bluuebunny/crossref_metadata_2025 huggingface dataset:
Computer simulation of hopper flow
Authors: Potapov Alexander V. , Campbell Charles S.
Published: July 2002

This paper describes two-dimensional computer simulations of granular flow in plane hoppers. The simulations can reproduce an experimentally observed asymmetric unsteadiness for monodispersed particle sizes, but also could eliminate it by adding a small amount of polydispersity. This appears to be a result of the strong packings that may be formed by monodispersed particles and is thus a noncontinuum effect. The internal stress state was also sampled, which among other things, allows an evaluation of common assumptions made in granular material models. These showed that the internal friction coefficient is far from a constant, which is in contradiction to common models based on plasticity theory which assume that the material is always at the point of imminent yield. Furthermore, it is demonstrated that rapid granular flow theory, another common modeling technique, is inapplicable to this problem even near the exit where the flow is moving its fastest.
A numerical investigation on the effect of the inflow conditions on the self-similar region of a round jet
Authors: Boersma B. J. , Brethouwer G. , Nieuwstadt F. T. M.
Published: July 2002

In this paper we consider the direct numerical simulation (DNS) of a spatially developing free round jet at low Reynolds numbers. Simulation of a spatially evolving flow such as the jet requires boundary conditions, which allow entrainment into the turbulent flow across the lateral boundaries of the computational domain. The boundary conditions which satisfy this requirement are so-called traction free boundary conditions. After showing that these boundary conditions lead to a correct behavior of the velocity near the lateral boundary of the jet, we will consider the DNS of the jet flow at a Reynolds number of 2.4×103 and compare the results with experimental data obtained by Hussein et al. [J. Fluid Mech. 258, 31 (1994)] and by Panchapakesan and Lumley [J. Fluid Mech. 246, 197 (1993)]. The results of our numerical simulations agree very well with the experimental data. Next we use the DNS to investigate the influence of the shape of the velocity profile at the jet orifice on the self-similarity scaling for the far-field velocity and shear stress profile. Evidence is presented in support of the suggestion by George [Advances in Turbulence (Springer, New York, 1989)] that the details of self-similarity depend on the initial conditions. This fact implies that there may exist no universally valid similarity scaling for the free jet.
Optimal and adaptive control of chaotic convection—Theory and experiments
Authors: Yuen Po Ki , Bau Haim H.
Published: July 2002

In theory and experiments, optimal and adaptive control strategies are employed to suppress chaotic convection in a thermal convection loop. The thermal convection loop is a relatively simple experimental paradigm that exhibits complex dynamic behavior and provides a convenient platform for evaluating and comparing various control strategies. The objective of this study is to evaluate the feasibility of employing optimal control and nonlinear estimator to alter naturally occurring flow patterns and to compare the performance of the optimal controller with that of other controllers such as neural network controllers. It is demonstrated that when the system’s model is not known, experimental data alone can be utilized for the construction of a proportional controller.
Numerical study of the influence of gravity on the heat conductivity on the basis of kinetic theory
Authors: Doi Toshiyuki , Santos Andrés , Tij Mohamed
Published: July 2002

The Boltzmann–Krook–Welander (or Bhatnagar–Gross–Krook) model of the Boltzmann equation is solved numerically for the heat transfer problem of a gas enclosed between two parallel, infinite plates kept at different temperatures, in the presence of a constant gravity field normal to the plates. At each point where the direct effect of the boundaries is negligible, a relation among the relevant local quantities (heat flux, temperature gradient, temperature, and density) holds even if the temperature varies over a length scale comparable to the mean free path. The ratio of the actual heat flux to the value predicted by the Fourier law is seen to be determined by the local Knudsen number and the local Froude number which are defined with the local mean free path, local characteristic length, and the magnitude of gravity. It is observed that the gravity produces an enhancement of the effective heat conductivity when the heat flux and the gravity field are parallel, while it produces an inhibition when both vectors are antiparallel. This deviation from the Fourier law, which vanishes in the absence of gravity, increases as the local Knudsen number increases and is more remarkable when the heat flux is parallel to the gravity field rather than otherwise. Comparison of the numerical data with an asymptotic analysis as well as with Padé approximants derived from it is also made.
The simulation and interpretation of free turbulence with a cognitive neural system
Authors: Giralt Francesc , Arenas A. , Ferre-Giné J. , Rallo R. , Kopp G. A.
Published: July 2002

An artificial neural network, based on fuzzy ARTMAP, that is capable of learning the basic nonlinear dynamics of a turbulent velocity field is presented. The neural system is capable of generating a detailed multipoint time record with the same structural characteristics and basic statistics as those of the original instantaneous velocity field used for training. The good performance of the proposed architecture is demonstrated by the generation of synthetic two-dimensional velocity data at eight different positions along the homogeneous (spanwise) direction in the far region (x/D=420) of a turbulent wake flow generated behind a cylinder at Re=1 200. The analysis of the synthetic velocity field, carried out with spectral techniques, POD and pattern recognition, reveals that the proposed neural system is capable of capturing the highly nonlinear dynamics of free turbulence and of reproducing the sequence of individual classes of relevant events present in turbulent wake flows. The trained neural system also yields patterns of the coherent structures embedded in the flow when presented with input data containing partial information of the instantaneous velocity maps of these events. In this way, the neural network is used as an expert system that helps in the structural interpretation of turbulence in a wake flow.
Velocity–space drag and diffusion in a model, two-dimensional plasma
Authors: Reynolds M. A. , Fried B. D. , Morales G. J.
Published: July 2002

The quasilinear fluctuation integral is calculated for a two-dimensional, unmagnetized plasma (composed of charged rods), and is expressed in terms of Fokker–Planck coefficients. It is found that in two dimensions, the enhanced fluctuations generated by fast electrons lead to anomalously large transport coefficients. In particular, the effect of a small population of fast electrons is only weakly dependent on their density. In three dimensions, the effect of fast electrons is masked by the dominant approximation, but higher-order terms describe processes similar to those in two dimensions, and these terms can become significant for weakly stable plasmas. The differences between two and three dimensions arise from the fact that both emission and damping of plasma waves are retained to lowest order in two dimensions, while the three-dimensional dominant approximation effectively includes only wave emission by test particles. An understanding of the differences between two and three dimensions is crucial to the interpretation of two-dimensional particle simulations.
The dynamics of bifurcating bright-spots in fiber Z-pinch plasmas
Authors: Chittenden J. P. , Mitchell I. H. , Aliaga-Rossel R. , Bayley J. M. , Beg F. N. , Lorenz A. , Haines M. G. , Decker G.
Published: July 2002

Results are presented from the diagnosis of the optical and x-ray emission from “bright-spots” in carbon fiber Z-pinch experiments using the MAGPIE (Mega-Ampere Generator for Plasma Implosion Experiments) generator [I. H. Mitchell et al., Rev. Sci. Instrum. 67, 1533 (1996)]. Inhomogeneities evolve very rapidly within the plasma with bright-spots becoming detectable after 15–20 ns. After a short (∼4 ns) duration formation phase, these bright-spots exhibit highly dynamic behavior. Bifurcation of the bright-spots is observed giving rise to rapid axial motion at 1–3×105 ms−1. The post-bifurcation bright-spots persist for up to 40 ns. Analysis of cross-filtered, time integrated, x-ray pinhole images yield bright-spot parameters during the formation phase (diameter ∼80 μm, temperature 250–300 eV, ion number densities ∼2×1026 m−3). With a spatial resolution of 175 μm, the strong temperature and density gradients within the post-bifurcation spots can be resolved in gated x-ray images with 2 ns exposure times. After the dynamic phase of bright-spot evolution, the pinch enters a quiescent phase where the time scale for evolution is much longer.
Deep donor model for the persistent photoconductivity effect
Authors: Hjalmarson Harold P. , Drummond T. J.
Published: July 2002

It is proposed that a persistent photoconductivity (PPC) effect is universally produced by deep donors. The general requirements of a class of models which explains the PPC effect in semiconductors are discussed. In particular, donor dopants such as Si and Te in Ga1−xAlxAs with x∼0.3 are conjectured to be deep and responsible for the PPC effect attributed to DX centers consisting of donor-vacancy pairs. It is shown that the Si donor has properties which explain the known data attributed to the DX center; these data include (1) the slow capture rate at low temperatures, (2) the thermally activated capture rate at high temperatures, and (3) the shape of the photoexcitation cross section. However, in contrast with the DX-center model, the deep donor model does not require a high trapped vacancy concentration ([V]∼1018 cm−3) to explain the PPC effect in highly doped semiconductors.
Reaction of titanium with silicon nitride under rapid thermal annealing
Authors: Morgan A. E. , Broadbent E. K. , Sadana D. K.
Published: July 2002

30–90 nm Ti films sputter deposited onto 50 nm Si3N4 have been rapid thermal annealed for 30 s in Ar and N2 ambients, and the phases formed identified using Auger electron spectroscopy, transmission electron microscopy, and electron diffraction. Reaction at 900 °C produces TiN surface and interfacial layers and an intermediate TiSi2 layer. The Ti-Si-N ternary phase diagram is used to explain the reaction sequence.
Effect of optical pulse duration on the XeCl laser ablation of polymers and biological tissue
Authors: Taylor R. S. , Singleton D. L. , Paraskevopoulos G.
Published: July 2002

Photoacoustic spectroscopy was used to measure the pulse duration dependence of the XeCl laser ablation of polyimide, polyethylene terephthalate, and post-mortem human aorta. It was observed that the ablation threshold exhibited only a weak dependence on pulse duration. Photoablation etch depth measurements of polyimide as a function of XeCl laser fluence indicated that over a practical etch depth range of 0.1 to 1 μm per laser pulse the etch depth was independent of the pulse duration.
Formation of thin superconducting films by the laser processing method
Authors: Narayan J. , Biunno N. , Singh R. , Holland O. W. , Auciello O.
Published: July 2002

We have prepared thin films of Y-Ba-Cu-O superconductors using a pulsed laser evaporation technique. Thin films were formed on (100) Si, (100) MgO, (1̄102) sapphire, (100) SrTiO3, and amorphous SiO2 substrates using a XeCl excimer laser (λ=0.308 μm, τ=45×10−9 s). The depositions were done in an ultrahigh vacuum chamber with pressure of about 10−6 Torr during thin-film formation. The deposition by pulsed nanosecond laser irradiation results in stoichiometry close to that of the target. The thickness of the film was controlled by varying the pulse energy density and the number of pulses. The substrate temperature was kept at 470 °C during deposition. Subsequent annealing treatments were carried out at 900 and 650 °C in oxygen atmosphere to recover the superconducting properties of these thin films. The resistance of these films was measured as a function of temperature using the four-point probe method. These thin films were analyzed using cross-section transmission electron microscopy, Rutherford backscattering spectrometry, and channeling techniques. The variation in the oxygen content and the interdiffusion of species into the substrate during subsequent annealing treatments are discussed.
Laser-frequency mixing in the junction of a scanning tunneling microscope
Authors: Arnold L. , Krieger W. , Walther H.
Published: July 2002

The frequency response and the frequency-mixing properties of the tunneling junction of a scanning tunneling microscope (STM) were investigated using the radiation of two CO2 lasers. Difference frequencies of up to 90 MHz were detected over a wide range of bias voltages and tunneling currents. At tunneling currents typical of STM operation the beat signal decreases as the bias voltage is increased. However, this dependence is reversed at higher tunneling currents, where the STM begins to resemble a point-contact metal-insulator-metal diode. For low tunneling currents the generation of the beat signal is attributed mainly to thermally assisted tunneling.
Resonant Raman scattering of diamondlike amorphous carbon films
Authors: Yoshikawa M. , Katagiri G. , Ishida H. , Ishitani A. , Akamatsu T.
Published: July 2002

Raman spectra of diamondlike amorphous carbon (a-C) films prepared by the sputtering method have been measured as a function of the excitation wavelength. The Raman spectral profiles vary sensitively, reflecting the change of absorption spectra associated with π-π* electronic transitions with the hydrogen content of the films. From a comparison between Raman and electronic absorption spectra, it is confirmed that the Raman spectral variation with the excitation wavelength is due to the π-π* resonant Raman scattering from π-bonded (sp2) carbon clusters.
Y-Ba-Cu-O superconducting thin films by simultaneous or sequential evaporation
Authors: Mogro-Campero A. , Hunt B. D. , Turner L. G. , Burrell M. C. , Balz W. E.
Published: July 2002

Superconducting thin films of Y-Ba-Cu-O near the 1:2:3 stoichiometry were produced by simultaneous (coevaporation) and sequential (multilayer) evaporation in the same evaporator. The best film obtained on yttria-stabilized zirconia (YSZ) had a superconducting onset temperature of 104 K, a midpoint Tc of 92 K, and zero resistance at T≤74 K. Stoichiometry was deduced by inductively coupled plasma emission spectroscopy, and elemental depth profiles were obtained by x-ray photoelectron spectroscopy. Film stoichiometry changes only near the film/substrate boundary for films on YSZ. Films on Si/SiO2 were not superconducting; depth profiling shows severe changes of film composition with depth. A major theme of this work is process reproducibility, which was found to be poor for coevaporation but improved considerably for sequential evaporation.
Domain images of ultrathin Fe films on Ag(100)
Authors: Robins J. L. , Celotta R. J. , Unguris J. , Pierce D. T. , Jonker B. T. , Prinz G. A.
Published: July 2002

Scanning electron microscopy with electron polarization analysis has been used to image domains of ultrathin Fe films grown epitaxially on a Ag(100) substrate. Room-temperature measurements show clearly the existence of large domains of in-plane magnetization for film thicknesses of 3.4 monolayers or more. No in-plane domains were observed for thinner films.
Conformational Abs recognizing a generic amyloid fibril epitope
Authors: O'Nuallain Brian , Wetzel Ronald
Published: July 2002

Disease-related amyloid fibrils appear to share a common, but poorly understood, structure. We describe here the generation and preliminary characterization of two conformation-specific mAbs, WO1 and WO2, that bind to the amyloid fibril state of the Alzheimer's peptide Aβ(1–40) but not to its soluble, monomeric state. Surprisingly, these Abs also bind to other disease-related amyloid fibrils and amyloid-like aggregates derived from other proteins of unrelated sequence, such as transthyretin, islet amyloid polypeptide, β2-microglobulin, and polyglutamine. At the same time, WO1 and WO2 do not bind to the native protein precursors of these amyloids, nor do they bind to other kinds of protein aggregates. This new class of Abs associated with a fundamental amyloid-folding motif appear to recognize a common conformational epitope with little apparent dependence on amino acid side chain information. These Abs should contribute to the understanding of amyloid structure, assembly, and toxicity and also may benefit the development of diagnostic and therapeutic agents for amyloid diseases.
Noise-based switches and amplifiers for gene expression
Authors: Hasty Jeff , Pradines Joel , Dolnik Milos , Collins J. J.
Published: July 2002

The regulation of cellular function is often controlled at the level of gene transcription. Such genetic regulation usually consists of interacting networks, whereby gene products from a single network can act to control their own expression or the production of protein in another network. Engineered control of cellular function through the design and manipulation of such networks lies within the constraints of current technology. Here we develop a model describing the regulation of gene expression and elucidate the effects of noise on the formulation. We consider a single network derived from bacteriophage λ and construct a two-parameter deterministic model describing the temporal evolution of the concentration of λ repressor protein. Bistability in the steady-state protein concentration arises naturally, and we show how the bistable regime is enhanced with the addition of the first operator site in the promotor region. We then show how additive and multiplicative external noise can be used to regulate expression. In the additive case, we demonstrate the utility of such control through the construction of a protein switch, whereby protein production is turned “on” and “off” by using short noise pulses. In the multiplicative case, we show that small deviations in the transcription rate can lead to large fluctuations in the production of protein, and we describe how these fluctuations can be used to amplify protein production significantly. These results suggest that an external noise source could be used as a switch and/or amplifier for gene expression. Such a development could have important implications for gene therapy.
Decreases in rat extracellular hippocampal glucose concentration associated with cognitive demand during a spatial task
Authors: McNay Ewan C. , Fries Thomas M. , Gold Paul E.
Published: July 2002

Using
in vivo
microdialysis, we measured hippocampal
extracellular glucose concentrations in rats while they performed
spontaneous alternation tests of spatial working memory in one of two
mazes. Extracellular glucose levels in the hippocampus decreased by
32% below baseline during the test period on the more complex maze,
but by a maximum of 11% on the less complex maze. Comparable decreases
were not observed in samples taken from rats tested on the more complex
maze but with probes located near but outside of the hippocampus.
Systemic glucose fully blocked any decrease in extracellular glucose
and enhanced alternation on the more complex maze. These findings
suggest that cognitive activity can deplete extracellular glucose in
the hippocampus and that exogenous glucose administration reverses the
depletion while enhancing task performance.
Mapping of contact sites in complex formation between transducin and light-activated rhodopsin by covalent crosslinking: Use of a photoactivatable reagent
Authors: Cai Kewen , Itoh Yoshiki , Khorana H. Gobind
Published: July 2002

Interaction of light-activated rhodopsin with transducin (T)
is the first event in visual signal transduction. We use covalent
crosslinking approaches to map the contact sites in interaction between
the two proteins. Here we use a photoactivatable reagent,
N
-[(2-pyridyldithio)-ethyl], 4-azido salicylamide. The
reagent is attached to the SH group of cytoplasmic monocysteine
rhodopsin mutants by a disulfide-exchange reaction with the pyridylthio
group, and the derivatized rhodopsin then is complexed with T by
illumination at λ >495 nm. Subsequent irradiation of the complex at
λ310 nm generates covalent crosslinks between the two proteins.
Crosslinking was demonstrated between T and a number of single cysteine
rhodopsin mutants. However, sites of crosslinks were investigated in
detail only between T and the rhodopsin mutant S240C (cytoplasmic loop
V-VI). Crosslinking occurred predominantly with T
α
. For
identification of the sites of crosslinks in T
α
, the
strategy used involved: (
i
) derivatization of all of the
free cysteines in the crosslinked proteins with
N
-ethylmaleimide; (
ii
) reduction of the
disulfide bond linking the two proteins and isolation of all of the
T
α
species carrying the crosslinked moiety with a free SH
group; (
iii
) adduct formation of the latter with the
N
-maleimide moiety of the reagent,
maleimido-butyryl-biocytin, containing a biotinyl group;
(
iv
) trypsin degradation of the resulting
T
α
derivatives and isolation of T
α
peptides
carrying maleimido-butyryl-biocytin by avidin-agarose chromatography;
and (
v
) identification of the isolated peptides by
matrix-assisted laser desorption/ionization time-of-flight mass
spectrometry. We found that crosslinking occurred mainly to two
C-terminal peptides in T
α
containing the amino acid
sequences 310–313 and 342–345.
Up-regulation of nitric oxide synthase and modulation of the guanylate cyclase activity by corticotropin-releasing hormone but not urocortin II or urocortin III in cultured human pregnant myometrial cells
Authors: Aggelidou Eleni , Hillhouse Edward W. , Grammatopoulos Dimitris K.
Published: July 2002

The biological actions of corticotropin-releasing hormone (CRH) in the human myometrium during pregnancy and labor are unknown. We hypothesized that CRH may modulate the nitric oxide system, and influence myometrial relaxation/contractility. Incubation of myometrial cells with CRH, but not urocortin II or urocortin III, for 8–16 h significantly induced mRNA and protein expression of endothelial and brain but not inducible nitric oxide synthase (NOS) isoforms. This action resulted in increased activity of soluble guanylate cyclase (GC
s
), demonstrated by the enhanced cGMP-producing capacity of the NO donor, sodium nitroprusside. CRH also caused acute activation of the membrane-bound GC, shown by increased basal or atrial natriuretic peptide (ANP)-stimulated cGMP production. These effects appeared to be mediated via the R1 receptors because the CRH receptor antagonists, astressin and antalarmin but not anti-sauvagine 30, could block them. The acute effects of CRH were significantly reduced by inhibition of protein kinase A (PKA) activity, suggesting it is partially PKA dependant. Activation of protein kinase C (PKC) resulted in significant inhibition of both ANP-and CRH-stimulated cGMP production, suggesting a direct effect of PKC on membrane-bound GC. In conclusion, CRH appears to have a dual effect on myometrial NOS/GC pathway, a short term effect predominantly mediated by PKA, and a long-term effect increasing constitutive NOS expression, mediated by a PKA-independent mechanism. This mechanism could potentially be active during human pregnancy, and, because cGMP stimulates myometrial relaxation, these findings further suggest that during pregnancy CRH primarily activates intracellular signals that contribute to the maintenance of myometrial quiescence.
Persistence of oligodendrocyte precursor cells and altered myelination in optic nerve associated to retina degeneration in mice devoid of all thyroid hormone receptors
Authors: Baas Dominique , Legrand Claude , Samarut Jacques , Flamant Frédéric
Published: July 2002

Thyroid hormone (3,5,3′-triiodo-
l
-thyronine or T3) exerts a pleiotropic activity during central nervous system development. Hypothyroidism during the fetal and postnatal life results in an irreversible mental retardation syndrome. At the cellular level, T3 is known to act on neuronal and glial lineages and to control cell proliferation, apoptosis, migration, and differentiation. Oligodendrocyte precursor cells (OPC) found at birth in the optic nerves are self-renewing cells that normally differentiate during the first 3 weeks of rodent postnatal life into postmitotic myelinating oligodendrocytes.
In vitro
, the addition of T3 to OPC is sufficient to trigger their terminal differentiation. The present analysis of T3 receptor knockout mice reveals that the absence of all T3 receptor results in the persistence of OPC proliferation in adult optic nerves, in a default in myelination, and sometimes in the degeneration of the retinal ganglion neurons. Thus, T3 signaling is necessary
in vivo
to promote the complete differentiation of OPC.
Quantitativein vivoassessment of lung microstructure at the alveolar level with hyperpolarized3He diffusion MRI
Authors: Yablonskiy Dmitriy A. , Sukstanskii Alexander L. , Leawoods Jason C. , Gierada David S. , Bretthorst G. Larry , Lefrak Stephen S. , Cooper Joel D. , Conradi Mark S.
Published: July 2002

The study of lung emphysema dates back to the beginning of the 17th century. Nevertheless, a number of important questions remain unanswered because a quantitative localized characterization of emphysema requires knowledge of lung structure at the alveolar level in the intact living lung. This information is not available from traditional imaging modalities and pulmonary function tests. Herein, we report the firstin vivomeasurements of lung geometrical parameters at the alveolar level obtained with3He diffusion MRI in healthy human subjects and patients with severe emphysema. We also provide the first experimental data demonstrating that3He gas diffusivity in the acinus of human lung is highly anisotropic. A theory of anisotropic diffusion is presented. Our results clearly demonstrate substantial differences between healthy and emphysematous lung at the acinar level and may provide new insights into emphysema progression. The technique offers promise as a clinical tool for early diagnosis of emphysema.
Apoptosis and melanogenesis in human melanoma cells induced by anthrax lethal factor inactivation of mitogen-activated protein kinase kinase
Authors: Koo Han-Mo , VanBrocklin Matt , McWilliams Mary Jane , Leppla Stephan H. , Duesbery Nicholas S. , Woude George F. Vande
Published: July 2002

Lethal factor, the principal virulence factor of
Bacillus anthracis
, inhibits mitogen-activated protein kinase (MAPK) signaling by proteolytically cleaving MAPK kinases. Edema factor, another component of anthrax toxin, is an adenylate cyclase, which increases intracellular cAMP. Inhibition of MAPK signaling with either anthrax lethal toxin (LeTx) or small molecule MAPK kinase inhibitors triggers apoptosis in human melanoma cells. Normal melanocytes do not undergo apoptosis in response to MAPK inhibition but arrest in the G
1
phase of the cell cycle. Importantly,
in vivo
treatment of human melanoma xenograft tumors in athymic nude mice with LeTx results in significant or complete tumor regression without apparent side effects, suggesting that inhibiting the MAPK signaling pathway may be a useful strategy for treating melanoma. Additionally, interrupting MAPK signaling with LeTx and elevating cAMP with anthrax edema toxin in both melanoma cells and melanocytes lead to dramatic melanin production, perhaps explaining the formation of blackened eschars in cutaneous anthrax.
Methylenetetrahydrofolate reductase (MTHFR) polymorphisms and risk of molecularly defined subtypes of childhood acute leukemia
Authors: Wiemels Joseph L. , Smith Rosalyn N. , Taylor G. Malcolm , Eden Osborn B. , Alexander Freda E. , Greaves Mel F. ,   United Kingdom Childhood Cancer Study Investigators
Published: July 2002

Low folate intake as well as alterations in folate metabolism as a
result of polymorphisms in the enzyme methylenetetrahydrofolate
reductase (
MTHFR
) have been associated with an increased
incidence of neural tube defects, vascular disease, and some cancers.
Polymorphic variants of
MTHFR
lead to enhanced thymidine
pools and better quality DNA synthesis that could afford some
protection from the development of leukemias, particularly those with
translocations. We now report associations of
MTHFR
polymorphisms in three subgroups of pediatric leukemias: infant
lymphoblastic or myeloblastic leukemias with
MLL
rearrangements and childhood lymphoblastic leukemias with either
TEL
-
AML1
fusions or hyperdiploid
karyotypes. Pediatric leukemia patients (
n
= 253
total) and healthy newborn controls (
n
= 200) were
genotyped for
MTHFR
polymorphisms at nucleotides 677
(C→T) and 1,298 (A→C). A significant association for carriers of
C677T
was demonstrated for leukemias with
MLL
translocations (
MLL
+,
n
= 37) when compared with controls [adjusted odd
ratios (OR) = 0.36 with a 95% confidence interval (CI) of
0.15–0.85;
P
= 0.017]. This protective effect was
not evident for
A1298C
alleles (OR = 1.14). In
contrast, associations for
A1298C
homozygotes (CC;
OR = 0.26 with a 95% CI of 0.07–0.81) and
C677T
homozygotes (TT; OR = 0.49 with a 95% CI of 0.20–1.17) were
observed for hyperdiploid leukemias (
n
= 138). No
significant associations were evident for either polymorphism with
TEL
-
AML1
+ leukemias
(
n
= 78). These differences in allelic associations
may point to discrete attributes of the two alleles in their ability to
alter folate and one-carbon metabolite pools and impact after DNA
synthesis and methylation pathways, but should be viewed cautiously
pending larger follow-up studies. The data provide evidence that
molecularly defined subgroups of pediatric leukemias have different
etiologies and also suggest a role of folate in the development of
childhood leukemia.
Wild-type and mutated presenilins 2 trigger p53-dependent apoptosis and down-regulate presenilin 1 expression in HEK293 human cells and in murine neurons
Authors: Alves da Costa Cristine , Paitel Erwan , Mattson Mark P. , Amson Robert , Telerman Adam , Ancolio Karine , Checler Frédéric
Published: July 2002

Presenilins 1 and 2 are two homologous proteins that, when mutated, account for most early onset Alzheimer's disease. Several lines of evidence suggest that, among various functions, presenilins could modulate cell apoptotic responses. Here we establish that the overexpression of presenilin 2 (PS2) and its mutated form Asn-141-Ile-PS2 alters the viability of human embryonic kidney (HEK)293 cells as established by combined trypan blue exclusion, sodium 3′-[1-(phenylamino-carbonyl)-3,4-tetrazolium]-bis(4-methoxy-6-nitro)benzene sulfonic acid hydrate assay, and propidium iodide incorporation FACS analyses. The two parent proteins increase the acetyl-DEVD-al-sensitive caspase-3-like activity in both HEK293 cells and Telencephalon specific murine neurons, modulate Bax and bcl-2 expressions, and enhance cytochrome C translocation into the cytosol. We show that overexpression of both wild-type and mutated PS2 increases p53-like immunoreactivity and transcriptional activity. We also establish that wild-type- and mutated PS2-induced caspase activation is reduced by p53 antisense approach and by pifithrin-α, a chemical inhibitor of p53. Furthermore, mouse fibroblasts in which the PS2 gene has been knocked out exhibited strongly reduced p53-transcriptional activity. Finally, we establish that the overexpression of both wild-type and mutated PS2 is accompanied by a drastic reduction of endogenous presenilin 1 (PS1) expression. Interestingly, pifithrin-α diminished endogenous PS2 immunoreactivity, whereas the inhibitor increases PS1 expression. Altogether, our data demonstrate that wild-type and familial Alzheimer's disease-linked PS2 trigger apoptosis and down-regulate PS1 expression through p53-dependent mechanisms.
Seeing properties of an invisible object: Feature inheritance and shine-through
Authors: Herzog Michael H. , Koch Christof
Published: July 2002

We characterize a class of spatio-temporal illusions with two
complementary properties. Firstly, if a vernier stimulus is flashed for
a short time on a monitor and is followed immediately by a grating, the
latter can express features of the vernier, such as its offset, its
orientation, or its motion (feature inheritance). Yet the vernier
stimulus itself remains perceptually invisible. Secondly, the vernier
can be rendered visible by presenting gratings with a larger number of
elements (shine-through). Under these conditions, subjects perceive two
independent “objects” each carrying their own features.
Transition between these two domains can be effected by subtle changes
in the spatio-temporal layout of the grating. This should allow
psychophysicists and electrophysiologists to investigate feature
binding in a precise and quantitative manner.
Evidence that ultraviolet markings are associated with patterns of molecular gene flow
Authors: Thorpe Roger S. , Richard Murielle
Published: July 2002

Recent studies have shown UV vision and markings to be important in
vertebrates, particularly birds, where behavioral experiments have
demonstrated its potential importance in sexual selection. However,
there has been no genetic evidence that UV markings determine patterns
of evolution among natural populations. Here we report molecular
evidence that UV markings are associated with the pattern of gene flow
in the Tenerife lizard (
Gallotia galloti
). This species
has vicariance-induced, approximate east–west lineages in Tenerife
closely congruent with the primary lineages of the sympatric gecko
species. Against expectations, these molecular phylogeographic lineages
(representing geological history) and isolation-by-distance do not
appear to influence gene flow. Sexually mature males from populations
either side of a latitudinal ecotone have different UV markings and
gene flow appears to be linked to this difference in UV markings. It
may be that these groups with different UV sexual markings mate
assortatively, restricting the gene flow between them. This has
implications for debate on the relative importance of vicariance and
biotopes in influencing biodiversity, with this evidence supporting the
latter.
A missense mutation in human fatty acid amide hydrolase associated with problem drug use
Authors: Sipe Jack C. , Chiang Kyle , Gerber Alexandra L. , Beutler Ernest , Cravatt Benjamin F.
Published: July 2002

Problem drug use and dependence are neurobehavioral disorders of complex origin. Although environmental factors contribute to drug abuse and addiction, genetic factors also play a significant role estimated at 40–60% of the total risk. Nonetheless, the precise identities of human genes that confer vulnerability to problem drug use remain mostly unknown. Here, we describe a natural single nucleotide polymorphism in the human gene that encodes the principal endocannabinoid-inactivating enzyme, fatty acid amide hydrolase (FAAH), that in homozygous form is strongly associated with both street drug use and problem drug/alcohol use. This single nucleotide polymorphism results in a missense mutation (385C→A) that converts a conserved proline residue to threonine (Pro129→Thr), producing a FAAH variant that displays normal catalytic properties but an enhanced sensitivity to proteolytic degradation. Collectively, these results suggest that genetic mutations in FAAH may constitute important risk factors for problem drug use and support a potential link between functional abnormalities in the endogenous cannabinoid system and drug abuse and dependence.
Human-caused environmental change: Impacts on plant diversity and evolution
Authors: Tilman David , Lehman Clarence
Published: July 2002

Human-caused environmental changes are creating regional combinations of environmental conditions that, within the next 50 to 100 years, may fall outside the envelope within which many of the terrestrial plants of a region evolved. These environmental modifications might become a greater cause of global species extinction than direct habitat destruction. The environmental constraints undergoing human modification include levels of soil nitrogen, phosphorus, calcium and pH, atmospheric CO2, herbivore, pathogen, and predator densities, disturbance regimes, and climate. Extinction would occur because the physiologies, morphologies, and life histories of plants limit each species to being a superior competitor for a particular combination of environmental constraints. Changes in these constraints would favor a few species that would competitively displace many other species from a region. In the long-term, the “weedy” taxa that became the dominants of the novel conditions imposed by global change should become the progenitors of a series of new species that are progressively less weedy and better adapted to the new conditions. The relative importance of evolutionary versus community ecology responses to global environmental change would depend on the extent of regional and local recruitment limitation, and on whether the suite of human-imposed constraints were novel just regionally or on continental or global scales.
cAMP facilitates EDHF-type relaxations in conduit arteries by enhancing electrotonic conduction via gap junctions
Authors: Griffith Tudor M. , Chaytor Andrew T. , Taylor Hannah J. , Giddings Beverley D. , Edwards David H.
Published: July 2002

We have investigated the role of cAMP in NO- and prostanoid-independent relaxations that are widely attributed to an endothelium-derived hyperpolarizing factor (EDHF). Under control conditions EDHF-type relaxations evoked by acetylcholine (ACh) in rabbit iliac arteries were transient, but in the presence of the cAMP phosphodiesterase inhibitor isobutylmethylxanthine (IBMX) or the cell permeant cAMP analog 8-bromo-cAMP, relaxations became sustained with their maxima potentiated ≈2-fold. Relaxation was associated with transient ≈1.5-fold elevations in smooth muscle cAMP levels with both mechanical and nucleotide responses being abolished by interrupting gap junctional communication with the connexin-mimetic peptide Gap 27 and by endothelial denudation. However, IBMX induced a sustained endothelium-independent ≈2-fold rise in cAMP levels, which was not further amplified by ACh, suggesting that the contribution of cAMP to the EDHF phenomenon is permissive. After selective loading of the endothelium with calcein AM, direct transfer of dye from the endothelium to the media was enhanced by IBMX or 8-bromo-cAMP, but not by 8-bromo-cGMP, whereas Gap 27 promoted sequestration within the intima. ACh-induced hyperpolarizations of subintimal smooth muscle in arterial strips with intact endothelium were abolished by Gap 27 and the adenylyl cyclase inhibitor 2′,5′-dideoxyadenosine but were unaffected by IBMX. By contrast, in strips partially denuded of endothelium, IBMX enhanced the transmission of hyperpolarization from the endothelium to remote smooth muscle cells. These findings support the hypothesis that endothelial hyperpolarization underpins the EDHF phenomenon, with cAMP governing subsequent electrotonic signaling via both myoendothelial and homocellular smooth muscle gap junctions.
Anandamide and diet: Inclusion of dietary arachidonate and docosahexaenoate leads to increased brain levels of the corresponding
N
-acylethanolamines in piglets
Authors: Berger Alvin , Crozier Gayle , Bisogno Tiziana , Cavaliere Paolo , Innis Sheila , Di Marzo Vincenzo
Published: July 2002

Endogenous ligands of cannabinoid receptors have been
discovered recently and include some
N
-acylethanolamines
(NAEs; e.g.,
N-
arachidonoylethanolamine) and some
2-acylglycerols (e.g.,
sn
-2-arachidonoylglycerol).
Previously, we found these compounds to be active biologically when
administered
per os
in large quantities to mice. In the
present work, piglets were fed diets with and without
20:4
n
−6 and 22:6
n
−3 fatty acid
precursors of NAEs, in levels similar to those found in porcine milk,
during the first 18 days of life, and corresponding brain NAEs were
assessed. In piglets fed diets containing 20:4
n
−6 and
22:6
n
−3, there were increases in several biologically
active NAEs in brain homogenates—20:4
n
−6 NAE (4-fold),
20:5
n
−3 NAE (5-fold), and 22:5
n
−3 and
22:6
n
−3 NAE (9- to 10-fold). These results support a
mechanism we propose for dietary long-chain polyunsaturated fatty acids
influences on brain biochemistry with presumed functional sequelae.
This paradigm will enable targeted investigations to determine whether
and why specific populations such as infants, elderly, or persons
suffering from certain clinical conditions may benefit from dietary
long-chain polyunsaturated fatty acids.
Genetic determination of the queen caste in an ant hybrid zone
Authors: Julian Glennis E. , Fewell Jennifer H. , Gadau Jürgen , Johnson Robert A. , Larrabee Debbie
Published: July 2002

The question of how reproductives and sterile workers differentiate within eusocial groups has long been a core issue in sociobiology because it requires the loss of individual direct fitness in favor of indirect or group-level fitness gains. The evolution of social behavior requires that differentiation between workers and female reproductives be environmentally determined, because genetically determined sterility would be quickly eliminated. Nevertheless, we report clear evidence of genetic caste determination in populations of two seed harvester ant species common to the southwestern USA,
Pogonomyrmex rugosus
and
Pogonomyrmex barbatus
. The genetic differentiation between workers and queens is found only in areas of sympatry of the two species, and thus appears to arisen from hybridization. Our data suggest that this hybridization has had a profound historical effect on the caste determination systems and mating patterns of each of these species.
Multilocus analysis of extracellular putative virulence proteins made by group A
Streptococcus:
Population genetics, human serologic response, and gene transcription
Authors: Reid Sean D. , Green Nicole M. , Buss Julie K. , Lei Benfang , Musser James M.
Published: July 2002

Species of pathogenic microbes are composed of an array of evolutionarily distinct chromosomal genotypes characterized by diversity in gene content and sequence (allelic variation). The occurrence of substantial genetic diversity has hindered progress in developing a comprehensive understanding of the molecular basis of virulence and new therapeutics such as vaccines. To provide new information that bears on these issues, 11 genes encoding extracellular proteins in the human bacterial pathogen group A
Streptococcus
identified by analysis of four genomes were studied. Eight of the 11 genes encode proteins with a LPXTG(L) motif that covalently links Gram-positive virulence factors to the bacterial cell surface. Sequence analysis of the 11 genes in 37 geographically and phylogenetically diverse group A
Streptococcus
strains cultured from patients with different infection types found that recent horizontal gene transfer has contributed substantially to chromosomal diversity. Regions of the inferred proteins likely to interact with the host were identified by molecular population genetic analysis, and Western immunoblot analysis with sera from infected patients confirmed that they were antigenic. Real-time reverse transcriptase–PCR (TaqMan) assays found that transcription of six of the 11 genes was substantially up-regulated in the stationary phase. In addition, transcription of many genes was influenced by the
covR
and
mga
trans-acting gene regulatory loci. Multilocus investigation of putative virulence genes by the integrated approach described herein provides an important strategy to aid microbial pathogenesis research and rapidly identify new targets for therapeutics research.
Tbx19
, a tissue-selective regulator of POMC gene expression
Authors: Liu Jianxiang , Lin Chijen , Gleiberman Anatoli , Ohgi Kenneth A. , Herman Thomas , Huang Hsiang-Po , Tsai Ming-Jer , Rosenfeld Michael G.
Published: July 2002

Pituitary cell types arise in a temporally and spatially specific fashion, in response to combinatorial actions of transcription factors induced by transient signaling gradients. The critical transcriptional determinants of the two pituitary cell types that express the pro-opiomelanocortin (POMC) gene, the anterior lobe corticotropes, producing adrenocorticotropin, and the intermediate lobe melanotropes, producing melanocyte-stimulating hormone (MSHα), have remained unknown. Here, we report that a member of the T-box gene family,
Tbx19
, which is expressed only in the rostral ventral diencephalon and pituitary gland, commencing on e11.5, marks pituitary cells that will subsequently express the
POMC
gene and is capable of altering progression of ventral cell types and inducing adrenocorticotropin in rostral tip cells. It is suggested that
Tbx19
, depending on the presence of synergizing transcription factors, can activate
POMC
gene expression and repress the α glycoprotein subunit and thyroid-stimulating hormone β promoters.
Spatial–temporal imaging of bacterial infection and antibiotic response in intact animals
Authors: Zhao Ming , Yang Meng , Baranov Eugene , Wang Xiaoen , Penman Sheldon , Moossa A. R. , Hoffman Robert M.
Published: July 2002

We describe imaging the luminance of green fluorescent protein
(GFP)-expressing bacteria from outside intact infected animals. This
simple, nonintrusive technique can show in great detail the
spatial–temporal behavior of the infectious process. The bacteria,
expressing the GFP, are sufficiently bright as to be clearly visible
from outside the infected animal and recorded with simple equipment.
Introduced bacteria were observed in several mouse organs including the
peritoneal cavity, stomach, small intestine, and colon. Instantaneous
real-time images of the infectious process were acquired by using a
color charge-coupled device video camera by simply illuminating mice at
490 nm. Most techniques for imaging the interior of intact animals may
require the administration of exogenous substrates, anesthesia, or
contrasting substances and require very long data collection times. In
contrast, the whole-body fluorescence imaging described here is fast
and requires no extraneous agents. The progress of
Escherichia
coli
-GFP through the mouse gastrointestinal tract after gavage
was followed in real-time by whole-body imaging. Bacteria, seen first
in the stomach, migrated into the small intestine and subsequently into
the colon, an observation confirmed by intravital direct imaging. An
i.p. infection was established by i.p. injection of
E.
coli
-GFP. The development of infection over 6 h and its
regression after kanamycin treatment were visualized by whole-body
imaging. This imaging technology affords a powerful approach to
visualizing the infection process, determining the tissue specificity
of infection, and the spatial migration of the infectious agents.