bluuebunny/crossref_metadata_2025 huggingface dataset:
The Bohm–Chodura plasma sheath criterion
Authors: Stangeby P. C.
Published: July 2002

The ion flow velocity entering the Debye sheath is constrained to satisfy the Bohm criterion: velocity must be equal to or greater than sonic. The ion flow velocity entering the magnetic presheath (which arises upstream of the Debye sheath when a magnetic field, oblique to the solid surface is present) is constrained to satisfy the Chodura criterion: velocity-parallel to B must be equal to or greater than sonic. The Bohm criterion, in its marginal form where v=cs, is associated with a ‘‘gentle entry’’ into the sheath with Δne=Δni, while v≳cs corresponds to ‖Δne‖≳‖Δni‖. The magnetic presheath, in contrast with the Debye sheath, is a region of quasineutrality, and thus only Δne=Δni is permitted. This might appear to prohibit supersonic flow parallel to B at the entrance to the magnetic presheath, which the analysis of Chodura and Riemann has found to be permitted, in fact. This apparent contradiction is resolved by analyzing the magnetic presheath region to bring out more explicitly the role played by inertia in the E×B direction, thus confirming that such supersonic flow is permitted.
Solitary kinetic Alfvén waves in the two-fluid model
Authors: Wu De-Jin , Huang Guang-Li , Wang De-Yu , Fälthammar Carl-Gunne
Published: July 2002

Employing the two-fluid model, a generalized Sagdeev equation governing solitary kinetic Alfvén waves (SKAWs) and the criterion for the existence of SKAWs, which are valid for different ranges of plasma pressure parameter β, are presented. In the limit cases of β≫me/mi and β≪me/mi, the present results correspond, respectively, with conclusions obtained by Hasegawa et al. [Phys. Rev. Lett. 37, 690 (1976)] and by Shukla et al. [J. Plasma Phys. 28, 125 (1982)], that is, SKAWs accompanied by, respectively, hump and dip density solitons for β≫me/mi and β≪me/mi. However, for the case of β∼me/mi, the present results show that SKAWs accompanied by both hump and dip density solitons are possible, and lead to KdV solitons in the small amplitude limit. In addition, the possibility for applying these results to electromagnetic spikes observed by the Freja scientific satellite is discussed [detailed information about the Freja satellite experiments can be found in serial papers presented in Space Sci. Rev. 70, Nos. 3/4 (1994)].
Ion extraction from plasma by using a radio frequency resonant electric field
Authors: Matsui Tetsuya , Tsuchida Kazuki , Tsuda Shinji , Suzuki Kazumichi , Shoji Tatsuo
Published: July 2002

In order to raise an ion extraction efficiency from a plasma, a new method using an rf field has been proposed and demonstrated. The resonant frequencies of the rf field were theoretically evaluated to excite the eigenwave of the plasma. The lower frequency of the two plasma-sheath resonances under the magnetic field was selected because it has hardly any dependence on the plasma density when the density is over a critical value. Verification of this method was carried out using Xe discharge plasma (electron density, 1×1016 m−3; electron temperature, 8 eV) between the parallel plate electrodes (length, 0.5 m). The resonance was found at about 10 MHz, which agreed with the theoretical result. The ion current at the resonance was anisotropic and was twice as large as the ion saturated current, which is the limiting value of the conventional electrostatic method.
Two-dimensional solitary kinetic Alfvén waves and dipole vortex structures
Authors: Wu D. J. , Wang D. Y. , Huang G. L.
Published: July 2002

A new type of density soliton, which we call “dipole density soliton,’’ is discovered in data from the Freja satellite. Like the dip or hump density solitons that were recently discovered in the Freja data [D.-J. Wu, G.-L. Huang, and D.-Y. Wang, Phys. Plasmas 3, 2879 (1996)], the dipole density solitons are also associated with strong electric spikes (∼ a few 100 mV/m) and have a spatial scale length of a few 100 m. This indicates that the three types of density solitons (dip, hump, and dipole) probably have the same physical nature. In this paper, a two-dimensional solitary kinetic Alfvén wave (SKAW) model with a dipole vortex structure is proposed to account for the three kinds of density solitons (dip, hump, and dipole), in which the differences in their appearances can naturally be attributed to differences in the positions and directions at which the satellite crosses dipole vortex structures. Some features of this two-dimensional SKAW model are discussed, and the results are compared to the one-dimensional cases.
Modeling and design of millimeter wave gyroklystrons
Authors: Levush B. , Blank M. , Calame J. , Danly B. , Nguyen K. , Pershing D. , Cooke S. , Latham P. , Petillo J. , Antonsen T.
Published: July 2002

A series of high power, high efficiency Ka-band and W-band gyroklystron experiments has been conducted recently at the Naval Research Laboratory (NRL). Stagger tuning of the cavities for bandwidth enhancement is commonly used in the conventional multicavity klystrons. The desired stagger tuning is usually achieved via mechanical tuning of the individual cavities. However, in the millimeter wave regime, particularly, in the case of the high average power operation, it is desirable to be able to achieve the required stagger tuning by design. The NRL gyroklystron experiments explored the tradeoffs between power, bandwidth, efficiency, and gain to study the effects of large stagger tuning in millimeter wave without resorting to mechanical tuning of the cavities. Both, Ka-band and W-band, experiments demonstrated a record power-bandwidth product. The success of the experiments was due in large part to a battery of improved large-signal, stability, and cold test codes employed in the modeling and design stage. Theoretical models that provide the basis for these design simulation tools and the design methodology will be presented.
Solitary kinetic Alfvén waves in the inertial limit region
Authors: Chen Yao , Li Zhong-yuan , Liu Wei , Shi Zhi-Dong
Published: July 2002

Considering the effects of hot ions and Lorentz force, a numerical study on the properties of solitary kinetic Alfvén waves (SKAWs) in the inertial limit region in the magnetosphere is presented. In contrast to the results obtained by Hasegawa and Mima [Phys. Rev. Lett. 37, 690 (1976)], Shukla et al. [J. Plasma Phys. 28, 125 (1982)], and Wu et al. [Phys. Plasmas 3, 2879 (1996)], both hump and dip density Alfvénic solitons can exist in the inertial limit region (β≪2me/mi, where β(=2μ0nTe/B02) is the ratio of thermal pressure to magnetic pressure). These results provide a more realistic interpretation for the SKAWs phenomena observed by the Freja satellite, in which not only SKAWs accompanied by dip density solitons, but also SKAWs accompanied by hump density solitons were found at the Earth’s ionospheric altitude.
The effect of insulating coatings on exploding wire plasma formation
Authors: Sinars D. B. , Shelkovenko T. A. , Pikuz S. A. , Hu Min , Romanova V. M. , Chandler K. M. , Greenly J. B. , Hammer D. A. , Kusse B. R.
Published: July 2002

Substantial increases are reported in the expansion rates of exploding, dense wire cores under conditions simulating the prepulse phase of wire array z-pinch experiments [R. B. Spielman et al., Phys. Plasmas 5, 2105 (1998)] using wires with insulating coatings. The insulation apparently allows additional wire heating by delaying the formation of plasma around the wires. Once plasma is formed it terminates significant current flow in the residual wire cores. This effect is demonstrated for 25-μm diameter W and 25-μm diameter Ag wires.
Plasmas as antennas: Theory, experiment and applications
Authors: Borg G. G. , Harris J. H. , Martin N. M. , Thorncraft D. , Milliken R. , Miljak D. G. , Kwan B. , Ng T. , Kircher J.
Published: July 2002

In certain applications, the surface wave driven plasma column can replace metal as the guiding medium in radio frequency antennas. Such plasma antennas offer the possibility of low radar detectability and negligible mutual coupling when de-energized. Experimental results are presented confirming that the two most important physical issues, namely antenna efficiency and noise, are not compromised by the use of a plasma. It is also shown that the relatively high efficiency of the surface wave driven plasma column can be predicted by a simple calculation.
Growth characteristics of oxide precipitates in heavily doped silicon crystals
Authors: Matsumoto Satoru , Ishihara Ichiro , Kaneko Hiroyuki , Harada Hirofumi , Abe Takao
Published: July 2002

The doping concentration dependence on the growth of oxide precipitates has been studied using transmission electron microscopy in phosphorus and boron-doped silicon crystals. Samples were annealed at 800 and 850 °C for 24–384 h in dry nitrogen. In phosphorus-doped silicon, the precipitate density is not affected by the doping concentration, and the growth of precipitates is controlled by the diffusion of oxygen. On the other hand, the precipitate growth is suppressed in heavily boron-doped silicon as compared with that of lightly boron-doped silicon.
Tunneling hot-electron transfer amplifier: A hot-electron GaAs device with current gain
Authors: Heiblum M. , Thomas D. C. , Knoedler C. M. , Nathan M. I.
Published: July 2002

Tunneling hot-electron transfer amplifier (THETA) devices, based on GaAs-AlGaAs heterojunctions, were fabricated and tested. Hot-electron transfer (α) through a 1100-Å base in excess of 70% was found at 4.2 K. This resulted in a corresponding current gain ( β) in a common emitter configuration of about 2.3. In the temperature range of 4.2–80 K and under constant biasing conditions, α was nearly temperature independent. Electron energy distributions for motion normal to the layers and electron total energy loss while traversing the device were estimated. Typical widths of the energy distributions were less than 200 meV, and both widths and energy peak positions were only slightly dependent on temperature and initial injection energy.
Simple technique for separating the effects of interface traps and trapped-oxide charge in metal-oxide-semiconductor transistors
Authors: McWhorter P. J. , Winokur P. S.
Published: July 2002

A new technique is presented for separating the threshold-voltage shift of a metal-oxide-semiconductor transistor into shifts due to interface traps and trapped-oxide charge. This technique is applied to threshold-voltage shifts on an n-channel transistor that result from ionizing radiation.
Determination of the interdiffusion of Al and Ga in undoped (Al,Ga)As/GaAs quantum wells
Authors: Schlesinger T. E. , Kuech T.
Published: July 2002

We have employed photoluminescence spectroscopy to determine the temperature dependence of the interdiffusion coefficient of Al and Ga in GaAs/Al0.3Ga0.7As quantum wells. The position of the photoluminescence peaks, due to the n=1 electron to heavy-hole transition, was measured before and after annealing the samples. A variational calculation was employed to determine the expected position of these photoluminescence peaks and from this a value of the interdiffusion coefficient was extracted. The interdiffusion process is characterized by an activation energy of about 6 eV leading to an interdiffusion coefficient at 850 °C of 4×10−19 cm2/s. This technique allows for the measurement of small diffusion coefficients in a wide variety of material systems.
Morphology of Au/GaAs interfaces
Authors: Liliental-Weber Z. , Washburn J. , Newman N. , Spicer W. E. , Weber E. R.
Published: July 2002

The interface morphology of gold contacts on ultrahigh vacuum (UHV) cleaved, air-exposed, and chemically prepared GaAs surfaces has been studied by electron microscopy. Diodes formed on atomically clean cleaved (110) GaAs surfaces, subsequently annealed at 405 °C, were found to have flat interfaces. In contrast, diodes formed on air-exposed and chemically prepared GaAs surfaces, also subsequently annealed at 405 °C, were found to have rough and uneven interfaces with a large number of protrusions extending into the semiconductor. They have different orientation relationships with the GaAs substrate than the diodes prepared in situ in UHV. The results of this study show that, upon annealing, the interfacial chemistry and morphology depend strongly on the surface preparation of GaAs before gold deposition.
Photon-induced recovery of photoquenched EL2 intracenter absorption in GaAs
Authors: Fischer David W.
Published: July 2002

After the EL2 absorption band at 1.2 eV is fully photoquenched [i.e., EL2 defect completely transferred from the normal (EL20) to metastable (EL2*) state] it can be partially recovered by photon excitation. This EL2*→EL20 recovery exhibits peaks at 0.80 and 0.90 eV with shoulders at 0.86 and 0.94 eV. Comparison is made to the previously published photon-induced photoconductivity recovery and the results are used to construct a modified configuration coordinate model for the EL2 defect.
Continuum modeling of argon radio frequency glow discharges
Authors: Richards Albert D. , Thompson Brian E. , Sawin Herbert H.
Published: July 2002

A continuum model has been developed which successfully describes the concentration, movement, and energetics of charged particles within a rf discharge. This model includes continuity equations for all charged particles, Poisson’s equation to determine the local electric fields, and an electron energy balance to determine the ionization and energy-loss rates. All input parameters (diffusivity, mobility, ionization, and energy-loss rate) were defined using reported values determined in dc field experiments.
Grain boundary segregation of oxygen and carbon in polycrystalline silicon
Authors: Pizzini S. , Cagnoni P. , Sandrinelli A. , Anderle M. , Canteri R.
Published: July 2002

The electrical activity of grain boundaries (GB’s) in polycrystalline silicon is strongly affected by heat treatments, which are known to induce the segregation of oxygen. The large, quantitative variations of the electrical activity of GB’s observed experimentally, which are a function not only of the heat treatments but also of the carbon and oxygen content of the specific sample examined, could not be explained however, without assuming that carbon and oxygen play a synergistic role. We demonstrate in this work, by using secondary ion mass spectrometry, that oxygen and carbon segregate simultaneously, albeit spatially resolved, at grain boundaries. This result appears to be of major importance when interpreting electron or light beam induced current profiles at grain boundaries in polycrystalline silicon.
Optical characterization of semi-insulating GaAs: Determination of the Fermi energy, the concentration of the midgap EL2 level and its occupancy
Authors: Lagowski J. , Bugajski M. , Matsui M. , Gatos H. C.
Published: July 2002

The key electronic characteristics of semi-insulating GaAs, i.e., the Fermi energy, concentration, and occupancy of the midgap donor EL2, and the net concentration of ionized acceptors can all be determined from high-resolution measurements of the EL2 intracenter absorption. The procedure is based on the measurement of zero-phonon line intensity before and after the complete transfer of EL2 to its metastable state followed by thermal recovery. The procedure is quantitative, involves no fitting parameters, and unlike existing methods, is applicable even when a significant part of the EL2 is ionized.
Haploinsufficiency of mTR results in defects in telomere elongation
Authors: Hathcock Karen S. , Hemann Michael T. , Opperman Kay Keyer , Strong Margaret A. , Greider Carol W. , Hodes Richard J.
Published: July 2002

Telomeres are usually maintained about an equilibrium length, and the set point for this equilibrium differs between species and between strains of a given species. To examine the requirement for telomerase in mediating establishment of a new telomere length equilibrium, we generated interspecies crosses with telomerase mTR knockout mice. In crosses between C57BL/6J (B6) and either of two unrelated mouse species, CAST/Ei and SPRET/Ei, telomerase mediated establishment of a new telomere length equilibrium in wild-type mTR+/+mice. This new equilibrium was characterized by elongation of the short telomeres of CAST/Ei or SPRET/Ei origin. In contrast, mTR−/−offspring of interspecies crosses failed to elongate telomeres. Unexpectedly, haploinsufficiency was observed in mTR+/−heterozygous interspecies mice, which had an impaired ability to elongate short SPRET/Ei or CAST/Ei telomeres to the new equilibrium set point that was achieved in wild-type mTR+/+mice. These results demonstrate that elongation of telomeres to a new telomere set point requires telomerase and indicate that telomerase RNA may be limitingin vivo.
Rhesus macaque dendritic cells efficiently transmit primate lentiviruses independently of DC-SIGN
Authors: Wu Li , Bashirova Arman A. , Martin Thomas D. , Villamide Loreley , Mehlhop Erin , Chertov Andrei O. , Unutmaz Derya , Pope Melissa , Carrington Mary , KewalRamani Vineet N.
Published: July 2002

Here, we describe the isolation and characterization of the rhesus macaque homolog for human DC-SIGN, a dendritic cell-specific C-type lectin. mac-DC-SIGN is 92% identical to hu-DC-SIGN. mac-DC-SIGN preserves the virus transmission function of hu-DC-SIGN, capturing and efficiently transducing simian and human immunodeficiency virus to target CD4+T cells. Surprisingly, however, mac-DC-SIGN plays no discernable role in the ability of rhesus macaque dendritic cells to capture and transmit primate lentiviruses. Expression and neutralization analyses suggest that this process is DC-SIGN independent in macaque, although the participation of other lectin molecules cannot be ruled out. The ability of primate lentiviruses to effectively use human and rhesus dendritic cells in virus transmission without the cells becoming directly infected suggests that these viruses have taken advantage of a conserved dendritic cell mechanism in which DC-SIGN family molecules are significant contributors but not the only participants.
Viral persistencein vivothrough selection of neutralizing antibody-escape variants
Authors: Ciurea Adrian , Klenerman Paul , Hunziker Lukas , Horvath Edit , Senn Beatrice M. , Ochsenbein Adrian F. , Hengartner Hans , Zinkernagel Rolf M.
Published: July 2002

Despite initial virus control by CD8+cytotoxic T lymphocytes (CTLs), noncytopathic or variably cytopathic viruses (e.g., hepatitis B and C viruses, HIV) are able to establish persistent infections. The role of neutralizing antibodies (nAbs) in controlling disease progression is unclear. Therefore, the phenomenon of viral evasion from the nAb response and its implications for virus persistence remain controversial. Here we demonstrate nAb-mediated viral clearance in CTL-deficient mice infected with the prototypic noncytopathic lymphocytic choriomeningitis virus (strain WE). During prolonged CTL absence, neutralization-resistant virus mutants were selected in individual mice within 70–90 days. In naïve animals infected with these virus variants only low nAb responses were induced, resulting in an increased tendency of virus to persist.
Marking synaptic activity in dendritic spines with a calpain substrate exhibiting fluorescence resonance energy transfer
Authors: Vanderklish Peter W. , Krushel Leslie A. , Holst Brent H. , Gally Joseph A. , Crossin Kathryn L. , Edelman Gerald M.
Published: July 2002

Excitatory synaptic activity can evoke transient and substantial elevations of postsynaptic calcium. Downstream effects of elevated calcium include the activation of the calcium-dependent protease calpain. We have developed a reagent that identifies dendritic spines in which calpain has been activated. A fusion protein was expressed that contained enhanced yellow and enhanced cyan fluorescent protein (EYFP and ECFP, respectively) linked by a peptide that included the μ-calpain cleavage site from α-spectrin. A PDZ-binding site fused to ECFP anchored this protein to postsynaptic densities. The fusion protein exhibited fluorescence resonance energy transfer (FRET), and diminution of FRET by proteolysis was used to localize calpain activity
in situ
by fluorescence microscopy. Incubation of the fusion protein with calpain in the presence of calcium resulted in the separation of EYFP and ECFP into monomeric fluorophores. In transiently transfected cell lines and dissociated hippocampal neurons, FRET was diminished by raising intracellular calcium levels with an ionophore or with glutamatergic agonists. Calpain inhibitors blocked these changes. Under control conditions, FRET levels in different dendritic spines of cultured neurons and in hippocampal slices were heterogeneous but showed robust decreases upon treatment with glutamatergic agonists. Immunostaining of cultured neurons with antibodies to a spectrin epitope produced by calpain-mediated digestion revealed an inverse correlation between the amount of FRET present at postsynaptic elements and the concentration of spectrin breakdown products. These results suggest that the FRET methodology identifies sites of synaptically induced calpain activity and that it may be useful in analyzing synapses undergoing changes in efficacy.
Anatomical and physiological evidence for involvement of tuberoinfundibular peptide of 39 residues in nociception
Authors: Dobolyi Arpad , Ueda Hiroshi , Uchida Hitoshi , Palkovits Miklós , Usdin Ted B.
Published: July 2002

The parathyroid hormone 2 (PTH2) receptor's anatomical distribution suggests that, among other functions, it may be involved in modulation of nociception. We localized PTH2 receptor protein to spinal cord lamina II and showed that it is synthesized by subpopulations of primary sensory neurons and intrinsic spinal cord dorsal horn neurons. Tuberoinfundibular peptide of 39 residues (TIP39) selectively activates the PTH2 receptor. Intraplantar microinjection of TIP39 caused a paw-withdrawal response and intrathecal injection caused scratching, biting, and licking, a nocifensive response. Intrathecal administration of a TIP39 antibody decreased sensitivity in tail-flick and paw-pressure assays. Intrathecal administration of TIP39 potentiated responses in these assays. We determined the sequence of TIP39's precursor and found that mRNA encoding TIP39 and TIP39-like immunoreactivity is concentrated in two brainstem areas, the subparafascicular area and the caudal paralemniscal nucleus. Cells in these areas project to the superficial dorsal horn of the spinal cord. Our data suggest that TIP39 released from supraspinal fibers potentiates aspects of nociception within the spinal cord.
A comparative radiation hybrid map of bovine chromosome 18 and homologous chromosomes in human and mice
Authors: Goldammer Tom , Kata Srinivas R. , Brunner Ronald M. , Dorroch Ute , Sanftleben Hanka , Schwerin Manfred , Womack James E.
Published: July 2002

A comprehensive radiation hybrid (RH) map and a high resolution comparative map of Bos taurus (BTA) chromosome 18 were constructed, composed of 103 markers and 76 markers, respectively, by using a cattle-hamster somatic hybrid cell panel and a 5,000 rad whole-genome radiation hybrid (WGRH) panel. These maps include 65 new assignments (56 genes, 3 expressed-sequence tags, 6 microsatellites) and integrate 38 markers from the first generation WGRH
5,000
map of BTA18. Fifty-nine assignments of coding sequences were supported by somatic hybrid cell mapping to markers on BTA18. The total length of the comprehensive map was 1666 cR
5,000
. Break-point positions within the chromosome were refined and a new telomeric RH linkage group was established. Conserved synteny between cattle, human, and mouse was found for 76 genes of BTA18 and human chromosomes (HSA) 16 and 19 and for 34 cattle genes and mouse chromosomes (MMU) 7 and 8. The new RH map is potentially useful for the identification of candidate genes for economically important traits, contributes to the expansion of the existing BTA18 gene map, and provides new information about the chromosome evolution in cattle, humans, and mice.
Cooperativity of
Nkx3.1
and
Pten
loss of function in a mouse model of prostate carcinogenesis
Authors: Kim Minjung J. , Cardiff Robert D. , Desai Nishita , Banach-Petrosky Whitney A. , Parsons Ramon , Shen Michael M. , Abate-Shen Cory
Published: July 2002

Mouse models have provided significant insights into the molecular mechanisms of tumor suppressor gene function. Here we use mouse models of prostate carcinogenesis to demonstrate that the
Nkx3.1
homeobox gene undergoes epigenetic inactivation through loss of protein expression. Loss of function of
Nkx3.1
in mice cooperates with loss of function of the
Pten
tumor suppressor gene in cancer progression. This cooperativity results in the synergistic activation of Akt (protein kinase B), a key modulator of cell growth and survival. Our findings underscore the significance of interactions between tissue-specific regulators such as
Nkx3.1
and broad-spectrum tumor suppressors such as
Pten
in contributing to the distinct phenotypes of different cancers.
Sensitivity to carcinogenesis is increased and chemoprotective efficacy of enzyme inducers is lost in
nrf2
transcription factor-deficient mice
Authors: Ramos-Gomez Minerva , Kwak Mi-Kyoung , Dolan Patrick M. , Itoh Ken , Yamamoto Masayuki , Talalay Paul , Kensler Thomas W.
Published: July 2002

Induction of phase 2 enzymes, which neutralize reactive
electrophiles and act as indirect antioxidants, appears to be an
effective means for achieving protection against a variety of
carcinogens in animals and humans. Transcriptional control of the
expression of these enzymes is mediated, at least in part, through the
antioxidant response element (ARE) found in the regulatory regions of
their genes. The transcription factor Nrf2, which binds to the ARE,
appears to be essential for the induction of prototypical phase 2
enzymes such as glutathione
S
-transferases (GSTs) and
NAD(P)H:quinone oxidoreductase (NQO1). Constitutive hepatic and
gastric activities of GST and NQO1 were reduced by 50–80% in
nrf2
-deficient mice compared with wild-type mice.
Moreover, the 2- to 5-fold induction of these enzymes in wild-type mice
by the chemoprotective agent oltipraz, which is currently in clinical
trials, was almost completely abrogated in the
nrf2
-deficient mice. In parallel with the enzymatic
changes,
nrf2
-deficient mice had a significantly higher
burden of gastric neoplasia after treatment with
benzo[
a
]pyrene than did wild-type mice. Oltipraz
significantly reduced multiplicity of gastric neoplasia in wild-type
mice by 55%, but had no effect on tumor burden in
nrf2
-deficient mice. Thus, Nrf2 plays a central role in
the regulation of constitutive and inducible expression of phase 2
enzymes
in vivo
and dramatically influences
susceptibility to carcinogenesis. Moreover, the total loss of
anticarcinogenic efficacy of oltipraz in the
nrf2
-disrupted mice highlights the prime importance of
elevated phase 2 gene expression in chemoprotection by this and similar
enzyme inducers.
Mechanisms underlying losses of heterozygosity in human colorectal cancers
Authors: Thiagalingam Sam , Laken Steve , Willson James K. V. , Markowitz Sanford D. , Kinzler Kenneth W. , Vogelstein Bert , Lengauer Christoph
Published: July 2002

Losses of heterozygosity are the most common molecular genetic
alteration observed in human cancers. However, there have been few
systematic studies to understand the mechanism(s) responsible for
losses of heterozygosity in such tumors. Here we report a detailed
investigation of the five chromosomes lost most frequently in human
colorectal cancers. A total of 10,216 determinations were made with 88
microsatellite markers, revealing 245 chromosomal loss events. The
mechanisms of loss were remarkably chromosome-specific. Some
chromosomes displayed complete loss such as that predicted to result
from mitotic nondisjunction. However, more than half of the losses were
associated with losses of only part of a chromosome rather than a whole
chromosome. Surprisingly, these losses were due largely to structural
alterations rather than to mitotic recombination, break-induced
replication, or gene conversion, suggesting novel mechanisms for the
generation of much of the aneuploidy in this common tumor type.
Mouse strain differences determine severity of iron accumulation in
Hfe
knockout model of hereditary hemochromatosis
Authors: Fleming Robert E. , Holden Christopher C. , Tomatsu Shunji , Waheed Abdul , Brunt Elizabeth M. , Britton Robert S. , Bacon Bruce R. , Roopenian Derry C. , Sly William S.
Published: July 2002

Hereditary hemochromatosis (HH) is a common disorder of iron
metabolism caused by mutation in
HFE
, a gene encoding an
MHC class I-like protein. Clinical studies demonstrate that the
severity of iron loading is highly variable among individuals with
identical
HFE
genotypes. To determine whether genetic
factors other than
Hfe
genotype influence the severity
of iron loading in the murine model of HH, we bred the disrupted murine
Hfe
allele onto three different genetically defined
mouse strains (AKR, C57BL/6, and C3H), which differ in basal iron
status and sensitivity to dietary iron loading. Serum transferrin
saturations (percent saturation of serum transferrin with iron),
hepatic and splenic iron concentrations, and hepatocellular iron
distribution patterns were compared for wild-type (
Hfe
+/+), heterozygote (
Hfe
+/−), and knockout
(
Hfe
−/−) mice from each strain. Although the
Hfe
−/− mice from all three strains demonstrated
increased transferrin saturations and liver iron concentrations
compared with
Hfe
+/+ mice, strain differences in
severity of iron accumulation were striking. Targeted disruption of the
Hfe
gene led to hepatic iron levels in
Hfe
−/− AKR mice that were 2.5 or 3.6 times higher
than those of
Hfe
−/− C3H or
Hfe
−/− C57BL/6 mice, respectively. The
Hfe
−/−
mice also demonstrated strain-dependent differences in transferrin
saturation, with the highest values in AKR mice and the lowest values
in C3H mice. These observations demonstrate that heritable factors
markedly influence iron homeostasis in response to
Hfe
disruption. Analysis of mice from crosses between C57BL/6 and AKR
mice should allow the mapping and subsequent identification of genes
modifying the severity of iron loading in this murine model of HH.
DC-SIGNR, a DC-SIGN homologue expressed in endothelial cells, binds to human and simian immunodeficiency viruses and activates infection in trans
Authors: Pöhlmann Stefan , Soilleux Elizabeth J. , Baribaud Frédéric , Leslie George J. , Morris Lesley S. , Trowsdale John , Lee Benhur , Coleman Nicholas , Doms Robert W.
Published: July 2002

DC-SIGN, a C-type lectin expressed on the surface of dendritic cells (DCs), efficiently binds and transmits HIVs and simian immunodeficiency viruses to susceptible cells in trans. A DC-SIGN homologue, termed DC-SIGNR, has recently been described. Herein we show that DC-SIGNR, like DC-SIGN, can bind to multiple strains of HIV-1, HIV-2, and simian immunodeficiency virus and transmit these viruses to both T cell lines and human peripheral blood mononuclear cells. Binding of virus to DC-SIGNR was dependent on carbohydrate recognition. Immunostaining with a DC-SIGNR-specific antiserum showed that DC-SIGNR was expressed on sinusoidal endothelial cells in the liver and on endothelial cells in lymph node sinuses and placental villi. The presence of this efficient virus attachment factor on multiple endothelial cell types indicates that DC-SIGNR could play a role in the vertical transmission of primate lentiviruses, in the enabling of HIV to traverse the capillary endothelium in some organs, and in the presentation of virus to CD4-positive cells in multiple locations including lymph nodes.
GATA-1 binding sites mapped in the β-globin locus by using mammalian chIp-chip analysis
Authors: Horak Christine E. , Mahajan Milind C. , Luscombe Nicholas M. , Gerstein Mark , Weissman Sherman M. , Snyder Michael
Published: July 2002

The expression of the β-like globin genes is intricately regulated by a series of both general and tissue-restricted transcription factors. The hemapoietic lineage-specific transcription factor GATA-1 is important for erythroid differentiation and has been implicated in regulating the expression of the erythroid-specific genes including the genes of the β-globin locus. In the human erythroleukemic K562 cell line, only one DNA region has been identified previously as a putative site of GATA-1 interaction by
in vivo
footprinting studies. We mapped GATA-1 binding throughout the β-globin locus by using chIp-chip analysis of K562 cells. We found that GATA-1 binds in a region encompassing the HS2 core element, as was previously identified, and an additional region of GATA-1 binding upstream of the γG gene. This approach will be of general utility for mapping transcription factor binding sites within the β-globin locus and throughout the genome.
FHIT
gene therapy prevents tumor development in Fhit-deficient mice
Authors: Dumon Kristoffel R. , Ishii Hideshi , Fong Louise Y. Y. , Zanesi Nicola , Fidanza Vincenzo , Mancini Rita , Vecchione Andrea , Baffa Raffaele , Trapasso Francesco , During Matthew J. , Huebner Kay , Croce Carlo M.
Published: July 2002

The tumor suppressor gene
FHIT
spans a common
fragile site and is highly susceptible to environmental carcinogens.
FHIT
inactivation and loss of expression is found in a
large fraction of premaligant and malignant lesions. In this study, we
were able to inhibit tumor development by oral gene transfer, using
adenoviral or adenoassociated viral vectors expressing the human
FHIT
gene, in heterozygous
Fhit
+/−
knockout mice, that are prone to
tumor development after carcinogen exposure. We therefore suggest that
FHIT
gene therapy could be a novel clinical approach not
only in treatment of early stages of cancer, but also in prevention of
human cancer.
The dual role of ultraspiracle, the
Drosophila
retinoid X receptor, in the ecdysone response
Authors: Ghbeish Nora , Tsai Chih-Cheng , Schubiger Margrit , Zhou Joel Y. , Evans Ronald M. , McKeown Michael
Published: July 2002

The
Drosophila
homolog of the retinoid X receptor,
ultraspiracle (USP), heterodimerizes with the ecdysone receptor (EcR)
to form a functional complex that mediates the effects of the steroid
molting hormone ecdysone by activating and repressing expression of
ecdysone response genes. As with other retinoid X receptor
heterodimers, EcR/USP affects gene transcription in a
ligand-modulated manner. We used
in vivo
, cell culture,
and biochemical approaches to analyze the functions of two
usp
alleles,
usp
3
and
usp
4
, which encode stable proteins with
defective DNA-binding domains. We observed that USP is able to activate
as well as repress the Z1 isoform of the ecdysone-responsive
broad complex
(
BrC-Z1
). Activation of
BrC-Z1
as well as
EcR
, itself an ecdysone
response gene, can be mediated by both the USP3 and USP4 mutant
proteins. USP3 and USP4 also activate an ecdysone-responsive element,
hsp27EcRE, in cultured cells. These results differ from the protein
null allele,
usp
2
, which is unable to
mediate activation [Schubiger, M. & Truman, J. W. (2000)
Development
127, 1151–1159].
BrC-Z1
repression is compromised in all three
usp
alleles,
suggesting that repression involves the association of USP with DNA.
Our results distinguish two mechanisms by which USP modulates the
properties of EcR: one that involves the USP DNA-binding domain and one
that can be achieved solely through the ligand-binding domain. These
newly revealed properties of USP might implicate similar properties for
retinoid X receptor.
Design of an HIV-1 lentiviral-based gene-trap vector to detect developmentally regulated genes in mammalian cells
Authors: Lai Zhennan , Han Ina , Park Misun , Brady Roscoe O.
Published: July 2002

The recent development of HIV-1 lentiviral vectors is especially useful for gene transfer because they achieve efficient integration into nondividing cell genomes and successful long-term expression of the transgene. These attributes make the vector useful for gene delivery, mutagenesis, and other applications in mammalian systems. Here we describe two HIV-1-based lentiviral vector derivatives, pZR-1 and pZR-2, that can be used in gene-trap experiments in mammalian cells
in vitro
and
in vivo
. Each lentiviral gene-trap vector contains a reporter gene, either β-lactamase or enhanced green fluorescent protein (EGFP), that is inserted into the U3 region of the 3′ long terminal repeat. Both of the trap vectors readily integrate into the host genome by using a convenient infection technique. Appropriate insertion of the vector into genes causes EGFP or β-lactamase expression. This technique should facilitate the rapid enrichment and cloning of the trapped cells and provides an opportunity to select subpopulations of trapped cells based on the subcellular localization of reporter genes. Our findings suggest that the reporter gene is driven by an upstream, cell-specific promoter during cell culture and cell differentiation, which further supports the usefulness of lentivirus-based gene-trap vectors. Lentiviral gene-trap vectors appear to offer a wealth of possibilities for the study of cell differentiation and lineage commitment, as well as for the discovery of new genes.
Reelin function in neural stem cell biology
Authors: Kim H. M. , Qu T. , Kriho V. , Lacor P. , Smalheiser N. , Pappas G. D. , Guidotti A. , Costa E. , Sugaya K.
Published: July 2002

In the adult brain, neural stem cells (NSC) must migrate to express their neuroplastic potential. The addition of recombinant reelin to human NSC (HNSC) cultures facilitates neuronal retraction in the neurospheroid. Because we detected reelin, α3-integrin receptor subunits, and disabled-1 immunoreactivity in HNSC cultures, it is possible that integrin-mediated reelin signal transduction is operative in these cultures. To investigate whether reelin is important in the regulation of NSC migration, we injected HNSCs into the lateral ventricle of null reeler and wild-type mice. Four weeks after transplantation, we detected symmetrical migration and extensive neuronal and glial differentiation of transplanted HNSCs in wild-type, but not in reeler mice. In reeler mice, most of the injected HNSCs failed to migrate or to display the typical differentiation pattern. However, a subpopulation of transplanted HNSCs expressing reelin did show a pattern of chain migration in the reeler mouse cortex. We also analyzed the endogenous NSC population in the reeler mouse using bromodeoxyuridine injections. In reeler mice, the endogenous NSC population in the hippocampus and olfactory bulb was significantly reduced compared with wild-type mice; in contrast, endogenous NSCs expressed in the subventricular zonewere preserved. Hence, it seems likely that the lack of endogenous reelin may have disrupted the migration of the NSCs that had proliferated in the SVZ. We suggest that a possible inhibition of NSC migration in psychiatric patients with a reelin deficit may be a potential problem in successful NSC transplantation in these patients.
New supramolecular trigonal prisms from zinc(II)– 1,4,7,10-tetraazacyclododecane (cyclen) complexes and trithiocyanurate in aqueous solution
Authors: Aoki Shin , Zulkefeli Mohd , Shiro Motoo , Kimura Eiichi
Published: July 2002

The multiple bonding between multinuclear zinc(II)–1,4,7,10-tetraazacyclododecane (cyclen, a 12-membered tetraamine) complexes and multidentate ligands is an effective method for constructing supramolecular complexes having well defined and distinct structures in aqueous solution. Herein we present examples of supramolecularD3hprisms formed by self-assembly of linearly dimeric or trimeric zinc(II)–cyclen complexes with a potentially trianionicC3subunit trithiocyanuric acid (TCA3−), wherein Zn2+—S−or Zn2+—N−coordination bonds and hydrogen bonds are responsible for stability of the multicomponent architectures in aqueous solution at neutral pH.
Muir–Torre-like syndrome in Fhit-deficient mice
Authors: Fong Louise Y. Y. , Fidanza Vincenzo , Zanesi Nicola , Lock Leslie F. , Siracusa Linda D. , Mancini Rita , Siprashvili Zurab , Ottey Michelle , Martin S. Eric , Druck Teresa , McCue Peter A. , Croce Carlo M. , Huebner Kay
Published: July 2002

To investigate the role of theFhitgene in carcinogen induction of neoplasia, we have inactivated oneFhitallele in mouse embryonic stem cells and produced (129/SvJ × C57BL/6J) F1mice with aFhitallele inactivated (+/−).Fhit+/+ and +/− mice were treated intragastrically with nitrosomethylbenzylamine and observed for 10 wk posttreatment. A total of 25% of the +/+ mice developed adenoma or papilloma of the forestomach, whereas 100% of the +/− mice developed multiple tumors that were a mixture of adenomas, squamous papillomas, invasive carcinomas of the forestomach, as well as tumors of sebaceous glands. The visceral and sebaceous tumors, which lacked Fhit protein, were similar to those characteristic of Muir–Torre familial cancer syndrome.
SUMO-1 conjugation to topoisomerase I: A possible repair response to topoisomerase-mediated DNA damage
Authors: Mao Yong , Sun Mei , Desai Shyamal D. , Liu Leroy F.
Published: July 2002

Ubiquitin/26S proteasome-dependent degradation of topoisomerase I (TOP1) has been suggested to be a unique repair response to TOP1-mediated DNA damage. In the current study, we show that treatment of mammalian cells or yeast cells expressing human DNA TOP1 with camptothecin (CPT) induces covalent modification of the TOP1 by SUMO-1/Smt3p, a ubiquitin-like protein. This conclusion is based on the following observations: (i) Mammalian DNA TOP1 conjugates induced by CPT were cross-reactive with SUMO-1/Smt3p-specific antibodies both in yeast expressing human DNA TOP1 as well as mammalian cells. (ii) The formation of TOP1 conjugates was shown to be dependent on UBC9, the E2 enzyme for SUMO-1/Smt3p. (iii) TOP1 physically interacts with UBC9. (iv) Ubc9 mutant yeast cells expressing human DNA TOP1 was hypersensitive to CPT, suggesting that UBC9/SUMO-1 may be involved in the repair of TOP1-mediated DNA damage.
Raf induces NF-κB by membrane shuttle kinase MEKK1, a signaling pathway critical for transformation
Authors: Baumann Bernd , Weber Christoph K. , Troppmair Jakob , Whiteside Simon , Israel Alain , Rapp Ulf R. , Wirth Thomas
Published: July 2002

NF-κB is regulated by inhibitor proteins (IκBs), which retain NF-κB in the cytoplasm. Signal-induced phosphorylation by the IκB-kinase complex containing the IκB-kinases 1 and 2 (IKK-1/2 or IKK-α/β) and subsequent degradation of the IκB proteins are prerequisites for NF-κB activation. Many signals induce NF-κB, one of them being oncogenic Raf kinase. We investigated whether NF-κB induction is critical for Raf-mediated transformation. Here, we demonstrate that inhibition of NF-κB interferes with transformation by the Raf-oncogene, and we characterized the mechanism of NF-κB induction by activated Raf kinase and the tumor promoter phorbol 12-myristate 13-acetate (PMA). NF-κB activation by PMA and Raf critically depends on the IκB-kinase complex, most notably on IKK-2. A major signaling pathway induced by Raf is the mitogenic cytoplasmic kinase cascade. However, different inhibitors of this cascade do not affect PMA- and Raf-mediated NF-κB activation. Raf does not phosphorylate the IκB-kinase proteins directly. Raf rather synergizes with another membrane shuttle kinase MEKK1, and Raf-mediated activation of NF-κB is blocked by a dominant negative form of MEKK1. These results suggest that Raf induction of NF-κB is relayed by MEKK1, but not by the classical mitogenic cytoplasmic kinase cascade.
Hemagglutinin sequence clusters and the antigenic evolution of influenza A virus
Authors: Plotkin Joshua B. , Dushoff Jonathan , Levin Simon A.
Published: July 2002

Continual mutations to the hemagglutinin (HA) gene of influenza A virus generate novel antigenic strains that cause annual epidemics. Using a database of 560 viral RNA sequences, we study the structure and tempo of HA evolution over the past two decades. We detect a critical length scale, in amino acid space, at which HA sequences aggregate into clusters, or swarms. We investigate the spatio-temporal distribution of viral swarms and compare it to the time series of the influenza vaccines recommended by the World Health Organization. We introduce a method for predicting future dominant HA amino acid sequences and discuss its potential relevance to vaccine choice. We also investigate the relationship between cluster structure and the primary antibody-combining regions of the HA protein.
Overexpression of the cytotoxic T cell GalNAc transferase in skeletal muscle inhibits muscular dystrophy in mdx mice
Authors: Nguyen Holly H. , Jayasinha Vianney , Xia Bing , Hoyte Kwame , Martin Paul T.
Published: July 2002

Duchenne muscular dystrophy (DMD) is a congenital X-linked myopathy caused by lack of dystrophin protein expression. In DMD, the expression of many dystrophin-associated proteins (DAPs) is reduced along the sarcolemmal membrane, but the same proteins remain concentrated at the neuromuscular junction where utrophin, a dystrophin homologue, is expressed [Matsumura, K., Ervasti, J. M., Ohlendieck, K., Kahl, K. D. & Campbell, K. (1992)
Nature (London)
360, 588–591]. This outcome has led to the concept that ectopic expression of a “synaptic scaffold” of DAPs and utrophin along myofibers might compensate for the molecular defects in DMD. Here we show that transgenic overexpression of the synaptic CT GalNAc transferase in the skeletal muscles of mdx animals (mdx/CT) increases the expression of utrophin and many DAPs, including dystroglycans, sarcoglycans, and dystrobrevins, along myofibers. Protein expression of utrophin and DAPs was equal to or above that of wild-type mice. In addition, α-dystroglycan was glycosylated with the CT carbohydrate antigen in mdx/CT but not in mdx muscles. mdx/CT mice have little or no evidence of muscular dystrophy by several standard measures; Serum creatine kinase levels, percentage of centrally located myofiber nuclei, and variance in myofiber diameter in mdx/CT muscles were dramatically reduced compared with mdx mice. These data suggest that ectopic expression of the CT GalNAc transferase creates a functional dystrophin-related complex along myofibers in the absence of dystrophin and should be considered as a target for therapeutic intervention in DMD.
Organization of the interior of molecular capsules by hydrogen bonding
Authors: Atwood Jerry L. , Barbour Leonard J. , Jerga Agoston
Published: July 2002

The enclosure of functional entities within a protective boundary is an essential feature of biological systems. On a molecular scale, free-standing capsules with an internal volume sufficiently large to house molecular species have been synthesized and studied for more than a decade. These capsules have been prepared by either covalent synthesis or self-assembly, and the internal volumes have ranged from 200 to 1,500 Å
3
. Although biological systems possess a remarkable degree of order within the protective boundaries, to date only steric constraints have been used to order the guests within molecular capsules. In this article we describe the synthesis and characterization of hexameric molecular capsules held together by hydrogen bonding. These capsules possess internal order of the guests brought about by hydrogen bond donors within, but not used by, the framework of the capsule. The basic building blocks of the hexameric capsules are tetrameric macrocycles related to resorcin[4]arenes and pyrogallol[4]arenes. The former contain four 1,3-dihydroxybenzene rings bridged together by -CHR- units, whereas the latter contain four 1,2,3-trihydroxybenzene rings bridged together. We now report the synthesis of related mixed macrocycles, and the main focus is on the macrocycle composed of three 1,2,3-trihydroxybenzene rings and one 1,3-dihydroxybenzene ring bridged together. The mixed macrocycles self-assemble from a mixture of closely related compounds to form the hexameric capsule with internally ordered guests.