
Authors: Kalnenieks Uldis , Toma Malda M. , Galinina Nina , Poole Robert K.
Published: July 2003

The respiratory inhibitor cyanide stimulates growth of the ethanologenic bacteriumZymomonas mobilis, perhaps by diverting reducing equivalents from respiration to ethanol synthesis, thereby minimizing accumulation of toxic acetaldehyde. This study sought to identify cyanide-sensitive components of respiration. In aerobically grown, permeabilizedZ. mobiliscells, addition of 200 μM cyanide caused gradual inhibition of ADH II, the iron-containing alcohol dehydrogenase isoenzyme, which, in aerobic cultures, might be oxidizing ethanol and supplying NADH to the respiratory chain. In membrane preparations, NADH oxidase was inhibited more rapidly, but to a lesser extent, than ADH II. The time-course of inhibition of whole-cell respiration resembled that of NADH oxidase, yet the inhibition was almost complete, and was accompanied by an increase of intracellular NADH concentration. Cyanide did not significantly affect the activity of ADH I, the zinc-containing alcohol dehydrogenase isoenzyme. When an aerobic batch culture was grown in the presence of 200 μM cyanide, cyanide-resistant ADH II activity was observed, its appearance correlating with the onset of respiration. It is concluded that the membrane-associated respiratory chain, but not ADH II, is responsible for the whole-cell cyanide sensitivity, while the cyanide-resistant ADH II is needed for respiration in the presence of cyanide, and represents an adaptive response ofZ. mobilisto cyanide, analogous to the induction of alternative terminal oxidases in other bacteria.
Incorporation of iron into Tritrichomonas foetus cell compartments reveals ferredoxin as a major iron-binding protein in hydrogenosomes
Authors: Suchan Pavel , Vyoral Daniel , Petrák Jiří , Šut'ák Robert , Rasoloson Dominique , Nohýnková Eva , Doležal Pavel , Tachezy Jan
Published: July 2003

The intracellular transport of iron and its incorporation into organelles are poorly understood processes in eukaryotes and virtually unknown in parasitic protists. The transport of iron is of particular interest in trichomonads, which possess hydrogenosomes instead of mitochondria. The metabolic functions of hydrogenosomes, which contain a specific set of FeS proteins, entirely depend on iron acquisition. In this work the incorporation of iron into the cattle parasiteTritrichomonas foetuswas monitored. Iron was efficiently taken up from59Fe-nitrilotriacetic acid and accumulated in the cytosol (88·9 %) and hydrogenosomes (4·7 % of the total radioactivity). Using atomic absorption spectrophotometry, an unusually high steady-state iron concentration in hydrogenosomes was determined [54·4±1·1 nmol Fe (mg protein)−1]. The concentration of iron in the cytosol was 13·4±0·5 nmol Fe (mg protein)−1. Qualitative analysis of incorporated iron was performed using native gradient PAGE. The majority of the59Fe in the cytosol appeared as the labile-iron pool, which represents weakly bound iron associated with compounds of molecular mass ranging from 5000 to 30 000 Da. Ferritin was not observed inTt. foetus, nor in two other anaerobic protists,Entamoeba histolyticaandGiardia intestinalis. Analysis ofTt. foetushydrogenosomes showed at least nine iron-binding compounds, which were absent in metronidazole-resistant mutants. The major iron-binding compound was identified as [2Fe–2S] ferredoxin of the adrenodoxin type.
Genetic dissection of trehalose biosynthesis in Corynebacterium glutamicum: inactivation of trehalose production leads to impaired growth and an altered cell wall lipid composition
Authors: Tzvetkov Mladen , Klopprogge Corinna , Zelder Oskar , Liebl Wolfgang
Published: July 2003

The analysis of the availableCorynebacteriumgenome sequence data led to the proposal of the presence of all three known pathways for trehalose biosynthesis in bacteria, i.e. trehalose synthesis from UDP-glucose and glucose 6-phosphate (OtsA-OtsB pathway), from malto-oligosaccharides orα-1,4-glucans (TreY-TreZ pathway), or from maltose (TreS pathway). Inactivation of only one of the three pathways by chromosomal deletion did not have a severe impact onC. glutamicumgrowth, while the simultaneous inactivation of the OtsA-OtsB and TreY-TreZ pathway or of all three pathways resulted in the inability of the corresponding mutants to synthesize trehalose and to grow efficiently on various sugar substrates in minimal media. This growth defect was largely reversed by the addition of trehalose to the culture broth. In addition, a possible pathway for glycogen synthesis from ADP-glucose involving glycogen synthase (GlgA) was discovered.C. glutamicumwas found to accumulate significant amounts of glycogen when grown under conditions of sugar excess. Insertional inactivation of the chromosomalglgAgene led to the failure ofC. glutamicumcells to accumulate glycogen and to the abolition of trehalose production in a ΔotsABbackground, demonstrating that trehalose production via the TreY-TreZ pathway is dependent on a functional glycogen biosynthetic route. The trehalose-non-producing mutant with inactivated OtsA-OtsB and TreY-TreZ pathways displayed an altered cell wall lipid composition when grown in minimal broth in the absence of trehalose. Under these conditions, the mutant lacked both major trehalose-containing glycolipids, i.e. trehalose monocorynomycolate and trehalose dicorynomycolate, in its cell wall lipid fraction. The results suggest that a dramatically altered cell wall lipid bilayer of trehalose-lessC. glutamicummutants may be responsible for the observed growth deficiency of such strains in minimal medium. The results of the genetic and physiological dissection of trehalose biosynthesis inC. glutamicumreported here may be of general relevance for the whole phylogenetic group of mycolic-acid-containing coryneform bacteria.