bluuebunny/crossref_metadata_2025 huggingface dataset:
Numerical simulation and theory of generation of electromagnetic waves in the presence of whistler turbulence
Authors: Bujarbarua S. , Nambu M. , Saikia B. J. , Eda M. , Sakai J. I.
Published: July 2002

The generation of R-mode electromagnetic waves from whistler turbulence by plasma maser effect is studied both numerically and theoretically. Simulations using a two-dimensional electromagnetic and relativistic particle code show that high frequency electromagnetic waves with right-handed polarization (R-mode) can be generated by a plasma maser mechanism from low frequency whistler waves excited by electron temperature anisotropy. Results obtained theoretically are in good agreement with numerical findings.
Axisymmetric ideal magnetohydrodynamic equilibria with incompressible flows
Authors: Tasso H. , Throumoulopoulos G. N.
Published: July 2002

It is shown that the ideal magnetohydrodynamic (MHD) equilibrium states of an axisymmetric plasma with incompressible flows are governed by an elliptic partial differential equation for the poloidal magnetic flux function ψ containing five surface quantities along with a relation for the pressure. Exact equilibria are constructed including those with nonvanishing poloidal and toroidal flows and differentially varying radial electric fields. Unlike the case in cylindrical incompressible equilibria with isothermal magnetic surfaces which should have necessarily circular cross sections [G. N. Throumoulopoulos and H. Tasso, Phys. Plasmas 4, 1492 (1997)], no restriction appears on the shapes of the magnetic surfaces in the corresponding axisymmetric equilibria. The latter equilibria satisfy a set of six ordinary differential equations which for flows parallel to the magnetic field B can be solved semianalytically. In addition, it is proved the nonexistence of incompressible axisymmetric equilibria with (a) purely poloidal flows and (b) nonparallel flows with isothermal magnetic surfaces and |B|=|B|(ψ) (omnigenous equilibria).
Nonlinear electromagnetic gyrokinetic equation for plasmas with large mean flows
Authors: Sugama H. , Horton W.
Published: July 2002

A new nonlinear electromagnetic gyrokinetic equation is derived for plasmas with large flow velocities on the order of the ion thermal speed. The gyrokinetic equation derived here retains a collision term and is given in the form which is valid for general magnetic geometries including the slab, cylindrical and toroidal configurations. The source term for the anomalous viscosity arising through the Reynolds stress is identified in the gyrokinetic equation. For the toroidally rotating plasma, particle, energy and momentum balance equations as well as the detailed definitions of the anomalous transport fluxes and the anomalous entropy production are shown. The quasilinear anomalous transport matrix connecting the conjugate pairs of the anomalous fluxes and the forces satisfies the Onsager symmetry.
Magnetic field effects on cross section of electron capture in dense plasmas
Authors: Shokri B. , Tavassoli H. , Latifi H.
Published: July 2002

In magnetized dense plasmas, the magnetic field effects on the capture distance and cross section of electron capture from hydrogenic ions by fast fully stripped ions is calculated. The Bohr-Lindhard model is used to obtain the cross section of electron capture. The longitudinal dielectric function is applied to describe the interaction potential. The classical straight-line trajectory approximation is used to derive the motion of the projectile ion. The capture distance and cross section of electron capture are derived as a function of the impact parameter, projectile velocity, Larmor frequency, and plasma parameters. The electron capture probability in the presence of a magnetic field is always smaller than one without a magnetic field. When the magnitude of the magnetic field increases, the magnetic field effect decreases. For larger projectile velocity the difference between the capture probability for different magnitudes of magnetic field becomes more significant.
Antiresonant reflecting optical waveguides in SiO2-Si multilayer structures
Authors: Duguay M. A. , Kokubun Y. , Koch T. L. , Pfeiffer Loren
Published: July 2002

A new type of optical waveguide utilizing an antiresonant reflector is described. Implementation in the SiO2-Si system gave losses as low as 0.4 dB/cm for the TE mode. The TM mode loss is >60 dB/cm, making the device an excellent planar technology integrated optic polarizer.
Significant improvement in crystalline quality of molecular beam epitaxially grown GaAs on Si (100) by rapid thermal annealing
Authors: Chand N. , People R. , Baiocchi F. A. , Wecht K. W. , Cho A. Y.
Published: July 2002

Rapid thermal annealing (RTA) has been found to significantly improve the crystalline quality of epitaxial GaAs grown on Si (100) substrates. After RTA at 900 °C for 10 s, the percentage of displaced atoms near the GaAs/Si interface, as estimated by Rutherford backscattering/channeling, decreased from 20 to 7%. Photoluminescence intensity (PL) after RTA increased significantly (as much as sixfold in some cases), with the actual increase varying from sample to sample and with annealing conditions. In some cases, the PL intensity after RTA was comparable to the PL intensity obtained from GaAs grown on GaAs substrate under similar conditions. Rapid thermal annealing at 940 °C resulted in a degradation of the PL intensity as compared to annealing at 900 °C. Also, the PL peaks after RTA were found to shift to lower energies by 2–5 meV at low temperatures.
Giant magnetic coercivity and percolation effects in granular Fe-(SiO2) solids
Authors: Xiao Gang , Chien C. L.
Published: July 2002

We demonstrate a novel method for enhancing the coercivity of magnetic materials. Granular Fe-(SiO2) solids have been fabricated over a wide volume fraction range from 15% to 100%. Giant magnetic coercivity, as high as 2500 Oe, has been observed in granular solids in which the isolated Fe granules are only nanometers in size. Across the whole volume fraction range magnetic coercivity experiences dramatic variations due to the change of granular size and percolation effects.
Pleiotrophin signals increased tyrosine phosphorylation of β-catenin through inactivation of the intrinsic catalytic activity of the receptor-type protein tyrosine phosphatase β/ζ
Authors: Meng Kung , Rodríguez-Peña A. , Dimitrov Todor , Chen Wen , Yamin Moshe , Noda Masaharu , Deuel Thomas F.
Published: July 2002

Pleiotrophin (PTN) is a platelet-derived growth factor-inducible,
18-kDa heparin-binding cytokine that signals diverse phenotypes in
normal and deregulated cellular growth and differentiation. To seek the
mechanisms of PTN signaling, we studied the interactions of PTN with
the receptor protein tyrosine phosphatase (RPTP) β/ζ in U373-MG
cells. Our results suggest that PTN is a natural ligand for RPTP
β/ζ. PTN signals through “ligand-dependent receptor
inactivation” of RPTP β/ζ and disrupts its normal roles in the
regulation of steady-state tyrosine phosphorylation of downstream
signaling molecules. We have found that PTN binds to and functionally
inactivates the catalytic activity of RPTP β/ζ. We also have
found that an active site-containing domain of RPTP β/ζ both
binds β-catenin and functionally reduces its levels of tyrosine
phosphorylation when added to lysates of pervanidate-treated cells. In
contrast, an (inactivating) active-site mutant of RPTP β/ζ also
binds β-catenin but fails to reduce tyrosine phosphorylation of
β-catenin. Finally, in parallel to its ability to inactivate
endogenous RPTP β/ζ, PTN sharply increases tyrosine
phosphorylation of β-catenin in PTN-treated cells. The results
suggest that in unstimulated cells, RPTP β/ζ is intrinsically
active and functions as an important regulator in the reciprocal
control of the steady-state tyrosine phosphorylation levels of
β-catenin by tyrosine kinases and phosphatases. The results also
suggest that RPTP β/ζ is a functional receptor for PTN; PTN
signals through ligand-dependent receptor inactivation of RPTP
β/ζ to increase levels of tyrosine phosphorylation of β-catenin
to initiate downstream signaling. PTN is the first natural ligand
identified for any of the RPTP family; its identification provides a
unique tool to pursue the novel signaling pathway activated by PTN and
the relationship of PTN signaling with other pathways regulating
β-catenin.
Multiple hematopoietic defects and delayed globin switching in Ikaros null mice
Authors: Lopez Rocio A. , Schoetz Stuti , DeAngelis Kathryn , O'Neill David , Bank Arthur
Published: July 2002

We have previously reported the structure of a chromatin remodeling complex (PYR complex) with Ikaros as its DNA binding subunit that is specifically present in adult murine and human hematopoietic cells. We now show that homozygous Ikaros “knockout” (null) mice lack the PYR complex, demonstrating the requirement for Ikaros in the formation of the complex on DNA. Heterozygous Ikaros null mice have about half as much PYR complex, indicating a dosage effect for both Ikaros and PYR complex. We also show that Ikaros null mice have multiple hematopoietic cell defects including anemia and megakaryocytic abnormalities, in addition to previously reported lymphoid and stem cell defects. The null mice also have a delay in murine embryonic to adult β-globin switching and a delay in human γ to β switching, consistent with a previously suggested role for PYR complex in this process. Lastly, cDNA array analyses indicate that several hematopoietic cell-specific genes in all blood lineages are either up- or down-regulated in 14-day embryos from Ikaros null as compared with wild-type mice. These results indicate that Ikaros and PYR complex function together
in vivo
at many adult hematopoietic cell-specific genes and at intergenic sites, affecting their expression and leading to pleiotropic hematopoietic defects.
The tomato
Blind
gene encodes a MYB transcription factor that controls the formation of lateral meristems
Authors: Schmitz Gregor , Tillmann Edith , Carriero Filomena , Fiore Carola , Cellini Francesco , Theres Klaus
Published: July 2002

The multitude of forms observed in flowering plants is largely because of their ability to establish new axes of growth during postembryonic development. This process is initiated by the formation of secondary meristems that develop into vegetative or reproductive branches. In the
blind
and
torosa
mutants of tomato, initiation of lateral meristems is blocked during shoot and inflorescence development, leading to a strong reduction in the number of lateral axes. In this study, it is shown that
blind
and
torosa
are allelic. The
Blind
gene has been isolated by positional cloning, and it was found that the mutant phenotype is caused by a loss of function of an R2R3 class
Myb
gene. RNA interference-induced
blind
phenocopies confirmed the identity of the isolated gene. Double mutant analysis shows that
Blind
acts in a novel pathway different from the one to which the previously identified
Lateral suppressor
gene belongs. The findings reported add a new class of transcription factors to the group of genes controlling lateral meristem initiation and reveal a previously uncharacterized function of R2R3
Myb
genes.
Synchronizing genetic relaxation oscillators by intercell signaling
Authors: McMillen David , Kopell Nancy , Hasty Jeff , Collins J. J.
Published: July 2002

The ability to design and construct synthetic gene regulatory networks offers the prospect of studying issues related to cellular function in a simplified context; such networks also have many potential applications in biotechnology. A synthetic network exhibiting oscillatory behavior has recently been constructed [Elowitz, M. B. & Leibler, S. (2000)
Nature (London)
403, 335–338]. It has also been shown that a natural bacterial quorum-sensing mechanism can be used in a synthetic system to communicate a signal between two populations of cells, such that receipt of the signal causes expression of a target gene [Weiss, R. & Knight, T. F. (2000) in DNA6: Sixth International Meeting on DNA-Based Computers, June 13–17, 2000, Leiden, The Netherlands]. We propose a synthetic gene network in
Escherichia coli
which combines these two features: the system acts as a relaxation oscillator and uses an intercell signaling mechanism to couple the oscillators and induce synchronous oscillations. We model the system and show that the proposed coupling scheme does lead to synchronous behavior across a population of cells. We provide an analytical treatment of the synchronization process, the dominant mechanism of which is “fast threshold modulation.”
Prevention of ischemia-induced retinopathy by the natural ocular antiangiogenic agent pigment epithelium-derived factor
Authors: Stellmach Veronica , Crawford Susan E. , Zhou Wei , Bouck Noël
Published: July 2002

Aberrant blood vessel growth in the retina that underlies the
pathology of proliferative diabetic retinopathy and retinopathy of
prematurity is the result of the ischemia-driven disruption of the
normally antiangiogenic environment of the retina. In this study, we
show that a potent inhibitor of angiogenesis found naturally in the
normal eye, pigment epithelium-derived growth factor (PEDF), inhibits
such aberrant blood vessel growth in a murine model of ischemia-induced
retinopathy. Inhibition was proportional to dose and systemic delivery
of recombinant protein at daily doses as low as 2.2 mg/kg could
prevent aberrant endothelial cells from crossing the inner limiting
membrane. PEDF appeared to inhibit angiogenesis by causing
apoptosis of activated endothelial cells, because it induced
apoptosis in cultured endothelial cells and an 8-fold increase
in apoptotic endothelial cells could be detected
in
situ
when the ischemic retinas of PEDF-treated animals were
compared with vehicle-treated controls. The ability of low doses of
PEDF to curtail aberrant growth of ocular endothelial cells without
overt harm to retinal morphology suggests that this natural protein may
be beneficial in the treatment of a variety of retinal vasculopathies.
RNA hairpin-folding kinetics
Authors: Zhang Wenbing , Chen Shi-Jie
Published: July 2002

Based on the complete ensemble of hairpin conformations, a statistical mechanical model that combines the eigenvalue solutions of the rate matrix and the free-energy landscapes has been able to predict the temperature-dependent folding rate, kinetic intermediates, and folding pathways for hairpin-forming RNA sequences. At temperatures higher than a “glass transition” temperature,
T
g
, the eigenvalues show a distinct time separation, and the rate-limiting step is a two-state single exponential process determined by the slowest eigenmode. At temperatures lower than
T
g
, no distinct time separation exists for the eigenvalues, hence multiple (slow) eigenmodes contribute to the rate-determining processes, and the folding involves the trapping and detrapping of kinetic intermediates. For a 21-nt sequence we studied,
T
g
is lower than the transition temperature,
T
m
, for thermodynamic equilibrium folding. For
T
>
T
m
, starting from the native state, the chain undergoes a biphasic unfolding transition: a preequilibrated quasi-equilibrium macrostate is formed followed by a rate-limiting two-state transition from the macrostate to the unfolded state. For
T
g
<
T
<
T
m
, the chain undergoes a two-state on-pathway folding transition, at which a nucleus is formed by the base stacks close to the loop region before a rapid assembly of the whole hairpin structure. For
T
<
T
g
, the multistate kinetics involve kinetic trapping, causing the
roll-over
behavior in the rate-temperature Arrhenius plot. The complex kinetic behaviors of RNA hairpins may be a paradigm for the folding kinetics of large RNAs.
The
Bst
locus on mouse chromosome 16 is associated with age-related subretinal neovascularization
Authors: Smith Richard S. , John Simon W. M. , Zabeleta Adriana , Davisson Muriel T. , Hawes Norman L. , Chang Bo
Published: July 2002

Ocular neovascularization is the leading cause of blindness in developed countries and often causes rapid loss of vision in age-related macular degeneration. Acute visual loss is most often due to hemorrhage from new vessels that have extended from the choroid into the subretinal space. Growth of abnormal vessels beneath the retina in this condition is known as subretinal neovascularization (SRN). Age-related animal models of macular degeneration and SRN have not been described. Current animal models of SRN depend on chemical or physical stimuli to initiate growth of subretinal vessels. The genes responsible for age-related human macular degeneration with SRN have not been firmly identified. We report an angiogenic phenotype in
Bst
/
+
mice that is age-related, clinically evident, and resembles human SRN. This represents a spontaneous, genetically determined model of SRN.
Bst
/
+
mice offer the possibility of exploring the molecular mechanisms of SRN without the need for exogenous agents.
Positive and negative regulation of endogenous genes by designed transcription factors
Authors: Beerli Roger R. , Dreier Birgit , Barbas Carlos F.
Published: July 2002

Gene regulation by imposed localization was studied by using designed zinc finger proteins that bind 18-bp DNA sequences in the 5′ untranslated regions of the protooncogenes
erbB-2
and
erbB-3
. Transcription factors were generated by fusion of the DNA-binding proteins to repression or activation domains. When introduced into cells these transcription factors acted as dominant repressors or activators of, respectively, endogenous
erbB-2
or
erbB-3
gene expression. Significantly, imposed regulation of the two genes was highly specific, despite the fact that the transcription factor binding sites targeted in
erbB-2
and
erbB-3
share 15 of 18 nucleotides. Regulation of
erbB-2
gene expression was observed in cells derived from several species that conserve the DNA target sequence. Repression of
erbB-2
in SKBR3 breast cancer cells inhibited cell-cycle progression by inducing a G
1
accumulation, suggesting the potential of designed transcription factors for cancer gene therapy. These results demonstrate the willful up- and down-regulation of endogenous genes, and provide an additional means to alter biological systems.
The protease thrombin is an endogenous mediator of hippocampal neuroprotection against ischemia at low concentrations but causes degeneration at high concentrations
Authors: Striggow Frank , Riek Monika , Breder Jörg , Henrich-Noack Petra , Reymann Klaus G. , Reiser Georg
Published: July 2002

We have considered the extracellular serine protease thrombin and its receptor as endogenous mediators of neuronal protection against brain ischemia. Exposure of gerbils to prior mild ischemic insults, here two relatively short-lasting occlusions (2 min) of both common carotid arteries applied at 1-day intervals 2 days before a severe occlusion (6 min), caused a robust ischemic tolerance of hippocampal CA1 neurons. This resistance was impaired if the specific thrombin inhibitor hirudin was injected intracerebroventricularly before each short-lasting insult. Thus, efficient native neuroprotective mechanisms exist and endogenous thrombin seems to be involved therein.
In vitro
experiments using organotypic slice cultures of rat hippocampus revealed that thrombin can have protective but also deleterious effects on hippocampal CA1 neurons. Low concentrations of thrombin (50 pM, 0.01 unit/ml) or of a synthetic thrombin receptor agonist (10 μM) induced significant neuroprotection against experimental ischemia. In contrast, 50 nM (10 units/ml) thrombin decreased further the reduced neuronal survival that follows the deprivation of oxygen and glucose, and 500 nM even caused neuronal cell death by itself. Degenerative thrombin actions also might be relevant
in vivo
, because hirudin increased the number of surviving neurons when applied before a 6-min occlusion. Among the thrombin concentrations tested, 50 pM induced intracellular Ca
2+
spikes in fura-2-loaded CA1 neurons whereas higher concentrations caused a sustained Ca
2+
elevation. Thus, distinct Ca
2+
signals may define whether or not thrombin initiates protection. Taken together,
in vivo
and
in vitro
data suggest that thrombin can determine neuronal cell death or survival after brain ischemia.
Protein phosphatase 1 regulation by inhibitors and targeting subunits
Authors: Watanabe Takuo , Huang Hsien-Bin , Horiuchi Atsuko , da Cruze Silva Edgar F. , Hsieh-Wilson Linda , Allen Patrick B. , Shenolikar Shirish , Greengard Paul , Nairn Angus C.
Published: July 2002

Regulation of protein phosphatase 1 (PP1) by protein inhibitors and
targeting subunits has been previously studied through the use of
recombinant protein expressed in
Escherichia coli
. This
preparation is limited by several key differences in its properties
compared with native PP1. In the present study, we have analyzed
recombinant PP1 expressed in Sf9 insect cells using baculovirus. Sf9
PP1 exhibited properties identical to those of native PP1, with respect
to regulation by metals, inhibitor proteins, and targeting subunits,
and failure to dephosphorylate a phosphotyrosine-containing substrate
or phospho-DARPP-32 (Dopamine and cAMP-regulated phosphoprotein,
M
r
32,000). Mutations at Y272 in the β12/β13
loop resulted in a loss of activity and reduced the sensitivity to
thiophospho-DARPP-32 and inhibitor-2. Mutations of Y272 also increased
the relative activity toward a phosphotyrosine-containing substrate or
phospho-DARPP-32. Mutation of acidic groove residues caused no change
in sensitivity to thiophospho-DARPP-32 or inhibitor-2, but one mutant
(E252A:D253A:E256R) exhibited an increased
K
m
for phosphorylase
a
.
Several PP1/PP2A chimeras were prepared in which C-terminal sequences
of PP2A were substituted into PP1. Replacement of residues 274–330 of
PP1 with the corresponding region of PP2A resulted in a large loss of
sensitivity to thiophospho-DARPP-32 and inhibitor-2, and also resulted
in a loss of interaction with the targeting subunits, spinophilin and
PP1 nuclear targeting subunit (PNUTS). More limited alterations in
residues in β12, β13, and β14 strands highlighted a key role for
M290 and C291 in the interaction of PP1 with thiophospho-DARPP-32, but
not inhibitor-2.
An unusual pathway of excitation energy deactivation in carotenoids: Singlet-to-triplet conversion on an ultrafast timescale in a photosynthetic antenna
Authors: Gradinaru Claudiu C. , Kennis John T. M. , Papagiannakis Emmanouil , van Stokkum Ivo H. M. , Cogdell Richard J. , Fleming Graham R. , Niederman Robert A. , van Grondelle Rienk
Published: July 2002

Carotenoids are important biomolecules that are ubiquitous in
nature and find widespread application in medicine. In photosynthesis,
they have a large role in light harvesting (LH) and photoprotection.
They exert their LH function by donating their excited singlet state to
nearby (bacterio)chlorophyll molecules. In photosynthetic bacteria, the
efficiency of this energy transfer process can be as low as 30%. Here,
we present evidence that an unusual pathway of excited state relaxation
in carotenoids underlies this poor LH function, by which carotenoid
triplet states are generated directly from carotenoid singlet states.
This pathway, operative on a femtosecond and picosecond timescale,
involves an intermediate state, which we identify as a new, hitherto
uncharacterized carotenoid singlet excited state. In LH complex-bound
carotenoids, this state is the precursor on the reaction pathway to the
triplet state, whereas in extracted carotenoids in solution, this state
returns to the singlet ground state without forming any triplets. We
discuss the possible identity of this excited state and argue that
fission of the singlet state into a pair of triplet states on
individual carotenoid molecules constitutes the mechanism by which the
triplets are generated. This is, to our knowledge, the first ever
direct observation of a singlet-to-triplet conversion process on an
ultrafast timescale in a photosynthetic antenna.
The nucleotide changes governing cuticular hydrocarbon variation and their evolution in
Drosophila melanogaster
Authors: Takahashi Aya , Tsaur Shun-Chern , Coyne Jerry A. , Wu Chung-I
Published: July 2002

The cuticular hydrocarbon (CH) pheromones in
Drosophila melanogaster
exhibit strong geographic
variation. African and Caribbean populations have a high ratio of 5,9
heptacosadiene/7,11 heptacosadiene (the “High” CH type),
whereas populations from all other areas have a low ratio (“Low”
CH type). Based on previous genetic mapping, DNA markers were developed
that localized the genetic basis of this CH polymorphism to within a
13-kb region. We then carried out a hierarchical search for diagnostic
nucleotide sites starting with four lines, and increasing to 24 and 43
lines from a worldwide collection. Within the 13-kb region, only one
variable site shows a complete concordance with the CH phenotype. This
is a 16-bp deletion in the 5′ region of a desaturase gene
(
desat2
) that was recently suggested to be responsible
for the CH polymorphism on the basis of its expression [Dallerac, R.,
Labeur, C., Jallon, J.-M., Knipple, D. C., Roelofs, W. L. &
Wicker-Thomas, C. (2000)
Proc. Natl. Acad. Sci.
97,
9449–9454]. The cosmopolitan Low type is derived from the ancestral
High type, and DNA sequence variations suggest that the former spread
worldwide with the aid of positive selection. Whether this CH variation
could be a component of the sexual isolation between Zimbabwe and other
cosmopolitan populations remains an interesting and unresolved
question.
Social intelligence, innovation, and enhanced brain size in primates
Authors: Reader Simon M. , Laland Kevin N.
Published: July 2002

Despite considerable current interest in the evolution of intelligence, the intuitively appealing notion that brain volume and “intelligence” are linked remains untested. Here, we use ecologically relevant measures of cognitive ability, the reported incidence of behavioral innovation, social learning, and tool use, to show that brain size and cognitive capacity are indeed correlated. A comparative analysis of 533 instances of innovation, 445 observations of social learning, and 607 episodes of tool use established that social learning, innovation, and tool use frequencies are positively correlated with species' relative and absolute “executive” brain volumes, after controlling for phylogeny and research effort. Moreover, innovation and social learning frequencies covary across species, in conflict with the view that there is an evolutionary tradeoff between reliance on individual experience and social cues. These findings provide an empirical link between behavioral innovation, social learning capacities, and brain size in mammals. The ability to learn from others, invent new behaviors, and use tools may have played pivotal roles in primate brain evolution.
Cytomegalovirus in autoimmunity: T cell crossreactivity to viral antigen and autoantigen glutamic acid decarboxylase
Authors: Hiemstra Hoebert S. , Schloot Nanette C. , van Veelen Peter A. , Willemen Sabine J. M. , Franken Kees L. M. C. , van Rood Jon J. , de Vries René R. P. , Chaudhuri Abhijit , Behan Peter O. , Drijfhout Jan W. , Roep Bart O.
Published: July 2002

Antigens of pathogenic microbes that mimic autoantigens are thought to be responsible for the activation of autoreactive T cells. Viral infections have been associated with the development of the neuroendocrine autoimmune diseases type 1 diabetes and stiff-man syndrome, but the mechanism is unknown. These diseases share glutamic acid decarboxylase (GAD65) as a major autoantigen. We screened synthetic peptide libraries dedicated to bind to HLA-DR3, which predisposes to both diseases, using clonal CD4+T cells reactive to GAD65 isolated from a prediabetic stiff-man syndrome patient. Here we show that these GAD65-specific T cells crossreact with a peptide of the human cytomegalovirus (hCMV) major DNA-binding protein. This peptide was identified after database searching with a recognition pattern that had been deduced from the library studies. Furthermore, we showed that hCMV-derived epitope can be naturally processed by dendritic cells and recognized by GAD65 reactive T cells. Thus, hCMV may be involved in the loss of T cell tolerance to autoantigen GAD65 by a mechanism of molecular mimicry leading to autoimmunity.
Curing metastatic testicular cancer
Authors: Einhorn Lawrence H.
Published: July 2002

Our initial studies with cisplatin + vinblastine + bleomycin began 27 years ago in 1974, changing the cure rate for disseminated disease from 5 to 60%. Subsequently, through random prospective clinical trials, we have modified the treatment regimen to reduce both the duration and dosages of the chemotherapy drugs. Cisplatin + etoposide was first used at Indiana University as salvage chemotherapy in 1978, representing the first time that a solid tumor had been cured with second-line chemotherapy. We next did a clinical trial comparing bleomycin + etoposide + cisplatin (BEP) to cisplatin + vinblastine + bleomycin. The BEP regimen was proven to have less toxicity and a higher cure rate and therefore, since 1984, has been standard chemotherapy. More recent studies have evaluated the use of lesser chemotherapy to maintain the same cure rate for patients with good-prognosis disease. Standard therapy for these patients is either three courses of BEP or four courses of EP, and over 90% of these patients will be cured of their disease. Patients who are not cured with their initial BEP chemotherapy are usually treated with salvage chemotherapy. Approximately 50% of these testicular cancer patients will subsequently be cured with salvage chemotherapy with tandem transplant of high-dose chemotherapy with peripheral stem cell rescue. Testicular cancer has become a model for a curable neoplasm. In the early 1970s, metastatic testicular cancer was associated with only 5% survival. Today, with modern chemotherapy and surgery techniques, 80% of patients will survive their disease.
A role for survivin in chemoresistance of endothelial cells mediated by VEGF
Authors: Tran Jennifer , Master Zubin , Yu Joanne L. , Rak Janusz , Dumont Daniel J. , Kerbel Robert S.
Published: July 2002

Although standard anticancer chemotherapeutic drugs have been designed to inhibit the survival or growth of rapidly dividing tumor cells, it is possible to enhance the efficacy of such drugs by targeting the proliferating host endothelial cells (ECs) of the tumor vasculature. A theoretical advantage of this strategy lies in the possibility of circumventing, or significantly delaying, acquired drug resistance driven by the genetic instability of tumor cells. Here, we show that both vascular endothelial growth factor (VEGF) and basic fibroblast growth factor significantly reduce the pro-apoptotic potency of chemotherapy on both micro- and macrovascular ECs. This cytoprotection to drug toxicity was found to be phosphatidylinositol 3-kinase-dependent and could be recapitulated in the absence of VEGF by overexpressing the dominant-active form of the serine/threonine kinase protein kinase B/Akt. Downstream of phosphatidylinositol 3-kinase, we also show that survivin plays a pivotal role in VEGF-mediated EC protection by preserving the microtubule network. In this respect, its induction effectively protects ECs against chemotherapeutic damage, whereas overexpression of its dominant-interfering mutant (C84A) abrogates the protective effects of VEGF. Accordingly, the potency of VEGF as a chemoprotectant was more pronounced with drugs that interfere with microtubule dynamics than those that damage DNA. These studies implicate a role for survivin up-regulation as a novel mechanism of EC drug “resistance” and support the notion that angiogenic factors that induce the expression of survivin may act to shield tumor ECs from the apoptotic effects of chemotherapy. Thus, exploiting chemotherapeutic drugs as antiangiogenics is likely to be compromised by the high concentrations of proangiogenic survival/growth factors present in the tumor microenvironment; targeting EC survival pathways should improve the antiangiogenic efficacy of antineoplastic agents, particularly microtubule-inhibitor drugs.
The synaptic glycoprotein neuroplastin is involved in long-term potentiation at hippocampal CA1 synapses
Authors: Smalla K. -H. , Matthies H. , Langnäse K. , Shabir S. , Böckers T. M. , Wyneken U. , Staak S. , Krug M. , Beesley P. W. , Gundelfinger E. D.
Published: July 2002

Neuroplastin-65 and -55 (previously known as gp65 and gp55) are glycoproteins of the Ig superfamily that are enriched in rat forebrain synaptic membrane preparations. Whereas the two-Ig domain isoform neuroplastin-55 is expressed in many tissues, the three-Ig domain isoform neuroplastin-65 is brain-specific and enriched in postsynaptic density (PSD) protein preparations. Here, we have assessed the function of neuroplastin in long-term synaptic plasticity. Immunocytochemical studies with neuroplastin-65-specific antibodies differentially stain distinct synaptic neuropil regions of the rat hippocampus with most prominent immunoreactivity in the CA1 region and the proximal molecular layer of the dentate gyrus. Kainate-induced seizures cause a significant enhancement of neuroplastin-65 association with PSDs. Similarly, long-term potentiation (LTP) of CA1 synapses in hippocampal slices enhanced the association of neuroplastin-65 with a detergent-insoluble PSD-enriched protein fraction. Several antibodies against the neuroplastins, including one specific for neuroplastin-65, inhibited the maintenance of LTP. A similar effect was observed when recombinant fusion protein containing the three extracellular Ig domains of neuroplastin-65 was applied to hippocampal slices before LTP induction. Microsphere binding experiments using neuroplastin-F
c
chimeric proteins show that constructs containing Ig1–3 or Ig1 domains, but not Ig2–3 domains mediate homophilic adhesion. These data suggest that neuroplastin plays an essential role in implementing long-term changes in synaptic activity, possibly by means of a homophilic adhesion mechanism.
p19ARF targets certain E2F species for degradation
Authors: Martelli Fabio , Hamilton Timothy , Silver Daniel P. , Sharpless Norman E. , Bardeesy Nabeel , Rokas Mihail , DePinho Ronald A. , Livingston David M. , Grossman Steven R.
Published: July 2002

p19ARF suppresses the growth of cells lacking p53 through an
unknown mechanism. p19ARF was found to complex with transcription
factors E2F1, -2, and -3. Levels of endogenous or
ectopically expressed E2F1, -2, and -3, but not E2F6, were reduced
after synthesis of p19ARF, through a mechanism involving increased
turnover. p19ARF-induced degradation of E2F1 depended on a functional
proteasome, and E2F1 was relocalized to nucleoli when coexpressed with
p19ARF. Consistent with reduced levels of E2F1 and E2F3, the
proliferation of cells defective for p53 function was suppressed by
p19ARF, and the effect was partially reversed by ectopic overexpression
of E2F1. These results suggest a broader role for p19ARF as a tumor
suppressor, in which targeting of certain E2F species may cooperate
with stimulation of the p53 pathway to counteract oncogenic growth
signals.
Resting and circadian release of nitric oxide is controlled by leptin in male rats
Authors: Mastronardi C. A. , Yu W. H. , McCann S. M.
Published: July 2002

Because leptin stimulates nitric oxide (NO) release from the hypothalamus and anterior pituitary gland, we hypothesized that it also might release NO from adipocytes, the principal source of leptin. Consequently, plasma concentrations of leptin and NO, estimated from its metabolites NO
3
and NO
2
(NO
3
-NO
2
), were measured in adult male rats. There was a linear increase of both leptin and NO
3
-NO
2
with body weight that was associated with a parallel rise in fat mass. These findings indicate that release of leptin and NO is directly related to adipocyte mass. Furthermore, there was a parallelism in circadian rhythm of both substances, with peaks at 0130 h and nadirs at 0730 h. Measurement of both leptin and NO
3
-NO
2
in plasma from individual rats revealed that NO
3
-NO
2
increased linearly with leptin. Incubation of epididymal fat pads with leptin or its i.v. injection in conscious rats increased NO
3
-NO
2
release. The release of NO
3
-NO
2
in vivo
and
in vitro
exceeded that of leptin by many fold, indicating that leptin activates NO synthase. Leptin increased tumor necrosis factor (TNF)-α release at a 100-fold lower dose than required for NO release
in vitro
and
in vivo
, suggesting that it also may participate in leptin-induced NO release. However, because many molecules of leptin were required to release a molecule of TNF-α
in vivo
and
in vitro
, we believe that leptin-induced TNF-α release is an associated phenomenon not involved in NO production. The results support the hypothesis that adipocytes play a major role in NO release by activating NO synthase in the adipocytes and the adjacent capillary endothelium.
A biological function for cadmium in marine diatoms
Authors: Lane Todd W. , Morel François M. M.
Published: July 2002

The oceanic distribution of cadmium follows closely that of major algal nutrients such as phosphate. The reasons for this “nutrient-like” distribution are unclear, however, because cadmium is not generally believed to have a biological function. Herein, we provide evidence of a biological role for Cd in the marine diatom
Thalassiosira weissflogii
under conditions of low zinc, typical of the marine environment. Addition of Cd to Zn-limited cultures enhances the growth rate of
T. weissflogii
, particularly at low pCO
2
. This increase in growth rate is reflected in increased levels of cellular carbonic anhydrase (CA) activity, although the levels of TWCA1, the major intracellular Zn-requiring isoform of CA in
T. weissflogii
, remain low.
109
Cd label comigrates with a protein band that shows CA activity and is distinct from TWCA1 on native PAGE of radiolabeled
T. weissflogii
cell lysates. The levels of the Cd protein are modulated by CO
2
in a manner that is consistent with a role for this enzyme in carbon acquisition. Purification of the CA-active fraction leads to the isolation of a Cd-containing protein of 43 kDa. It is now clear that
T. weissflogii
expresses a Cd-specific CA, which, particularly under conditions of Zn limitation, can replace the Zn enzyme TWCA1 in its carbon-concentrating mechanism.
RNA is a structural element in retrovirus particles
Authors: Muriaux Delphine , Mirro Jane , Harvin Demetria , Rein Alan
Published: July 2002

A single retroviral protein, Gag, is sufficient for virus particle
assembly. While Gag is capable of specifically packaging the genomic
RNA into the particle, this RNA species is unnecessary for particle
assembly
in vivo
.
In vitro
, nucleic acids
profoundly enhance the efficiency of assembly by recombinant Gag
proteins, apparently by acting as “scaffolding” in the particle.
To address the participation of RNA in retrovirus assembly
in
vivo
, we analyzed murine leukemia virus particles that lack
genomic RNA because of a deletion in the packaging signal of the viral
RNA. We found that these particles contain cellular mRNA in place of
genomic RNA. This result was particularly evident when Gag was
expressed by using a Semliki Forest virus-derived vector: under these
conditions, the Semliki Forest virus vector-directed mRNA became very
abundant in the cells and was readily identified in the retroviral
virus-like particles. Furthermore, we found that the retroviral cores
were disrupted by treatment with RNase. Taken together, the data
strongly suggest that RNA is a structural element in retrovirus
particles.
Inactivation of the murine X-linked juvenile retinoschisis gene, Rs1h, suggests a role of retinoschisin in retinal cell layer organization and synaptic structure
Authors: Weber Bernhard H. F. , Schrewe Heinrich , Molday Laurie L. , Gehrig Andrea , White Karen L. , Seeliger Mathias W. , Jaissle Gesine B. , Friedburg Christoph , Tamm Ernst , Molday Robert S.
Published: July 2002

Deleterious mutations in
RS1
encoding retinoschisin are associated with X-linked juvenile retinoschisis (RS), a common form of macular degeneration in males. The disorder is characterized by a negative electroretinogram pattern and by a splitting of the inner retina. To gain further insight into the function of the retinoschisin protein and its role in the cellular pathology of RS, we have generated knockout mice deficient in
Rs1h
, the murine ortholog of the human
RS1
gene. We show that pathologic changes in hemizygous
Rs1h
−/Y
male mice are evenly distributed across the retina, apparently contrasting with the macula-dominated features in human. Similar functional anomalies in human and
Rs1h
−/Y
mice, however, suggest that both conditions are a disease of the entire retina affecting the organization of the retinal cell layers as well as structural properties of the retinal synapse.
Increased metalloproteinase activity, oxidant production, and emphysema in surfactant protein D gene-inactivated mice
Authors: Wert Susan E. , Yoshida Mitsuhiro , LeVine Ann Marie , Ikegami Machiko , Jones Tracy , Ross Gary F. , Fisher James H. , Korfhagen Thomas R. , Whitsett Jeffrey A.
Published: July 2002

Targeted ablation of the surfactant protein D (SP-D) gene caused chronic inflammation, emphysema, and fibrosis in the lungs of SP-D (−/−) mice. Although lung morphology was unperturbed during the first 2 weeks of life, airspace enlargement was observed by 3 weeks and progressed with advancing age. Inflammation consisted of hypertrophic alveolar macrophages and peribronchiolar-perivascular monocytic infiltrates. These abnormalities were associated with increased activity of the matrix metalloproteinases, MMP2 and MMP9, and immunostaining for MMP9 and MMP12 in alveolar macrophages. Hydrogen peroxide production by isolated alveolar macrophages also was increased significantly (10-fold). SP-D plays a critical role in the suppression of alveolar macrophage activation, which may contribute to the pathogenesis of chronic inflammation and emphysema.
Desert dust suppressing precipitation: A possible desertification feedback loop
Authors: Rosenfeld Daniel , Rudich Yinon , Lahav Ronen
Published: July 2002

The effect of desert dust on cloud properties and precipitation has
so far been studied solely by using theoretical models, which predict
that rainfall would be enhanced. Here we present observations showing
the contrary; the effect of dust on cloud properties is to inhibit
precipitation. Using satellite and aircraft observations we show that
clouds forming within desert dust contain small droplets and produce
little precipitation by drop coalescence. Measurement of the size
distribution and the chemical analysis of individual Saharan dust
particles collected in such a dust storm suggest a possible mechanism
for the diminished rainfall. The detrimental impact of dust on rainfall
is smaller than that caused by smoke from biomass burning or
anthropogenic air pollution, but the large abundance of desert dust in
the atmosphere renders it important. The reduction of precipitation
from clouds affected by desert dust can cause drier soil, which in turn
raises more dust, thus providing a possible feedback loop to further
decrease precipitation. Furthermore, anthropogenic changes of land use
exposing the topsoil can initiate such a desertification feedback
process.
Leptin induces vascular permeability and synergistically stimulates angiogenesis with FGF-2 and VEGF
Authors: Cao Renhai , Brakenhielm Ebba , Wahlestedt Claes , Thyberg Johan , Cao Yihai
Published: July 2002

Most endocrine hormones are produced in tissues and organs with
permeable microvessels that may provide an excess of hormones to be
transported by the blood circulation to the distal target organ. Here,
we investigate whether leptin, an endocrine hormone, induces the
formation of vascular fenestrations and permeability, and we
characterize its angiogenic property in the presence of other
angiogenic factors. We provide evidence that leptin-induced new blood
vessels are fenestrated. Under physiological conditions, capillary
fenestrations are found in the leptin-producing adipose tissue in lean
mice. In contrast, no vascular fenestrations were detected in the
adipose tissue of leptin-deficient
ob/ob
mice. Thus,
leptin plays a critical role in the maintenance and regulation of
vascular fenestrations in the adipose tissue. Leptin induces a rapid
vascular permeability response when administrated intradermally.
Further, leptin synergistically stimulates angiogenesis with fibroblast
growth factor (FGF)-2 and vascular endothelial growth factor (VEGF),
the two most potent and commonly expressed angiogenic factors. These
findings demonstrate that leptin has another new function—the increase
of vascular permeability.
c-Jun interacts with the corepressor TG-interacting factor (TGIF) to suppress Smad2 transcriptional activity
Authors: Pessah Marcia , Prunier Céline , Marais Jacqueline , Ferrand Nathalie , Mazars Anne , Lallemand François , Gauthier Jean-Michel , Atfi Azeddine
Published: July 2002

The Sma and Mad related (Smad) family proteins are critical
mediators of the transforming growth factor-β (TGF-β) superfamily
signaling. After TGF-β-mediated phosphorylation and association with
Smad4, Smad2 moves to the nucleus and activates expression of specific
genes through cooperative interactions with DNA-binding proteins,
including members of the winged-helix family of transcription factors,
forkhead activin signal transducer (FAST)-1 and FAST2. TGF-β has also
been described to activate other signaling pathways, such as the c-Jun
N-terminal Kinase (JNK) pathway. Here, we show that activation of JNK
cascade blocked the ability of Smad2 to mediate TGF-β-dependent
activation of the FAST proteins. This inhibitory activity is mediated
through the transcriptional factor c-Jun, which enhances the
association of Smad2 with the nuclear transcriptional corepressor
TG-interacting factor (TGIF), thereby interfering with the assembly of
Smad2 and the coactivator p300 in response to TGF-β signaling.
Interestingly, c-Jun directly binds to the nuclear transcriptional
corepressor TGIF and is required for TGIF-mediated repression of Smad2
transcriptional activity. These studies thus reveal a mechanism for
suppression of Smad2 signaling pathway by JNK cascade through
transcriptional repression.
Secreted and membrane attractin result from alternative splicing of the humanATRNgene
Authors: Tang W. , Gunn T. M. , McLaughlin D. F. , Barsh G. S. , Schlossman S. F. , Duke-Cohan J. S.
Published: July 2002

Attractin, initially identified as a soluble human plasma protein with dipeptidyl peptidase IV activity that is expressed and released by activated T lymphocytes, also has been identified as the product of the murinemahoganygene with connections to control of pigmentation and energy metabolism. Themahoganyproduct, however, is a transmembrane protein, raising the possibility of a human membrane attractin in addition to the secreted form. The genomic structure of human attractin reveals that soluble attractin arises from transcription of 25 sequential exons on human chromosome 20p13, where the 3′ terminal exon contains sequence from a long interspersed nuclear element-1 (LINE-1) retrotransposon element that includes a stop codon and a polyadenylation signal. The mRNA isoform for membrane attractin splices over the LINE-1 exon and includes five exons encoding transmembrane and cytoplasmic domains with organization and coding potential almost identical to that of the mouse gene. The relative abundance of soluble and transmembrane isoforms measured by reverse transcription–PCR is differentially regulated in lymphoid tissues. Because activation of peripheral blood leukocytes with phytohemagglutinin induces strong expression of cell surface attractin followed by release of soluble attractin, these results suggest that a genomic event unique to mammals, LINE-1 insertion, has provided an evolutionary mechanism for regulating cell interactions during an inflammatory reaction.