bluuebunny/crossref_metadata_2025 huggingface dataset:
Observation of the low to high confinement transition in the large helical device
Authors: Toi K. , Ohdachi S. , Yamamoto S. , Sakakibara S. , Narihara K. , Tanaka K. , Morita S. , Morisaki T. , Goto M. , Takagi S. , Watanabe F. , Nakajima N. , Watanabe K. Y. , Ida K. , Ikeda K. , Inagaki S. , Kaneko O. , Kawahata K. , Komori A. , Masuzaki S. , Matsuoka K. , Miyazawa J. , Nagaoka K. , Nagayama Y. , Oka Y. , Osakabe M. , Ohyabu N. , Takeiri Y. , Tokuzawa T. , Tsumori K. , Yamada H. , Yamada I. , Yoshinuma K. , Group LHD Experimental
Published: January 2005

The low to high confinement transition has been observed on the large helical device [A. Iiyoshi, A. Komori, A. Ejiri et al., Nucl. Fusion 39, 1245 (1999)], exhibiting rapid increase in edge electron density with sharp depression of Hα emission. The transition occurs in low toroidal field (Bt=0.5–0.75T) discharges and are heated by high power neutral beam injection. The plasma thus has a relatively high value (∼1.5%) of the volume averaged β value. The electron temperature and density profiles have steep gradients at the edge region which has high magnetic shear but is at a magnetic hill. Formation of the edge transport barrier leads to enhanced activities of the interchange type of modes with m=2∕n=3 (m,n are the poloidal and toroidal mode numbers) in the edge region. At present, these magnetohydrodynamic activities limit the rise of the stored energy; the resultant increment of the stored energy remains modest.
Centroid motion in periodically focused beams
Authors: Moraes J. S. , Pakter R. , Rizzato F. B.
Published: January 2005

The role of the centroid dynamics in the transport of periodically focused particle beams is investigated. A Kapchinskij–Vladimirskij equilibrium distribution for an off-axis beam is derived. It is shown that centroid and envelope dynamics are uncoupled and that unstable regions for the centroid dynamics overlap with previously stable regions for the envelope dynamics alone. Multiparticle simulations validate the findings. The effects of a conducting pipe encapsulating the beam are also investigated. It is shown that the charge induced at the pipe may generate chaotic orbits which can be detrimental to the adequate functioning of the transport mechanism.
Kinetic theory for non-Hermitian dynamics of waves in shear flow
Authors: Yoshida Z.
Published: January 2005

Fluctuations in an ambient shear flow obey “non-Hermitian” evolution equations, and hence, the conventional kinetic equation for waves does not apply. Introducing a time-dependent effective mass (modeling the phase-mixing effect) and a potential term (including the stretching effect), we may cast the wave equation in a Hamiltonian form, which allows us to formulate a kinetic equation that can capture the nonconservative nature of a shear-flow system.
Stokes’ first problem for an Oldroyd-B fluid in a porous half space
Authors: Tan Wenchang , Masuoka Takashi
Published: January 2005

Based on a modified Darcy’s law for a viscoelastic fluid, Stokes’ first problem was extended to that for an Oldroyd-B fluid in a porous half space. By using Fourier sine transform, an exact solution was obtained. In contrast to the classical Stokes’ first problem for a clear fluid, there is a y-dependent steady state solution for an Oldroyd-B fluid in the porous half space, which is a damping exponential function with respect to the distance from the flat plate. The thickness of the boundary layer, which tends to be a limited value, is also different from that of a clear fluid. The effect of viscoelasticity on the unsteady flow in porous media is investigated. It was found if α>1∕4[(αt∕Re)+Re]2, oscillations in velocity occur obviously and the system exhibits viscoelastic behaviors, where α and αt are nondimensional relaxation and retardation times, respectively, Re is Reynold number in porous media. Some previous solutions of Stokes’ first problem corresponding to Maxwell fluid and Newtonian fluid in porous or nonporous half space can be easily obtained from our results in different limiting cases.
Radio frequency probe with improved sensitivity for diamond anvil cell nuclear magnetic resonance
Authors: Okuchi Takuo , Hemley Russell J. , Mao Ho-kwang
Published: January 2005

An alternative type of single-solenoid radio frequency (rf) probe for diamond anvil cell (DAC) NMR is described. The rf probe provides a higher signal-to-noise ratio (S∕N) than previous designs for DAC-NMR of liquid samples. It induces a practically homogeneous rf field that enables straightforward measurements even at a marginal S∕N. It can be installed and removed without changing the sample pressure, which enhances the efficiency of experimentation beyond that attainable with previous designs. This rf probe will facilitate the application of NMR to liquids at extreme pressures.
Super-hard diamond indenter prepared from high-purity synthetic diamond crystal
Authors: Sumiya Hitoshi
Published: January 2005

The Knoop hardness in (001)⟨110⟩ of high-purity synthetic type IIa diamond crystal synthesized under high pressure and high temperature is known to be extremely high. Knoop indenters were prepared from the synthetic type IIa diamonds by taking the tip orientation to the hard crystal orientation of the diamonds, i.e., the z axis and the longitudinal direction of the indenter tip are parallel to the ⟨001⟩ and ⟨110⟩ direction of the crystal, respectively. Numerous indentation tests on diamond crystals revealed that the indenter is substantially rigid and has very high performance. The lifetime of the indenter was more than ten times longer than that of the conventional natural diamond indenter.
Development of an analog processing circuit for IR-radiation power and noncontact position measurements
Authors: Perpiñà Xavier , Jordà Xavier , Vellvehi Miquel , Millán José , Mestres Narcís
Published: January 2005

An analog circuit which simultaneously performs radiation power and position measurement of an IR-laser spot (wavelength 1.3μm) on a four quadrant photodiode is presented and described. Its main features are 2MHz-bandwidth and low noise (14mVrms) for a nominal working radiation power of 2mW. This circuit has been implemented for the detection stage of an internal IR-laser deflection set-up, used to measure internal temperature gradients and free carrier concentration in vertical power devices. The measurements of the previously mentioned magnitudes inside the drift region of a 600V PT-IGBT are presented under critical operation conditions. This circuit, however, can also be used in other noncontact position and power radiation detection systems that require a high bandwidth and low noise levels. Moreover, the different noise sources along the detecting system have been identified. It is shown that the main contribution to the noise level at the processing circuit output is basically introduced by its second stage (analog divisor), assuring, for a 1mm laser spot centered at the photodetector, a maximum resolution in position measurement below 2μm.
Fast response thin-film thermistor for measurements in ocean waters
Authors: Kukuruznyak Dmitry A. , Miller Jack B. , Gregg Michael C. , Ohuchi Fumio S.
Published: January 2005

This work describes a very fast thin-film thermistor for temperature measurements in aggressive and conducting liquids. In order to minimize the thermal mass of the sensor, we employed a thin-gauge hollow glass capillary as both a hermetic encapsulation as well as substrate for the thin resistive film. The thermistor thin film is deposited onto an inner surface of the capillary using a solution deposition technique. Microscopic electrical wires are deeply inserted into the capillary tube and fused to the thermistor film. The resistance element thus fabricated is attached to the supporting members and sealed at the open ends. Consequently, detrimental influence of the massive prongs on the dynamic characteristics of the sensor was also eliminated. The prototype temperature probes were compared to the fastest commercially available bead thermistors (with response time of 7milliseconds). The new sensors exhibited superior temporal response.
Orientation-dependent strain tolerance of amorphous silicon transistors and pixel circuits for elastic organic light-emitting diode displays
Authors: Servati Peyman , Nathan Arokia
Published: January 2005

We examine the orientation dependence of strain-induced shifts in current and mobility of hydrogenated amorphous silicon thin-film transistors (TFTs). Longitudinal and transverse TFT mirrors are presented for design of strain-tolerant ΔVT-compensating pixel driver circuits for active-matrix organic light-emitting diode displays.
Concentration and ion-energy-independent annealing kinetics during ion-implanted-defect annealing
Authors: Karmouch R. , Mercure J.-F. , Anahory Y. , Schiettekatte F.
Published: January 2005

Nanocalorimetry revealed that the annealing kinetics of ion-implanted defects in polycrystalline Si is independent of ion fluence and implantation energy. Ion implantation of 30 keV Si−, 15 keV Si−, and 15 keV C− was performed at fluences ranging from 6×1011 to 1×1015atoms∕cm2, followed by temperature scans between 30 and 450 °C. The rate of heat release has the same shape for all fluences, featuring no peaks but rather a smooth, continuously increasing signal. This suggests that the heat release is dominated by the annealing of highly disordered zones generated by each implantation cascade. Such annealing depends primarily on the details of the damage zone–crystal interface kinetics, and not on the point defect concentration.
Suppression of intrinsic bistability in resonant-tunneling diode by in-plane magnetic field
Authors: Serov A. Yu. , Zegrya G. G.
Published: January 2005

Using the Bardeen formalism, we calculated the electron tunneling through a double barrier structure with an in-plane magnetic field. It is shown that the in-plane magnetic field has two effects on the current–voltage characteristics. First, it reduces the width of the bistable region. At high magnetic fields, the bistability can be completely suppressed. This can provide a method for tuning the bistable region in a double barrier structure. Second, it modifies the peak current. The dependence of the peak current on the magnetic field is different in the cases of high and low electron concentrations in the quantum well.
Effect of NH3 surface nitridation temperature on mobility of ultrathin atomic layer deposited HfO2
Authors: Akbar Mohammad S. , Moumen Naim , Barnett Joel , Sim Johnny , Lee Jack C.
Published: January 2005

Effect of NH3 predeposition anneal (pre-DA) temperature prior to ultrathin atomic layer deposition (ALD) HfO2 deposition (15–30 Å) on equivalent oxide thickness (EOT) and mobility of TiN∕HfO2∕Si metal-oxide field effect transistors has been studied systematically. At the same physical thickness, reduction of EOT by high temperature NH3 pre-DA treatment (∼900°C) has been achieved, with no apparent change in Jg (leakage current density), though no significant channel mobility reduction could be observed. Increase in nitrogen content with pre-DA temperature improved overall dielectric constant and bulk trapping immunity, though slight mobility reduction was attributed to positive charge pile up at the interface. The ultrathin EOT (∼7.4Å) with good mobility values sets ALD HfO2 as a very promising candidate for alternate gate oxide.
Growth of ferromagnetic nanoparticles in Ge:Fe thin films
Authors: Goswami R. , Kioseoglou G. , Hanbicki A. T. , van ’t Erve O. M. J. , Jonker B. T. , Spanos G.
Published: January 2005

The microstructure and magnetic properties of Ge:Fe thin films grown by molecular-beam epitaxy have been studied by transmission electron microscopy and superconducting quantum interference device magnetometry. Films were deposited on GaAs(001) at substrate temperatures (TS) ranging from 70to400°C. Nanoparticles of ferromagnetic Fe3Ge2 form in a single-crystalline Ge matrix for TS⩾150°C. The evolution of magnetic order has been evaluated as the particle size increases from 2nm at TS=150°C to 15nm at 400°C. The ferromagnetic order of Ge:Fe nanocomposite thin films originates solely from ferromagnetic second-phase particles.
Functional characteristics in asymmetric source/drain InAlAsSb∕InGaAs∕InPδ-doped high electron mobility transistor
Authors: Lee Ching-Sung , Hsu Wei-Chou
Published: January 2005

Functional characteristics, comprising enhance-mode linear amplification performance and N-shaped negative-differential resistance phenomenon, have been observed in an inverted δ-doped In0.34Al0.66As0.85Sb0.15∕In0.75Ga0.25As∕InP high electron mobility transistor with the asymmetric source/drain terminal structure. Unpassivated peak performances, including the transconductance of 268mS∕mm and saturation drain current density of 210mA∕mm, and significant negative differential resistance characteristics, including the peak-to-valley current ratio of 6.1, can be obtained on the same device by switching the source/drain electrical connection. The electric field aspects of the asymmetry in the contacts have also been investigated.

At the request of the authors, this article is being retracted effective 19 August 2005.
Noisy signal amplification in ultrasensitive signal transduction
Authors: Shibata Tatsuo , Fujimoto Koichi
Published: January 2005

Because intracellular processes are inherently noisy, stochastic reactions process noisy signals in cellular signal transduction. One essential feature of biological signal transduction systems is the amplification of small changes in input signals. However, small random changes in the input signals could also be amplified, and the transduction reaction can also generate noise. Here, we show theoretically how the abrupt response of ultrasensitive signal-transduction reactions results in the generation of large inherent noise and the high amplification of input noise. The inherently generated noise propagates with amplification through intracellular molecular network. We discuss how the contribution of such transmitted noise can be shown experimentally. Our results imply that the switch-like behavior of signal transduction could be limited by noise; however, high amplification reaction could be advantageous to generate large noise, which would be essential to maintain behavioral variability.
CD98hc (SLC3A2) mediates integrin signaling
Authors: Feral Chloe C. , Nishiya Naoyuki , Fenczik Csilla A. , Stuhlmann Heidi , Slepak Marina , Ginsberg Mark H.
Published: January 2005

Integrins regulate cellular behaviors through signaling pathways, including Rho GTPases and kinases. CD98 heterodimers, comprised of a heavy chain (CD98hc, SLC3A2) and one of several light chains, interact with integrins through CD98hc. CD98hc overexpression leads to anchorage-independent cell growth and tumorigenesis in 3T3 fibroblasts and activates certain integrin-regulated signaling pathways. To establish the biological function of CD98hc, we disrupted the gene and analyzed CD98hc-null cells. Here we report that CD98hc contributes to integrin-dependent cell spreading, cell migration, and protection from apoptosis. Furthermore, CD98hc is required for efficient adhesion-induced activation of Akt and Rac GTPase, major contributors to the integrin-dependent signals involved in cell survival and cell migration. CD98 promotes amino acid transport through its light chains; however, a CD98hc mutant that interacts with β1 integrins, but not CD98 light chains, restored integrin-dependent signaling and protection from apoptosis. β1 integrins are involved in the pathogenesis of certain cancers. CD98hc deletion markedly impaired the ability of embryonic stem cells to form teratocarcinomas in mice; teratocarcinoma formation was reconstituted by reexpression of CD98hc or of the mutant that interacts exclusively with integrins. Thus, CD98hc is an integrin-associated protein that mediates integrin-dependent signals, which promote tumorigenesis.
Sequence-independent upstream DNA–αCTD interactions strongly stimulate
Escherichia coli
RNA polymerase-
lacUV5
promoter association
Authors: Ross Wilma , Gourse Richard L.
Published: January 2005

The C-terminal domains of the two α-subunits (αCTD) in
Escherichia coli
RNA polymerase (RNAP) recognize specific sequences called UP elements in some promoters. These interactions can increase transcription dramatically. Previously, effects of upstream DNA–αCTD interactions on transcription were quantified relative to control promoters with nonspecific DNA sequences substituted for UP elements. However, contributions of nonspecific upstream DNA–αCTD interactions to promoter activity have not been evaluated extensively. Here, we examine effects of removal of αCTD, upstream promoter DNA, or both on the rate of open-complex formation with promoters that lack UP elements. Deletion of αCTD decreased the composite second-order association rate constant,
k
a
, of RNAP for the
lacUV5
promoter by ≈10-fold. Much of this effect was attributable to a decrease in the isomerization rate constant,
k
2
. Removal of promoter DNA upstream of the -35 element also decreased both
k
a
and
k
2
≈10-fold. Upstream DNA extending approximately to base pair -100 was sufficient for maximal association rates of wild-type RNAP with
lacUV5
promoter fragments. The αCTD and upstream DNA did not affect dissociation rates from the open complex. We suggest that sequence-independent upstream DNA interactions with αCTD are major contributors to initiation at many (or all) promoters (not merely promoters containing UP elements) and that these interactions facilitate isomerization events occurring well downstream of the α-binding sites. In addition to highlighting the functional importance of nonspecific protein–DNA interactions, these results suggest also that UP element–αCTD interactions play an even larger role in transcription initiation than appreciated previously.
The structure of coral allene oxide synthase reveals a catalase adapted for metabolism of a fatty acid hydroperoxide
Authors: Oldham Michael L. , Brash Alan R. , Newcomer Marcia E.
Published: January 2005

8R-Lipoxygenase and allene oxide synthase (AOS) are parts of a naturally occurring fusion protein from the coral
Plexaura homomalla.
AOS catalyses the production of an unstable epoxide (an allene oxide) from the fatty acid hydroperoxide generated by the lipoxygenase activity. Here, we report the structure of the AOS domain and its striking structural homology to catalase. Whereas nominal sequence identity between the enzymes had been previously described, the extent of structural homology observed was not anticipated, given that this enzyme activity had been exclusively associated with the P450 superfamily, and conservation of a catalase fold without catalase activity is unprecedented. Whereas the heme environment is largely conserved, the AOS heme is planar and the distal histidine is flanked by two hydrogen-bonding residues. These critical differences likely facilitate the switch from a catalatic activity to that of a fatty acid hydroperoxidase.
High rate of viral evolution associated with the emergence of carnivore parvovirus
Authors: Shackelton Laura A. , Parrish Colin R. , Truyen Uwe , Holmes Edward C.
Published: January 2005

Canine parvovirus (CPV) is an emerging DNA virus that was first observed to cause disease in canines in 1978 and has since become a ubiquitous pathogen worldwide. CPV emerged from feline panleukopenia parvovirus (FPLV) or a closely related virus, differing at several key amino acid residues. Here we characterize the evolutionary processes underlying the emergence of CPV. Although FPLV has remained an endemic infection in its host populations, we show that, since the 1970s, the newly emerged CPV has undergone an epidemic-like pattern of logistic/exponential growth, effectively doubling its population size every few years. This rapid population growth was associated with a lineage of CPV that acquired a broader host range and greater infectivity. Recombination played no role in the emergence of CPV. Rather, any preexisting variation in the donor species and the subsequent rapid adaptation of the virus to canines were likely dependent on a high rate of mutation and the positive selection of mutations in the major capsid gene. Strikingly, although these single-stranded viruses have a DNA genome and use cellular replication machinery, their rate of nucleotide substitution is closer to that of RNA viruses than to that of double-stranded DNA viruses.
A bipartite signal mediates the transfer of type IV secretion substrates of
Bartonella henselae
into human cells
Authors: Schulein Ralf , Guye Patrick , Rhomberg Thomas A. , Schmid Michael C. , Schröder Gunnar , Vergunst Annette C. , Carena Ilaria , Dehio Christoph
Published: January 2005

Bacterial type IV secretion (T4S) systems mediate the transfer of macromolecular substrates into various target cells, e.g., the conjugative transfer of DNA into bacteria or the transfer of virulence proteins into eukaryotic host cells. The T4S apparatus VirB of the vascular tumor-inducing pathogen
Bartonella henselae
causes subversion of human endothelial cell (HEC) function. Here we report the identification of multiple protein substrates of VirB, which, upon translocation into HEC, mediate all known VirB-dependent cellular changes. These
Bartonella
-translocated effector proteins (Beps) A-G are encoded together with the VirB system and the T4S coupling protein VirD4 on a
Bartonella
-specific pathogenicity island. The Beps display a modular architecture, suggesting an evolution by extensive domain duplication and reshuffling. The C terminus of each Bep harbors at least one copy of the Bep-intracellular delivery domain and a short positively charged tail sequence. This biparte C terminus constitutes a transfer signal that is sufficient to mediate VirB/VirD4-dependent intracellular delivery of reporter protein fusions. The Bep-intracellular delivery domain is also present in conjugative relaxases of bacterial conjugation systems. We exemplarily show that the C terminus of such a conjugative relaxase mediates protein transfer through the
Bartonella henselae
VirB/VirD4 system into HEC. Conjugative relaxases may thus represent the evolutionary origin of the here defined T4S signal for protein transfer into human cells.
Adhesion at calcium oxalate crystal surfaces and the effect of urinary constituents
Authors: Sheng Xiaoxia , Jung Taesung , Wesson Jeffrey A. , Ward Michael D.
Published: January 2005

Kidney stones, aggregates of microcrystals, most commonly contain calcium oxalate monohydrate (COM) as the primary constituent. The aggregation of COM microcrystals and their attachment to epithelial cells are thought to involve adhesion at COM crystal surfaces, mediated by anionic molecules or urinary macromolecules. Identification of the most important functional group–crystal face adhesive combinations is crucial to understanding the stability of COM aggregates and the strength of their attachments to epithelial cell surfaces under flow in the renal tubules of the kidney. Here, we describe direct measurements of adhesion forces, by atomic force microscopy, between various functional groups and select faces of COM crystals immersed in aqueous media. Tip-immobilized carboxylate and amidinium groups displayed the largest adhesion forces, and the adhesive strength of the COM crystal faces decreased in the order (100) > (

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) > (010), demonstrating that adhesion is sensitive to the structure and composition of crystal faces. The influence of citrate and certain urinary proteins on adhesion was examined, and it was curious that osteopontin, a suspected regulator of stone formation, increased the adhesion force between a carboxylate tip and the (100) crystal face. This behavior was unique among the various combinations of additives and COM crystal faces examined here. Collectively, the force measurements demonstrate that adhesion of functional groups and binding of soluble additives, including urinary macromolecules, to COM crystal surfaces are highly specific in nature, suggesting a path toward a better understanding of kidney stone disease and the eventual design of therapeutic agents.
Diagnostic tool for the identification of
MLL
rearrangements including unknown partner genes
Authors: Meyer Claus , Schneider Bjoern , Reichel Martin , Angermueller Sieglinde , Strehl Sabine , Schnittger Susanne , Schoch Claudia , Jansen Mieke W. J. C. , van Dongen Jacques J. , Pieters Rob , Haas Oskar A. , Dingermann Theo , Klingebiel Thomas , Marschalek Rolf
Published: January 2005

Approximately 50 different chromosomal translocations of the human
MLL
gene are currently known and associated with high-risk acute leukemia. The large number of different
MLL
translocation partner genes makes a precise diagnosis a demanding task. After their cytogenetic identification, only the most common
MLL
translocations are investigated by RT-PCR analyses, whereas infrequent or unknown
MLL
translocations are excluded from further analyses. Therefore, we aimed at establishing a method that enables the detection of any
MLL
rearrangement by using genomic DNA isolated from patient biopsy material. This goal was achieved by establishing a universal long-distance inverse-PCR approach that allows the identification of any kind of
MLL
rearrangement if located within the breakpoint cluster region. This method was applied to biopsy material derived from 40 leukemia patients known to carry
MLL
abnormalities. Thirty-six patients carried known
MLL
fusions (34 with der(11) and 2 with reciprocal alleles), whereas 3 patients were found to carry novel
MLL
fusions to
ACACA, SELB
, and
SMAP1
, respectively. One patient carried a genomic fusion between
MLL
and
TIRAP
, resulting from an interstitial deletion. Because of this interstitial deletion, portions of the
MLL
and
TIRAP
genes were deleted, together with 123 genes located within the 13-Mbp interval between both chromosomal loci. Therefore, this previously undescribed diagnostic tool has been proven successful for analyzing any
MLL
rearrangement including previously unrecognized partner genes. Furthermore, the determined patient-specific fusion sequences are useful for minimal residual disease monitoring of
MLL
associated acute leukemias.
Phosphate forms an unusual tripodal complex with the Fe–Mn center of sweet potato purple acid phosphatase
Authors: Schenk Gerhard , Gahan Lawrence R. , Carrington Lyle E. , Mitić Nataša , Valizadeh Mohsen , Hamilton Susan E. , de Jersey John , Guddat Luke W.
Published: January 2005

Purple acid phosphatases (PAPs) are a family of binuclear metalloenzymes that catalyze the hydrolysis of phosphoric acid esters and anhydrides. A PAP in sweet potato has a unique, strongly antiferromagnetically coupled Fe(III)–Mn(II) center and is distinguished from other PAPs by its increased catalytic efficiency for a range of activated and unactivated phosphate esters, its strict requirement for Mn(II), and the presence of a μ-oxo bridge at pH 4.90. This enzyme displays maximum catalytic efficiency (
k
cat
/
K
m
) at pH 4.5, whereas its catalytic rate constant (
k
cat
) is maximal at near-neutral pH, and, in contrast to other PAPs, its catalytic parameters are not dependent on the pK
a
of the leaving group. The crystal structure of the phosphate-bound Fe(III)–Mn(II) PAP has been determined to 2.5-Å resolution (final
R
free
value of 0.256). Structural comparisons of the active site of sweet potato, red kidney bean, and mammalian PAPs show several amino acid substitutions in the sweet potato enzyme that can account for its increased catalytic efficiency. The phosphate molecule binds in an unusual tripodal mode to the two metal ions, with two of the phosphate oxygen atoms binding to Fe(III) and Mn(II), a third oxygen atom bridging the two metal ions, and the fourth oxygen pointing toward the substrate binding pocket. This binding mode is unique among the known structures in this family but is reminiscent of phosphate binding to urease and of sulfate binding to λ protein phosphatase. The structure and kinetics support the hypothesis that the bridging oxygen atom initiates hydrolysis.
Biological spectra analysis: Linking biological activity profiles to molecular structure
Authors: Fliri Anton F. , Loging William T. , Thadeio Peter F. , Volkmann Robert A.
Published: January 2005

Establishing quantitative relationships between molecular structure and broad biological effects has been a longstanding challenge in science. Currently, no method exists for forecasting broad biological activity profiles of medicinal agents even within narrow boundaries of structurally similar molecules. Starting from the premise that biological activity results from the capacity of small organic molecules to modulate the activity of the proteome, we set out to investigate whether descriptor sets could be developed for measuring and quantifying this molecular property. Using a 1,567-compound database, we show that percent inhibition values, determined at single high drug concentration in a battery of
in vitro
assays representing a cross section of the proteome, provide precise molecular property descriptors that identify the structure of molecules. When broad biological activity of molecules is represented in spectra form, organic molecules can be sorted by quantifying differences between biological spectra. Unlike traditional structure–activity relationship methods, sorting of molecules by using biospectra comparisons does not require knowledge of a molecule's putative drug targets. To illustrate this finding, we selected as starting point the biological activity spectra of clotrimazole and tioconazole because their putative target, lanosterol demethylase (CYP51), was not included in the bioassay array. Spectra similarity obtained through profile similarity measurements and hierarchical clustering provided an unbiased means for establishing quantitative relationships between chemical structures and biological activity spectra. This methodology, which we have termed biological spectra analysis, provides the capability not only of sorting molecules on the basis of biospectra similarity but also of predicting simultaneous interactions of new molecules with multiple proteins.
Stochastic simulation of the mammalian circadian clock
Authors: Forger Daniel B. , Peskin Charles S.
Published: January 2005

Circadian (nearly 24-h) clocks are remarkably accurate at timing biological events despite the randomness of their biochemical reactions. Here we examine the causes of their immunity to molecular noise in the context of a detailed stochastic mathematical model of the mammalian circadian clock. This stochastic model is a direct generalization of the deterministic mammalian circadian clock model previously developed. A feature of that model is that it completely specifies all molecular reactions, leaving no ambiguity in the formulation of a stochastic version of the model. With parameters based on experimental data concerning clock protein concentrations within a cell, we find accurate circadian rhythms in our model only when promoter interaction occurs on the time scale of seconds. As the model is scaled up by proportionally increasing the numbers of molecules of all species and the reaction rates with the promoter, the observed variability scales as 1/
n
0.5
, where
n
is the number of molecules of any species. Our results show that gene duplication increases robustness by providing more promoters with which the transcription factors of the model can interact. Although PER2 mutants were not rhythmic in the deterministic version of this model, they are rhythmic in the stochastic version.
Use of targeted glycoproteomics to identify serum glycoproteins that correlate with liver cancer in woodchucks and humans
Authors: Block Timothy M. , Comunale Mary Ann , Lowman Melissa , Steel Laura F. , Romano Patrick R. , Fimmel Claus , Tennant Bud C. , London W. Thomas , Evans Alison A. , Blumberg Baruch S. , Dwek Raymond A. , Mattu Tajinder S. , Mehta Anand S.
Published: January 2005

Chronic infection with hepatitis B virus (HBV) is associated with the majority of hepatocellular carcinoma (HCC). The diagnosis of HCC is usually made in the late stages of the disease, when treatment options are limited and prognosis is poor. We therefore have developed a method of glycoproteomic analysis in an attempt to discover serum markers that can assist in the early detection of HBV-induced liver cancer. Briefly, a comparative method for analysis of oligosaccharides released from serum glycoproteins and for recovery and identification of proteins with aberrant glycosylation, as a function of cancer diagnosis, is described. The model we have used is the woodchuck (Marmota monax), which shares similarities in the glycosylation pattern associated with liver proteins in human HCC. In this report, we show that woodchucks diagnosed with HCC have dramatically higher levels of serum-associated core α-1,6-linked fucose, as compared with woodchucks without a diagnosis of HCC. The coupling of this methodology with 2D gel proteomics has permitted the identification of several glycoproteins with altered glycosylation as a function of cancer. One such glycoprotein, Golgi Protein 73 (GP73), was found to be elevated and hyperfucosylated in animals with HCC. Further, the study showed GP73 to be elevated in the serum of people with a diagnosis of HCC, providing a validation of our approach. The potential of this technology for biomarker discovery and the implications of increased levels of GP73 in liver cancer are discussed.
A potent small molecule inhibits polyglutamine aggregation in Huntington's disease neurons and suppresses neurodegeneration
in vivo
Authors: Zhang Xiaoqian , Smith Donna L. , Meriin Anatoli B. , Engemann Sabine , Russel Deborah E. , Roark Margo , Washington Shetia L. , Maxwell Michele M. , Marsh J. Lawrence , Thompson Leslie Michels , Wanker Erich E. , Young Anne B. , Housman David E. , Bates Gillian P. , Sherman Michael Y. , Kazantsev Aleksey G.
Published: January 2005

Polyglutamine (polyQ) disorders, including Huntington's disease (HD), are caused by expansion of polyQ-encoding repeats within otherwise unrelated gene products. In polyQ diseases, the pathology and death of affected neurons are associated with the accumulation of mutant proteins in insoluble aggregates. Several studies implicate polyQ-dependent aggregation as a cause of neurodegeneration in HD, suggesting that inhibition of neuronal polyQ aggregation may be therapeutic in HD patients. We have used a yeast-based high-throughput screening assay to identify small-molecule inhibitors of polyQ aggregation. We validated the effects of four hit compounds in mammalian cell-based models of HD, optimized compound structures for potency, and then tested them
in vitro
in cultured brain slices from HD transgenic mice. These efforts identified a potent compound (IC
50
= 10 nM) with long-term inhibitory effects on polyQ aggregation in HD neurons. Testing of this compound in a
Drosophila
HD model showed that it suppresses neurodegeneration
in vivo
, strongly suggesting an essential role for polyQ aggregation in HD pathology. The aggregation inhibitors identified in this screen represent four primary chemical scaffolds and are strong lead compounds for the development of therapeutics for human polyQ diseases.
Long-Term Negative Priming: Support for Retrieval of Prior Attentional Processes
Authors: Grison Sarah , Tipper Steven P. , Hewitt Olivia
Published: January 2005

Negative priming reveals that participants respond slowly to a probe target that was a task-irrelevant distractor in the preceding prime display (e.g., Tipper, 1985) and is thought to reflect processes mediating short-term behaviour. However, since the first surprising reports that negative priming is found with meaningless stimuli across delays of 30 days (e.g., DeSchepper & Treisman, 1996), researchers have questioned the existence of long-term negative priming effects. Because long-term negative priming could indicate that task-irrelevant information leaves a memory trace that impacts performance over time, such a finding is of immense theoretical importance. Indeed, the current research finds support for the existence of long-term negative priming as well as its generality across different stimuli and conditions. The authors propose that the initial processes that prevent response to irrelevant stimuli may be stored in memory, where retrieval of these processes can mediate behaviour over time.
BACE overexpression alters the subcellular processing of APP and inhibits Aβ deposition in vivo
Authors: Lee Edward B. , Zhang Bin , Liu Kangning , Greenbaum Eric A. , Doms Robert W. , Trojanowski John Q. , Lee Virginia M.-Y.
Published: January 2005

Introducing mutations within the amyloid precursor protein (APP) that affect β- and γ-secretase cleavages results in amyloid plaque formation in vivo. However, the relationship between β-amyloid deposition and the subcellular site of Aβ production is unknown. To determine the effect of increasing β-secretase (BACE) activity on Aβ deposition, we generated transgenic mice overexpressing human BACE. Although modest overexpression enhanced amyloid deposition, high BACE overexpression inhibited amyloid formation despite increased β-cleavage of APP. However, high BACE expression shifted the subcellular location of APP cleavage to the neuronal perikarya early in the secretory pathway. These results suggest that the production, clearance, and aggregation of Aβ peptides are highly dependent on the specific neuronal subcellular domain wherein Aβ is generated and highlight the importance of perikaryal versus axonal APP proteolysis in the development of Aβ amyloid pathology in Alzheimer's disease.
Ect2 and MgcRacGAP regulate the activation and function of Cdc42 in mitosis
Authors: Oceguera-Yanez Fabian , Kimura Kazuhiro , Yasuda Shingo , Higashida Chiharu , Kitamura Toshio , Hiraoka Yasushi , Haraguchi Tokuko , Narumiya Shuh
Published: January 2005

Although Rho regulates cytokinesis, little was known about the functions in mitosis of Cdc42 and Rac. We recently suggested that Cdc42 works in metaphase by regulating bi-orient attachment of spindle microtubules to kinetochores. We now confirm the role of Cdc42 by RNA interference and identify the mechanisms for activation and down-regulation of Cdc42. Using a pull-down assay, we found that the level of GTP-Cdc42 elevates in metaphase, whereas the level of GTP-Rac does not change significantly in mitosis. Overexpression of dominant-negative mutants of Ect2 and MgcRacGAP, a Rho GTPase guanine nucleotide exchange factor and GTPase activating protein, respectively, or depletion of Ect2 by RNA interference suppresses this change of GTP-Cdc42 in mitosis. Depletion of Ect2 also impairs microtubule attachment to kinetochores and causes prometaphase delay and abnormal chromosomal segregation, as does depletion of Cdc42 or expression of the Ect2 and MgcRacGAP mutants. These results suggest that Ect2 and MgcRacGAP regulate the activation and function of Cdc42 in mitosis.
Essential role of p53 phosphorylation by p38 MAPK in apoptosis induction by the HIV-1 envelope
Authors: Perfettini Jean-Luc , Castedo Maria , Nardacci Roberta , Ciccosanti Fabiola , Boya Patricia , Roumier Thomas , Larochette Nathanael , Piacentini Mauro , Kroemer Guido
Published: January 2005

The proapoptotic activity of the transcription factor p53 critically depends on the phosphorylation of serine 46 (p53S46P). Here, we show that syncytia containing p53S46P could be detected in lymph node biopsies from human immunodeficiency virus (HIV)-1 carriers, in the brain of patients with HIV-1–associated dementia and in cocultures of HeLa expressing the HIV-1 envelope glycoprotein complex (Env) with HeLa cells expressing CD4. In this latter model, cell death was the result of a sequential process involving cell fusion, nuclear fusion (karyogamy), phosphorylation of serine 15 (p53S15P), later on serine 46 (p53S46P), and transcription of p53 target genes. Cytoplasmic p38 mitogen-activated protein kinase (MAPK) was found to undergo an activating phosphorylation (p38T180/Y182P [p38 with phosphorylated threonine 180 and tyrosine 182]) before karyogamy and to translocate into karyogamic nuclei. p38T180/Y182P colocalized and coimmunoprecipitated with p53S46P. Recombinant p38 phosphorylated recombinant p53 on serine 46 in vitro. Inhibition of p38 MAPK by pharmacological inhibitors, dominant-negative p38, or small interfering RNA, suppressed p53S46P (but not p53S15P), the expression of p53-inducible genes, the conformational activation of proapoptotic Bax and Bak, the release of cytochrome c from mitochondria, and consequent apoptosis. p38T180/Y182P was also detected in HIV-1–induced syncytia, in vivo, in patients' lymph nodes and brains. Dominant-negative MKK3 or MKK6 inhibited syncytial activation of p38, p53S46P, and apoptosis. Altogether, these findings indicate that p38 MAPK-mediated p53 phosphorylation constitutes a critical step of Env-induced apoptosis.
NK cell activation through the NKG2D ligand MULT-1 is selectively prevented by the glycoprotein encoded by mouse cytomegalovirus gene m145
Authors: Krmpotic Astrid , Hasan Milena , Loewendorf Andrea , Saulig Tanja , Halenius Anne , Lenac Tihana , Polic Bojan , Bubic Ivan , Kriegeskorte Anja , Pernjak-Pugel Ester , Messerle Martin , Hengel Hartmut , Busch Dirk H. , Koszinowski Ulrich H. , Jonjic Stipan
Published: January 2005

The NK cell–activating receptor NKG2D interacts with three different cellular ligands, all of which are regulated by mouse cytomegalovirus (MCMV). We set out to define the viral gene product regulating murine UL16-binding protein-like transcript (MULT)-1, a newly described NKG2D ligand. We show that MCMV infection strongly induces MULT-1 gene expression, but surface expression of this glycoprotein is nevertheless completely abolished by the virus. Screening a panel of MCMV deletion mutants defined the gene m145 as the viral regulator of MULT-1. The MCMV m145-encoded glycoprotein turned out to be necessary and sufficient to regulate MULT-1 by preventing plasma membrane residence of MULT-1. The importance of MULT-1 in NK cell regulation in vivo was confirmed by the attenuating effect of the m145 deletion that was lifted after NK cell depletion. Our findings underline the significance of escaping MULT-1/NKG2D signaling for viral survival and maintenance.
Reciprocal and dynamic control of CD8 T cell homing by dendritic cells from skin- and gut-associated lymphoid tissues
Authors: Mora J. Rodrigo , Cheng Guiying , Picarella Dominic , Briskin Michael , Buchanan Natasha , von Andrian Ulrich H.
Published: January 2005

T cell activation by intestinal dendritic cells (DC) induces gut-tropism. We show that, reciprocally, DC from peripheral lymph nodes (PLN-DC) induce homing receptors promoting CD8 T cell accumulation in inflamed skin, particularly ligands for P- and E-selectin. Differential imprinting of tissue-tropism was independent of Th1/Th2 cytokines and not restricted to particular DC subsets. Fixed PLN-DC retained the capacity to induce selectin ligands on T cells, which was suppressed by addition of live intestinal DC. By contrast, fixed intestinal DC failed to promote gut-tropism and instead induced skin-homing receptors. Moreover, the induction of selectin ligands driven by antigen-pulsed PLN-DC could be suppressed “in trans” by adding live intestinal DC, but PLN-DC did not suppress gut-homing receptors induced by intestinal DC. Reactivation of tissue-committed memory cells modified their tissue-tropism according to the last activating DC's origin. Thus, CD8 T cells activated by DC acquire selectin ligands by default unless they encounter fixation-sensitive signal(s) for gut-tropism from intestinal DC. Memory T cells remain responsive to these signals, allowing for dynamic migratory reprogramming by skin- and gut-associated DC.
BAFF is produced by astrocytes and up-regulated in multiple sclerosis lesions and primary central nervous system lymphoma
Authors: Krumbholz Markus , Theil Diethilde , Derfuss Tobias , Rosenwald Andreas , Schrader Frank , Monoranu Camelia-Maria , Kalled Susan L. , Hess Donna M. , Serafini Barbara , Aloisi Francesca , Wekerle Hartmut , Hohlfeld Reinhard , Meinl Edgar
Published: January 2005

We report that B cell–activating factor of the tumor necrosis factor (TNF) family (BAFF) is expressed in the normal human brain at ∼10% of that in lymphatic tissues (tonsils and adenoids) and is produced by astrocytes. BAFF was regularly detected by enzyme-linked immunosorbent assay in brain tissue lysates and in normal spinal fluid, and in astrocytes by double fluorescence microscopy. Cultured human astrocytes secreted functionally active BAFF after stimulation with interferon-γ and TNF-α via a furin-like protease-dependent pathway. BAFF secretion per cell was manifold higher in activated astrocytes than in monocytes and macrophages. We studied brain lesions with B cell components, and found that in multiple sclerosis plaques, BAFF expression was strongly up-regulated to levels observed in lymphatic tissues. BAFF was localized in astrocytes close to BAFF-R–expressing immune cells. BAFF receptors were strongly expressed in situ in primary central nervous system (CNS) lymphomas. This paper identifies astrocytes as a nonimmune source of BAFF. CNS-produced BAFF may support B cell survival in inflammatory diseases and primary B cell lymphoma.
Five consecutive positive odd numbers, none of which can be expressed as a sum of two prime powers
Authors: Chen Yong-Gao
Published: January 2005

In this paper, we prove that there is an arithmetic progression of positive odd numbers for each term

M
M

of which none of five consecutive odd numbers

M
,
M
−
2
,
M
−
4
,
M
−
6

M, M-2, M-4, M-6

and

M
−
8

M-8

can be expressed in the form

2
n

±

p
α

2^n \pm p^\alpha

, where

p
p

is a prime and

n
,
α

n, \alpha

are nonnegative integers.
Exploring the Plant Transcriptome through Phylogenetic Profiling
Authors: Vandepoele Klaas , Van de Peer Yves
Published: January 2005

Publicly available protein sequences represent only a small fraction of the full catalog of genes encoded by the genomes of different plants, such as green algae, mosses, gymnosperms, and angiosperms. By contrast, an enormous amount of expressed sequence tags (ESTs) exists for a wide variety of plant species, representing a substantial part of all transcribed plant genes. Integrating protein and EST sequences in comparative and evolutionary analyses is not straightforward because of the heterogeneous nature of both types of sequence data. By combining information from publicly available EST and protein sequences for 32 different plant species, we identified more than 250,000 plant proteins organized in more than 12,000 gene families. Approximately 60% of the proteins are absent from current sequence databases but provide important new information about plant gene families. Analysis of the distribution of gene families over different plant species through phylogenetic profiling reveals interesting insights into plant gene evolution, and identifies species- and lineage-specific gene families, orphan genes, and conserved core genes across the green plant lineage. We counted a similar number of approximately 9,500 gene families in monocotyledonous and eudicotyledonous plants and found strong evidence for the existence of at least 33,700 genes in rice (Oryza sativa). Interestingly, the larger number of genes in rice compared to Arabidopsis (Arabidopsis thaliana) can partially be explained by a larger amount of species-specific single-copy genes and species-specific gene families. In addition, a majority of large gene families, typically containing more than 50 genes, are bigger in rice than Arabidopsis, whereas the opposite seems true for small gene families.