bluuebunny/crossref_metadata_2025 huggingface dataset:
Nonlinear equation for a curved stationary flame and the flame velocity
Authors: Bychkov Vitaliy V.
Published: July 2002

A nonlinear equation for a curved stationary flame subject to the Darrieus–Landau instability is obtained for an arbitrary ratio of the fuel density and the density of the burnt matter under the assumptions of a thin flame front and weak nonlinearity. On the basis of the nonlinear equation the velocity of a two-dimensional curved stationary flame is calculated. The obtained velocity is in a good agreement with the results of two-dimensional simulations of flame dynamics in tubes.
Influence of the geometry on the structure of the flow between a pair of corotating disks
Authors: Herrero Joan , Giralt Francesc , Humphrey Joseph A. C.
Published: July 2002

Constant-property laminar flow in the space between two coaxial disks corotating in a fixed cylindrical enclosure is investigated numerically over the Reynolds number range 0⩽Re⩽82 380 for interdisk spacing to disk radius aspect ratios in the range 0.05⩽S⩽0.20. Most of the 3D calculations correspond to regions in the (Re, S) map slightly above the 2D–3D transition, where the 2D (axisymmetric) steady flow can bifurcate into two different families of unsteady 3D flow; (a) at sufficiently large values of S or Re, into a flow that is asymmetric with respect to the interdisk midplane; (b) at intermediate values of S and Re, into a flow that displays shift-and-reflect symmetry with respect to the interdisk midplane. Qualitative and quantitative comparisons with previous experimental and numerical results are established. The structure of the 3D flow is analyzed as well as the jumps in wave frequency when it experiences a change in its circumferential wave length. It is shown that each family of 3D flows is characterized by a distinct behavior in the frequency/wave length transitions. Present calculations and analysis provide the necessary additional evidence about the duality of this class of flows to reinterpret the numerical and experimental results previously reported by Humphrey et al. [Phys. Fluids 7, 1225 (1995)] and Abrahamson et al. [Phys. Fluids A 1, 241 (1989)].
Characterization of helicon waves in a magnetized inductive discharge
Authors: Degeling Alex , Mikhelson Nikolai , Boswell Rod , Sadeghi Nader
Published: July 2002

The propagation of helicon waves and the plasma density has been measured in a cylindrical, magnetized plasma for a range of magnetic fields and input power levels. A transition in the coupling mechanism from electrostatic (E mode) to inductive (H mode) coupling is evidenced by a sharp change in the plasma density coinciding with a change in the wave fields from a linearly polarized standing wave, with highest amplitude close to the antenna to a right-hand elliptically polarized traveling wave with a phase velocity of about 6×106 m/s extending into the downstream region. An explanation of the transition to the H mode is put forward in terms of the conductivity across the magnetic field and an associated skin depth for power deposition. The polarization of the wave fields in the H mode is interpreted in terms of the interference between m=+1 and −1 modes (where m is the azimuthal mode number).
Non local-thermodynamical-equilibrium effects in the simulation of laser-produced plasmas
Authors: Klapisch M. , Bar-Shalom A. , Oreg J. , Colombant D.
Published: July 2002

Local thermodynamic equilibrium (LTE) breaks down in directly or indirectly driven laser plasmas because of sharp gradients, energy deposition, etc. For modeling non-LTE effects in hydrodynamical simulations, Busquet’s model [Phys. Fluids B 5, 4191 (1993)] is very convenient and efficient. It uses off-line generated LTE opacities and equation of states via an effective, radiation-dependent ionization temperature Tz. An overview of the model is given. The results are compared with an elaborate collisional radiative model based on superconfigurations. The agreements for average charge Z* and opacities are surprisingly good, even more so when the plasma is immersed in a radiation field. Some remaining discrepancy at low density is attributed to dielectronic recombination. Improvement appears possible, especially for emissivities, because the concept of ionization temperature seems to be validated.
Nonlinear field line resonances: Dispersive effects
Authors: Frycz P. , Rankin R. , Samson J. C. , Tikhonchuk V. T.
Published: July 2002

A model is presented which describes the nonlinear interaction of dispersive shear Alfvén wave (SAW) field line resonances (FLRs) and ion acoustic waves (IAWs), with applications to the Earth’s magnetosphere. Two limits are considered: In low-β plasma (β<me/mi), dispersion is dominated by electron inertia (EI), while for higher β it is dominated by the electron thermal effect. In each case, the ponderomotive force steepens the SAW in the radial direction, taken as earthward in the equatorial plane. Following the time of nonlinear steepening, the dynamics strongly depends on dispersion. In the EI case, standing SAWs excited in FLRs exhibit a parametric decay instability (PDI) into secondary SAWs and IAWs. Nonlinearity and dispersion broaden the FLR in the radial direction, leading to rapid density and parallel electric field fluctuations and scale lengths comparable to the EI length. In warm plasmas, SAWs are stable to the PDI, and in this case the FLR emits short perpendicular scale SAW-IAW solitons in the anti-earthward direction. Observational consequences of both scenarios are discussed.
Experimental studies of bandwidth and power production in a three-cavity, 35 GHz gyroklystron amplifier
Authors: Calame J. P. , Garven M. , Choi J. J. , Nguyen K. , Wood F. , Blank M. , Danly B. G. , Levush B.
Published: July 2002

The operating characteristics of a three-cavity, Ka-Band gyroklystron employing a large amount of stagger-tuning are reported. Particular attention is given to examining how the frequency response (peak power, bandwidth, and overall shape) is altered by changes in operating parameters. A peak power of 225 kW at 34.90 GHz, with a 2 μs pulse length, 32% efficiency, 30.3 dB saturated gain, and a 3 dB bandwidth of 0.82% (286 MHz) was obtained with a 70.2 kV, 10.0 A beam at a magnetic field of 13.07 kG. This operating point represents a compromise between the output power and the bandwidth. The operating magnetic field was found to have a dramatic influence on the power–bandwidth tradeoff; a lower field of 12.91 kG produced 245 kW with 0.63% bandwidth, while a higher field of 13.39 kG increased the bandwidth to 0.94% at a lower power of 200 kW. The results are in excellent agreement with large signal simulations.
Richtmyer–Meshkov-like instabilities and early-time perturbation growth in laser targets and Z-pinch loads
Authors: Velikovich A. L. , Dahlburg J. P. , Schmitt A. J. , Gardner J. H. , Phillips L. , Cochran F. L. , Chong Y. K. , Dimonte G. , Metzler N.
Published: July 2002

The classical Richtmyer–Meshkov (RM) instability develops when a planar shock wave interacts with a corrugated interface between two different fluids. A larger family of so-called RM-like hydrodynamic interfacial instabilities is discussed. All of these feature a perturbation growth at an interface, which is driven mainly by vorticity, either initially deposited at the interface or supplied by external sources. The inertial confinement fusion relevant physical conditions that give rise to the RM-like instabilities range from the early-time phase of conventional ablative laser acceleration to collisions of plasma shells (like components of nested-wire-arrays, double-gas-puff Z-pinch loads, supernovae ejecta and interstellar gas). In the laser ablation case, numerous additional factors are involved: the mass flow through the front, thermal conduction in the corona, and an external perturbation drive (laser imprint), which leads to a full stabilization of perturbation growth. In contrast with the classical RM case, mass perturbations can exhibit decaying oscillations rather than a linear growth. It is shown how the early-time perturbation behavior could be controlled by tailoring the density profile of a laser target or a Z-pinch load, to diminish the total mass perturbation seed for the Rayleigh–Taylor instability development.
The role of Trivelpiece–Gould waves in antenna coupling to helicon waves
Authors: Arnush Donald
Published: July 2002

It is well known that the simple theory of helicon waves, in which the electron mass me is neglected, is valid only if Ez also vanishes, a condition which is not satisfied in experiment. Exact solutions of cold plasma theory with finite me and Ez predict the existence of additional highly damped Trivelpiece–Gould (TG) modes (H-TG theory), which can greatly modify the nature of helicon discharges. However, most experiments have been explained using only the simple theory for which the helicon waves are undamped. In that case, antenna-plasma-coupling calculations predict infinite resonances. To avoid this problem theorists have set Ez=0 and included finite me effects (the TE-H theory). By comparing the TE-H theory with exact (i.e., closed form) solutions for uniform density, the role of TG modes has been clarified. To do so for nonuniform density, a new algorithm is developed to treat the case of high magnetic fields, when the wave equation becomes singular. The results show that, though the wave patterns are not greatly affected by TG modes except at low magnetic fields or near the radial boundary, the kz spectrum and radial profile of the energy deposition are greatly modified. In particular, the peaks in the TE-H-mode spectrum, which lead to predictions of erroneously high antenna loading, are suppressed and broadened by the TG modes which also produce high edge absorption. Both the TE-H and exact theories give maximum antenna loading for 12me(ω/k)2≈10–100 eV, in contrast to several hundred electron volts predicted by the simple theory.
Defect reduction in GaAs epitaxial layers using a GaAsP-InGaAs strained-layer superlattice
Authors: Tischler M. A. , Katsuyama T. , El-Masry N. A. , Bedair S. M.
Published: July 2002

GaAsP-InGaAs strained-layer superlattices grown lattice matched to GaAs have been used to reduce the density of threading dislocations originating from the GaAs substrate. GaAs epitaxial layers grown on the GaAsP-InGaAs superlattice buffer layers showed a dislocation density lower by at least an order of magnitude than that obtained from epitaxial layers grown directly on GaAs substrates. Transmission electron microscopy showed that dislocations originating from the GaAs substrate do not penetrate the GaAsP-InGaAs superlattice layers.
Photoreflectance study of GaAs/AlAs superlattices: Fit to electromodulation theory
Authors: Shen H. , Parayanthal P. , Pollak Fred H. , Tomkiewicz Micha , Drummond T. J. , Schulman J. N.
Published: July 2002

The photoreflectance (PR) spectra of several GaAs/AlAs superlattices have been measured at 300 and 77 K using monochromatic light sources (laser or monochromator) as a secondary (pump) beam, thus enabling us to study the wavelength dependence of the PR. We demonstrate for the first time that electromodulation spectra from superlattices can be fit by a third derivative functional line shape, thus making it possible to precisely determine energies, broadening parameters, amplitudes, and phases of the spectral features. This result greatly enhances the usefulness of electromodulation to study and characterize these structures. The wavelength dependence of the PR shows that there is more than one PR mechanism in superlattices, in contrast to bulk material.
Finite element design of diamond anvils
Authors: Moss William C. , Goettel Kenneth A.
Published: July 2002

We have performed finite element analyses of beveled diamond anvils. Our analyses show that double beveling can improve the performance of the diamond anvil cell and maintain the stability of the sample, which is often sacrificed when large angle single bevel diamonds are used.
Increase of doping efficiency by light soaking in boron-doped hydrogenated amorphous silicon
Authors: Jang Jin , Park Seung Chul , Kim Sung Chul , Lee Choochon
Published: July 2002

Boron-doped hydrogenated amorphous silicon deposited at 100 °C exhibits a decrease of dark conductivity and an increase of doping efficiency, simultaneously, during band-gap light illumination. We prove that these two effects are bulk effects and that their origins are different. The decrease in dark conductivity is due to the creation of dangling bonds. On the other hand, the increase in doping efficiency anneals out with an activation energy of 1.66 eV. The increase in stretching mode absorption of boron-hydrogen has been observed after light soaking for the amorphous silicon-boron alloy film, and this appears to be related with the increase in doping efficiency of boron.
Quantum well avalanche multiplication initiated by 10 μm intersubband absorption and photoexcited tunneling
Authors: Levine B. F. , Choi K. K. , Bethea C. G. , Walker J. , Malik R. J.
Published: July 2002

We have achieved avalanche gain at a wavelength of 10.3 μm in AlxGa1−xAs/GaAs quantum well superlattices. The photoelectrons are generated by resonant intersubband absorption and tunneling, and then avalanche via hot-electron impact ionization of carriers out of the quantum wells. Good agreement is obtained between a theoretical calculation of this process and our experiments.
Identification of gene function and functional pathways by systemic plasmid-based ribozyme targeting in adult mice
Authors: Kashani-Sabet Mohammed , Liu Yong , Fong Sylvia , Desprez Pierre-Yves , Liu Shuqing , Tu Guanghuan , Nosrati Mehdi , Handumrongkul Chakkrapong , Liggitt Denny , Thor Ann D. , Debs Robert J.
Published: July 2002

To date, functional genomic studies have been confined to either cell-based assays or germline mutations, using transgenic or knockout animals. However, these approaches are often unable either to recapitulate complex biologic phenotypes, such as tumor metastasis, or to identify the specific genes and functional pathways that produce serious diseases in adult animals. Although the transcription factor NF-κB transactivates many metastasis-related genes in cells, the precise genes and functional-pathways through which NF-κB regulates metastasis in tumor-bearing hosts are poorly understood. Here, we show that the systemic delivery of plasmid-based ribozymes targeting NF-κB in adult, tumor-bearing mice suppressed NF-κB expression in metastatic melanoma cells, as well as in normal cell types, and significantly reduced metastatic spread. Plasmid-based ribozymes suppressed target-gene expression with sequence specificity not achievable by using synthetic oligonucleotide-based approaches. NF-κB seemed to regulate tumor metastasis through invasion-related, rather than angiogenesis-, cell-cycle- or apoptosis-related pathways in tumor-bearing mice. Furthermore, ribozymes targeting either of the NF-κB-regulated genes, integrin β
3
or PECAM-1 (a ligand-receptor pair linked to cell adhesion), reduced tumor metastasis at a level comparable to NF-κB. These studies demonstrate the utility of gene targeting by means of systemic, plasmid-based ribozymes to dissect out the functional genomics of complex biologic phenotypes, including tumor metastasis.
Apoptosis in neural crest cells by functional loss of APC tumor suppressor gene
Authors: Hasegawa Sumitaka , Sato Tomoyuki , Akazawa Hiroshi , Okada Hitoshi , Maeno Akiteru , Ito Masaki , Sugitani Yoshinobu , Shibata Hiroyuki , Miyazaki Jun-ichi , Katsuki Motoya , Yamauchi Yasutaka , Yamamura Ken-ichi , Katamine Shigeru , Noda Tetsuo
Published: July 2002

Apc
is a gene associated with familial adenomatous
polyposis coli (FAP) and its inactivation is a critical step in
colorectal tumor formation. The protein product, adenomatous
polyposis coli (APC), acts to down-regulate intracellular levels of
β-catenin, a key signal transducer in the Wnt signaling. Conditional
targeting of
Apc
in the neural crest of mice caused
massive apoptosis of cephalic and cardiac neural crest cells at
about 11.5 days post coitum, resulting in craniofacial and cardiac
anomalies at birth. Notably, the apoptotic cells localized in
the regions where β-catenin had accumulated. In contrast to its role
in colorectal epithelial cells, inactivation of APC leads to
dysregulation of β-catenin/Wnt signaling with resultant
apoptosis in certain tissues including neural crest cells.
IL-6 transgenic mouse model for extraosseous plasmacytoma
Authors: Kovalchuk Alexander L. , Kim Joong Su , Park Sung Sup , Coleman Allen E. , Ward Jerrold M. , Morse Herbert C. , Kishimoto Tadamitsu , Potter Michael , Janz Siegfried
Published: July 2002

Plasma cell neoplasms in humans comprise plasma cell myeloma, otherwise known as multiple myeloma, Ig deposition and heavy chain diseases, and plasmacytoma (PCT). A subset of PCT, designated extramedullary PCT, is distinguished from multiple myeloma and solitary PCT of bone by its distribution among various tissue sites but not the bone marrow. Extramedullary (extraosseus) PCT are rare spontaneous neoplasms of mice but are readily induced in a susceptible strain, BALB/c, by treatment with pristane. The tumors develop in peritoneal granulomas and are characterized by
Myc
-activating T(12;15) chromosomal translocations and, most frequently, by secretion of IgA. A uniting feature of human and mouse plasma cell neoplasms is the critical role played by IL-6, a B cell growth, differentiation, and survival factor. To directly test the contribution of IL-6 to PCT development, we generated BALB/c mice carrying a widely expressed IL-6 transgene. All mice exhibited lymphoproliferation and plasmacytosis. By 18 months of age, over half developed readily transplantable PCT in lymph nodes, Peyer's patches, and sometimes spleen. These neoplasms also had T(12;15) translocations, but remarkably, none expressed IgA. Unexpectedly, ≈30% of the mice developed follicular and diffuse large cell B cell lymphomas that often coexisted with PCT. These findings provide a unique model of extramedullary PCT for studies on pathogenesis and treatment and suggest a previously unappreciated role for IL-6 in the genesis of germinal center-derived lymphomas.
Direct visualization at the single-cell level of electrically mediated gene delivery
Authors: Golzio Muriel , Teissié Justin , Rols Marie-Pierre
Published: July 2002

Electropermeabilization is one of the nonviral methods successfully used to transfer genes into living cells
in vitro
and
in vivo
. Although this approach shows promise in the field of gene therapy, very little is known about the basic processes supporting DNA transfer. The present investigation studies this process at the single-cell level by using digitized fluorescence microscopy. Permeabilization is a prerequisite for gene transfer. Its assay by propidium-iodide (PI) penetration shows that it occurs at the sides of the cell membrane facing the two electrodes, whereas fluorescently labeled plasmids only interact with the electropermeabilized side of the cell facing the cathode. The plasmid interaction with the electropermeabilized part of the cell surface results in the formation of localized aggregates. These membrane-associated spots are formed only when pulses with a longer duration than a critical value are applied. These complexes are formed within 1 s after the pulses and cannot be destroyed by pulses of reversed polarities. They remain at the membrane level up to 10 min after pulsing. Although freely accessible to DNA dye (TOTO-1) 1 min after the pulses, they are fully protected when the addition takes place 10 min after. They diffuse in the cytoplasm 30 min after pulses and are present around the nucleus 24 h later.
A space-time structure determination of human CD2 reveals the CD58-binding mode
Authors: Kitao Akio , Wagner Gerhard
Published: July 2002

We describe a procedure for a space-time description of protein structures. The method is capable of determining populations of conformational substates, and amplitudes and directions of internal protein motions. This is achieved by fitting static and dynamic NMR data. The approach is based on the jumping-among-minima concept. First, a wide conformational space compatible with structural NMR data is sampled to find a large set of substates. Subsequently, intrasubstate motions are sampled by using molecular dynamics calculations with force field energy terms. Next, the populations of substates are fitted to NMR relaxation data. By diagonalizing a second moment matrix, directions and amplitudes of motions are identified. The method was applied to the adhesion domain of human CD2. We found that very few substates can account for most of the experimental data. Furthermore, only two types of collective motions have high amplitudes. They represent transitions between a concave (closed) and flat (open) binding face and resemble the change upon counter-receptor (CD58) binding.
High-quality life extension by the enzyme peptide methionine sulfoxide reductase
Authors: Ruan Hongyu , Tang Xiang Dong , Chen M.-L. , Joiner M. A. , Sun Guangrong , Brot Nathan , Weissbach Herbert , Heinemann Stephen H. , Iverson Linda , Wu Chun-Fang , Hoshi Toshinori
Published: July 2002

Cumulative oxidative damages to cell constituents are considered to contribute to aging and age-related diseases. The enzyme peptide methionine sulfoxide reductase A (MSRA) catalyzes the repair of oxidized methionine in proteins by reducing methionine sulfoxide back to methionine. However, whether MSRA plays a role in the aging process is poorly understood. Here we report that overexpression of the
msrA
gene predominantly in the nervous system markedly extends the lifespan of the fruit fly
Drosophila
. The MSRA transgenic animals are more resistant to paraquat-induced oxidative stress, and the onset of senescence-induced decline in the general activity level and reproductive capacity is delayed markedly. The results suggest that oxidative damage is an important determinant of lifespan, and MSRA may be important in increasing the lifespan in other organisms including humans.
5-Lipoxygenase is phosphorylated by p38 kinase-dependent MAPKAP kinases
Authors: Werz Oliver , Klemm Jenny , Samuelsson Bengt , Rådmark Olof
Published: July 2002

5-lipoxygenase (5-LO) catalyzes the initial steps in the formation of leukotrienes, a group of inflammatory mediators derived from arachidonic acid (AA). Here we describe that activation of p38 mitogen-activated protein kinase in human polymorphonuclear leukocytes and in Mono Mac 6 cells leads to activation of downstream kinases, which can subsequently phosphorylate 5-LOin vitro. Different agents activated the 5-LO kinase activities, including stimuli for cellular leukotriene biosynthesis (A23187, thapsigargin,N-formyl-leucyl-phenylalanine), compounds that up-regulate the capacity for leukotriene biosynthesis (phorbol 12-myristate 13-acetate, tumor necrosis factor α, granulocyte/macrophage colony-stimulating factor), and well known p38 stimuli as sodium arsenite and sorbitol. For all stimuli, 5-LO kinase activation was counteracted by SB203580 (3 μM or less), an inhibitor of p38 kinase. At least two p38-dependent 5-LO kinase activities were found. Based on migration properties in in-gel kinase assays and immunoreactivity, one of these was identified as mitogen-activated protein kinase-activated protein kinase 2 (MAPKAP kinase 2). The other appeared to be MAPKAP kinase 3; however, it could not be excluded that also other p38-dependent kinases contributed. When polymorphonuclear leukocytes were incubated with sodium arsenite (strong activator of 5-LO kinases), platelet-activating factor and exogenous AA, there was a 4-fold increase in 5-LO activity as compared with incubations with only platelet-activating factor and AA. This indicates that 5-LO phosphorylation can be one factor determining cellular 5-LO activity.
A yeast-like mRNA capping apparatus in
Plasmodium falciparum
Authors: Ho C. Kiong , Shuman Stewart
Published: July 2002

Analysis of the mRNA capping apparatus of the malaria parasite
Plasmodium falciparum
illuminates an evolutionary
connection to fungi rather than metazoans. We show that
P.
falciparum
encodes separate RNA guanylyltransferase (Pgt1) and
RNA triphosphatase (Prt1) enzymes and that the triphosphatase component
is a member of the fungal/viral family of metal-dependent
phosphohydrolases, which are structurally and mechanistically unrelated
to the cysteine-phosphatase-type RNA triphosphatases found in metazoans
and plants. These results highlight the potential for discovery of
mechanism-based antimalarial drugs designed to specifically block the
capping of
Plasmodium
mRNAs. A simple heuristic scheme
of eukaryotic phylogeny is suggested based on the structure and
physical linkage of the triphosphatase and guanylyltransferase enzymes
that catalyze cap formation.
Role of the arginine-nitric oxide pathway in the regulation of vascular smooth muscle cell proliferation
Authors: Ignarro Louis J. , Buga Georgette M. , Wei Liu Hua , Bauer Philip M. , Wu Guoyao , del Soldato Piero
Published: July 2002

The objective of this study was to elucidate the mechanisms
by which nitric oxide (NO) inhibits rat aortic smooth muscle cell
(RASMC) proliferation. Two products of the arginine-NO pathway
interfere with cell growth by distinct mechanisms.
N
G
-hydroxyarginine and NO appear to interfere with cell
proliferation by inhibiting arginase and ornithine decarboxylase (ODC),
respectively.
S
-nitroso-
N
-acetylpenicillamine,
(
Z
)-1-[
N
-(2-aminoethyl)-
N
-(2-aminoethyl)-amino]-diazen-1-ium-1,2-diolate,
and a nitroaspirin derivative (NCX 4016), each of which is a NO donor
agent, inhibited RASMC growth at concentrations of 1–3 μM by
cGMP-independent mechanisms. The cytostatic action of the NO donor
agents as well as α-difluoromethylornithine (DFMO), a known ODC
inhibitor, was prevented by addition of putrescine but not ornithine.
These observations suggested that NO, like DFMO, may directly inhibit
ODC. Experiments with purified, recombinant mammalian ODC revealed that
NO inhibits ODC possibly by S-nitrosylation of the active site cysteine
in ODC. DFMO, as well as the NO donor agents, interfered with cellular
polyamine (putrescine, spermidine, spermine) production. Conversely,
increasing the expression and catalytic activity of arginase I in RASMC
either by transfection of cells with the arginase I gene or by
induction of arginase I mRNA with IL-4 resulted in increased urea and
polyamine production as well as cell proliferation. Finally, coculture
of rat aortic endothelial cells, which had been pretreated with
lipopolysaccharide plus a cytokine mixture to induce NO synthase and
promote NO production, caused NO-dependent inhibition of target RASMC
proliferation. This study confirms the inhibitory role of the
arginine-NO pathway in vascular smooth muscle proliferation and
indicates that one mechanism of action of NO is cGMP-independent and
attributed to its capacity to inhibit ODC.
From reactants to products via simple hydrogen-bonding networks: Information transmission in chemical reactions
Authors: Brancato Giuseppe , Coutrot Frédéric , Leigh David A. , Murphy Aden , Wong Jenny K. Y. , Zerbetto Francesco
Published: July 2002

The transmission of information is ubiquitous in nature and often occurs through supramolecular hydrogen bonding processes. Here we report that there is a remarkable correlation during synthesis between the efficiency of the hydrogen-bond-directed assembly of peptide-based [2]rotaxanes and the symmetry distortion of the macrocycle in the structure of the final product. It transpires that the ability of the flexible macrocycle-precursor to wrap around an unsymmetrical hydrogen bonding template affects both the reaction yield and a quantifiable measure of the symmetry distortion of the macrocycle in the product. When the yields of peptide rotaxane-forming reactions are high, so is the symmetry distortion in the macrocycle; when the yields are low, indicating a poor fit between the components, the macrocycle symmetry is relatively unaffected by the thread. Thus during a synthetic sequence, as in complex biological assembly processes, hydrogen bonding can code and transmit “information”—in this case a distortion from symmetry—between chemical entities by means of a supramolecularly driven multicomponent assembly process. If this phenomenon is general, it could have far reaching consequences for the use of supramolecular-directed reactions in organic chemistry.
Genetic programs of epithelial cell plasticity directed by transforming growth factor-β
Authors: Zavadil Jiri , Bitzer Markus , Liang Dan , Yang Yaw-Ching , Massimi Aldo , Kneitz Susanne , Piek Ester , Böttinger Erwin P.
Published: July 2002

Epithelial–mesenchymal transitions (EMTs) are an essential
manifestation of epithelial cell plasticity during morphogenesis, wound
healing, and tumor progression. Transforming growth factor-β
(TGF-β) modulates epithelial plasticity in these physiological
contexts by inducing EMT. Here we report a transcriptome screen of
genetic programs of TGF-β-induced EMT in human keratinocytes and
propose functional roles for extracellular response kinase (ERK)
mitogen-activated protein kinase signaling in cell motility and
disruption of adherens junctions. We used DNA arrays of 16,580 human
cDNAs to identify 728 known genes regulated by TGF-β within 4 hours
after treatment. TGF-β-stimulated ERK signaling mediated regulation
of 80 target genes not previously associated with this pathway. This
subset is enriched for genes with defined roles in cell–matrix
interactions, cell motility, and endocytosis. ERK-independent genetic
programs underlying the onset of EMT involve key pathways and
regulators of epithelial dedifferentiation, undifferentiated
transitional and mesenchymal progenitor phenotypes, and mediators of
cytoskeletal reorganization. The gene expression profiling approach
delineates complex context-dependent signaling pathways and
transcriptional events that determine epithelial cell plasticity
controlled by TGF-β. Investigation of the identified pathways and
genes will advance the understanding of molecular mechanisms that
underlie tumor invasiveness and metastasis.
Neuronal loss and brain atrophy in mice lacking cathepsins B and L
Authors: Felbor Ute , Kessler Benedikt , Mothes Walther , Goebel Hans H. , Ploegh Hidde L. , Bronson Roderick T. , Olsen Bjorn R.
Published: July 2002

Cathepsins B and L are widely expressed cysteine proteases implicated in both intracellular proteolysis and extracellular matrix remodeling. However, specific roles remain to be validated
in vivo
. Here we show that combined deficiency of cathepsins B and L in mice is lethal during the second to fourth week of life. Cathepsin B
−/−
/L
−/−
mice reveal a degree of brain atrophy not previously seen in mice. This is because of massive apoptosis of select neurons in the cerebral cortex and the cerebellar Purkinje and granule cell layers. Neurodegeneration is accompanied by pronounced reactive astrocytosis and is preceded by an accumulation of ultrastructurally and biochemically unique lysosomal bodies in large cortical neurons and by axonal enlargements. Our data demonstrate a pivotal role for cathepsins B and L in maintenance of the central nervous system.
The transcription factor EPAS-1/hypoxia-inducible factor 2α plays an important role in vascular remodeling
Authors: Peng Jun , Zhang Liyong , Drysdale Linsay , Fong Guo-Hua
Published: July 2002

We have studied the role of the basic helix–loop–helix–PAS transcription factor EPAS-1/hypoxia-inducible factor 2α in vascular development by gene targeting. In ICR/129 Sv outbred background, more than half of the mutants displayed varying degrees of vascular disorganization, typically in the yolk sac, and died
in utero
between embryonic day (E)9.5 and E13.5. In mutant embryos directly derived from
EPAS-1
−/−
embryonic stem cells (hence in 129 Sv background), all embryos developed severe vascular defects both in the yolk sac and embryo proper and died between E9.5 and E12.5. Normal blood vessels were formed by vasculogenesis but they either fused improperly or failed to assemble into larger vessels later during development. Our results suggest that EPAS-1 plays an important role at postvasculogenesis stages and is required for the remodeling of the primary vascular network into a mature hierarchy pattern.
Brain-wave representation of words by superposition of a few sine waves
Authors: Suppes Patrick , Han Bing
Published: July 2002

Data from three previous experiments were analyzed to test the hypothesis that brain waves of spoken or written words can be represented by the superposition of a few sine waves. First, we averaged the data over trials and a set of subjects, and, in one case, over experimental conditions as well. Next we applied a Fourier transform to the averaged data and selected those frequencies with high energy, in no case more than nine in number. The superpositions of these selected sine waves were taken as prototypes. The averaged unfiltered data were the test samples. The prototypes were used to classify the test samples according to a least-squares criterion of fit. The results were seven of seven correct classifications for the first experiment using only three frequencies, six of eight for the second experiment using nine frequencies, and eight of eight for the third experiment using five frequencies.
Evidence of nonspecific surface interactions between laser-polarized xenon and myoglobin in solution
Authors: Rubin Seth M. , Spence Megan M. , Goodson Boyd M. , Wemmer David E. , Pines Alexander
Published: July 2002

The high sensitivity of the magnetic resonance properties of xenon to its local chemical environment and the large
129
Xe NMR signals attainable through optical pumping have motivated the use of xenon as a probe of macromolecular structure and dynamics. In the present work, we report evidence for nonspecific interactions between xenon and the exterior of myoglobin in aqueous solution, in addition to a previously reported internal binding interaction.
129
Xe chemical shift measurements in denatured myoglobin solutions and under native conditions with varying xenon concentrations confirm the presence of nonspecific interactions. Titration data are modeled quantitatively with treatment of the nonspecific interactions as weak binding sites. Using laser-polarized xenon to measure
129
Xe spin-lattice relaxation times (
T
1
), we observed a shorter
T
1
in the presence of 1 mM denatured apomyoglobin in 6 M deuterated urea (
T
1
= 59 ± 1 s) compared with that in 6 M deuterated urea alone (
T
1
= 291 ± 2 s), suggesting that nonspecific xenon-protein interactions can enhance
129
Xe relaxation. An even shorter
T
1
was measured in 1 mM apomyoglobin in D
2
O (
T
1
= 15 ± 0.3 s), compared with that in D
2
O alone (
T
1
= 506 ± 5 s). This difference in relaxation efficiency likely results from couplings between laser-polarized xenon and protons in the binding cavity of apomyoglobin that may permit the transfer of polarization between these nuclei via the nuclear Overhauser effect.
Brain glucose utilization in mice with a targeted mutation in the thyroid hormone α or β receptor gene
Authors: Itoh Yoshiaki , Esaki Takanori , Kaneshige Masahiro , Suzuki Hideyo , Cook Michelle , Sokoloff Louis , Cheng Sheue-Yann , Nunez Jacques
Published: July 2002

Brain glucose utilization is markedly depressed in adult rats made
cretinous after birth. To ascertain which subtype of thyroid hormone
(TH) receptors, TRα1 or TRβ, is involved in the regulation of
glucose utilization during brain development, we used the
2-[
14
C]deoxyglucose method in mice with a mutation in
either their TRα or TRβ gene. A C insertion produced a frameshift
mutation in their carboxyl terminus. These mutants lacked TH binding
and transactivation activities and exhibited potent dominant negative
activity. Glucose utilization in the homozygous TRβPV mutant mice and
their wild-type siblings was almost identical in 19 brain regions,
whereas it was markedly reduced in all brain regions of the
heterozygous TRα1PV mice. These suggest that the α1 receptor
mediates the TH effects in brain. Inasmuch as local cerebral glucose
utilization is closely related to local synaptic activity, we also
examined which thyroid hormone receptor is involved in the expression
of synaptotagmin-related gene 1 (
Srg1
), a TH-positively
regulated gene involved in the formation and function of synapses
[Thompson, C. C. (1996)
J. Neurosci.
16,
7832–7840]. Northern analysis showed that Srg1 expression was
markedly reduced in the cerebellum of
TRα
PV/+
mice but not
TRβ
PV/PV
mice. These results show that the
same receptor, TRα1, is involved in the regulation by TH of both
glucose utilization and Srg1 expression.
The importance of being discrete: Life always wins on the surface
Authors: Shnerb Nadav M. , Louzoun Yoram , Bettelheim Eldad , Solomon Sorin
Published: July 2002

Many systems in chemistry, biology, finance, and social sciences present emerging features that are not easy to guess from the elementary interactions of their microscopic individual components. In the past, the macroscopic behavior of such systems was modeled by assuming that the collective dynamics of microscopic components can be effectively described collectively by equations acting on spatially continuous density distributions. It turns out that, to the contrary, taking into account the actual individual/discrete character of the microscopic components of these systems is crucial for explaining their macroscopic behavior. In fact, we find that in conditions in which the continuum approach would predict the extinction of all of the population (respectively the vanishing of the invested capital or the concentration of a chemical substance, etc.), the microscopic granularity insures the emergence of macroscopic localized subpopulations with collective adaptive properties that allow their survival and development. In particular it is found that in two dimensions “life” (the localized proliferating phase) always prevails.
Genomic organization of α1 and β1 subunits of the mammalian soluble guanylyl cyclase genes
Authors: Sharina I. G. , Krumenacker J. S. , Martin E. , Murad F.
Published: July 2002

The structures of the genes encoding the α
1
and
β
1
subunits of murine soluble guanylyl cyclase (sGC) were
determined. Full-length cDNAs isolated from mouse lungs encoding the
α
1
(2.5 kb) and β
1
(3.3 kb) subunits are
presented in this report. The α
1
sGC gene is
approximately 26.4 kb and contains nine exons, whereas the
β
1
sGC gene spans 22 kb and consists of 14 exons. The
positions of exon/intron boundaries and the sizes of introns for both
genes are described. Comparison of mouse genomic organization with the
Human Genome Database predicted the exon/intron boundaries of the
human genes and revealed that human and mouse α1 and β1 sGC genes
have similar structures. Both mouse genes are localized on the third
chromosome, band 3E3-F1, and are separated by a fragment that is 2% of
the chromosomal length. The 5′ untranscribed regions of
α
1
and β
1
subunit genes were subcloned into
luciferase reporter constructs, and the functional analysis of promoter
activity was performed in murine neuroblastoma N1E-115 cells. Our
results indicate that the 5′ untranscribed regions for both genes
possess independent promoter activities and, together with the data on
chromosomal localization, suggest independent regulation of both genes.
The kinetic basis of peptide exchange catalysis by HLA-DM
Authors: Zarutskie Jennifer A. , Busch Robert , Zavala-Ruiz Zarixia , Rushe Mia , Mellins Elizabeth D. , Stern Lawrence J.
Published: July 2002

The mechanism by which the peptide exchange factor HLA-DM catalyzes peptide loading onto structurally homologous class II MHC proteins is an outstanding problem in antigen presentation. The peptide-loading reaction of class II MHC proteins is complex and includes conformational changes in both empty and peptide-bound forms in addition to a bimolecular binding step. By using a fluorescence energy transfer assay to follow the kinetics of peptide binding to the human class II MHC protein HLA-DR1, we find that HLA-DM catalyzes peptide exchange by facilitating a conformational change in the peptide-bound complex, and not by promoting the bimolecular MHC–peptide reaction or the conversion between peptide-receptive and -averse forms of the empty protein. Thus, HLA-DM serves essentially as a protein-folding or conformational catalyst.
Formation of high molecular weight complexes of mutant Cu,Zn-superoxide dismutase in a mouse model for familial amyotrophic lateral sclerosis
Authors: Johnston Jennifer A. , Dalton Muffie J. , Gurney Mark E. , Kopito Ron R.
Published: July 2002

Deposition of aggregated protein into neurofilament-rich
cytoplasmic inclusion bodies is a common cytopathological feature of
neurodegenerative disease. How—or indeed whether—protein aggregation
and inclusion body formation cause neurotoxicity are presently unknown.
Here, we show that the capacity of superoxide dismutase (SOD) to
aggregate into biochemically distinct, high molecular weight, insoluble
protein complexes (IPCs) is a gain of function associated with
mutations linked to autosomal dominant familial amyotrophic lateral
sclerosis. SOD IPCs are detectable in spinal cord extracts from
transgenic mice expressing mutant SOD several months before inclusion
bodies and motor neuron pathology are apparent. Sequestration of mutant
SOD into cytoplasmic inclusion bodies resembling aggresomes requires
retrograde transport on microtubules. These data indicate that
aggregation and inclusion body formation are mechanistically and
temporally distinct processes.
Aquaporin 5-deficient mouse lungs are hyperresponsive to cholinergic stimulation
Authors: Krane Carissa M. , Fortner Christopher N. , Hand Arthur R. , McGraw Dennis W. , Lorenz John N. , Wert Susan E. , Towne Jennifer E. , Paul Richard J. , Whitsett Jeffrey A. , Menon Anil G.
Published: July 2002

Although aquaporin 5 (AQP5) is the major water channel expressed in alveolar type I cells in the lung, its actual role in the lung is a matter of considerable speculation. By using immunohistochemical staining, we show that AQP5 expression in mouse lung is not restricted to type I cells, but is also detected in alveolar type II cells, and in tracheal and bronchial epithelium.
Aqp5
knockout (
Aqp5
−/−
) mice were used to analyze AQP5 function in pulmonary physiology. Compared with
Aqp5
+/+
mice,
Aqp5
−/−
mice show a significantly increased concentration-dependent bronchoconstriction to intravenously administered Ach, as shown by an increase in total lung resistance and a decrease in dynamic lung compliance (
P
< 0.05). Likewise, Penh, a measure of bronchoconstriction, was significantly enhanced in
Aqp5
−/−
mice challenged with aerosolized methacholine (
P
< 0.05). The hyperreactivity to bronchoconstriction observed in the
Aqp5
−/−
mice was not due to differences in tracheal smooth muscle contractility in isolated preparations or to altered levels of surfactant protein B. These data suggest a novel pathway by which AQP5 influences bronchoconstriction. This observation is of special interest because studies to identify genetic loci involved in airway hyperresponsiveness associated with asthma bracket genetic intervals on human chromosome 12q and mouse chromosome 15, which contain the
Aqp5
gene.
Higher macrophage inflammatory protein (MIP)-1α and MIP-1β levels from CD8+T cells are associated with asymptomatic HIV-1 infection
Authors: Cocchi Fiorenza , DeVico Anthony L. , Yarchoan Robert , Redfield Robert , Cleghorn Farley , Blattner William A. , Garzino-Demo Alfredo , Colombini-Hatch Sandra , Margolis David , Gallo Robert C.
Published: July 2002

To test the hypothesis that β-chemokine levels may be relevant to the control of HIVin vivo, we compared RANTES, MIP-1α, and MIP-1β production from purified CD8+T cells from 81 HIV-infected subjects and from 28 uninfected donors. Asymptomatic HIV+subjects produced significantly higher levels of MIP-1α and MIP-1β, but not RANTES, than uninfected donors or patients that progressed to AIDS. In contrast, β chemokines in plasma were either nondetectable or showed no correlation with clinical status. The high β-chemokine-mediated anti-HIV activity was against the macrophage tropic isolate HIV-1BAL, with no demonstrable effect on the replication of the T-cell tropic HIV-1IIIB. These findings suggest that constitutive β-chemokine production may play an important role in the outcome of HIV-1 infection.
Structural determinants of ligand binding selectivity between the peroxisome proliferator-activated receptors
Authors: Xu H. Eric , Lambert Millard H. , Montana Valerie G. , Plunket Kelli D. , Moore Linda B. , Collins Jon L. , Oplinger Jeffery A. , Kliewer Steven A. , Gampe Robert T. , McKee David D. , Moore John T. , Willson Timothy M.
Published: July 2002

The peroxisome proliferator-activated receptors (PPARs) are transcriptional regulators of glucose, lipid, and cholesterol metabolism. We report the x-ray crystal structure of the ligand binding domain of PPARα (NR1C1) as a complex with the agonist ligand GW409544 and a coactivator motif from the steroid receptor coactivator 1. Through comparison of the crystal structures of the ligand binding domains of the three human PPARs, we have identified molecular determinants of subtype selectivity. A single amino acid, which is tyrosine in PPARα and histidine in PPARγ, imparts subtype selectivity for both thiazolidinedione and nonthiazolidinedione ligands. The availability of high-resolution cocrystal structures of the three PPAR subtypes will aid the design of drugs for the treatments of metabolic and cardiovascular diseases.
AtHKT1 is a salt tolerance determinant that controls Na
+
entry into plant roots
Authors: Rus Ana , Yokoi Shuji , Sharkhuu Altanbadralt , Reddy Muppala , Lee Byeong-ha , Matsumoto Tracie K. , Koiwa Hisashi , Zhu Jian-Kang , Bressan Ray A. , Hasegawa Paul M.
Published: July 2002

Two
Arabidopsis thaliana
extragenic mutations that suppress NaCl hypersensitivity of the
sos3–1
mutant were identified in a screen of a T-DNA insertion population in the genetic background of Col-0
gl1 sos3–1
. Analysis of the genome sequence in the region flanking the T-DNA left border indicated that
sos3–1 hkt1–1
and
sos3–1 hkt1–2
plants have allelic mutations in
AtHKT1. AtHKT1
mRNA is more abundant in roots than shoots of wild-type plants but is not detected in plants of either mutant, indicating that this gene is inactivated by the mutations.
hkt1–1
and
hkt1–2
mutations can suppress to an equivalent extent the Na
+
sensitivity of
sos3–1
seedlings and reduce the intracellular accumulation of this cytotoxic ion. Moreover,
sos3–1 hkt1–1
and
sos3–1 hkt1–2
seedlings are able to maintain [K
+
]
int
in medium supplemented with NaCl and exhibit a substantially higher intracellular ratio of K
+
/Na
+
than the
sos3–1
mutant. Furthermore, the
hkt1
mutations abrogate the growth inhibition of the
sos3–1
mutant that is caused by K
+
deficiency on culture medium with low Ca
2+
(0.15 mM) and <200 μM K
+
. Interestingly, the capacity of
hkt1
mutations to suppress the Na
+
hypersensitivity of the
sos3–1
mutant is reduced substantially when seedlings are grown in medium with low Ca
2+
(0.15 mM). These results indicate that AtHKT1 is a salt tolerance determinant that controls Na
+
entry and high affinity K
+
uptake. The
hkt1
mutations have revealed the existence of another Na
+
influx system(s) whose activity is reduced by high [Ca
2+
]
ext
.