bluuebunny/crossref_metadata_2025 huggingface dataset:
Translational and radial motions of a bubble in an acoustic standing wave field
Authors: Watanabe T. , Kukita Y.
Published: July 2002

The dynamic responses of a spherical bubble in an acoustic standing wave field are studied numerically. The equations of motion in the translational and the radial directions are solved simultaneously. It is shown that a bubble which is larger than the resonance size moves to a node of the pressure field and its radial oscillations become small. A sufficiently small bubble is shown to move to an antinode and radially oscillates under the maximum pressure amplitude. It is found using Poincaré maps and power spectra that a bubble which is slightly smaller than the resonance size oscillates chaotically in both the radial and the translational directions. It is demonstrated that the range of the equilibrium bubble size which shows chaotic motions broadens with the pressure amplitude. Finally, the radial responses of the bubble are shown to be dependent not only on the pressure amplitude but also on the drag force in the translational direction.
Anomalous radiation from Langmuir turbulence
Authors: Nambu M. , Sarma S. N. , Bujarbarua S.
Published: July 2002

The stability of stationary Langmuir turbulence against a test high-frequency electromagnetic perturbation is studied. The enhanced growth of the electromagnetic radiation through the new mode–mode coupling process is obtained for an open system plasma with a particle source and sink. The growth rate of the electromagnetic mode comes from the direct and polarization mode coupling terms even for an unmagnetized plasma.
Double-diffusive convection with sidewalls
Authors: McFadden G. B. , Coriell S. R. , Boisvert R. F.
Published: July 2002

The effect of rigid vertical boundaries on the onset of convective instability is calculated for the salt finger regime of double-diffusive convection. The unperturbed state is a quiescent fluid with constant vertical gradients of temperature and solute, which are stabilizing and destabilizing, respectively. The horizontal boundaries are taken to be stress-free and perfectly conducting. The lateral boundaries are perfectly insulating for solute. Changing from thermally insulating to thermally conducting sidewalls results in a strong destabilization of the flow for large thermal Rayleigh numbers even in the limit that the separation between the sidewalls approaches infinity. Further, for thermally conducting sidewalls, a decrease in the separation of the sidewalls may destabilize the system.
Surface waves in closed basins under parametric and internal resonances
Authors: Nayfeh Ali H.
Published: July 2002

The method of multiple scales is used to analyze the nonlinear response of the free surface of a liquid in a cylindrical container to a harmonic vertical oscillation in the presence of a two-to-one internal (autoparametric) resonance. Four first-order ordinary-differential equations are derived for the modulation of the amplitudes and phases of the two modes involved in the internal resonance with the lower mode is excited by a principal parametric resonance. In the presence of small damping, the long-time response may be any of (a) a trivial motion, (b) a limit cycle involving both modes, (c) an amplitude- and phase-modulated sinusoid (motion on a two torus), and (d) a chaotically modulated sinusoid.
Fluid flow due to a stretching cylinder
Authors: Wang C. Y.
Published: July 2002

The fluid flow outside of a stretching cylinder is studied. The problem is governed by a third-order nonlinear ordinary differential equation that leads to exact similarity solutions of the Navier–Stokes equations. Because of algebraic decay, an exponential transform is used to facilitate numerical integration. Asymptotic solutions for large Reynolds numbers compare well with numerical results. The heat transfer is determined.
Chaotic flows and fast magnetic dynamos
Authors: Finn John M. , Ott Edward
Published: July 2002

Given a prescribed flow of an initially unmagnetized conducting fluid, one can ask if a small seed magnetic field will amplify exponentially with time. This is called the kinematic dynamo problem. In many cases of interest (particularly in astrophysics), very high electrical conductivity of the fluid (high magnetic Reynolds number Rm ) is relevant. In this paper the kinematic dynamo problem is considered in the Rm →∞ limit (the ‘‘fast’’ kinematic dynamo). It appears that an important ingredient for a kinematic dynamo in this limit is that the orbits of fluid elements in the flow be chaotic. In this paper it is shown that the magnetic field tends to concentrate on a zero volume fractal set, and, in addition, tends to exhibit arbitrarily fine-scaled oscillations between parallel and antiparallel directions. Idealized analyzable examples exhibiting these properties are presented, along with numerical computations on more typical examples. For the latter a numerical technique for treating fast dynamos is developed and its properties are discussed. The relation of the dynamo growth rate to quantitative measures of chaos, namely, the Lyapunov exponent and topological entropy, is also discussed.
Phase diagrams for sonoluminescing bubbles
Authors: Hilgenfeldt Sascha , Lohse Detlef , Brenner Michael P.
Published: July 2002

Sound driven gas bubbles in water can emit light pulses. This phenomenon is called sonoluminescence (SL). Two different phases of single bubble SL have been proposed: diffusively stable and diffusively unstable SL. We present phase diagrams in the gas concentration versus forcing pressure state space and also in the ambient radius versus gas concentration and versus forcing pressure state spaces. These phase diagrams are based on the thresholds for energy focusing in the bubble and two kinds of instabilities, namely (i) shape instabilities and (ii) diffusive instabilities. Stable SL only occurs in a tiny parameter window of large forcing pressure amplitude Pa∼1.2–1.5 atm and low gas concentration of less than 0.4% of the saturation. The upper concentration threshold becomes smaller with increased forcing. Our results quantitatively agree with experimental results of Putterman’s UCLA group on argon, but not on air. However, air bubbles and other gas mixtures can also successfully be treated in this approach if in addition (iii) chemical instabilities are considered. All statements are based on the Rayleigh–Plesset ODE approximation of the bubble dynamics, extended in an adiabatic approximation to include mass diffusion effects. This approximation is the only way to explore considerable portions of parameter space, as solving the full PDEs is numerically too expensive. Therefore, we checked the adiabatic approximation by comparison with the full numerical solution of the advection diffusion PDE and find good agreement.
Probability density function and Reynolds-stress modeling of near-wall turbulent flows
Authors: Dreeben Thomas D. , Pope Stephen B.
Published: July 2002

Probability density function (pdf) methods are extended to include modeling of wall-bounded turbulent flows. A pdf near-wall model is developed in which the generalized Langevin model is combined with an exact model for viscous transport. Then the method of elliptic relaxation is used to incorporate the wall effects without the use of wall functions or damping functions. Information about the proximity of the wall is provided only in the boundary conditions so that the model can be implemented without ad hoc assumptions about the geometry of the flow. A Reynolds-stress closure is derived from this pdf model, and its predictions are compared with DNS and experimental results for fully developed turbulent channel flow.
Instability analysis of internal solitary waves in a nearly uniformly stratified fluid
Authors: Pelinovsky Dmitry E. , Grimshaw Roger H. J.
Published: July 2002

Long finite-amplitude internal solitary waves propagating in a stratified fluid with nearly uniform stratification are considered within an asymptotic approximation leading to a nonlocal evolution equation of the Korteweg–de Vries (KdV) type. Analytical properties of this equation and its solitary wave solutions are studied and a criterion for solitary wave instability is derived. This criterion coincides with that for solitary waves in a local generalized KdV equation. Applications of these results reveal that strengthening of the stratification might lead to destabilization of smooth solitary waves and their blow-up into vortex-type wave structures.
An approximate deconvolution procedure for large-eddy simulation
Authors: Stolz S. , Adams N. A.
Published: July 2002

An alternative approach to large-eddy simulation based on approximate deconvolution (ADM) is developed. The main ingredient is an approximation of the nonfiltered field by truncated series expansion of the inverse filter operator. A posteriori tests for decaying compressible isotropic turbulence show excellent agreement with direct numerical simulation. The computational overhead of ADM is similar to that of a scale-similarity model and considerably less than for dynamic models.
Direct numerical simulation of the flow in a lid-driven cubical cavity
Authors: Leriche E. , Gavrilakis S.
Published: July 2002

Direct numerical simulation of the flow in a lid-driven cubical cavity has been carried out at a Reynolds number above 10 000. Both transient and steady-in-the-mean states of the flow posses long time scales requiring long integration times. A large fraction of the total kinetic energy and dissipation is concentrated in the near-lid mean flow. The flow over most of the domain is laminar with distinct wall-jet profiles found in three of the walls. The high momentum fluid near the lid transmits its energy into a downflowing nonparallel wall jet which separates ahead of the bottom wall. From the collision of this separated layer against the bottom wall two wall jets emerge. In this process the energy lost to turbulence by the impingement is partly recovered by the emerging wall jets.
Noncircular, finite aspect ratio, local equilibrium model
Authors: Miller R. L. , Chu M. S. , Greene J. M. , Lin-Liu Y. R. , Waltz R. E.
Published: July 2002

A tokamak equilibrium model, local to a flux surface, is introduced which is completely described in terms of nine parameters including aspect ratio, elongation, triangularity, and safety factor. By allowing controlled variation of each of these nine parameters, the model is particularly suitable for localized stability studies such as those carried out using the ballooning mode representation of the gyrokinetic equations.
Interaction of fast particles with neoclassical tearing modes
Authors: Sesnic S. , Günter S. , Gude A. , Maraschek M. ,   ASDEX Upgrade Team
Published: July 2002

Fast particle driven m=1/n=1 modes in the form of fishbones frequently initiate neoclassical tearing modes (NTMs) on Axisymmetric Divertor Experiment Upgrade [W. Köppendörfer et al., 14th International Conference on Plasma Physics and Controlled Fusion (International Atomic Energy Agency, Vienna, 1993), Vol. I, p. 127] and other neutral-beam-injection heated tokamaks, but disappear after the NTMs have reached a quasistationary state. A burst of other magnetohydrodynamic phenomena, described in this paper, appear instead, similar in repetition rate and time signature of frequency and amplitude. They are associated with the growth of the m=2/n=2 satellite of the m=3/n=2 neoclassical tearing mode, and a transient increase (termed FJ=frequency jump event) in the rotation frequency of the coupled mode system. They lead to a thermal crash, originating at q=3/2, propagating inwards up to the q=1 surface. With a lower repetition rate (more characteristic of sawteeth) similar events occur, where a large 1/1 component also appears and the fast crash propagates to the plasma center frequency jump with sawtooth character (FJST). The analogies to the fishbone case suggest that this phenomenon is caused by the interaction with fast particles, which transiently impress their precession frequency on the pre-existing magnetic perturbation of the NTM.
Formation of amorphous alloys by the mechanical alloying of crystalline powders of pure metals and powders of intermetallics
Authors: Schwarz Ricardo B. , Koch Carl C.
Published: July 2002

Amorphous powders of Ni32Ti68 and of Ni45Nb55 were synthesized by mechanical alloying (MA) starting from either a mixture of pure metal powders (in the appropriate molar ratio) or from powders of the crystalline intermetallics NiTi2 and Ni45Nb55, respectively. For both alloys, the peak temperature increase (above the average processing temperature) in the powder particles trapped between colliding balls is estimated at 38 K. Thus, the amorphization is attributed to a process other than the formation of local melts followed by the rapid solidification of these melts into the amorphous phase. The amorphization by MA starting from a mixture of pure crystalline powders is attributed to a solid state interdiffusion reaction, the kinetics of which is controlled by the excess point and lattice defects generated by plastic deformation. The amorphization by MA starting from powders of crystalline intermetallics is attributed to the accumulation of point and lattice defects which raise the free energy of the faulted intermetallic above that of the amorphous alloy.
Organic electroluminescent diodes
Authors: Tang C. W. , VanSlyke S. A.
Published: July 2002

A novel electroluminescent device is constructed using organic materials as the emitting elements. The diode has a double-layer structure of organic thin films, prepared by vapor deposition. Efficient injection of holes and electrons is provided from an indium-tin-oxide anode and an alloyed Mg:Ag cathode. Electron-hole recombination and green electroluminescent emission are confined near the organic interface region. High external quantum efficiency (1% photon/electron), luminous efficiency (1.5 lm/W), and brightness (>1000 cd/m2) are achievable at a driving voltage below 10 V.
Extreme selectivity in the lift-off of epitaxial GaAs films
Authors: Yablonovitch Eli , Gmitter T. , Harbison J. P. , Bhat R.
Published: July 2002

We have discovered conditions for the selective lift-off of large area epitaxial AlxGa1−xAs films from the substrate wafers on which they were grown. A 500-Å-thick AlAs release layer is selectivity etched away, leaving behind a high-quality epilayer and a reusable GaAs substrate. We have measured a selectivity of ≳107 between the release layer and Al0.4Ga0.6As. This process relies upon the creation of a favorable geometry for the outdiffusion of dissolved H2 gas from the etching zone.
Copper chaperone for superoxide dismutase is essential to activate mammalian Cu/Zn superoxide dismutase
Authors: Wong Philip C. , Waggoner Darrel , Subramaniam Jamuna R. , Tessarollo Lino , Bartnikas Thomas B. , Culotta Valeria C. , Price Donald L. , Rothstein Jeffrey , Gitlin Jonathan D.
Published: July 2002

Recent studies in
Saccharomyces cerevisiae
suggest that the delivery of copper to Cu/Zn superoxide dismutase
(SOD1) is mediated by a cytosolic protein termed the copper chaperone
for superoxide dismutase (CCS). To determine the role of CCS in
mammalian copper homeostasis, we generated mice with targeted
disruption of
CCS
alleles
(
CCS
−/−
mice). Although
CCS
−/−
mice are viable and possess normal
levels of SOD1 protein, they reveal marked reductions in SOD1 activity
when compared with control littermates. Metabolic labeling with
64
Cu demonstrated that the reduction of SOD1 activity in
CCS
−/−
mice is the direct result of
impaired Cu incorporation into SOD1 and that this effect was specific
because no abnormalities were observed in Cu uptake, distribution, or
incorporation into other cuproenzymes. Consistent with this loss of
SOD1 activity,
CCS
−/−
mice showed
increased sensitivity to paraquat and reduced female fertility,
phenotypes that are characteristic of SOD1-deficient mice. These
results demonstrate the essential role of any mammalian copper
chaperone and have important implications for the development of novel
therapeutic strategies in familial amyotrophic lateral sclerosis.
Plant growth in elevated CO2alters mitochondrial number and chloroplast fine structure
Authors: Griffin Kevin L. , Anderson O. Roger , Gastrich Mary D. , Lewis James D. , Lin Guanghui , Schuster William , Seemann Jeffrey R. , Tissue David T. , Turnbull Matthew H. , Whitehead David
Published: July 2002

With increasing interest in the effects of elevated atmospheric CO2on plant growth and the global carbon balance, there is a need for greater understanding of how plants respond to variations in atmospheric partial pressure of CO2. Our research shows that elevated CO2produces significant fine structural changes in major cellular organelles that appear to be an important component of the metabolic responses of plants to this global change. Nine species (representing seven plant families) in several experimental facilities with different CO2-dosing technologies were examined. Growth in elevated CO2increased numbers of mitochondria per unit cell area by 1.3–2.4 times the number in control plants grown in lower CO2and produced a statistically significant increase in the amount of chloroplast stroma (nonappressed) thylakoid membranes compared with those in lower CO2treatments. There was no observable change in size of the mitochondria. However, in contrast to the CO2effect on mitochondrial number, elevated CO2promoted a decrease in the rate of mass-based dark respiration. These changes may reflect a major shift in plant metabolism and energy balance that may help to explain enhanced plant productivity in response to elevated atmospheric CO2concentrations.
5-Hydroxytryptamine 2B receptor regulates cell-cycle progression: Cross-talk with tyrosine kinase pathways
Authors: Nebigil Canan G. , Launay Jean-Marie , Hickel Pierre , Tournois Claire , Maroteaux Luc
Published: July 2002

In this paper, we present evidence that activation of
5-hydroxytryptamine 2B (5-HT2B) receptors by serotonin (5-HT) leads to
cell-cycle progression through retinoblastoma protein
hyperphosphorylation and through activation of both cyclin D1/cdk4
and cyclin E/cdk2 kinases by a mechanism that depends on induction of
cyclin D1 and cyclin E protein levels. The induction of cyclin D1
expression, but not that of cyclin E, is under mitogen-activated
protein kinase (MAPK) control, indicating an independent regulation of
these two cyclins in the 5-HT2B receptor mitogenesis. Moreover, by
using the specific platelet-derived growth factor receptor (PDGFR)
inhibitor AG 1296 or by overexpressing a kinase-mutant PDGFR, we show
that PDGFR kinase activity is essential for 5-HT2B-triggered
MAPK/cyclin D1, but not cyclin E, signaling pathways. 5-HT2B receptor
activation also increases activity of the Src family kinase, c-Src,
Fyn, and c-Yes. Strikingly, c-Src, but not Fyn or c-Yes, is the crucial
molecule between the G
q
protein-coupled 5-HT2B receptor and
the cell-cycle regulators. Inhibition of c-Src activity by
4-amino-5-(4-methylphenyl)-7-(
t
-butyl)pyrazolo[3,4-
d
]pyrimidine
(PP1) or depletion of c-Src is sufficient to abolish the 5-HT-induced
(
i
) PDGFR tyrosine kinase phosphorylation and MAPK
activation, (
ii
) cyclin D1 and cyclin E expression
levels, and (
iii
) thymidine incorporation. This paper
elucidates a model of 5-HT2B receptor mitogenesis in which c-Src acts
alone to control cyclin E induction and in concert with the receptor
tyrosine kinase PDGFR to induce cyclin D1 expression via the MAPK/ERK
pathway.
Selenoprotein oxidoreductase with specificity for thioredoxin and glutathione systems
Authors: Sun Qi-An , Kirnarsky Leo , Sherman Simon , Gladyshev Vadim N.
Published: July 2002

Thioredoxin (Trx) and glutathione (GSH) systems are
considered to be two major redox systems in animal cells. They are
reduced by NADPH via Trx reductase (TR) or oxidized GSH (GSSG)
reductase and further supply electrons for deoxyribonucleotide
synthesis, antioxidant defense, and redox regulation of signal
transduction, transcription, cell growth, and apoptosis. We
cloned and characterized a pyridine nucleotide disulfide
oxidoreductase, Trx and GSSG reductase (TGR), that exhibits specificity
for both redox systems. This enzyme contains a selenocysteine residue
encoded by the TGA codon. TGR can reduce Trx, GSSG, and a GSH-linked
disulfide in
in vitro
assays. This unusual substrate
specificity is achieved by an evolutionary conserved fusion of the TR
and glutaredoxin domains. These observations, together with the
biochemical probing and molecular modeling of the TGR structure,
suggest a mechanism whereby the C-terminal selenotetrapeptide serves a
role of a protein-linked GSSG and shuttles electrons from the disulfide
center within the TR domain to either the glutaredoxin domain or Trx.
Estimation of divergence times from multiprotein sequences for a few mammalian species and several distantly related organisms
Authors: Nei Masatoshi , Xu Ping , Glazko Galina
Published: July 2002

When many protein sequences are available for estimating the time of divergence between two species, it is customary to estimate the time for each protein separately and then use the average for all proteins as the final estimate. However, it can be shown that this estimate generally has an upward bias, and that an unbiased estimate is obtained by using distances based on concatenated sequences. We have shown that two concatenation-based distances, i.e., average gamma distance weighted with sequence length (d2) and multiprotein gamma distance (d3), generally give more satisfactory results than other concatenation-based distances. Using these two distance measures for 104 protein sequences, we estimated the time of divergence between mice and rats to be approximately 33 million years ago. Similarly, the time of divergence between humans and rodents was estimated to be approximately 96 million years ago. We also investigated the dependency of time estimates on statistical methods and various assumptions made by using sequence data from eubacteria, protists, plants, fungi, and animals. Our best estimates of the times of divergence between eubacteria and eukaryotes, between protists and other eukaryotes, and between plants, fungi, and animals were 3, 1.7, and 1.3 billion years ago, respectively. However, estimates of ancient divergence times are subject to a substantial amount of error caused by uncertainty of the molecular clock, horizontal gene transfer, errors in sequence alignments, etc.
Targeted new membrane addition in the cleavage furrow is a late, separate event in cytokinesis
Authors: Shuster C. B. , Burgess D. R.
Published: July 2002

Cytokinesis in animal cells is accomplished in part by an actomyosin contractile ring. Recent work on amphibian,
Drosophila
, and
Caenorhabditis elegans
embryos implicates membrane trafficking and delivery as essential for cytokinesis. However, the relative contributions of contractile ring constriction versus membrane insertion to cytokinesis and the temporal relationship between these processes are largely unexplored. Here we monitor secretion of the extracellular matrix protein, hyalin, as a marker for new plasma membrane addition in dividing sea urchin zygotes. We find that new membrane addition occurs specifically in the cleavage furrow late in telophase independent of contractile ring constriction. The directed equatorial deposition of new furrow membrane requires astral microtubules and release of internal stores of Ca
2+
, but not the presence of a central spindle. Further, cells arrested in M phase do not secrete hyalin, suggesting that mitotic exit is required for new membrane addition. These results demonstrate that astral overlap in equilaterally dividing cells not only serves to specify positioning and contraction of the contractile ring, but also to direct the delivery of new membrane to the furrow as a late, independent event during cytokinesis.
A prototypic platelet septin and its participation in secretion
Authors: Dent Judith , Kato Kazunobu , Peng Xiao-Rong , Martinez Constantino , Cattaneo Marco , Poujol Christel , Nurden Paquita , Nurden Alan , Trimble William S. , Ware Jerry
Published: July 2002

Studies are presented characterizing platelet CDCrel-1, a protein expressed to high levels by megakaryocytes and belonging to a family of conserved proteins, termed septin. Septin filaments originally were identified in yeast as essential for budding but have become increasingly associated with processes in higher eukaryotic cells involving active membrane movement such as cytokinesis and vesicle trafficking. Direct proof of an
in vivo
function for septins in higher eukaryotes is limited to the characterization of the
Drosophila
septin, termed PNUT. We present studies identifying platelet CDCrel-1 as a protein kinase substrate in the presence of known platelet agonists. The immunopurification of CDCrel-1 revealed it to be part of a macromolecular complex containing a protein involved in platelet secretion, syntaxin 4. Moreover, CDCrel-1 was localized
in situ
to areas surrounding platelet-storage granules. The relevance of CDCrel-1 to normal platelet function was established with the characterization of platelets from a CDCrel-1
Null
mouse. As compared with platelets from wild-type littermates, CDCrel
-
1
Null
platelets aggregate and release stored [
14
C]serotonin in the presence of subthreshold levels of collagen. These results provide new insights into the mechanisms regulating platelet secretion and identify platelet septins as a protein family contributing to membrane trafficking within the megakaryocyte and platelet.
Adenosine deaminase-related growth factors stimulate cell proliferation in
Drosophila
by depleting extracellular adenosine
Authors: Zurovec Michal , Dolezal Tomas , Gazi Michal , Pavlova Eva , Bryant Peter J.
Published: July 2002

We describe a protein family in
Drosophila
containing six adenosine deaminase-related growth factors (ADGFs), which are homologous to a mitogenic growth factor discovered in conditioned medium from cells of a different fly species,
Sarcophaga
. Closely related proteins have been identified in other animals, and a human homolog is implicated in the genetic disease Cat-Eye Syndrome. The two most abundantly expressed ADGFs in
Drosophila
larvae are ADGF-A, which is strongly expressed in the gut and lymph glands, and ADGF-D, which is mainly expressed in the fat body and brain. Recombinant ADGF-A and ADGF-D are active adenosine deaminases (ADAs), and they cause polarization and serum-independent proliferation of imaginal disk and embryonic cells
in vitro
. The enzymatic activity of these proteins is required for their mitogenic function, making them unique among growth factors. A culture medium prepared without adenosine, or depleted of adenosine by using bovine ADA, also stimulates proliferation of imaginal disk cells, and addition of adenosine to this medium inhibits proliferation. Thus ADGFs secreted
in vivo
may control tissue growth by modulating the level of extracellular adenosine.
Diagnosis of multiple cancer types by shrunken centroids of gene expression
Authors: Tibshirani Robert , Hastie Trevor , Narasimhan Balasubramanian , Chu Gilbert
Published: July 2002

We have devised an approach to cancer class prediction from gene expression profiling, based on an enhancement of the simple nearest prototype (centroid) classifier. We shrink the prototypes and hence obtain a classifier that is often more accurate than competing methods. Our method of “nearest shrunken centroids” identifies subsets of genes that best characterize each class. The technique is general and can be used in many other classification problems. To demonstrate its effectiveness, we show that the method was highly efficient in finding genes for classifying small round blue cell tumors and leukemias.
Dilated cardiomyopathy in mice deficient for the lysosomal cysteine peptidase cathepsin L
Authors: Stypmann Jörg , Gläser Kerstin , Roth Wera , Tobin Desmond J. , Petermann Ivonne , Matthias Rainer , Mönnig Gerold , Haverkamp Wilhelm , Breithardt Günter , Schmahl Wolfgang , Peters Christoph , Reinheckel Thomas
Published: July 2002

Dilated cardiomyopathy is a frequent cause of heart failure and is associated with high mortality. Progressive remodeling of the myocardium leads to increased dimensions of heart chambers. The role of intracellular proteolysis in the progressive remodeling that underlies dilated cardiomyopathy has not received much attention yet. Here, we report that the lysosomal cysteine peptidase cathepsin L (CTSL) is critical for cardiac morphology and function. One-year-old CTSL-deficient mice show significant ventricular and atrial enlargement that is associated with a comparatively small increase in relative heart weight. Interstitial fibrosis and pleomorphic nuclei were found in the myocardium of the knockout mice. By electron microscopy, CTSL-deficient cardiomyocytes contained multiple large and apparently fused lysosomes characterized by storage of electron-dense heterogeneous material. Accordingly, the assessment of left ventricular function by echocardiography revealed severely impaired myocardial contraction in the CTSL-deficient mice. In addition, echocardiographic and electrocardiographic findings to some degree point to left ventricular hypertrophy that most likely represents an adaptive response to cardiac impairment. The histomorphological and functional alterations of CTSL-deficient hearts result in valve insufficiencies. Furthermore, abnormal heart rhythms, like supraventricular tachycardia, ventricular extrasystoles, and first-degree atrioventricular block, were detected in the CTSL-deficient mice.
Human chronic lymphocytic leukemia modeled in mouse by targetedTCL1expression
Authors: Bichi Roberta , Shinton Susan A. , Martin Eric S. , Koval Anatoliy , Calin George A. , Cesari Rossano , Russo Giandomenico , Hardy Richard R. , Croce Carlo M.
Published: July 2002

TheTCL1gene at 14q32.1 is involved in chromosomal translocations and inversions in mature T cell leukemias. These leukemias are classified either as T prolymphocytic leukemias, which occur very late in life, or as T chronic lymphocytic leukemias, which often arise in patients with ataxia telangiectasia (AT) at a young age. In transgenic animals, the deregulated expression ofTCL1leads to mature T cell leukemia, demonstrating the role ofTCL1in the initiation of malignant transformation in T cell neoplasia. Expression of high levels of Tcl1 have also been found in a variety of human tumor-derived B cell lines ranging from pre-B cell to mature B cell. Here we describe the phenotype of transgenic mice, Eμ-TCL1, established withTCL1under the control of a VHpromoter-IgH-Eμ enhancer to targetTCL1expression to immature and mature B cells. Flow cytometric analysis reveals a markedly expanded CD5+population in the peritoneal cavity of Eμ-TCL1mice starting at 2 mo of age that becomes evident in the spleen by 3–5 mo and in the bone marrow by 5–8 mo. Analysis of Ig gene rearrangements indicates monoclonality or oligoclonality in these populations, suggesting a preneoplastic expansion of CD5+B cell clones, with the elder mice eventually developing a chronic lymphocytic leukemia (CLL)-like disorder resembling human B-CLL. Our findings provide an animal model for CLL, the most common human leukemia, and demonstrate that deregulation of the Tcl1 pathway plays a crucial role in CLL pathogenesis.
Think globally, translate locally: What mitotic spindles and neuronal synapses have in common
Authors: Richter Joel D.
Published: July 2002

Early metazoan development is programmed by maternal mRNAs inherited by the egg at the time of fertilization. These mRNAs are not translated en masse at any one time or at any one place, but instead their expression is regulated both temporally and spatially. Recent evidence has shown that one maternal mRNA, cyclin B1, is concentrated on mitotic spindles in the early
Xenopus
embryo, where its translation is controlled by CPEB (cytoplasmic polyadenylation element binding protein), a sequence-specific RNA binding protein. Disruption of the spindle-associated translation of this mRNA results in a morphologically abnormal mitotic apparatus and inhibited cell division. Mammalian neurons, particularly in the synapto-dendritic compartment, also contain localized mRNAs such as that encoding α-CaMKII. Here, synaptic activation drives local translation, an event that is involved in synaptic plasticity and possibly long-term memory storage. Synaptic translation of α-CaMKII mRNA also appears to be controlled by CPEB, which is enriched in the postsynaptic density. Therefore, CPEB-controlled local translation may influence such seemingly disparate processes as the cell cycle and synaptic plasticity.
Neanderthal diet at Vindija and Neanderthal predation: The evidence from stable isotopes
Authors: Richards Michael P. , Pettitt Paul B. , Trinkaus Erik , Smith Fred H. , Paunović Maja , Karavanić Ivor
Published: July 2002

Archeological analysis of faunal remains and of lithic and bone tools has suggested that hunting of medium to large mammals was a major element of Neanderthal subsistence. Plant foods are almost invisible in the archeological record, and it is impossible to estimate accurately their dietary importance. However, stable isotope (δ13C and δ15N) analysis of mammal bone collagen provides a direct measure of diet and has been applied to two Neanderthals and various faunal species from Vindija Cave, Croatia. The isotope evidence overwhelmingly points to the Neanderthals behaving as top-level carnivores, obtaining almost all of their dietary protein from animal sources. Earlier Neanderthals in France and Belgium have yielded similar results, and a pattern of European Neanderthal adaptation as carnivores is emerging. These data reinforce current taphonomic assessments of associated faunal elements and make it unlikely that the Neanderthals were acquiring animal protein principally through scavenging. Instead, these findings portray them as effective predators.
Aeolian dust in Colorado Plateau soils: Nutrient inputs and recent change in source
Authors: Reynolds Richard , Belnap Jayne , Reheis Marith , Lamothe Paul , Luiszer Fred
Published: July 2002

Aeolian dust (windblown silt and clay) is an important component in arid-land ecosystems because it may contribute to soil formation and furnish essential nutrients. Few geologic surfaces, however, have been characterized with respect to dust-accumulation history and resultant nutrient enrichment. We have developed a combination of methods to identify the presence of aeolian dust in arid regions and to evaluate the roles of this dust in ecosystem processes. Unconsolidated sandy sediment on isolated surfaces in the Canyonlands region of the Colorado Plateau differs greatly in mineralogical and chemical composition from associated bedrock, mainly aeolian sandstone. Detrital magnetite in the surficial deposits produces moderately high values of magnetic susceptibility, but magnetite is absent in nearby bedrock. A component of the surficial deposits must be aeolian to account for the abundance of magnetite, which formed originally in far-distant igneous rocks. Particle-size analysis suggests that the aeolian dust component is typically as much as 20–30%. Dust inputs have enriched the sediments in many elements, including P, Mg, Na, K, and Mo, as well as Ca, at sites where bedrock lacks calcite cement. Soil-surface biologic crusts are effective dust traps that apparently record a change in dust sources over the past several decades. Some of the recently fallen dust may result from human disturbance of land surfaces that are far from the Canyonlands, such as the Mojave Desert. Some land-use practices in the study area have the potential to deplete soil fertility by means of wind-erosion removal of aeolian silt.
Implications ofEPHB6,EFNB2, andEFNB3expressions in human neuroblastoma
Authors: Tang Xao X. , Zhao Huaqing , Robinson Marjorie E. , Cohen Brian , Cnaan Avital , London Wendy , Cohn Susan L. , Cheung Nai-Kong V. , Brodeur Garrett M. , Evans Audrey E. , Ikegaki Naohiko
Published: July 2002

Neuroblastoma (NB) is a common pediatric tumor that exhibits a wide range of biological and clinical heterogeneity. EPH (erythropoietin-producing hepatoma amplified sequence) family receptor tyrosine kinases and ligand ephrins play pivotal roles in neural and cardiovascular development. High-level expression of transcripts encoding EPHB6 receptors (EPHB6) and its ligands ephrin-B2 and ephrin-B3 (EFNB2,EFNB3) is associated with low-stage NB (stages 1, 2, and 4S) and highTrkAexpression. In this study, we showed thatEFNB2andTrkAexpressions were associated with both tumor stage and age, whereasEPHB6andEFNB3expressions were solely associated with tumor stage, suggesting that these genes were expressed in distinct subsets of NB. Kaplan-Meier and Cox regression analyses revealed that high-level expression ofEPHB6,EFNB2, andEFNB3predicted favorable NB outcome (P< 0.005), and their expression combined withTrkAexpression predicted the disease outcome more accurately than each variable alone (P< 0.00005). Interestingly, if any one of the four genes (EPHB6,EFNB2,EFNB3, orTrkA) was expressed at high levels in NB, the patient survival was excellent (>90%). To address whether a good disease outcome of NB was a consequence of high-level expression of a “favorable NB gene,” we examined the effect ofEPHB6on NB cell lines. Transfection ofEPHB6cDNA into IMR5 and SY5Y expressing little endogenousEPHB6resulted in inhibition of their clonogenicity in culture. Furthermore, transfection ofEPHB6suppressed the tumorigenicity of SY5Y in a mouse xenograft model, demonstrating that high-level expressions of favorable NB genes, such asEPHB6, can in fact suppress malignant phenotype of unfavorable NB.
Opposing roles of pRB and p107 in adipocyte differentiation
Authors: Classon Marie , Kennedy Brian K. , Mulloy Roseann , Harlow Ed
Published: July 2002

The retinoblastoma (RB) family of proteins, pRB, p107, and p130,
have been postulated to be partially redundant in their ability to
regulate progression through the G
1
phase of the cell
cycle. However, pRB appears to be unique in its capacity as a classical
tumor suppressor, possibly because of a specialized role in maintaining
the balance between proliferation and differentiation. A variety of
studies have in fact revealed an apparent role for pRB in cellular
differentiation and development. However, roles for p107 and p130 in
differentiation have not yet been established, and knockout mouse
studies have indicated that they may be functionally redundant during
development, and possibly perform a role in differentiation distinct
from that of pRB. Using adipogenesis as a model, we have indeed found
distinct roles for the pRB family proteins in regulating
differentiation. 3T3 fibroblasts deficient in p107 and p130
differentiate with high efficiency, whereas pRB
−/−
3T3
cells exhibit defects in their differentiation potential. Moreover,
over-expression of pRB in wild-type cells promotes differentiation,
whereas over-expression of p107 antagonizes differentiation. The
seemingly opposing roles of pRB family members in adipocyte
differentiation can be explained, at least in part, by a requirement
for pRB in maintaining cell cycle exit as well as potentiating the
activity of the differentiation-associated transcription factor,
C/EBPα. p107 does not affect C/EBPα-driven
transcription and is not required for cell cycle exit, but instead,
loss of p107 lowers the requirement for the differentiation factor
PPARγ. These findings suggest contrasting biological roles for
individual members of the pRB family of proteins that may explain why
pRB, but not p107, is commonly mutated during human tumor development.
Crystal structure of the human CD4 N-terminal two-domain fragment complexed to a class II MHC molecule
Authors: Wang Jia-huai , Meijers Rob , Xiong Yi , Liu Jin-huan , Sakihama Toshiko , Zhang Rongguang , Joachimiak Andrzej , Reinherz Ellis L.
Published: July 2002

The structural basis of the interaction between the CD4 coreceptor and a class II major histocompatibility complex (MHC) is described. The crystal structure of a complex containing the human CD4 N-terminal two-domain fragment and the murine I-Akclass II MHC molecule with associated peptide (pMHCII) shows that only the “top corner” of the CD4 molecule directly contacts pMHCII. The CD4 Phe-43 side chain extends into a hydrophobic concavity formed by MHC residues from both α2 and β2 domains. A ternary model of the CD4-pMHCII-T-cell receptor (TCR) reveals that the complex appears V-shaped with the membrane-proximal pMHCII at the apex. This configuration excludes a direct TCR–CD4 interaction and suggests how TCR and CD4 signaling is coordinated around the antigenic pMHCII complex. Human CD4 binds to HIV gp120 in a manner strikingly similar to the way in which CD4 interacts with pMHCII. Additional contacts between gp120 and CD4 give the CD4–gp120 complex a greater affinity. Thus, ligation of the viral envelope glycoprotein to CD4 occludes the pMHCII-binding site on CD4, contributing to immunodeficiency.
Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications
Authors: Sørlie Therese , Perou Charles M. , Tibshirani Robert , Aas Turid , Geisler Stephanie , Johnsen Hilde , Hastie Trevor , Eisen Michael B. , van de Rijn Matt , Jeffrey Stefanie S. , Thorsen Thor , Quist Hanne , Matese John C. , Brown Patrick O. , Botstein David , Lønning Per Eystein , Børresen-Dale Anne-Lise
Published: July 2002

The purpose of this study was to classify breast carcinomas based on variations in gene expression patterns derived from cDNA microarrays and to correlate tumor characteristics to clinical outcome. A total of 85 cDNA microarray experiments representing 78 cancers, three fibroadenomas, and four normal breast tissues were analyzed by hierarchical clustering. As reported previously, the cancers could be classified into a basal epithelial-like group, an
ERBB2
-overexpressing group and a normal breast-like group based on variations in gene expression. A novel finding was that the previously characterized luminal epithelial/estrogen receptor-positive group could be divided into at least two subgroups, each with a distinctive expression profile. These subtypes proved to be reasonably robust by clustering using two different gene sets: first, a set of 456 cDNA clones previously selected to reflect intrinsic properties of the tumors and, second, a gene set that highly correlated with patient outcome. Survival analyses on a subcohort of patients with locally advanced breast cancer uniformly treated in a prospective study showed significantly different outcomes for the patients belonging to the various groups, including a poor prognosis for the basal-like subtype and a significant difference in outcome for the two estrogen receptor-positive groups.
A universal protein–protein interaction motif in the eubacterial DNA replication and repair systems
Authors: Dalrymple Brian P. , Kongsuwan Kritaya , Wijffels Gene , Dixon Nicholas E. , Jennings Philip A.
Published: July 2002

The interaction between DNA polymerases and sliding clamp proteins
confers processivity in DNA synthesis. This interaction is critical for
most DNA replication machines from viruses and prokaryotes to higher
eukaryotes. The clamp proteins also participate in a variety of dynamic
and competing protein–protein interactions. However, clamp-protein
binding sequences have not so far been identified in the eubacteria.
Here we show from three lines of evidence, bioinformatics, yeast
two-hybrid analysis, and inhibition of protein–protein interaction by
modified peptides, that variants of a pentapeptide motif (consensus
QL[SD]LF) are sufficient to enable interaction of a number of
proteins with an archetypal eubacterial sliding clamp (the β subunit
of
Escherichia coli
DNA polymerase III holoenzyme).
Representatives of this motif are present in most sequenced members of
the eubacterial DnaE, PolC, PolB, DinB, and UmuC families of DNA
polymerases and the MutS1 mismatch repair protein family. The component
tripeptide DLF inhibits the binding of the α (DnaE) subunit of
E. coli
DNA polymerase III to β at μM concentration,
identifying key residues. Comparison of the eubacterial, eukaryotic,
and archaeal sliding clamp binding motifs suggests that the basic
interactions have been conserved across the evolutionary landscape.
Cloning and characterization of two splice variants of human phosphodiesterase 11A
Authors: Hetman Joanna M. , Robas Nicola , Baxendale Rhona , Fidock Mark , Phillips Stephen C. , Soderling Scott H. , Beavo Joseph A.
Published: July 2002

Phosphodiesterase 11A (PDE11A) is a recently identified
family of cAMP and cGMP hydrolyzing enzymes. Thus far, a single splice
variant designated as PDE11A1 has been reported. In this study, we
identify and characterize two additional splice variants of PDE11A,
PDE11A2 and PDE11A3. The full-length cDNAs are 2,141 bp for PDE11A2 and
2205 bp for PDE11A3. The ORF of PDE11A2 predicts a protein of 576 aa
with a molecular mass of 65.8 kDa. The ORF of PDE11A3 predicts a
protein of 684 aa with a molecular mass of 78.1 kDa. Comparison of the
PDE11A2 sequence with that of PDE11A1 indicates an additional 86 aa at
the N terminus of PDE11A2. Part of this sequence extends the potential
cGMP binding region (GAF domain) present in PDE11A1. Compared with
PDE11A2, PDE11A3 has an additional 108 N-terminal amino acids. Sequence
analysis of PDE11A3 indicates the presence of another GAF domain in
this region. This diversification of regulatory sequences in the
N-terminal region of PDE11A splice variants suggests the interesting
possibility of differential regulation of these enzymes. Recombinant
PDE11A2 and -A3 proteins expressed in the Baculovirus expression system
have the ability to hydrolyze both cAMP and cGMP. The
K
m
values for cAMP hydrolysis are 3.3 μM
and 5.7 μM for PDE11A2 and PDE11A3, respectively. The
K
m
values for cGMP hydrolysis are 3.7 μM
and 4.2 μM for PDE11A2 and PDE11A3, respectively. Both PDEs showed a
V
max
ratio for cAMP/cGMP of approximately
1.0. PDE11A2 is sensitive to dipyridamole, with an IC
50
of
1.8 μM, and to zaprinast, with an IC
50
of 28 μM.
PDE11A3 demonstrated similar pattern of inhibitor sensitivity with
IC
50
values of 0.82 and 5 μM for dipyridamole and
zaprinast, respectively.
Evidence that the WNT-inducible
growth arrest-specific gene 1
encodes an antagonist of sonic hedgehog signaling in the somite
Authors: Lee Catherine S. , Buttitta Laura , Fan Chen-Ming
Published: July 2002

The dorsal–ventral polarity of the somite is controlled by
antagonistic signals from the dorsal neural tube/surface ectoderm,
mediated by WNTs, and from the ventral notochord, mediated by sonic
hedgehog (SHH). Each factor can act over a distance greater than a
somite diameter
in vitro
, suggesting they must limit
each other's actions within their own patterning domains
in
vivo
. We show here that the
growth-arrest specific gene
1
(
Gas1
), which is expressed in the dorsal
somite, is induced by WNTs and encodes a protein that can bind to SHH.
Furthermore, ectopic expression of
Gas1
in presomitic
cells attenuates the response of these cells to SHH
in
vitro
. Taken together, these data suggest that GAS1 functions
to reduce the availability of active SHH within the dorsal somite.